Victor W. Henderson, MD, MS

All Publications

• Vascular complications of diabetes: natural history and corresponding risks of dementia in a national cohort of adults with diabetes. Acta diabetologica Chang, P., Wang, I. I., Chiang, C., Chen, C., Yeh, W., Henderson, V. W., Tsai, Y., Cheng, H. 2021

  Abstract

  AIMS: This study aimed to determine the trajectory of diabetic vascular diseases and to investigate the association between vascular diseases and dementia.METHODS: We included adults aged≥50years with newly diagnosed type 2 diabetes (n=173,118) from 2001 to 2005 who were followed-up until December 31, 2013 in the Taiwan's National Health Insurance Research Database. Multivariable Cox regression models were constructed to estimate hazard ratios (HRs) and confidence limits (CLs) for all-cause dementia in relation to the number, types, and occurrence patterns of vascular disease.RESULTS: Within 1year of diabetes diagnosis, 26.3% of adults developed their first vascular disease. During the 1,864,279 person-years offollow-up, 17,426 adults had all-cause dementia, corresponding to an incidence of 97.9 cases/10,000 person-years in 127,718 adults with at least one vascular disease and 67.5 cases/10,000 person-years in 45,400 adults without vascular diseases. Across all age groups, adults who subsequently developed a vascular disease in two one-year windows since diabetes diagnosis had the highest incidence of all-cause dementia. In comparison with adults without vascular diseases, HR for all-cause dementia was 1.99 (CL: 1.92-2.07) for those with one vascular disease only; 2.04 (CL: 1.98-2.13) for two or more vascular diseases; 3.56 (CL: 3.44-3.70) for stroke only; and 2.06 (CL: 1.99-2.14) for neuropathy alone. Similar associations were also observed with a smaller magnitude for adults with nephropathy, retinopathy, cardiovascular disease, or peripheral arterial disease.CONCLUSIONS: Patients with diabetes-related complications, particularly stroke and neuropathy, and those with rapidly developed vascular diseases appeared to have a high risk of dementia.

  View details for DOI 10.1007/s00592-021-01685-y

  View details for PubMedID 33624125

• Nationwide Trends in Incidence and Mortality of Stroke among Younger and Older Adults in Denmark. Neurology Skajaa, N., Adelborg, K., Horvath-Puho, E., Rothman, K. J., Henderson, V. W., Thygesen, L. C., Sorensen, H. T. 2021

  Abstract

  OBJECTIVE: To investigate the extent to which the incidence and mortality of a first-time stroke among younger and older adults changed from 2005 to 2018 in Denmark using nationwide registries.METHODS: We used the Danish Stroke Registry and the Danish National Patient Registry to identify patients aged 18-49 years (younger adults) and those aged 50+ years (older adults) with a first-time ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. We computed age-standardized incidence rates and 30-day and one-year mortality risks separately for younger and older adults and according to smaller age groups, stroke subtype, sex, and severity (Scandinavian Stroke Scale). Average annual percentage changes (AAPC) were computed to assess temporal trends.RESULTS: We identified 8,680 younger adults and 105,240 older adults with an ischemic stroke or intracerebral hemorrhage. The incidence rate per 100,000 person-years of ischemic stroke (20.8 in 2005 and 21.9 in 2018, AAPC: -0.6 [95% CI: -1.5 to 0.3]) and intracerebral hemorrhage (2.2 in 2005 and 2.5 in 2018, AAPC: 0.6 [95% CI: -1.0 to 2.3]) remained steady in younger adults. In older adults, rates of ischemic stroke and intracerebral hemorrhage declined, particularly in those aged 70 or older. Rates of subarachnoid hemorrhage declined, but more so in younger than older adults. Stroke mortality declined over time in both age groups, largely attributable to declines in the mortality after severe strokes. Most trends were similar for men and women.CONCLUSION: Incidence of ischemic stroke and intracerebral hemorrhage was steady in younger adults from 2005 to 2018, while it dropped in adults older than 70 years. Stroke mortality declined during this time.

  View details for DOI 10.1212/WNL.0000000000011636

  View details for PubMedID 33568547

• Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia. Journal of Alzheimer's disease : JAD Arendt, J. F., Horvath-Puho, E., Sorensen, H. T., Nexo, E., Pedersen, L., Ording, A. G., Henderson, V. W. 2021

  Abstract

  BACKGROUND: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia.OBJECTIVE: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer's disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes).METHODS: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000-2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia.RESULTS: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia.CONCLUSION: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.

  View details for DOI 10.3233/JAD-201096

  View details for PubMedID 33459639

• Methods to investigate intrathecal adaptive immunity in neurodegeneration. Molecular neurodegeneration Oh, H., Leventhal, O., Channappa, D., Henderson, V. W., Wyss-Coray, T., Lehallier, B., Gate, D. 2021; 16 (1): 3

  Abstract

  Cerebrospinal fluid (CSF) provides basic mechanical and immunological protection to the brain. Historically, analysis of CSF has focused on protein changes, yet recent studies have shed light on cellular alterations. Evidence now exists for involvement of intrathecal T cells in the pathobiology of neurodegenerative diseases. However, a standardized method for long-term preservation of CSF immune cells is lacking. Further, the functional role of CSF T cells and their cognate antigens in neurodegenerative diseases are largely unknown.We present a method for long-term cryopreservation of CSF immune cells for downstream single cell RNA and T cell receptor sequencing (scRNA-TCRseq) analysis. We observe preservation of CSF immune cells, consisting primarily of memory CD4+ and CD8+ T cells. We then utilize unbiased bioinformatics approaches to quantify and visualize TCR sequence similarity within and between disease groups. By this method, we identify clusters of disease-associated, antigen-specific TCRs from clonally expanded CSF T cells of patients with neurodegenerative diseases.Here, we provide a standardized approach for long-term storage of CSF immune cells. Additionally, we present unbiased bioinformatic approaches that will facilitate the discovery of target antigens of clonally expanded T cells in neurodegenerative diseases. These novel methods will help improve our understanding of adaptive immunity in the central nervous system.

  View details for DOI 10.1186/s13024-021-00423-w

  View details for PubMedID 33482851

• PM2.5 associated with gray matter atrophy reflecting increased Alzheimers risk in older women. Neurology Younan, D., Wang, X., Casanova, R., Barnard, R., Gaussoin, S. A., Saldana, S., Petkus, A. J., Beavers, D. P., Resnick, S. M., Manson, J. E., Serre, M. L., Vizuete, W., Henderson, V. W., Sachs, B. C., Salinas, J. A., Gatz, M., Espeland, M. A., Chui, H. C., Shumaker, S. A., Rapp, S. R., Chen, J., Women's Health Initiative 2020

  Abstract

  OBJECTIVE: To examine whether late-life exposure to PM2.5 (particulate matter with aerodynamic diameters <2.5-m) contributes to progressive brain atrophy predictive of Alzheimer's disease (AD) using a community-dwelling cohort of women (aged 70-89) with up to two brain MRI scans (MRI-1: 2005-6; MRI-2: 2010-11).METHODS: AD pattern similarity (AD-PS) scores, developed by supervised machine learning and validated with MRI data from the AD Neuroimaging Initiative, was used to capture high-dimensional gray matter atrophy in brain areas vulnerable to AD (e.g., amygdala, hippocampus, parahippocampal gyrus, thalamus, inferior temporal lobe areas and midbrain). Based on participants' addresses and air monitoring data, we implemented a spatiotemporal model to estimate 3-year average exposure to PM2.5 preceding MRI-1. General linear models were used to examine the association between PM2.5 and AD-PS scores (baseline and 5-year standardized change), accounting for potential confounders and white matter lesion volumes.RESULTS: For 1365 women aged 77.9±3.7 years in 2005-6, there was no association between PM2.5 and baseline AD-PS score in cross-sectional analyses (beta=-0.004; 95% CI: -0.019, 0.011). Longitudinally, each interquartile range increase of PM2.5 (2.82-g/m3) was associated with increased AD-PS scores during the follow-up, equivalent to a 24% (hazard ratio=1.24; 95% CI: 1.14, 1.34) increase in AD risk over 5-years (n=712; aged 77.4±3.5 years). This association remained after adjustment for socio-demographics, intracranial volume, lifestyle, clinical characteristics, and white matter lesions, and was present with levels below US regulatory standards (<12-g/m3).CONCLUSIONS: Late-life exposure to PM2.5 is associated with increased neuroanatomical risk of AD, which may not be explained by available indicators of cerebrovascular damage.

  View details for DOI 10.1212/WNL.0000000000011149

  View details for PubMedID 33208540

• Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis. JAMA neurology Kunkle, B. W., Schmidt, M., Klein, H., Naj, A. C., Hamilton-Nelson, K. L., Larson, E. B., Evans, D. A., De Jager, P. L., Crane, P. K., Buxbaum, J. D., Ertekin-Taner, N., Barnes, L. L., Fallin, M. D., Manly, J. J., Go, R. C., Obisesan, T. O., Kamboh, M. I., Bennett, D. A., Hall, K. S., Goate, A. M., Foroud, T. M., Martin, E. R., Wang, L., Byrd, G. S., Farrer, L. A., Haines, J. L., Schellenberg, G. D., Mayeux, R., Pericak-Vance, M. A., Reitz, C., Writing Group for the Alzheimers Disease Genetics Consortium (ADGC), Graff-Radford, N. R., Martinez, I., Ayodele, T., Logue, M. W., Cantwell, L. B., Jean-Francois, M., Kuzma, A. B., Adams, L. D., Vance, J. M., Cuccaro, M. L., Chung, J., Mez, J., Lunetta, K. L., Jun, G. R., Lopez, O. L., Hendrie, H. C., Reiman, E. M., Kowall, N. W., Leverenz, J. B., Small, S. A., Levey, A. I., Golde, T. E., Saykin, A. J., Starks, T. D., Albert, M. S., Hyman, B. T., Petersen, R. C., Sano, M., Wisniewski, T., Vassar, R., Kaye, J. A., Henderson, V. W., DeCarli, C., LaFerla, F. M., Brewer, J. B., Miller, B. L., Swerdlow, R. H., Van Eldik, L. J., Paulson, H. L., Trojanowski, J. Q., Chui, H. C., Rosenberg, R. N., Craft, S., Grabowski, T. J., Asthana, S., Morris, J. C., Strittmatter, S. M., Kukull, W. A., Abner, E., Adams, P. M., Albin, R. L., Apostolova, L. G., Arnold, S. E., Atwood, C. S., Baldwin, C. T., Barber, R. C., Barral, S., Beach, T. G., Becker, J. T., Beecham, G. W., Bigio, E. H., Bird, T. D., Blacker, D., Boeve, B. F., Bowen, J. D., Boxer, A., Burke, J. R., Burns, J. M., Cairns, N. J., Cao, C., Carlsson, C. M., Carney, R. M., Carrasquillo, M. M., Cribbs, D. H., Cruchaga, C., Dick, M., Dickson, D. W., Doody, R. S., Duara, R., Faber, K. M., Fairchild, T. J., Fallon, K. B., Fardo, D. W., Farlow, M. R., Ferris, S., Frosch, M. P., Galasko, D. R., Gearing, M., Geschwind, D. H., Ghetti, B., Gilbert, J. R., Green, R. C., Growdon, J. H., Hakonarson, H., Hamilton, R. L., Hardy, J., Harrell, L. E., Honig, L. S., Huebinger, R. M., Huentelman, M. J., Hulette, C. M., Jarvik, G. P., Jin, L., Karydas, A., Katz, M. J., Kauwe, J. S., Keene, C. D., Kim, R., Kramer, J. H., Lah, J. J., Leung, Y. Y., Li, G., Lieberman, A. P., Lipton, R. B., Lyketsos, C. G., Malamon, J., Marson, D. C., Martiniuk, F., Masliah, E., McCormick, W. C., McCurry, S. M., McDavid, A. N., McDonough, S., McKee, A. C., Mesulam, M., Miller, B. L., Miller, C. A., Montine, T. J., Mukherjee, S., Myers, A. J., O'Bryant, S. E., Olichney, J. M., Parisi, J. E., Peskind, E., Pierce, A., Poon, W. W., Potter, H., Qu, L., Quinn, J. F., Raj, A., Raskind, M., Reisberg, B., Reisch, J. S., Ringman, J. M., Roberson, E. D., Rogaeva, E., Rosen, H. J., Royall, D. R., Sager, M. A., Schneider, J. A., Schneider, L. S., Seeley, W. W., Small, S., Sonnen, J. A., Spina, S., St George-Hyslop, P., Stern, R. A., Tanzi, R. E., Troncoso, J. C., Tsuang, D. W., Valladares, O., Van Deerlin, V. M., Vardarajan, B. N., Vinters, H. V., Vonsattel, J. P., Weintraub, S., Welsh-Bohmer, K. A., Wilhelmsen, K. C., Williamson, J., Wingo, T. S., Woltjer, R. L., Wu, C., Younkin, S. G., Yu, L., Yu, C., Zhao, Y. 2020

  Abstract

  Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.Design, Setting, and Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.Main Outcomes and Measures: Diagnosis of Alzheimer disease.Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P=8.9*10-7), near the immune response gene ALCAM (3q13; P=9.3*10-7), within GPC6 (13q31; P=4.1*10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P=3.5*10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P=1.7*10-9) and 6 additional loci with suggestive significance (P≤5*10-7) such as API5 at 11p12 (P=8.8*10-8) and RBFOX1 at 16p13 (P=5.4*10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain beta-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.Conclusions and Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

  View details for DOI 10.1001/jamaneurol.2020.3536

  View details for PubMedID 33074286

• Receipt of Eye Care Services among Medicare Beneficiaries with and without Dementia. Ophthalmology Pershing, S., Goldstein, M. K., Henderson, V. W., Bundorf, M. K., Lu, Y., Rahman, M., Stein, J. D. 2020

  Abstract

  PURPOSE: To examine the relationship between dementia status and receipt of eye care among US Medicare beneficiaries.DESIGN: Retrospective, claims-based analysis.PARTICIPANTS: A 20% representative sample of Medicare beneficiaries who received care between January 1, 2006, and December 31,2015.METHODS: Dementia was identified from diagnosis codes documented in a beneficiary's first 3 years of observed Medicare enrollment. Eye care visits were identified from provider specialty codes on each encounter claim. We used multivariable Cox proportional hazards regression models with time-varying covariates to compare the likelihood of receiving eye care between beneficiaries with and without dementia. All models were adjusted for potential confounders, including demographics, urban/rural residence, systemic health (Charlson Index), and ocular comorbidities.MAIN OUTCOME MEASURES: Hazard ratio (HR) and 95% confidence interval (CI) for (1) being seen by any eye care provider (ophthalmologist or optometrist); (2) being seen by an ophthalmologist specifically; and (3) receiving cataract surgery (among beneficiaries with ophthalmologist encounters).RESULTS: A total of 4451200 beneficiaries met inclusion criteria; 3805718 (85.5%) received eye care during the study period, and 391 556 (8.8%) had diagnosed dementia. Some 73.4% of beneficiaries diagnosed with dementia saw an eye care provider during the study period and 55.4% saw an ophthalmologist versus 86.7% and 74.0% of beneficiaries, respectively, without dementia diagnoses. Compared with those without dementia diagnoses, beneficiaries with diagnosed dementia had lower likelihood of seeing any eye care provider (adjusted HR, 0.69; 95% CI, 0.69-0.70) and were less likely to see an ophthalmologist (adjusted HR, 0.55; 95% CI, 0.55-0.55). Among the subset of beneficiaries who did see ophthalmologists, those with diagnosed dementia were also less likely to receive cataract surgery than beneficiaries without diagnosed dementia (HR, 0.62; 95% CI, 0.62-0.63) and less likely to receive a cataract diagnosis (18% vs. 82%).CONCLUSIONS: US Medicare beneficiaries diagnosed with dementia are less likely to receive eye care thanthose without diagnosed dementia. Depending on visual acuity and functional status, this may have implications for injury prevention, physical and cognitive function, and quality of life. Further work is needed to identify barriers to receiving eye care, determine eye care services and settings that provide greatest value topatients with dementia, and implement measures to improve access to appropriate eye care.

  View details for DOI 10.1016/j.ophtha.2020.02.022

  View details for PubMedID 32317179

• Association of Visual Impairment With Risk of Incident Dementia in a Women's Health Initiative Population. JAMA ophthalmology Tran, E. M., Stefanick, M. L., Henderson, V. W., Rapp, S. R., Chen, J. C., Armstrong, N. M., Espeland, M. A., Gower, E. W., Shadyab, A. H., Li, W., Stone, K. L., Pershing, S. 2020

  Abstract

  Dementia affects a large and growing population of older adults. Although past studies suggest an association between vision and cognitive impairment, there are limited data regarding longitudinal associations of vision with dementia.To evaluate associations between visual impairment and risk of cognitive impairment.A secondary analysis of a prospective longitudinal cohort study compared the likelihood of incident dementia or mild cognitive impairment (MCI) among women with and without baseline visual impairment using multivariable Cox proportional hazards regression models adjusting for characteristics of participants enrolled in Women's Health Initiative (WHI) ancillary studies. The participants comprised community-dwelling older women (age, 66-84 years) concurrently enrolled in WHI Sight Examination (enrollment 2000-2002) and WHI Memory Study (enrollment 1996-1998, ongoing). The study was conducted from 2000 to the present.Objectively measured visual impairment at 3 thresholds (visual acuity worse than 20/40, 20/80, or 20/100) and self-reported visual impairment (determined using composite survey responses).Hazard ratios (HRs) and 95% CIs for incident cognitive impairment after baseline eye examination were determined. Cognitive impairment (probable dementia or MCI) was based on cognitive testing, clinical assessment, and centralized review and adjudication. Models for (1) probable dementia, (2) MCI, and (3) probable dementia or MCI were evaluated.A total of 1061 women (mean [SD] age, 73.8 [3.7] years) were identified; 206 of these women (19.4%) had self-reported visual impairment and 183 women (17.2%) had objective visual impairment. Forty-two women (4.0%) were ultimately classified with probable dementia and 28 women (2.6%) with MCI that did not progress to dementia. Mean post-eye examination follow-up was 3.8 (1.8) years (range, 0-7 years). Women with vs without baseline objective visual impairment were more likely to develop dementia. Greatest risk for dementia was among women with visual acuity of 20/100 or worse at baseline (HR, 5.66; 95% CI, 1.75-18.37), followed by 20/80 or worse (HR, 5.20; 95% CI, 1.94-13.95), and 20/40 or worse (HR, 2.14; 95% CI, 1.08-4.21). Findings were similar for risk of MCI, with the greatest risk among women with baseline visual acuity of 20/100 or worse (HR, 6.43; 95% CI, 1.66-24.85).In secondary analysis of a prospective longitudinal cohort study of older women with formal vision and cognitive function testing, objective visual impairment appears to be associated with an increased risk of incident dementia. However, incident cases of dementia and the proportion of those with visual impairment were low. Research is needed to evaluate the effect of specific ophthalmic interventions on dementia.

  View details for DOI 10.1001/jamaophthalmol.2020.0959

  View details for PubMedID 32297918

• Low-fat dietary pattern and global cognitive function: Exploratory analyses of the Women's Health Initiative (WHI) randomized Dietary Modification trial. EClinicalMedicine Chlebowski, R. T., Rapp, S., Aragaki, A. K., Pan, K., Neuhouser, M. L., Snetselaar, L. G., Manson, J. E., Wactawski-Wende, J., Johnson, K. C., Hayden, K., Baker, L. D., Henderson, V. W., Garcia, L., Qi, L., Prentice, R. L. 2020; 18: 100240

  Abstract

  Background: Meta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function.Methods: The Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini-Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611.Findings: Among the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n=126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38-0. 91, P=0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35-1.19) and HR of 0.63 (95% CI 0.19-2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P=0.16).Interpretation: Adoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women.Funding: Several Institutes of the US National Institutes of Health.

  View details for DOI 10.1016/j.eclinm.2019.100240

  View details for PubMedID 31938786

• Leisure activity for dementia prevention: More work to be done. Neurology Henderson, V. W., Elias, M. F. 2020

  View details for DOI 10.1212/WNL.0000000000010962

  View details for PubMedID 33115774

• Cancer and risk of Alzheimer's disease: Small association in a nationwide cohort study. Alzheimer's & dementia : the journal of the Alzheimer's Association Ording, A. G., Horváth-Puhó, E., Veres, K., Glymour, M. M., Rørth, M., Sørensen, H. T., Henderson, V. W. 2020

  Abstract

  Small observational studies with short-term follow-up suggest that cancer patients are at reduced risk of Alzheimer's disease (AD) compared to the general population.A nationwide cohort study using Danish population-based health registries (1980-2013) with cancer patients (n = 949,309) to identify incident diagnoses of AD. We computed absolute reductions in risk attributed to cancer and standardized incidence rate ratios (SIRs) accounting for survival time, comparing the observed to expected number of AD cases.During up to 34 years of follow-up of cancer survivors, the attributable risk reduction was 1.3 per 10,000 person-years, SIR = 0.94 (95% confidence interval 0.92-0.96). SIRs were similar after stratification by sex, age, and cancer stage, and approached that of the general population for those surviving >10 years.Inverse associations between cancer and AD were small and diminished over time. Incidence rates in cancer survivors approached those of the general population, suggesting limited association between cancer and AD risk.

  View details for DOI 10.1002/alz.12090

  View details for PubMedID 32432415

• Motor Neuron Disease and Risk of Cancer: A Population-Based Cohort Study in Denmark. Clinical epidemiology Sørensen, T. T., Farkas, D. K., Riahi, E. Z., Ehrenstein, V., Henderson, V. W. 2020; 12: 1347–53

  Abstract

  Some neurogenerative diseases have been linked to a reduced risk of cancer, but the association between motor neuron disease and cancer risk is not well understood. We hypothesized that cancer risk would be lower among those with motor neuron disease and its most common subtype, amyotrophic lateral sclerosis.We conducted a population-based cohort study of motor neuron disease and cancer risk using routinely collected data from population-based registries in Denmark. We examined cancer incidence among patients diagnosed with motor neuron disease between January 1980 and December 2013 followed through 2013. Using Danish national cancer rates for the study period, we computed standardized incidence ratios as a measure of relative risks.In the cohort of 5053 patients with a motor neuron disease, the overall standardized incidence ratio of any cancer was 1.17 (95% confidence interval [CI], 1.03-1.31); the corresponding standardized incidence ratio for amyotrophic lateral sclerosis was 1.24 (95% CI, 0.96-1.57). The standardized incidence ratios of any cancer in the cohort with motor neuron disease was 1.52 (95% CI, 1.22-1.87) for <1 year of follow-up; 0.87 (95% CI, 0.68-1.09) for years 1-5 of follow-up; and 1.22 (95% CI, 1.01-1.46) for >5 years of follow-up. Beyond one year of follow-up, patients in the motor neuron disease had elevated standardized incidence ratios for lymphoid leukemia, non-Hodgkin lymphoma, and basal cell skin cancer.Findings fail to support the hypothesis that motor neuron disease or amyotrophic lateral sclerosis is associated with reduced cancer incidence. An elevated risk of cancer during the first year of follow-up may be attributable to heightened surveillance.

  View details for DOI 10.2147/CLEP.S271543

  View details for PubMedID 33324108

  View details for PubMedCentralID PMC7733394

• Association of Insulin Resistance With Depression Severity and Remission Status: Defining a Metabolic Endophenotype of Depression. JAMA psychiatry Watson, K. T., Simard, J. F., Henderson, V. W., Nutkiewicz, L., Lamers, F., Rasgon, N., Penninx, B. 2020

  View details for DOI 10.1001/jamapsychiatry.2020.3669

  View details for PubMedID 33263725

• Cataract Surgery Complexity and Surgical Complication Rates among Medicare Beneficiaries with and without Dementia. American journal of ophthalmology Pershing, S., Henderson, V. W., Goldstein, M. K., Lu, Y., Bundorf, M. K., Rahman, M., Stein, J. D. 2020

  Abstract

  To evaluate cataract surgery complexity and complications among US Medicare beneficiaries with and without dementia.Retrospective claims-based cohort study PARTICIPANTS: A 20% representative sample of Medicare beneficiaries, 2006-2015.Dementia was identified from diagnosis codes on or prior to each beneficiary's first-eye cataract surgery. For each surgery, we identified setting, routine versus complex coding, anesthesia provider type, duration, and any postoperative hospitalization. We evaluated 30- and 90-day complication rates-return to operating room, endophthalmitis, suprachoroidal hemorrhage, retinal detachment, retinal tear, macular edema, glaucoma, or choroidal detachment-and used adjusted regression models to evaluate likelihood of surgical characteristics and complications. Complications analyses were stratified by second-eye cataract surgery within 90 days postoperatively.We identified 457,128 beneficiaries undergoing first-eye cataract surgery, 23,332 (5.1%) with dementia. None of the evaluated surgical complications were more likely in dementia-diagnosed beneficiaries. There was also no difference in likelihood of non-ambulatory surgery center setting, anesthesiologist provider, or postoperative hospitalization. Dementia-diagnosed beneficiaries were more likely to have surgeries coded as complex (15.6% of cases versus 8.8%, p<0.0001), and surgeries exceeding 30 minutes (OR=1.21, 95%CI=1.17-1.25).Among US Medicare beneficiaries undergoing cataract surgery, those with dementia are more likely to have "complex" surgery" lasting over 30 minutes. However, they do not have greater likelihood of surgical complications, higher-acuity setting, advanced anesthesia care, or postoperative hospitalization. This may be influenced by case selection and may suggest missed opportunities to improve vision. Future research is needed to identify dementia patients likely to benefit from cataract surgery.

  View details for DOI 10.1016/j.ajo.2020.08.025

  View details for PubMedID 32828874

• Alzheimer's and Parkinson's Diseases and the Risk of Cancer: A Cohort Study. Journal of Alzheimer's disease : JAD Ording, A. G., Veres, K., Horvath-Puho, E., Glymour, M. M., Rorth, M., Henderson, V. W., Sorensen, H. T. 2019

  Abstract

  Observational studies have shown inverse associations between neurological diseases, particularly dementia, and subsequent cancer risk, but is unknown whether this association is valid or arises from bias. We conducted a Danish nationwide cohort study using population-based health registries (1980-2012). The study included patients with dementia (n = 173,434) and with Parkinson's disease (n = 28,835). We followed patients for 10 years to assess subsequent cancer diagnoses. We computed absolute reduction in cancer risk attributable to dementia or Parkinson's disease (expected minus the observed number of cancer cases divided by the person time) and standardized incidence rate ratios (SIRs) as the observed to expected number of cancers, based on sex-, age-, and calendar year-standardized national incidence rates. During 10 years, the reduction in cancer cases were 79.9 per 10,000 person-years for Alzheimer's disease [SIR = 0.68 (95% CI: 0.66, 0.70)], 74.4 per 10,000 person-years for vascular dementia [SIR = 0.71 (95% CI: 0.67, 0.74)], 55.8 per 10,000 person-years [SIR = 0.77 (95% CI: 0.75, 0.78)] for all-cause dementia, and 4.0 per 10,000 person-years [SIR = 0.98 (95% CI: 0.95, 1.02) for Parkinson's disease. Associations were nearly similar for solid tumors diagnosed at localized, regional, or distant stages. We found an inverse association between dementia and cancer risk, with similar associations when considering only cancers diagnosed at distant stage. The cancer risk varied by type of dementia, with a gradient toward a stronger protective effect associated with Alzheimer's disease and vascular dementia, which may favor a biological explanation. Overall results do not show an inverse association between Parkinson's disease and cancer.

  View details for DOI 10.3233/JAD-190867

  View details for PubMedID 31707368

• Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy: A Randomized Trial. Annals of internal medicine Manson, J. E., Aragaki, A. K., Bassuk, S. S., Chlebowski, R. T., Anderson, G. L., Rossouw, J. E., Howard, B. V., Thomson, C. A., Stefanick, M. L., Kaunitz, A. M., Crandall, C. J., Eaton, C. B., Henderson, V. W., Liu, S., Luo, J., Rohan, T., Shadyab, A. H., Wells, G., Wactawski-Wende, J., Prentice, R. L., WHI Investigators 2019

  Abstract

  Background: Whether health outcomes of menopausal estrogen therapy differ between women with and without bilateral salpingo-oophorectomy (BSO) is unknown.Objective: To examine estrogen therapy outcomes by BSO status, with additional stratification by 10-year age groups.Design: Subgroup analyses of the randomized Women's Health Initiative Estrogen-Alone Trial. (ClinicalTrials.gov: NCT00000611).Setting: 40 U.S. clinical centers.Participants: 9939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status.Intervention: Conjugated equine estrogens (CEE) (0.625 mg/d) or placebo for a median of 7.2 years.Measurements: Incidence of coronary heart disease and invasive breast cancer (the trial's 2 primary end points), all-cause mortality, and a "global index" (these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture) during the intervention phase and 18-year cumulative follow-up.Results: The effects of CEE alone did not differ significantly according to BSO status. However, age modified the effect of CEE in women with prior BSO. During the intervention phase, CEE was significantly associated with a net adverse effect (hazard ratio for global index, 1.42 [95% CI, 1.09 to 1.86]) in older women (aged ≥70 years), but the global index was not elevated in younger women (P trend by age = 0.016). During cumulative follow-up, women aged 50 to 59 years with BSO had a treatment-associated reduction in all-cause mortality (hazard ratio, 0.68 [CI, 0.48 to 0.96]), whereas older women with BSO had no reduction (P trend by age = 0.034). There was no significant association between CEE and outcomes among women with conserved ovaries, regardless of age.Limitations: The timing of CEE in relation to BSO varied; several comparisons were made without adjustment for multiple testing.Conclusion: The effects of CEE did not differ by BSO status in the overall cohort, but some findings varied by age. Among women with prior BSO, in those aged 70 years or older, CEE led to adverse effects during the treatment period, whereas women randomly assigned to CEE before age 60 seemed to derive mortality benefit over the long term.Primary Funding Source: The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.

  View details for DOI 10.7326/M19-0274

  View details for PubMedID 31499528

• Physical function and age at natural menopause: two take-home messages. Menopause (New York, N.Y.) Henderson, V. W. 2019

  View details for DOI 10.1097/GME.0000000000001401

  View details for PubMedID 31389857

• Risk of amyotrophic lateral sclerosis and other motor neuron disease among men with benign prostatic hyperplasia: a population-based cohort study. BMJ open Sorensen, T. T., Horvath-Puho, E., Norgaard, M., Ehrenstein, V., Henderson, V. W. 2019; 9 (7): e030015

  Abstract

  OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder. Sleep disturbance may interfere with clearance of abnormal proteins that aggregate in neurodegenerative diseases. The objective of this study was to examine the association between benign prostatic hyperplasia (BPH), a common disorder causing nocturia and sleep disturbance, and risk of ALS and other motor neuron disease (MND). We hypothesised that men with BPH, in comparison to men in the general population, would be at increased risk.DESIGN: This is a nationwide, population-based cohort study.SETTING: This study was conducted among the population of Denmark.PARTICIPANTS: We used linked Danish medical databases to identify all men with a first-time diagnosis of BPH between 1 January 1980 and 30 November 2013 and no prior diagnosis of MND (BPH cohort, n=223131) and an age-matched general population comparison cohort of men without BPH or MND (n=1115642).PRIMARY OUTCOME MEASURE: The primary outcome is diagnosis of MND after the BPH diagnosis (index) date, with follow-up until MND diagnosis, emigration, death or 30 November 2013.RESULTS: We used Cox regression to compute adjusted HR, comparing men with and without BPH. After 34 years of follow-up, there were 227 cases of MND in the BPH cohort (incidence rate 0.13/1000 person-years) and 1094 MND cases in the comparison cohort (0.12/1000 person-years; HR 1.05, 95% CI 0.90 to 1.22). Risk did not vary by follow-up time.CONCLUSIONS: BPH is not associated with an increased risk of ALS and other MND. Future studies should examine the relation between other disorders that disrupt sleep and MND risk in men and women.

  View details for DOI 10.1136/bmjopen-2019-030015

  View details for PubMedID 31278107

• An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF A beta 42 and an APOE epsilon 4 allele NEUROBIOLOGY OF DISEASE Shahid, M., Kim, J., Leaver, K., Hendershott, T., Zhu, D., Cholerton, B., Henderson, V. W., Tian, L., Poston, K. L. 2019; 127: 278–86

  View details for DOI 10.1016/j.nbd.2019.02.023

  View details for Web of Science ID 000472990100023

• Differences in Cataract Surgery Rates Based on Dementia Status. Journal of Alzheimer's disease : JAD Pershing, S., Henderson, V. W., Bundorf, M. K., Lu, Y., Rahman, M., Andrews, C. A., Goldstein, M., Stein, J. D. 2019

  Abstract

  BACKGROUND: Cataract surgery substantially improves patient quality of life. Despite the rising prevalence of dementia in the US, little is known about use of cataract surgery among this group.OBJECTIVE: To evaluate the relationship between dementia status and cataract surgery.METHODS: Using administrative insurance claims for a representative sample of 1,125,387 US Medicare beneficiaries who received eye care between 2006 and 2015, we compared cataract surgery rates between patients with and without dementia via multivariable regression models to adjust for patient characteristics. Main outcome measures were annual rates of cataract surgery and hazard ratio and 95% confidence interval (CI) for receiving cataract surgery.RESULTS: Cataract surgery was performed in 457,128 patients, 23,331 with a prior diagnosis of dementia. 16.7% of dementia patients underwent cataract surgery, compared to 43.8% of patients without dementia. 59 cataract surgeries were performed per 1000 dementia patients annually, versus 105 surgeries per 1000 nondementia patients. After adjusting for patient characteristics, dementia patients were approximately half as likely to receive cataract surgery compared to nondementia patients (adjusted HR = 0.53, 95% CI 0.53-0.54). Among the subset of patients who received a first cataract surgery, those with dementia were also less likely to receive second-eye cataract surgery (adjusted HR = 0.87, 95% CI 0.86-0.88).CONCLUSION: US Medicare patients with dementia are less likely to undergo cataract surgery than those without dementia. This finding has implications for quality of care and dementia progression. More information is necessary to understand why rates of cataract surgery are lower for these patients, and to identify conditions where benefits of surgery may outweigh risks.

  View details for PubMedID 30958371

• Robust norms for neuropsychological tests of verbal episodic memory in Australian women. Neuropsychology Goodwill, A. M., Campbell, S., Henderson, V. W., Gorelik, A., Dennerstein, L., McClung, M., Szoeke, C. 2019

  Abstract

  OBJECTIVE: Robust norms for neuropsychological tests may offer superior clinical utility to conventional norms, in their ability to distinguish normal cognitive aging from prodromal dementia. However, the availability of robust norms from midlife, where cognitive changes in those at risk of disease may arise, is limited. This study presents demographically stratified robust norms for tests of verbal memory in Australian women.METHOD: Participants were from the population-based Women's Healthy Ageing Project. Baseline (1999 to 2002; n = 368; age range = 53-67years) and follow-up (2012 to 2014; n = 291; age range = 65-80years) measures of word-list and story recall were administered at least 10 years apart. Four samples were identified: conventional (derived from a cross-sectional sample), robust (derived from a longitudinal sample), mild cognitive impairment (MCI) or Alzheimer's disease (AD), and lost to follow-up. Area under the curve (AUC) values were generated to assess the diagnostic ability of conventional and robust norms using 1 standard deviation and 1.5 standard deviation cut-offs.RESULTS: There were differences between conventional Australian and American normative data for the Consortium to Establish a Registry for Alzheimer's Disease word-list recall. Individuals who declined to MCI/AD over the follow-up displayed poorer performance at baseline, however no differences in classification ability of robust (AUC range .54 to.64) and conventional (AUC range .51 to .65) norms were observed.CONCLUSION: Neuropsychological performance in midlife predicted clinical cognitive decline 1 decade later, but conventional and robust norms was similarly predictive of conversion to disease in this cohort. The use of country-specific, representative conventional norms remains a valuable tool for neuropsychologists to assess cognitive performance throughout midlife. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

  View details for PubMedID 30829514

• An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF ASS42 and an APOE epsilon4 allele. Neurobiology of disease Shahid, M., Kim, J., Leaver, K., Hendershott, T., Zhu, D., Cholerton, B., Henderson, V. W., Tian, L., Poston, K. L. 2019

  Abstract

  OBJECTIVE: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Abeta-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Abeta-42 compared to patients with normal levels.METHODS: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Abeta-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Abeta at baseline, PD participants with normal CSF Abeta, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education.RESULTS: 423 de novo PD participants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Abeta-42 (39 APOE epsilon4+, 64 APOE epsilon4-). Compared to participants with normal CSF Abeta-42, those with low CSF Abeta-42 declined faster on most cognitive tests. Within the low CSF Abeta-42 group, APOE epsilon4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72).DISCUSSION: PD patients with low CSF Abeta-42 and APOE epsilon4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Abeta-42 and APOE epsilon4 might interact to promote early cognitive changes in PD patients.

  View details for PubMedID 30826425

• Differential Effect of Plasma Estradiol on Subclinical Atherosclerosis Progression in Early vs Late Postmenopause JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Sriprasert, I., Hodis, H. N., Karim, R., Stanczyk, F. Z., Shoupe, D., Henderson, V. W., Mack, W. J. 2019; 104 (2): 293–300

  View details for DOI 10.1210/jc.2018-01600

  View details for Web of Science ID 000462864100011

• Differences in Cataract Surgery Rates Based on Dementia Status JOURNAL OF ALZHEIMERS DISEASE Pershing, S., Henderson, V. W., Bundorf, M., Lu, Y., Rahman, M., Andrews, C. A., Goldstein, M., Stein, J. D. 2019; 69 (2): 423–32

  View details for DOI 10.3233/JAD-181292

  View details for Web of Science ID 000470879800009

• Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer's disease. Brain : a journal of neurology Younan, D., Petkus, A. J., Widaman, K. F., Wang, X., Casanova, R., Espeland, M. A., Gatz, M., Henderson, V. W., Manson, J. E., Rapp, S. R., Sachs, B. C., Serre, M. L., Gaussoin, S. A., Barnard, R., Saldana, S., Vizuete, W., Beavers, D. P., Salinas, J. A., Chui, H. C., Resnick, S. M., Shumaker, S. A., Chen, J. C. 2019

  Abstract

  Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may increase the risk for Alzheimer's disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer's disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer's disease associated with exposure. Participants included older females (n = 998; aged 73-87) enrolled in both the Women's Health Initiative Study of Cognitive Aging and the Women's Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999-2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1-3; List B) and delayed free recall (short- and long-delay), and up to two brain scans (MRI-1: 2005-06; MRI-2: 2009-10). Subjects were assigned Alzheimer's disease pattern similarity scores (a brain-MRI measured neuroanatomical risk for Alzheimer's disease), developed by supervised machine learning and validated with data from the Alzheimer's Disease Neuroimaging Initiative. Based on residential histories and environmental data on air monitoring and simulated atmospheric chemistry, we used a spatiotemporal model to estimate 3-year average PM2.5 exposure preceding MRI-1. In multilevel structural equation models, PM2.5 was associated with greater declines in immediate recall and new learning, but no association was found with decline in delayed-recall or composite scores. For each interquartile increment (2.81 μg/m3) of PM2.5, the annual decline rate was significantly accelerated by 19.3% [95% confidence interval (CI) = 1.9% to 36.2%] for Trials 1-3 and 14.8% (4.4% to 24.9%) for List B performance, adjusting for multiple potential confounders. Long-term PM2.5 exposure was associated with increased Alzheimer's disease pattern similarity scores, which accounted for 22.6% (95% CI: 1% to 68.9%) and 10.7% (95% CI: 1.0% to 30.3%) of the total adverse PM2.5 effects on Trials 1-3 and List B, respectively. The observed associations remained after excluding incident cases of dementia and stroke during the follow-up, or further adjusting for small-vessel ischaemic disease volumes. Our findings illustrate the continuum of PM2.5 neurotoxicity that contributes to early decline of immediate free recall/new learning at the preclinical stage, which is mediated by progressive atrophy of grey matter indicative of increased Alzheimer's disease risk, independent of cerebrovascular damage.

  View details for DOI 10.1093/brain/awz348

  View details for PubMedID 31746986

• Physical function and age at natural menopause: two take-home messages. Menopause (New York, N.Y.) Henderson, V. W. 2019; 26 (9): 943–44

  View details for DOI 10.1097/GME.0000000000001401

  View details for PubMedID 31453953

• Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer's disease. Menopause (New York, N.Y.) Karim, R., Koc, M., Rettberg, J. R., Hodis, H. N., Henderson, V. W., St John, J. A., Allayee, H., Brinton, R. D., Mack, W. J. 2019; 26 (1): 7–15

  Abstract

  OBJECTIVE: We hypothesized the association of metabolic profile on cognition in postmenopausal women will be greater among ApoE4 carriers compared with noncarriers.METHODS: Metabolic biomarkers and measures of global cognition, executive functions, and verbal memory, collected among postmenopausal females, were used in this analysis. Clustering analyses of metabolic biomarkers revealed three phenotypes: healthy, predominantly hypertensive, and poor metabolic with (borderline normal laboratory values). General linear models tested whether an association of metabolic cluster with cognition differed by ApoE4 genotype.RESULTS: In the total sample of 497 women, verbal memory was lower in the poor metabolic cluster (P = 0.04). Among ApoE4+ women, performance in all cognitive domains was lowest in the poor metabolic cluster. Differences in executive functions among metabolic clusters were detected only in ApoE4+ women (P value for interaction = 0.003).CONCLUSIONS: In a general population of postmenopausal women, association between poor metabolic profile with reduction in cognitive performance is more apparent in women who carry an ApoE4 allele. These data indicate a window of opportunity for interventions to reverse the trajectory of the preclinical phase of Alzheimer's disease.

  View details for PubMedID 29975287

• Shining a Light on Some of the Most Famous 19th and 20th Century's Neuropsychologists. Frontiers of neurology and neuroscience Walusinski, O., Boller, F., Henderson, V. W. 2019; 44: 192–229

  Abstract

  This chapter pays homage to the masters who made neuropsychology an esteemed and legitimate field in the 19th and 20th centuries. Here we offer a brief biography for each of them and an analysis of their discoveries: Théophile Alajouanine (1890-1980), Henry Charlton Bastian (1837-1915), Arthur L. Benton (1909-2006), Julian de Ajuriaguerra (1911-1993), Ennio De Renzi (1924-2016), Norman Geschwind (1926-1984), Kurt Goldstein (1878-1965), Henry Head (1861-1940), Henry Hécaen (1912-1983), Pierre Janet (1859-1947), François Lhermitte (1921-1998), Jean Lhermitte (1877-1959), Hugo Karl Liepmann (1863-1925), Heinrich Lissauer (1861-1891), Alexander Romanovich Luria (1902-1977), Brenda Milner (1918-), Théodule Ribot (1839-1916), Charles Richet (1850-1935), Paul Sollier (1861-1933), and Carl Wernicke (1848-1905).

  View details for DOI 10.1159/000494964

  View details for PubMedID 31220830

• Alexia and Agraphia from 1861 to 1965. Frontiers of neurology and neuroscience Henderson, V. W. 2019; 44: 39–52

  Abstract

  Studies of alexia and agraphia have played historically important roles in efforts to understand the relation between brain and behavior. In the second half of the 19th century, works by Paul Broca and Carl Wernicke led to the concept of delimited cortical centers in the left cerebral hemisphere concerned with discrete aspects of spoken and written language. These specialized centers were linked by white matter pathways. Charlton Bastian, Jean-Martin Charcot, Sigmund Exner, and Jules Dejerine championed center-pathway models of reading and writing. Dejerine played a dominant role, rejecting the idea of a left frontal lobe center that mediated writing and proposing a unique, specialized role for the left angular gyrus in both reading and writing. In 1891 and 1892, he detailed the symptoms of alexia and agraphia that resulted from injury to the left angular gyrus and from the isolation of the left angular gyrus from visual input required for reading. During the early 20th century, his work and that of other so-called diagram makers was confronted and largely discredited by Pierre Marie, joined later by Henry Head and Kurt Goldstein. In the 1960s, the center-pathway model was resurrected and refined by Norman Geschwind. He drew upon foundational works of Dejerine, Hugo Liepmann, and others to describe syndromes resulting from cortical disconnections and, in doing so, helped to establish a framework for the modern discipline of behavioral neurology.

  View details for DOI 10.1159/000494951

  View details for PubMedID 31220840

• General and domain-specific cognitive reserve, mild cognitive impairment, and dementia risk in older women. Alzheimer's & dementia (New York, N. Y.) Petkus, A. J., Resnick, S. M., Rapp, S. R., Espeland, M. A., Gatz, M., Widaman, K. F., Wang, X., Younan, D., Casanova, R., Chui, H., Barnard, R. T., Gaussoin, S., Goveas, J. S., Hayden, K. M., Henderson, V. W., Sachs, B. C., Saldana, S., Shadyab, A. H., Shumaker, S. A., Chen, J. C. 2019; 5: 118–28

  Abstract

  In a geographically diverse sample of women, we asked whether cognitive reserve (CR) is best viewed as a general or cognitive domain-specific construct and whether some cognitive reserve domains but not others exert protective effects on risk of developing mild cognitive impairment (MCI) or dementia.Estimates of general and domain-specific CR were derived via variance decomposition in 972 cognitively intact women from the Women's Health Initiative Study of Cognitive Aging and Women's Health Memory Study Magnetic Resonance Imaging. Women were then followed up for 13 years.General CR was the strongest predictor of reduced risk for both MCI and dementia, compared to domain-specific CR measures. Verbal memory, figural memory, and spatial CR were independently protective of MCI, but only verbal memory was independently associated with reduced risk for dementia.Cognitive reserve is a heterogenous construct with valid quantitative measures identifiable across different neuropsychological processes associated with MCI and dementia.

  View details for PubMedID 31011622

• Stress Disorders and Dementia in the Danish Population. American journal of epidemiology Gradus, J. L., Horvath-Puho, E., Lash, T. L., Ehrenstein, V., Tamang, S., Adler, N. E., Milstein, A., Glymour, M. M., Henderson, V. W., Sorensen, H. T. 2018

  Abstract

  There is an association between stress and dementia. However, less is known about dementia among persons with varied stress responses and sex differences in these associations. This population-based cohort study examined dementia among persons with a range of clinician-diagnosed stress disorders, and the interaction between stress disorders and sex in predicting dementia, in Denmark from 1995 to 2011. This study included Danes 40 years or older with a stress disorder diagnosis (n=47,047) and a matched comparison cohort (n=232,141) without a stress disorder diagnosis from 1995 through 2011. Diagnoses were culled from national registries. We used Cox proportional-hazards regression to estimate associations between stress disorders and dementia. Risk of dementia was higher for persons with stress disorders than for persons without such diagnosis; adjusted hazard ratios ranged from 1.6 to 2.8. There was evidence of an interaction between sex and stress disorders in predicting dementia, with a greater rate of dementia among men with stress disorders except posttraumatic stress disorder, for which women had a greater rate. Results support existing evidence of an association between stress and dementia. This study contributes novel information regarding dementia risk across a range of stress responses, and interactions between stress disorders and sex.

  View details for PubMedID 30576420

• Preadmission use of glucocorticoids and risk of cardiovascular events in patients with ischemic stroke JOURNAL OF THROMBOSIS AND HAEMOSTASIS Sundboll, J., Darvalics, B., Horvath-Puho, E., Adelborg, K., Laugesen, K., Schmidt, M., Henderson, V. W., Sorensen, H. T. 2018; 16 (11): 2175–83

  Abstract

  Essentials The risk of thrombosis among ischemic stroke patients using glucocorticoids is unknown. We examined the risk of thrombosis in 98 487 ischemic stroke patients, by glucocorticoid use. Myocardial infarction and venous thromboembolism risk was increased in glucocorticoid users. Hemorrhagic stroke risk was lower and recurrent ischemic stroke the same in glucocorticoid users. SUMMARY: Background Glucocorticoid users have a high mortality rate following stroke, but the underlying clinical pathways are poorly understood. Objectives To examine the risk of cardiovascular events among ischemic stroke patients using glucocorticoids. Methods We conducted a nationwide population-based cohort study by using medical registries in Denmark. We identified all patients hospitalized with a first-time ischemic stroke (2004-2013). We categorized glucocorticoid use into current use (last prescription redemption ≤ 90 days before admission), former use, and non-use. With non-users as reference, we studied the risks of recurrent ischemic stroke, hemorrhagic stroke, myocardial infarction and venous thromboembolism associated with glucocorticoid use. Comorbidity and comedication-adjusted 1-year hazard ratios (aHRs) with 95% confidence intervals (CIs) were computed on the basis of Cox regression analysis. Results We identified 98 487 patients with a first-time (index) ischemic stroke. After the index stroke, the 1-year cumulative incidence of recurrent ischemic stroke was 16.4% among current glucocorticoid users, whereas risks were lower for hemorrhagic stroke (0.46%), myocardial infarction (1.35%), and venous thromboembolism (0.98%). Among current glucocorticoid users, aHRs were increased for myocardial infarction (1.32, 95% CI 0.98-1.76) and venous thromboembolism (1.39, 95% CI 0.99-1.94), whereas the risk of hemorrhagic stroke was reduced (aHR 0.60, 95% CI 0.38-0.93). There was no association with recurrent ischemic stroke (aHR 1.01, 95% CI 0.94-1.09). Conclusions During the first year after ischemic stroke, current glucocorticoid use was associated with moderately increased risks of myocardial infarction and venous thromboembolism, and a lower risk of hemorrhagic stroke, whereas the risk of recurrent ischemic stroke was not affected.

  View details for PubMedID 30179297

• Differential effect of plasma estradiol on subclinical atherosclerosis progression in early versus late postmenopause. The Journal of clinical endocrinology and metabolism Sriprasert, I., Hodis, H. N., Karim, R., Stanczyk, F. Z., Shoupe, D., Henderson, V. W., Mack, W. J. 2018

  Abstract

  Context: The Early versus Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced progression of atherosclerosis when initiated in early but not in late postmenopause.Objective: This post-trial analysis determined the association between plasma estradiol (E2) levels and atherosclerosis determined by rate of change in carotid artery intima-media thickness (CIMT) and tested whether this association is equally evident in early (<6 years) compared with late (≥10 years) postmenopause.Design: Randomized controlled trial stratified by time since menopause (ClinicalTrials.gov number NCT00114517). Mixed-effects linear models tested the association of E2 levels with CIMT rate of change.Setting: Los Angeles, California, USA.Participants: Healthy postmenopausal women.Intervention: Oral E2 with/without cyclic vaginal progesterone.Main outcome measures: Plasma E2 levels and CIMT assessed every 6 months over an average 4.8 years.Results: Among 596 postmenopausal women, higher E2 was inversely associated with CIMT progression in early-postmenopausal women (p=0.041) and positively associated with CIMT progression in late-postmenopausal women (p=0.006) (p-for-interaction<0.001). CIMT progression rate for the lowest versus highest quartiles of E2 levels among early-postmenopausal women was 8.5 mum/yr and 7.2 mum/yr, while among late-postmenopausal women was 9.8 mum/yr and 11.7 mum/yr, respectively.Conclusion: E2 levels are differentially associated with atherosclerosis progression according to timing of hormone therapy initiation. With higher E2 levels, CIMT progression rate is decreased among early-postmenopausal women, but increased among late-postmenopausal women. These results support the timing hypothesis of HT initiation on cardiovascular benefit, with reduced atherosclerosis progression for initiation during early postmenopause.

  View details for PubMedID 30272234

• Pre-admission use of platelet inhibitors and short-termstroke mortality: a population-based cohort study EUROPEAN HEART JOURNAL-CARDIOVASCULAR PHARMACOTHERAPY Wurtz, M., Schmidt, M., Grove, E., Horvath-Puho, E., Henderson, V. W., Christiansen, C., Sorensen, H. 2018; 4 (3): 158–65

  Abstract

  The impact of pre-admission antiplatelet treatment on prognosis after stroke is poorly understood. We, therefore, investigated whether pre-admission use of aspirin and clopidogrel was associated with mortality in patients hospitalized with ischaemic stroke, intracerebral haemorrhage (ICH), or subarachnoid haemorrhage (SAH).We used nationwide population-based registries to identify all first-time hospitalizations for stroke and subsequent mortality in patients treated with aspirin and clopidogrel in Denmark during 2004-2012. Based on redeemed prescriptions, we computed absolute 30-day mortality rates and mortality rate ratios (MRRs) for current platelet inhibitor users and non-users. We used Cox regression to control for potentially confounding factors. Among platelet inhibitor non-users, 30-day stroke mortality was 12.0% (8.8% for ischaemic stroke, 29.6% for ICH, and 21.2% for SAH). Compared with non-users, the adjusted 30-day MRR (aMRR) was increased among ICH patients using aspirin [1.19, 95% confidence interval (CI) 1.09-1.31]. Although wider CIs, similar increased point estimates were observed in users of both aspirin and clopidogrel (aMRR = 1.26, 95% CI 0.84-1.91). In contrast, current use of both aspirin and clopidogrel was associated with reduced mortality from ischaemic stroke (aMRR = 0.67, 95% CI 0.48-0.94), while use of aspirin alone was not.Among patients hospitalized for first-time ICH, pre-admission platelet inhibitor use was associated with increased 30-day mortality compared with non-use. In patients hospitalized for ischaemic stroke, 30-day mortality was reduced in users of both aspirin and clopidogrel, but not in users of aspirin alone.

  View details for PubMedID 29528386

• Progesterone and human cognition. Climacteric : the journal of the International Menopause Society Henderson, V. W. 2018: 1–8

  Abstract

  Progesterone is a neurosteroid and a neuroactive steroid, produced primarily by the corpus luteum and the placenta. In some animal models, progesterone affects cognitive performance, and its potential role in human cognition is especially germane to women. This role can be investigated through associations between peripheral concentrations of progesterone in blood or saliva and neuropsychological test results, through differences in cognitive profiles between women using menopausal hormone therapy with and without a progestogen, and through clinical trials. In naturally cycling reproductive-age women and pregnant women, there is no consistent relation between progesterone levels and cognition. In postmenopausal women within 6 years of menopause and not using hormone therapy, progesterone levels are positively associated with verbal memory and global cognition, but reported associations in older postmenopausal women are null. Some observational studies of postmenopausal women using hormone therapy raise concern of a small deleterious cognitive effect of progestogen (medroxyprogesterone acetate was most often reported in these studies), but this association may due to confounding factors. Small, short-term clinical trials of progesterone show no meaningful effect on cognition. The quality of evidence is low, but overall findings do not reveal consistent, clinically important effects of progesterone on cognitive function in women.

  View details for PubMedID 29852783

• Risk of Dementia in Adults With Congenital Heart Disease: Population-Based Cohort Study CIRCULATION Bagge, C. N., Henderson, V. W., Laursen, H. B., Adelborg, K., Olsen, M., Madsen, N. L. 2018; 137 (18): 1912–20

  Abstract

  More children with congenital heart disease (CHD) are surviving to adulthood, and CHD is associated with risk factors for dementia. We compared the risk of dementia in CHD adults to that of the general population.In this cohort study, we used medical registries and a medical record review covering all Danish hospitals to identify adults with CHD diagnosed between 1963 and 2012. These individuals with CHD were followed from January 1, 1981, 30 years of age, or date of first CHD registration (index date for matched members of the general population cohort) until hospital diagnosis of dementia, death, emigration, or end of study (December 31, 2012). For each individual with CHD, we identified 10 members of the general population utilizing the Danish Civil Registration System matched on sex and birth year. We computed cumulative incidences and hazard ratios (HRs) of dementia, adjusting for sex and birth year.The cumulative incidence of dementia was 4% by 80 years of age in 10 632 adults with CHD (46% male). The overall HR comparing adults with CHD with the general population cohort was 1.6 (95% confidence interval [CI], 1.3-2.0). The HR among individuals with CHD without extracardiac defects was 1.4 (95% CI, 1.1-1.8). Adults with mild-to-moderate CHD had an HR of 1.5 (95% CI, 1.1-2.0), whereas the HR was 2.0 (95% CI, 1.2-3.3) for severe CHD, including univentricular hearts. The HR for early onset dementia (<65 years of age) was 2.6 (95% CI, 1.8-3.8), whereas the late-onset HR was 1.3 (95% CI, 1.0-1.8).CHD was associated with an increased risk of dementia compared with the general population, in particular for early onset dementia. Further understanding of dementia risk in the population with CHD is a potential target for future investigation.

  View details for PubMedID 29440121

  View details for PubMedCentralID PMC5930034

• In utero exposure to the 1918 pandemic influenza in Denmark and risk of dementia INFLUENZA AND OTHER RESPIRATORY VIRUSES Cocoros, N. M., Ording, A. G., Horvath-Puho, E., Henderson, V. W., Sorensen, H. T. 2018; 12 (3): 314–18

  Abstract

  Substantial but inconclusive evidence suggests in utero exposure to influenza infection may be linked with Alzheimer's disease.We examined whether individuals exposed in utero to the 1918 influenza pandemic are at increased risk of dementia.In this cohort study, surveillance data were used to identify months when influenza activity was at its peak during the pandemic. Using birth dates, exposed and unexposed individuals were identified based on whether they were in utero during ≥1 of the peak months. The outcome, any type of dementia, was identified in population-based medical registries. Time and age at risk were restricted so exposed and unexposed had equal time at risk; diagnoses for dementia were assessed between ages 62 and 92, with a maximum of 30 years at risk. Poisson regression was used to estimate sex-adjusted incidence rate ratios (IRRs).We identified 106 479 exposed and 177 918 unexposed persons. Using the cumulative risk function, there were similar proportions of exposed and unexposed with a dementia diagnosis at 11.9% and 11.7%, respectively. Across all ages, the IRR for the association between in utero influenza exposure and any dementia was 1.01 (95% CI 0.99-1.04); for Alzheimer's disease, it was 0.97 (0.93-1.01). When stratified by age and sex, and when dementia type was examined, estimates of association were also null or close to null.Our study suggests there is likely not an association between in utero exposure to the 1918 influenza pandemic and dementia among those 62 and older.

  View details for PubMedID 29356338

  View details for PubMedCentralID PMC5907820

• Respiratory distress syndrome in preterm infants and risk of epilepsy in a Danish cohort EUROPEAN JOURNAL OF EPIDEMIOLOGY Thygesen, S., Olsen, M., Pedersen, L., Henderson, V. W., Ostergaard, J., Sorensen, H. 2018; 33 (3): 313–21

  Abstract

  Infant respiratory distress syndrome (IRDS) may be complicated by intracerebral hemorrhage, a known trigger of epilepsy. However, few data exist on long term epilepsy risk following IRDS. We therefore examined the association between IRDS in preterm infants and childhood epilepsy. We conducted a population-based cohort study using individual-level data linkage among nationwide registries. All infants born at 32-36 weeks of gestation in 1978-2009 were identified in the Medical Birth Registry. We identified children with IRDS and those with epilepsy using the Danish National Patient Registry. We computed the cumulative incidence of epilepsy with follow-up from birth until epilepsy, emigration, death, age 15, or December 31, 2014. We used Cox's regression analysis to compute hazard ratios comparing children with and without IRDS, adjusting for sex, birth year, gestational age, multiplicity, major malformations, and maternal age. We identified 95,026 infants, of whom 6426 (6.8%) had IRDS. The cumulative incidence of epilepsy was 3.4% by age 15 in children with IRDS and 2.1% in children without IRDS. The adjusted hazard ratio of epilepsy among children with IRDS compared to those without was 1.4 (95% CI 1.2-1.6). When we restricted the IRDS cohort to children with no simultaneous morbidities that had clinical symptoms overlapping with IRDS, the overall adjusted HR was 1.1 (95% CI 0.9-1.4). In children born preterm at 32-36 weeks' gestation, IRDS was associated with increased risk of childhood epilepsy.

  View details for PubMedID 28887607

• Higher Risk of Vascular Dementia in Myocardial Infarction Survivors CIRCULATION Sundboll, J., Horvath-Puho, E., Adelborg, K., Schmidt, M., Pedersen, L., Botker, H., Henderson, V. W., Sorensen, H. 2018; 137 (6): 567–77

  Abstract

  Increased risk of dementia after myocardial infarction (MI) may be mediated by shared risk factors (eg, atherosclerosis) and post-MI stroke. We examined risk of dementia in 1-year survivors of MI.Using Danish medical registries, we conducted a nationwide population-based cohort study of all patients with first-time MI and a sex-, birth year-, and calendar year-matched general population comparison cohort without MI (1980-2012). Cox regression analysis was used to compute 1- to 35-year adjusted hazard ratios (aHRs) for dementia, controlled for matching factors and adjusted for comorbidities and socioeconomic status.We identified 314 911 patients with MI and 1 573 193 matched comparison cohort members randomly sampled from the general population (median age, 70 years; 63% male). After 35 years of follow-up, the cumulative incidence of all-cause dementia in the MI cohort was 9% (2.8% for Alzheimer disease, 1.6% for vascular dementia, and 4.5% for other dementias). Compared with the general population cohort, MI was not associated with all-cause dementia (aHR, 1.01; 95% confidence interval [CI], 0.98-1.03). Risk of Alzheimer disease (aHR, 0.92; 95% CI, 0.88-0.95) and other dementias (aHR, 0.98; 95% CI, 0.95-1.01) also approximated unity. However, MI was associated with higher risk of vascular dementia (aHR, 1.35; 95% CI, 1.28-1.43), which was substantially strengthened for patients experiencing stroke after MI (aHR, 4.48; 95% CI, 3.29-6.12).MI was associated with higher risk of vascular dementia throughout follow-up, and this association was stronger in patients with stroke. The risk of Alzheimer disease and other dementias was not higher in patients with MI.

  View details for PubMedID 29025764

• Comorbidity and the increased mortality after hospitalization for stroke: a population-based cohort study JOURNAL OF THROMBOSIS AND HAEMOSTASIS Corraini, P., Szepligeti, S. K., Henderson, V. W., Ording, A. G., Horvath-Puho, E., Sorensen, H. T. 2018; 16 (2): 242–52

  Abstract

  Essentials Comorbidity is prevalent in the stroke population and affects post-stroke survival. A stroke patient cohort (n = 201 691) and a general population cohort were followed for survival. Cancer and advanced renal/liver disease substantially increased one-year stroke mortality. Tailoring stroke interventions according to comorbidity may reduce excess mortality.Background Comorbidity is prevalent among stroke patients, affecting post-stroke survival. It remains unknown whether comorbidity impacts post-stroke mortality beyond the combined individual effects of stroke and comorbidity. Methods Using nationwide Danish databases, we performed a cohort study of 201 691 patients ≥ 18 years old with incident ischemic stroke, intracerebral or subarachnoid hemorrhage, or unspecified stroke during 1995-2012, and 992 942 adults from the general population, matched to stroke patients by birth year, sex and individual comorbidities in the Charlson Comorbidity Index. During up to 5 years of follow-up, we computed standardized mortality rates (SMRs) to assess interaction contrasts as a measure of excess mortality not explained by the additive effects of stroke and comorbidity acting alone. Results Five-year post-stroke mortality was 48%, corresponding to an SMR of 187 deaths per 1000 person-years. During the 30-day peak post-stroke mortality (SMR, 180 per 1000 person-months), interaction with comorbidity represented 23%, 34% and 51% of post-stroke mortality rates among patients with low (score = 1), moderate (score = 2-3) and high (score = 4+) comorbidity based on Charlson Comorbidity Index scores. The interaction accounted for 5% to 32% of subsequent 31-365-day post-stroke mortality rates, depending on comorbidity level. The interaction contrasts were most notable among comorbid patients with cancer, particularly with hematological or metastatic disease, followed by patients with moderate-to-severe liver or renal disease. Conclusion Comorbidity, notably cancer and advanced renal or liver disease, increased 1-year mortality after stroke beyond the combined effects expected from either disease acting alone.

  View details for PubMedID 29171148

• Tonsillectomy and Risk of Parkinson's Disease: A Danish Nationwide Population-Based Cohort Study MOVEMENT DISORDERS Svensson, E., Henderson, V. W., Szepligeti, S., Stokholm, M., Klug, T., Sorensen, H., Borghammer, P. 2018; 33 (2): 321–24

  Abstract

  We hypothesized that tonsillectomy modifies the risk of PD.To test the hypothesis in a nationwide population-based cohort study.We used Danish medical registries to construct a cohort of all patients in Denmark with an operation code of tonsillectomy 1980-2010 (n = 195,169) and a matched age and sex general population comparison cohort (n = 975,845). Patients were followed until PD diagnosis, death, censoring, or end of follow-up 30 November 2013. Using Cox regression, we computed hazard ratios for PD and corresponding 95% confidence intervals, adjusting for age and sex by study design, and potential confounders.We identified 100 and 568 patients diagnosed with PD among the tonsillectomy and general population comparison cohort, respectively, finding similar risks of PD (adjusted hazard ratio = 0.95 [95% confidence interval: 0.76-1.19]; for > 20 years' follow-up (adjusted hazard ratio = 0.96 [95% confidence interval: 0.64-1.41]).Tonsillectomy is not associated with risk of PD, especially early-onset PD. © 2017 International Parkinson and Movement Disorder Society.

  View details for PubMedID 29193401

  View details for PubMedCentralID PMC5809198

• Migraine and risk of cardiovascular diseases: Danish population based matched cohort study BMJ-BRITISH MEDICAL JOURNAL Adelborg, K., Szepligeti, S., Holland-Bill, L., Ehrenstein, V., Horvath-Puho, E., Henderson, V. W., Sorensen, H. 2018; 360

  View details for DOI 10.1136/bmj.k96

  View details for Web of Science ID 000423845900017

• Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ (Clinical research ed.) Adelborg, K., Szépligeti, S. K., Holland-Bill, L., Ehrenstein, V., Horváth-Puhó, E., Henderson, V. W., Sørensen, H. T. 2018; 360: k96

  Abstract

  To examine the risks of myocardial infarction, stroke (ischaemic and haemorrhagic), peripheral artery disease, venous thromboembolism, atrial fibrillation or atrial flutter, and heart failure in patients with migraine and in a general population comparison cohort.Nationwide, population based cohort study.All Danish hospitals and hospital outpatient clinics from 1995 to 2013.51 032 patients with migraine and 510 320 people from the general population matched on age, sex, and calendar year.Comorbidity adjusted hazard ratios of cardiovascular outcomes based on Cox regression analysis.Higher absolute risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. After 19 years of follow-up, the cumulative incidences per 1000 people for the migraine cohort compared with the general population were 25 v 17 for myocardial infarction, 45 v 25 for ischaemic stroke, 11 v 6 for haemorrhagic stroke, 13 v 11 for peripheral artery disease, 27 v 18 for venous thromboembolism, 47 v 34 for atrial fibrillation or atrial flutter, and 19 v 18 for heart failure. Correspondingly, migraine was positively associated with myocardial infarction (adjusted hazard ratio 1.49, 95% confidence interval 1.36 to 1.64), ischaemic stroke (2.26, 2.11 to 2.41), and haemorrhagic stroke (1.94, 1.68 to 2.23), as well as venous thromboembolism (1.59, 1.45 to 1.74) and atrial fibrillation or atrial flutter (1.25, 1.16 to 1.36). No meaningful association was found with peripheral artery disease (adjusted hazard ratio 1.12, 0.96 to 1.30) or heart failure (1.04, 0.93 to 1.16). The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men. In a subcohort of patients, the associations persisted after additional multivariable adjustment for body mass index and smoking.Migraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. Migraine may be an important risk factor for most cardiovascular diseases.

  View details for PubMedID 29386181

• Progesterone and human cognition CLIMACTERIC Henderson, V. W. 2018; 21 (4): 333–40

  View details for DOI 10.1080/13697137.2018.1476484

  View details for Web of Science ID 000438289400007

• Differential Effect of Plasma Estradiol Levels Achieved with Hormone Therapy on the Progression of Subclinical Atherosclerosis in Early and Late Postmenopausal Women Sriprasert, I., Hodis, H., Karim, R., Stanczyk, F., Shoupe, D., Henderson, V., Mack, W. J. LIPPINCOTT WILLIAMS & WILKINS. 2017: 1424

  View details for Web of Science ID 000423298900040

• Unlocking Neurocognitive Substrates of Late-Life Affective Symptoms Using the Research Domain Criteria: Worry Is an Essential Dimension FRONTIERS IN AGING NEUROSCIENCE Beaudreau, S. A., Hantke, N. C., Mashal, N., Gould, C. E., Henderson, V. W., O'Hara, R. 2017; 9: 380

  Abstract

  While investigations have sought to identify the distinct and shared contributions of anxiety and depression to neurocognitive processes in late life, less is known regarding the further contribution of worry, a unique and critical dimension of affective dysregulation. Capturing the full range of symptoms, as inspired by the NIH Research Domain Criteria (RDoC), may provide finer-grained information on inter-relationships among worry, anxiety and depression on neurocognitive processing in later life. The objective of this study was to determine if the dimensional trait of worry intensifies known negative associations of dimensional measures of anxiety and depressive symptoms with neurocognitive processes, specifically cognitive control and memory processes. Using a cross-sectional and observational design, this study was conducted within a translational research center located with a Veterans medical center in Northern California. One hundred and nineteen community-residing older adults ages 65-91 years participated, and were characterized with psychiatric and neurocognitive dimensional measures. Affective symptom severity was assessed with the Penn State Worry Questionnaire, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory-II. Primary neurocognitive outcomes were inhibitory control assessed using a Stroop paradigm and delayed verbal memory assessed with the Rey Auditory Verbal Learning Test. Secondary outcomes included other less frequently examined cognitive control mechanisms (working memory, information processing, and verbal fluency) and memory processes (visual delayed memory). Contrary to prediction, the dimensional trait of worry attenuated negative associations between anxiety and depressive symptoms and inhibitory control on the one hand, and between depressive symptoms and delayed verbal memory processes on the other. In the secondary models, symptom dimensions were not associated with other cognitive control or visual delayed memory processes. Our fine-grained approach, in line with the NIMH RDoC model, suggests the neurocognitive processes associated with dimensional measures of late-life affective symptoms are dissociable. Specifically, dimensional measures of worry operate independently from other anxiety and depression symptoms to reveal differential patterns of neurocognitive processes associated with affective dysregulation.

  View details for PubMedID 29249958

• Semantic Memory in the Clinical Progression of Alzheimer Disease COGNITIVE AND BEHAVIORAL NEUROLOGY Tchakoute, C. T., Sainani, K. L., Henderson, V. W. 2017; 30 (3): 81–89

  Abstract

  Semantic memory measures may be useful in tracking and predicting progression of Alzheimer disease. We investigated relationships among semantic memory tasks and their 1-year predictive value in women with Alzheimer disease.We conducted secondary analyses of a randomized clinical trial of raloxifene in 42 women with late-onset mild-to-moderate Alzheimer disease. We assessed semantic memory with tests of oral confrontation naming, category fluency, semantic recognition and semantic naming, and semantic density in written narrative discourse. We measured global cognition (Alzheimer Disease Assessment Scale, cognitive subscale), dementia severity (Clinical Dementia Rating sum of boxes), and daily function (Activities of Daily Living Inventory) at baseline and 1 year.At baseline and 1 year, most semantic memory scores correlated highly or moderately with each other and with global cognition, dementia severity, and daily function. Semantic memory task performance at 1 year had worsened one-third to one-half standard deviation. Factor analysis of baseline test scores distinguished processes in semantic and lexical retrieval (semantic recognition, semantic naming, confrontation naming) from processes in lexical search (semantic density, category fluency). The semantic-lexical retrieval factor predicted global cognition at 1 year. Considered separately, baseline confrontation naming and category fluency predicted dementia severity, while semantic recognition and a composite of semantic recognition and semantic naming predicted global cognition. No individual semantic memory test predicted daily function.Semantic-lexical retrieval and lexical search may represent distinct aspects of semantic memory. Semantic memory processes are sensitive to cognitive decline and dementia severity in Alzheimer disease.

  View details for PubMedID 28926415

  View details for PubMedCentralID PMC5617354

• Risk of Stroke in Patients With Heart Failure: A Population-Based 30-Year Cohort Study. Stroke Adelborg, K., Szépligeti, S., Sundbøll, J., Horváth-Puhó, E., Henderson, V. W., Ording, A., Pedersen, L., Sørensen, H. T. 2017; 48 (5): 1161-1168

  Abstract

  The long-term risk of specific stroke subtypes among heart failure patients is largely unknown. We examined short-term and long-term risk of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) in heart failure patients and in a general population comparison cohort.In this nationwide cohort study (1980-2012), we used Danish population-based medical registries to identify and follow (1) all patients hospitalized for the first time with heart failure and (2) a birth year-, sex-, and calendar year-matched general population comparison cohort. Age-, sex-, and comorbidity-adjusted stroke rate ratios were computed based on Cox regression analysis.We included 289 353 patients with heart failure and 1 446 765 individuals from the general population in the analysis. One- and 5-year risks among heart failure patients were 1.4% and 3.9% for ischemic stroke, 0.2% and 0.5% for ICH, and 0.03% and 0.07% for SAH. The 30-day adjusted stroke rate ratio was increased markedly for ischemic stroke (5.08; 95% confidence interval, 4.58-5.63] and was also elevated for ICH (2.13; 95% confidence interval, 1.53-2.97) and SAH (3.52; 95% confidence interval, 1.54-8.08). Between 31 days and 30 years, risk of all stroke subtypes remained positively associated with heart failure (1.5- to 2.1-fold for ischemic stroke, 1.4- to 1.8-fold for ICH, and 1.1- to 1.7-fold for SAH) in comparison with the general population cohort.Heart failure was associated with increased short-term and long-term risk of all stroke subtypes, suggesting that heart failure is a potent and persistent risk factor for ischemic stroke, ICH, and SAH.

  View details for DOI 10.1161/STROKEAHA.116.016022

  View details for PubMedID 28377383

• Heart failure and risk of dementia: a Danish nationwide population-based cohort study. European journal of heart failure Adelborg, K., Horváth-Puhó, E., Ording, A., Pedersen, L., Toft Sørensen, H., Henderson, V. W. 2017; 19 (2): 253-260

  Abstract

  The association between heart failure and dementia remains unclear. We assessed the risk of dementia among patients with heart failure and members of a general population comparison cohort.Individual-level data from Danish medical registries were linked in this nationwide population-based cohort study comparing patients with a first-time hospitalization for heart failure between 1980 and 2012 and a year of birth-, sex-, and calendar year-matched comparison cohort from the general population. Stratified Cox regression analysis was used to compute 1-35-year hazard ratios (HRs) for the risk of all-cause dementia and, secondarily, Alzheimer's disease, vascular dementia, and other dementias. Analyses included 324 418 heart failure patients and 1 622 079 individuals from the general population (median age 77 years, 52% male). Compared with the general population cohort, risk of all-cause dementia was increased among heart failure patients [adjusted HR 1.21, 95% confidence interval (CI) 1.18-1.24]. The associations were stronger in men and in heart failure patients under age 70. Heart failure patients had higher risks of vascular dementia (adjusted HR 1.49, 95% CI 1.40-1.59) and other dementias (adjusted HR 1.30, 95% CI 1.26-1.34) than members of the general population cohort. Heart failure was not associated with Alzheimer's disease (adjusted HR 1.00, 95% CI 0.96-1.04).Heart failure was associated with an increased risk of all-cause dementia. Heart failure may represent a risk factor for dementia, but not necessarily for Alzheimer's disease.

  View details for DOI 10.1002/ejhf.631

  View details for PubMedID 27612177

• Long-Term Risk of Dementia Among Survivors of Ischemic or Hemorrhagic Stroke STROKE Corraini, P., Henderson, V. W., Ording, A. G., Pedersen, L., Horvath-Puho, E., Sorensen, H. T. 2017; 48 (1): 180-?

  Abstract

  Stroke is a risk factor for dementia, but the risk of dementia after different stroke types is poorly understood. We examined the long-term risk of dementia among survivors of any first-time stroke and of first-time ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.We conducted a 30-year nationwide population-based cohort study using data from Danish medical databases (1982-2013) covering all Danish hospitals. We identified 84 220 ischemic stroke survivors, 16 723 intracerebral hemorrhage survivors, 9872 subarachnoid hemorrhage survivors, and 104 303 survivors of unspecified stroke types. Patients were aged ≥18 years and survived for at least 3 months after diagnosis. We formed a comparison cohort from the general population (1 075 588 patients without stroke, matched to stroke patients by age and sex). We computed absolute risks and hazard ratios of dementia up to 30 years after stroke.The 30-year absolute risk of dementia among stroke survivors was 11.5% (95% confidence interval, 11.2%-11.7%). Compared with the general population, the hazard ratio (95% confidence interval) for dementia among stroke survivors was 1.80 (1.77-1.84) after any stroke, 1.72 (1.66-1.77) after ischemic stroke, 2.70 (2.53-2.89) after intracerebral hemorrhage, and 2.74 (2.45-3.06) after subarachnoid hemorrhage. Younger patients regardless of stroke type faced higher risks of poststroke dementia than older patients. The pattern of hazard ratios by stroke type did not change during follow-up and was not altered appreciably by age, sex, or preexisting diagnoses of vascular conditions.Stroke increases dementia risk. Survivors of intracerebral hemorrhage and subarachnoid hemorrhage are at particularly high long-term risk of poststroke dementia.

  View details for DOI 10.1161/STROKEAHA.116.015242

  View details for Web of Science ID 000391944900032

  View details for PubMedID 27899749

• Non-melanoma skin cancer and risk of Alzheimer's disease and all-cause dementia. PloS one Schmidt, S. A., Ording, A. G., Horváth-Puhó, E., Sørensen, H. T., Henderson, V. W. 2017; 12 (2)

  Abstract

  Cancer patients may be at decreased risk of Alzheimer's disease. This hypothesis is best developed for non-melanoma skin cancer (NMSC), but supportive epidemiological data are sparse. We therefore conducted a nationwide cohort study of the association between NMSC and Alzheimer's disease (main outcome) and all-cause dementia. Using Danish medical databases, we identified adults diagnosed with NMSC between 1 January 1980 and 30 November 2013 (n = 216,221) and a comparison cohort of five individuals matched to each NMSC patient by sex and birth year (n = 1,081,097). We followed individuals from the time of diagnosis, or corresponding date for matched comparators, until a dementia diagnosis, death, emigration, or 30 November 2013, whichever came first. We used stratified Cox regression adjusted for comorbidities to compute hazard ratios (HRs) associating NMSC with dementia. We computed cumulative risks of dementia, treating death as a competing risk. NMSC was associated with a HR of 0.95 (95% confidence interval [CI]: 0.92-0.98) for Alzheimer's disease and 0.92 (95% CI: 0.90-0.94) for all-cause dementia. HRs were similar for basal cell and squamous cell carcinoma, the two most common forms of NMSC. Estimates of risk reduction were more pronounced in the beginning of follow-up, reaching null after 5-10 years. At the end of follow-up (34 years), cumulative risk of Alzheimer's disease was 4.6% (95% CI: 4.4%-4.8%) among patients with NMSC vs. 4.7% (95% CI: 4.6%-4.9%) in the comparison cohort. In conclusion, NMSC was associated with 2%-10% reductions in relative risks of Alzheimer's disease and all-cause dementia. However, these small inverse associations may have been caused by ascertainment bias due to decreased awareness of NMSC tumors in persons with undiagnosed early cognitive impairment or by confounding from a more neuroprotective lifestyle among persons with NMSC.

  View details for DOI 10.1371/journal.pone.0171527

  View details for PubMedID 28225789

  View details for PubMedCentralID PMC5321271

• Appendectomy and Risk of Parkinson's Disease: A Nationwide Cohort Study With More Than 10 Years of Follow-Up MOVEMENT DISORDERS Svensson, E., Horvath-Puho, E., Stokholm, M. G., Sorensen, H. T., Henderson, V. W., Borghammer, P. 2016; 31 (12): 1918-1922

  Abstract

  The appendix may be a key site for the initiation of Parkinson's disease (PD) pathology. We examined the hypothesis that appendectomy is associated with lower PD risk.We used Danish medical and administrative registries to construct a cohort of all patients in Denmark with an operation code of appendectomy during 1980-2010 (n = 265,758) and a matched general population comparison cohort (n = 1,328,790). Using Cox regression, we computed hazard ratios and corresponding 95% confidence intervals for PD, adjusting for potential confounders and stratifying on age at appendectomy (≤45 years / > 45 years), sex, and follow-up time.During follow-up ( > 10 years), PD incidence was 0.19 and 0.15 per 1,000 person-years at risk in the appendectomy cohort and in the general population comparison cohort, respectively, yielding a slightly increased risk of PD (adjusted hazard ratio = 1.14; 95% confidence interval 1.03-1.27). Findings were consistent after more than 20 years of follow-up and when stratified on age of appendectomy and sex.Appendectomy was associated with a small increase in PD risk 10 or more years after surgery. © 2016 International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.26761

  View details for Web of Science ID 000393123200025

  View details for PubMedID 27621223

• ApoE4 Genotype Modifies the Association Between Metabolic Risk Profile and Cognition in Postmenopausal Women Karim, R., Koc, M., Rettberg, J., Hodis, H. N., Henderson, V., St John, J., Allayee, H., Diaz, R., Mack, W. J. LIPPINCOTT WILLIAMS & WILKINS. 2016: 1376–77

  View details for Web of Science ID 000389254000053

• Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Karim, R., Dang, H., Henderson, V. W., Hodis, H. N., St John, J., Brinton, R. D., Mack, W. J. 2016; 64 (12): 2448-2456

  Abstract

  To investigate the association between reproductive history indicators of hormonal exposure, including reproductive period, pregnancy, and use of hormonal contraceptives, and mid- and late-life cognition in postmenopausal women.Analysis of baseline data from two randomized clinical trials: the Women's Isoflavone Soy Health and the Early vs Late Intervention Trial of Estradiol.University academic research center.Naturally menopausal women (N = 830).Participants were uniformly evaluated using a cognitive battery and a structured reproductive history questionnaire. Outcomes were composite scores for verbal episodic memory, executive function, and global cognition. Reproductive variables included ages at pregnancies, menarche, and menopause; reproductive period; number of pregnancies; and use of hormones for contraception and menopausal symptoms. Multivariable linear regression was used to evaluate associations between cognitive scores (dependent variable) and reproductive factors (independent variables), adjusting for age, race and ethnicity, income, and education.On multivariable modeling, age at menarche of 13 and older was inversely associated with global cognition (P = .05). Last pregnancy after age 35 was positively associated with verbal memory (P = .03). Use of hormonal contraceptives was positively associated with global cognition (P trend = .04), and verbal memory (P trend = .007). The association between hormonal contraceptive use and verbal memory and executive function was strongest for more than 10 years of use. Reproductive period was positively associated with global cognition (P = .04) and executive function (P = .04).In this sample of healthy postmenopausal women, reproductive life events related to sex hormones, including earlier age at menarche, later age at last pregnancy, longer reproductive period, and use of oral contraceptives are positively related to aspects of cognition in later life.

  View details for DOI 10.1111/jgs.14658

  View details for Web of Science ID 000393589200022

  View details for PubMedID 27996108

  View details for PubMedCentralID PMC5180359

• Cancer, other comorbidity, and risk of venous thromboembolism after stroke: a population-based cohort study. Thrombosis research Corraini, P., Ording, A. G., Henderson, V. W., Szépligeti, S., Horváth-Puhó, E., Sørensen, H. T. 2016; 147: 88-93

  Abstract

  The impact of cancer and other comorbidity on the risk of venous thromboembolism (VTE) after stroke is poorly understood.We used Danish population-based national databases to conduct a cohort study encompassing 201,025 patients diagnosed with a first-time ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage or unspecified stroke between 1995 and 2012. As a comparison cohort, 983,222 members of the general population were matched to the stroke patients by date of diagnosis, year of birth, sex, and specific comorbidities, using conditions in the Charlson Comorbidity Index and other VTE risk factors. We computed VTE cumulative risks, rates, and rate ratios. We examined the interaction with comorbidity, defined as the excess VTE rates not explained by stroke and comorbidity alone, for up to five years following stroke.Five-year VTE risks were 2.1% and 1.9% in the stroke and comparison cohorts, respectively. Three-month VTE rates peaked at a 5-fold increase (95% confidence interval [CI]: 4.4; 5.2) in stroke patients and remained 13% to 43% increased relative to the general population during subsequent follow-up. During the first three months after stroke, 15% to 33% of the VTE rates were attributable to the interaction between stroke and moderate (2-3) to high (≥4) comorbidity based on Charlson Comorbidity Index scores. Non-metastatic solid tumors and metastatic disease accounted for most observed interaction with stroke, representing 41% and 56% of attributable three-month VTE rates, respectively. No such interaction between comorbidity and stroke was observed during subsequent follow-up.Comorbidity, particularly cancer, increased the risk of VTE within three months following stroke.

  View details for DOI 10.1016/j.thromres.2016.09.029

  View details for PubMedID 27710857

• Predictive Factors for Verbal Memory Performance Over Decades of Aging: Data from the Women's Healthy Ageing Project. American journal of geriatric psychiatry Szoeke, C., Lehert, P., Henderson, V. W., Dennerstein, L., Desmond, P., Campbell, S. 2016; 24 (10): 857-867

  Abstract

  Abnormalities in brain structure and function can occur several decades prior to the onset of cognitive decline. It is in the preceding decades that an intervention is most likely to be effective, when informed by an understanding of factors contributing to the disease prodrome. Few studies, however, have sufficient longitudinal data on relevant risks to determine the optimum targets for interventions to improve cognition in aging. In this article we examine the timing and exposure of factors contributing to verbal memory performance in later life.387 participants from the population-based Women's Healthy Ageing Project, mean age at baseline of 49.6 years (range: 45-55 years), had complete neuropsychiatric assessments, clinical information, physical measures, and biomarkers collected at baseline, with at least three follow-up visits that included at least one cognitive reassessment. Mixed linear models were conducted to assess the significance of risk factors on later-life verbal memory. We explored the influence of early, contemporaneous, and cumulative exposures.Younger age and better education were associated with baseline memory test performance (CERAD). Over the 20 years of study follow-up, cumulative mid- to late-life physical activity had the strongest effect on better later life verbal memory (0.136 [0.058, 0.214]). The next most likely contributors to verbal memory in late life were the negative effect of cumulative hypertension (-0.033 [-0.047, -0.0.18] and the beneficial effect of HDL cholesterol (0.818 [0.042, 1.593]).Findings suggest that midlife interventions focused on physical activity, hypertension control, and achieving optimal levels of HDL cholesterol will help maintain later-life verbal memory skills.

  View details for DOI 10.1016/j.jagp.2016.05.008

  View details for PubMedID 27562941

• Association of bilateral oophorectomy with cognitive function in healthy, postmenopausal women. Fertility and sterility Kurita, K., Henderson, V. W., Gatz, M., St John, J., Hodis, H. N., Karim, R., Mack, W. J. 2016; 106 (3): 749-756 e2

  Abstract

  To investigate the association between bilateral oophorectomy and cognitive performance in healthy, older women.Retrospective analysis of clinical trial data.Academic research institution.Healthy postmenopausal women without signs or symptoms of cardiovascular disease or diabetes (n = 926).Randomized interventions (not the focus of this analysis) in analyzed trials included B-vitamins, soy isoflavones, oral estradiol, and matching placebos.Measures in five cognitive domains (executive functions, semantic memory, logical memory, visual memory, and verbal learning) and global cognitive function.Using data from three clinical trials conducted under uniform conditions, bilateral oophorectomy and its timing were analyzed cross-sectionally and longitudinally in relation to cognitive function in linear regression models. Covariates included age, education, race/ethnicity, body mass index, trial, and randomized treatment (in longitudinal models). Duration of menopausal hormone use was considered as a possible mediator and effect modifier. Median age of oophorectomy was 45 years. When evaluating baseline cognition, we found that surgical menopause after 45 years of age was associated with lower performance in verbal learning compared with natural menopause. Evaluating the change in cognition over approximately 2.7 years, surgical menopause was associated with performance declines in visual memory for those who had an oophorectomy after 45 years of age and in semantic memory for those who had oophorectomy before 45 years of age compared with natural menopause. Oophorectomy after natural menopause was not associated with cognitive performance. Adjustment for duration of hormone use did not alter these associations.Cognitive associations with ovarian removal vary by timing of surgery relative to both menopause and age.

  View details for DOI 10.1016/j.fertnstert.2016.04.033

  View details for PubMedID 27183047

• Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology Henderson, V. W., St John, J. A., Hodis, H. N., McCleary, C. A., Stanczyk, F. Z., Shoupe, D., Kono, N., Dustin, L., Allayee, H., Mack, W. J. 2016; 87 (7): 699-708

  Abstract

  To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to, and further from, menopause.In this randomized, double-blind, placebo-controlled trial, healthy women within 6 years of menopause or 10+ years after menopause were randomly assigned to oral 17β-estradiol 1 mg/d or placebo. Women with a uterus received cyclic micronized progesterone vaginal gel or placebo. The primary outcome assessed at 2.5 and 5 years, compared between treatment groups, was change in a standardized composite of neuropsychological test scores assessing verbal episodic memory. Secondary outcomes assessed executive functions and global cognition.A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months. For verbal memory, the mean estradiol minus placebo standardized difference in composite scores (-0.06, 95% confidence interval -0.22 to 0.09) was not significant (2-tailed p = 0.33). Differences were similar in early and late postmenopause groups (2-tailed interaction p = 0.88). Interactions between postmenopause groups and differences between treatment groups were not significant for executive functions or global cognition.Estradiol initiated within 6 years of menopause does not affect verbal memory, executive functions, or global cognition differently than therapy begun 10+ years after menopause. Estradiol neither benefits nor harms these cognitive abilities regardless of time since menopause.This study provides Class I evidence that estradiol initiated within 6 years of menopause does not affect cognition at 2.5 years differently than estradiol initiated 10+ years after menopause.

  View details for DOI 10.1212/WNL.0000000000002980

  View details for PubMedID 27421538

  View details for PubMedCentralID PMC4999165

• Long-Term Risk of Stroke in Myocardial Infarction Survivors Thirty-Year Population-Based Cohort Study STROKE Sundboll, J., Horvath-Puho, E., Schmidt, M., Pedersen, L., Henderson, V. W., Botker, H. E., Sorensen, H. T. 2016; 47 (7): 1727-1733

  Abstract

  Improved survival after myocardial infarction (MI) has increased the number of patients at risk of post-MI stroke. We examined risks of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) in patients with MI compared with the general population.We conducted a nationwide population-based cohort study using Danish medical registries. During 1980 to 2009, we identified all patients with a first-time inpatient diagnosis of MI and formed a sex- and age-matched comparison cohort. We computed cumulative stroke risks and adjusted stroke rate ratios with 95% confidence intervals (CIs).We identified 258 806 patients with an MI and 1 244 773 individuals from the general population. For patients with MI, the cumulative stroke risks after 1 to 30 years were 12.6% for ischemic stroke, 1.2% for ICH, and 0.24% for SAH. During the first 30 days after MI, the adjusted stroke rate ratio was 30-fold increased for ischemic stroke (31.9; 95% CI, 28.4-35.8), 20-fold for ICH (21.8; 95% CI, 16.6-28.5), and 15-fold for SAH (16.6; 95% CI, 8.7-32.0). The adjusted stroke rate ratio remained increased during 31 to 365 days (3-fold for ischemic stroke, 2-fold for ICH, and 1.5-fold for SAH). During the ensuing 1 to 30 years, the risks remained increased for ischemic stroke (1.6; 95% CI, 1.6-1.6) but decreased to near unity for ICH (1.1; 95% CI, 1.0-1.2) and SAH (1.1; 95% CI, 0.94-1.2).MI was a risk factor for all stroke subtypes during the first year of follow-up, but only for ischemic stroke thereafter.

  View details for DOI 10.1161/STROKEAHA.116.013321

  View details for Web of Science ID 000379844900021

  View details for PubMedID 27301935

• Cognition and the menopause transition MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Maki, P. M., Henderson, V. W. 2016; 23 (7): 803-805

  Abstract

  Complaints about forgetfulness, "brain fog," and difficulty concentrating are common in women transitioning through menopause. Women with these cognitive complaints often express concern about whether these problems are normal, related to menopause, or represent a symptom of Alzheimer disease or another serious cognitive disorder. In this Practice Pearl, we provide a brief summary of the scientific literature on the frequency of cognitive complaints in midlife women, the validity of complaints in relation to performance on standardized cognitive tests, and the influence of menopause on cognitive performance. We then offer recommendations for healthcare providers and women to address cognitive concerns.

  View details for DOI 10.1097/GME.0000000000000681

  View details for Web of Science ID 000379370600016

  View details for PubMedID 27272226

• Constipation and risk of Parkinson's disease: A Danish population-based cohort study PARKINSONISM & RELATED DISORDERS Svensson, E., Henderson, V. W., Borghammer, P., Horvath-Puho, E., Sorensen, H. T. 2016; 28: 18-22

  Abstract

  To examine long-term associations between constipation and Parkinson's disease (PD) in men and women, we conducted a population-based cohort study using prospectively collected registry data on hospital contacts for constipation and PD, stratified by follow-up time and sex.We linked Danish registries to construct a cohort of all patients in Denmark with an outpatient hospital diagnosis of constipation 1995-2012 and a matched general population comparison cohort. Using Cox regression, we computed hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders, stratified by sex and follow-up time.The 31,905 patients with constipation had a higher risk of PD than 159,092 comparison cohort members (adjusted (a) HR = 3.03, 95% CI 2.50-3.66), which was sustained to 11-15 years follow-up (aHR = 3.65, 95% CI 1.67-7.95). Increased risk was apparent in both sexes but stronger in men [aHR = 3.52 (2.67-4.64] than women [aHR = 2.64 (95% CI 2.02-3.44].In this large population-based cohort study, constipation was associated with sustained increased risk of a PD diagnosis, and the relative risk was higher for men than for women.

  View details for DOI 10.1016/j.parkreldis.2016.05.016

  View details for Web of Science ID 000379705500003

  View details for PubMedID 27234704

• Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype. Neurobiology of aging Rettberg, J. R., Dang, H., Hodis, H. N., Henderson, V. W., St John, J. A., Mack, W. J., Brinton, R. D. 2016; 40: 155-163

  Abstract

  Detecting at-risk individuals within a healthy population is critical for preventing or delaying Alzheimer's disease. Systems biology integration of brain and body metabolism enables peripheral metabolic biomarkers to serve as reporters of brain bioenergetic status. Using clinical metabolic data derived from healthy postmenopausal women in the Early versus Late Intervention Trial with Estradiol (ELITE), we conducted principal components and k-means clustering analyses of 9 biomarkers to define metabolic phenotypes. Metabolic clusters were correlated with cognitive performance and analyzed for change over 5 years. Metabolic biomarkers at baseline generated 3 clusters, representing women with healthy, high blood pressure, and poor metabolic phenotypes. Compared with healthy women, poor metabolic women had significantly lower executive, global and memory cognitive performance. Hormone therapy provided metabolic benefit to women in high blood pressure and poor metabolic phenotypes. This panel of well-established clinical peripheral biomarkers represents an initial step toward developing an affordable, rapidly deployable, and clinically relevant strategy to detect an at-risk phenotype of late-onset Alzheimer's disease.

  View details for DOI 10.1016/j.neurobiolaging.2016.01.011

  View details for PubMedID 26973115

• Cancer and the risk of venous thromboembolism in stroke patients Corraini, P., Ording, A. G., Henderson, V. W., Szepligeti, S., Hovath-Puho, E., Sorensen, H. T. PERGAMON-ELSEVIER SCIENCE LTD. 2016: S178

  Abstract

  The impact of comorbidity and in particular cancer on the risk of venous thromboembolism (VTE) after stroke is poorly understood.We aimed to determine the impact of comorbidity, in particular cancer, on the risk of venous thromboembolism in stroke patients as the excess VTE rates not explained by stroke and comorbidity alone.We used Danish national databases to conduct a cohort study including 110,833 patients diagnosed with an incident stroke (72% ischemic) between 1995 and 2012. A comparison cohort of 545,960 members of the general population was matched to the stroke patients by date of diagnosis, year of birth, sex, and specific comorbidities using the Charlson Comorbidity Index and other VTE risk factors. We computed VTE cumulative risks, rates and rate ratios, as well as the interaction with comorbidity (as the excess VTE rates not explained by stroke and comorbidity alone) during five years of follow-up.Five-year VTE risks were 2.16% and 1.85% in the stroke and general population comparison cohorts, respectively. Three-month VTE rate ratios peaked at a 6-fold increase (95% confidence interval: 4.9;6.2) in stroke patients and remained increased by 52%-20% relative to the general population at subsequent follow-up. 20% to 38% of the three-month VTE rates in the stroke cohort were attributable to the interaction between stroke and comorbidity in patients with moderate (2-3) to high (≥4) Charlson Comorbidity Index scores. Non-metastatic and metastatic solid tumors accounted for most of the observed interaction with stroke, representing 44% and 60% of their attributable three-month VTE rates. No interaction between comorbidity and stroke was observed during subsequent follow-up to 5 years.Cancer increased the risk of VTE within three months after the stroke.

  View details for PubMedID 27161694

• Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. New England journal of medicine Hodis, H. N., Mack, W. J., Henderson, V. W., Shoupe, D., Budoff, M. J., Hwang-Levine, J., Li, Y., Feng, M., Dustin, L., Kono, N., Stanczyk, F. Z., Selzer, R. H., Azen, S. P. 2016; 374 (13): 1221-1231

  Abstract

  Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).

  View details for DOI 10.1056/NEJMoa1505241

  View details for PubMedID 27028912

• Raloxifene for women with Alzheimer disease: A randomized controlled pilot trial. Neurology Henderson, V. W., Ala, T., Sainani, K. L., Bernstein, A. L., Stephenson, B. S., Rosen, A. C., Farlow, M. R. 2015; 85 (22): 1937-1944

  Abstract

  To determine whether raloxifene, a selective estrogen receptor modulator, improves cognitive function compared with placebo in women with Alzheimer disease (AD) and to provide an estimate of cognitive effect.This pilot study was conducted as a randomized, double-blind, placebo-controlled trial, with a planned treatment of 12 months. Women with late-onset AD of mild to moderate severity were randomly allocated to high-dose (120 mg) oral raloxifene or identical placebo provided once daily. The primary outcome compared between treatment groups at 12 months was change in the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog).Forty-two women randomized to raloxifene or placebo were included in intent-to-treat analyses (mean age 76 years, range 68-84), and 39 women contributed 12-month outcomes. ADAS-cog change scores at 12 months did not differ significantly between treatment groups (standardized difference 0.03, 95% confidence interval -0.39 to 0.44, 2-tailed p = 0.89). Raloxifene and placebo groups did not differ significantly on secondary analyses of dementia rating, activities of daily living, behavior, or a global cognition composite score. Caregiver burden and caregiver distress were similar in both groups.Results on the primary outcome showed no cognitive benefits in the raloxifene-treated group.This study provides Class I evidence that for women with AD, raloxifene does not have a significant cognitive effect. The study lacked the precision to exclude a small effect.

  View details for DOI 10.1212/WNL.0000000000002171

  View details for PubMedID 26537053

  View details for PubMedCentralID PMC4664126

• Hospital-Diagnosed Pertussis Infection in Children and Long-term Risk of Epilepsy JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Olsen, M., Thygesen, S. K., Ostergaard, J. R., Nielsen, H., Henderson, V. W., Ehrenstein, V., Norgaard, M., Sorensen, H. T. 2015; 314 (17): 1844-1849

  Abstract

  Pertussis is associated with encephalopathy and seizures in infants. However, the risk of childhood epilepsy following pertussis is unknown.To examine whether pertussis is associated with the long-term risk of epilepsy.We used individually linked data from population-based medical registries covering all Danish hospitals to identify a cohort of all patients with pertussis born between 1978 and 2011, followed up through 2011. We used the Civil Registration System to identify 10 individuals from the general population for each patient with pertussis, matched on sex and year of birth.Inpatient or hospital-based outpatient diagnosis of pertussis.Cumulative incidence and hazard ratio of time to hospital-based epilepsy diagnosis (pertussis cohort vs general population cohort), adjusted for birth year, sex, maternal history of epilepsy, presence of congenital malformations, and gestational age. Unique personal identifiers permitted unambiguous data linkage and complete follow-up for death, emigration, and hospital contacts.We identified 4700 patients with pertussis (48% male), of whom 90 developed epilepsy during the follow-up. The cumulative incidence of epilepsy at age 10 years was 1.7% (95% CI, 1.4%-2.1%) for patients with pertussis and 0.9% (95% CI, 0.8%-1.0%) for the matched comparison cohort. The corresponding adjusted overall hazard ratio was 1.7 (95% CI, 1.3-2.1).In Denmark, risk of epilepsy was increased in children with hospital-diagnosed pertussis infections compared with the general population; however, the absolute risk was low.

  View details for DOI 10.1001/jama.2015.13971

  View details for Web of Science ID 000363960200016

  View details for PubMedID 26529162

• Individually modifiable risk factors to ameliorate cognitive aging: a systematic review and meta-analysis. Climacteric Lehert, P., Villaseca, P., Hogervorst, E., Maki, P. M., Henderson, V. W. 2015; 18 (5): 678-689

  Abstract

  A number of health and lifestyle factors are thought to contribute to cognitive decline associated with age but cannot be easily modified by the individual patient. We identified 12 individually modifiable interventions that can be implemented during midlife or later with the potential to ameliorate cognitive aging. For ten of these, we used PubMed databases for a systematic review of long-duration (at least 6 months), randomized, controlled trials in midlife and older adults without dementia or mild cognitive impairment with objective measures of neuropsychological performance. Using network meta-analysis, we performed a quantitative synthesis for global cognition (primary outcome) and episodic memory (secondary outcome). Of 1038 publications identified by our search strategy, 24 eligible trials were included in the network meta-analysis. Results suggested that the Mediterranean diet supplemented by olive oil and tai chi exercise may improve global cognition, and the Mediterranean diet plus olive oil and soy isoflavone supplements may improve memory. Effect sizes were no more than small (standardized mean differences 0.11-0.22). Cognitive training may have cognitive benefit as well. Most individually modifiable risk factors have not yet been adequately studied. We conclude that some interventions that can be self-initiated by healthy midlife and older adults may ameliorate cognitive aging.

  View details for DOI 10.3109/13697137.2015.1078106

  View details for PubMedID 26361790

• Prehypertension in midlife is associated with worse cognition a decade later in middle-aged and older women. Age and ageing Chen, K. H., Henderson, V. W., Stolwyk, R. J., Dennerstein, L., Szoeke, C. 2015; 44 (3): 439-445

  Abstract

  previous studies raised the possibility that adverse health effects associated with elevated blood pressure (BP) begin at prehypertension levels (BP = 120-139/80-89 mmHg), yet few studies have examined the effects of prehypertension on cognitive functioning.to examine the relationship between BP categories and cognitive functions in middle-aged and older women.two hundred and forty-seven women from the Women's Healthy Ageing Project had their BP measured twice, at mean ages 50 and 60 years. Tests of executive function, processing speed and verbal episodic memory were also administered at follow-up. Analyses of co-variance were performed to evaluate the associations between BP categories and cognitive performance.prehypertensive BP at age 50 years is a significant predictor of reduced processing speed and verbal episodic memory a decade later. Cross-sectional measurements at age 60 years showed that untreated hypertensive women performed significantly worse on verbal episodic memory compared with their prehypertensive peers.hypertension is a modifiable cardiovascular risk factor, and our results suggest that reducing midlife BP, even at prehypertensive levels, may be an effective prevention strategy to reduce risk for subsequent cognitive decline in middle-aged and older women.

  View details for DOI 10.1093/ageing/afv026

  View details for PubMedID 25814553

• Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Hodis, H. N., Mack, W. J., Shoupe, D., Azen, S. P., Stanczyk, F. Z., Hwang-Levine, J., Budoff, M. J., Henderson, V. W. 2015; 22 (4): 391-401

  Abstract

  This study aims to present methods and baseline data from the Early versus Late Intervention Trial with Estradiol (ELITE), the only clinical trial designed to specifically test the timing hypothesis of postmenopausal hormone therapy (HT). The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time since menopause.ELITE is a randomized, double-blind, placebo-controlled trial with a 2 × 2 factorial design. Six hundred forty-three healthy postmenopausal women without cardiovascular disease were randomized to oral estradiol or placebo for up to 6 to 7 years according to time since menopause (<6 or ≥10 y). Carotid artery intima-media thickness (CIMT) and cardiac computed tomography were conducted to determine HT effects on subclinical atherosclerosis across menopause strata.Participants in the early and late postmenopausal strata were well-separated by mean age (55.4 vs 65.4 y) and median time since menopause (3.5 vs 14.3 y). Expected risk factors (age, blood pressure, and body mass index) were associated with CIMT at baseline in both strata. In the early postmenopausal group, but not in the late postmenopausal group, we observed significant associations between CIMT and factors that may play a role in the responsiveness of atherosclerosis progression according to timing of HT initiation. These include low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sex hormone-binding globulin, and serum total estradiol.The ELITE randomized controlled trial is timely and unique. Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease.

  View details for DOI 10.1097/gme.0000000000000343

  View details for Web of Science ID 000351886400007

  View details for PubMedID 25380275

  View details for PubMedCentralID PMC4376597

• Three midlife strategies to prevent cognitive impairment due to Alzheimer's disease CLIMACTERIC Henderson, V. W. 2014; 17: 38-46

  Abstract

  The slow, progressive accumulation of pathology characteristic of Alzheimer's disease is the principal determinant of cognitive decline leading to dementia. Risk-reduction strategies during midlife focus on raising the clinical threshold for the appearance of cognitive symptoms and on reducing the extent of Alzheimer pathology. Best available evidence suggests an approach based on three, conceptually distinct strategies. (1) Raise the threshold for cognitive symptoms by improving brain health. To achieve this goal, the tactic is to reduce cerebrovascular risks mediated by hypertension, diabetes, cigarette smoking, and hyperlipidemia. (2) Raise the threshold for cognitive symptoms by enhancing cognitive reserve. Here, tactics focus on mental stimulation associated with occupation, leisure activities and social engagement. (3) Reduce the burden of Alzheimer pathology. The most promising tactic toward this end is regular aerobic exercise. Tactics in support of strategies to reduce cognitive impairment due to Alzheimer pathology are not yet substantiated by robust, consistent clinical trial evidence. There is pressing need for well-designed pragmatic trials to provide stronger evidence on preventive strategies for late-life cognitive decline and dementia.

  View details for DOI 10.3109/13697137.2014.929650

  View details for Web of Science ID 000345212700009

  View details for PubMedID 24893836

  View details for PubMedCentralID PMC4236238

• Cognitive outcomes from the Early versus Late Intervention Trial with Estradiol: A test of the critical window hypothesis Mack, W. J., Hodis, H. N., St John, J. A., McCleary, C. A., Stanczyk, F. Z., Shoupe, D., Kono, N., Dustin, L., Allayee, H., Henderson, V. W. LIPPINCOTT WILLIAMS & WILKINS. 2014: 1330

  View details for Web of Science ID 000345846600051

• The North American Menopause Society Recommendations for Clinical Care of Midlife Women MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Shifren, J. L., Gass, M. L. 2014; 21 (10): 1038-1062

  View details for DOI 10.1097/gme.0000000000000319

  View details for Web of Science ID 000342768000005

  View details for PubMedID 25225714

• Premature menopause and surgical menopause: cognitive outcomes later in life CLIMACTERIC Henderson, V. W. 2014; 17 (5): 619–20

  View details for Web of Science ID 000342277400018

• Role of grandparenting in postmenopausal women's cognitive health: results from the Women's Healthy Aging Project. Menopause (New York, N.Y.) Burn, K. F., Henderson, V. W., Ames, D., Dennerstein, L., Szoeke, C. 2014; 21 (10): 1069-1074

  Abstract

  Preserving aging cognition improves quality of life and delays dementia onset. Previous studies have shown that social engagement can maintain cognition; however, none has examined the effects of grandparenting, an important role among postmenopausal women. This study aims to examine the role of grandparenting in cognition among postmenopausal women.Participants were 186 Australian women from the longitudinal prospective Women's Healthy Aging Project. Cognition was assessed using the Symbol-Digit Modalities Test (SDMT), California Verbal Learning Test, and Tower of London.Amount of time spent minding grandchildren predicted differences in SDMT performance (P < 0.01). The highest cognitive scores for most tests were seen in participants who minded grandchildren for 1 day/week. Minding grandchildren for 1 day/week was also a significant positive predictor of California Verbal Learning Test immediate recall performance (P < 0.05). However, minding grandchildren for 5 days or more per week predicted lower SDMT performance (P < 0.05).The data suggest that the highest cognitive performance is demonstrated by postmenopausal women who spend 1 day/week minding grandchildren; however, minding grandchildren for 5 days or more per week predicts lower working memory performance and processing speed. These results indicate that highly frequent grandparenting predicts lower cognitive performance.

  View details for DOI 10.1097/GME.0000000000000236

  View details for PubMedID 24714623

• Prevention of diseases after menopause CLIMACTERIC Lobo, R. A., Davis, S. R., De Villiers, T. J., Gompel, A., Henderson, V. W., Hodis, H. N., Lumsden, M. A., Mack, W. J., Shapiro, S., Baber, R. J. 2014; 17 (5): 540-556

  Abstract

  Women may expect to spend more than a third of their lives after menopause. Beginning in the sixth decade, many chronic diseases will begin to emerge, which will affect both the quality and quantity of a woman's life. Thus, the onset of menopause heralds an opportunity for prevention strategies to improve the quality of life and enhance longevity. Obesity, metabolic syndrome and diabetes, cardiovascular disease, osteoporosis and osteoarthritis, cognitive decline, dementia and depression, and cancer are the major diseases of concern. Prevention strategies at menopause have to begin with screening and careful assessment for risk factors, which should also include molecular and genetic diagnostics, as these become available. Identification of certain risks will then allow directed therapy. Evidence-based prevention for the diseases noted above include lifestyle management, cessation of smoking, curtailing excessive alcohol consumption, a healthy diet and moderate exercise, as well as mentally stimulating activities. Although the most recent publications from the follow-up studies of the Women's Health Initiative do not recommend menopause hormonal therapy as a prevention strategy, these conclusions may not be fully valid for midlife women, on the basis of the existing data. For healthy women aged 50-59 years, estrogen therapy decreases coronary heart disease and all-cause mortality; this interpretation is entirely consistent with results from other randomized, controlled trials and observational studies. Thus. as part of a comprehensive strategy to prevent chronic disease after menopause, menopausal hormone therapy, particularly estrogen therapy may be considered as part of the armamentarium.

  View details for DOI 10.3109/13697137.2014.933411

  View details for Web of Science ID 000342277400005

  View details for PubMedID 24969415

• Education and cognitive reserve CLIMACTERIC Henderson, V. W. 2014; 17 (4): 510-511

  View details for Web of Science ID 000339698900027

  View details for PubMedID 25023047

• Alzheimer's disease: Review of hormone therapy trials and implications for treatment and prevention after menopause JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY Henderson, V. W. 2014; 142: 99-106

  Abstract

  Hormonal changes associated with the menopausal transition and postmenopause have the potential to influence processes linked to Alzheimer's disease symptoms and pathogenesis, but effects of menopause on Alzheimer risk can be addressed only indirectly. Nine randomized clinical trials of estrogen-containing hormone therapy in Alzheimer's disease patients were identified by a systematic literature search. Findings suggest that hormone therapy does not improve cognitive symptoms of women with Alzheimer's disease. No clinical trials of hormone therapy address Alzheimer prevention, but one clinical trial provides moderate evidence that continuous, combined estrogen plus progestogen initiated at age 65 years or older increases the risk of dementia. The timing, or critical window, hypothesis suggests that hormone therapy initiated at a younger age in closer temporal proximity to menopause may reduce the risk of Alzheimer's disease. This hypothesis is supported by observational research but is not addressed by clinical trial data. Unrecognized confounding is of concern in interpreting observational results, and research that helps resolve this issue will have important public health implications. Well-designed cohort studies, convergent evidence from appropriate laboratory models, and long-term clinical trials using surrogate biomarkers of brain function and neural pathology could provide relevant answers. Other estrogenic compounds are of theoretical interest with respect to Alzheimer treatment and risk. Effects of selective estrogen receptor modulators such as raloxifene may differ from those of estrogens; potential effects of phytoestrogens are not well studied.

  View details for DOI 10.1016/j.jsbmb.2013.05.010

  View details for Web of Science ID 000336704600015

  View details for PubMedID 23727128

• Dehydroepiandrosterone sulfate and cognition in midlife, post- menopausal women NEUROBIOLOGY OF AGING Chua, C. K., Henderson, V. W., Dennerstein, L., Ames, D., Szoeke, C. 2014; 35 (7): 1654-1655

  Abstract

  The association between serum dehydroepiandrosterone sulfate (DHEAS) and cognition was assessed in 218 healthy, midlife, post-menopausal women, aged 55-65 years. In cross-sectional analyses, DHEAS level was not significantly associated with a standardized score of global cognition or with individual test scores from a comprehensive neuropsychological battery (all p-values >0.05). In longitudinal analyses of 176 women, DHEAS level was unassociated with cognition 2 years later or with 2-year change in cognition. These findings fail to support the view that DHEAS is substantially related to cognitive function in midlife, post-menopausal women.

  View details for DOI 10.1016/j.neurobiolaging.2014.01.140

  View details for Web of Science ID 000336575100017

  View details for PubMedID 24612674

• Associations Between Urine Excretion of Isoflavonoids and Cognition in Postmenopausal Women in the Women's Isoflavone Soy Health Clinical Trial JOURNAL OF THE AMERICAN GERIATRICS SOCIETY St John, J. A., Henderson, V. W., Hodis, H. N., Kono, N., McCleary, C. A., Franke, A. A., Mack, W. J. 2014; 62 (4): 629-635

  Abstract

  To determine effect of change in urine excretion of isoflavonoids on cognitive change.Post hoc analysis of isoflavonoid exposure (mean 2.7 years) during the randomized, placebo-controlled, double-blind Women's Isoflavone Soy Health trial.General community.Healthy postmenopausal women (N = 350).Twenty-five grams of isoflavone-rich soy protein (91 mg of aglycone weight isoflavones: 52 mg genistein, 36 mg daidzein, 3 mg glycitein) or milk protein-matched placebo provided daily.Overnight urine excretion, fasting plasma levels of isoflavonoids, and cognitive function measured at baseline and endpoint.Three hundred women (age: mean 61, range 45-92) completed both cognitive assessments and did not use hormone replacement therapy during the trial. Mean on-trial change from baseline in urine excretion of isoflavonoids was not significantly associated with change in a composite score of global cognition (P = .39). Secondary analyses indicated that change in urine excretion of isoflavonoids was inversely associated with change in a factor score representing general intelligence (P = .02) but not with factor scores representing verbal or visual episodic memory. Mean differences in this general intelligence factor score between women in the lowest and highest quartiles of isoflavonoid change were equivalent to an approximate 4.4-year age-associated decline. Analyses based on plasma isoflavonoid levels yielded similar but attenuated results.In healthy postmenopausal women, long-term changes in isoflavonoids are not associated with global cognition, supporting clinical trial results, although greater isoflavonoid exposure from dietary supplements is associated with decrements in general intelligence but not memory; this finding requires confirmation in future studies.

  View details for DOI 10.1111/jgs.12752

  View details for Web of Science ID 000334289900005

  View details for PubMedID 24617349

• Sex modifies the APOE-related risk of developing Alzheimer disease. Annals of neurology Altmann, A., Tian, L., Henderson, V. W., Greicius, M. D. 2014; 75 (4): 563-573

  Abstract

  The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative.Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women).APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis.

  View details for DOI 10.1002/ana.24135

  View details for PubMedID 24623176

• Dementia Prevention: optimizing the use of observational data for personal, clinical, and public health decision-making. The journal of prevention of Alzheimer's disease Dacks, P. A., Andrieu, S., Blacker, D., Carman, A. J., Green, A. M., Grodstein, F., Henderson, V. W., James, B. D., Lane, R. F., Lau, J., Lin, P., Reeves, B. C., Shah, R. C., Vellas, B., Yaffe, K., Yurko-Mauro, K., Shineman, D. W., Bennett, D. A., Fillit, H. M. 2014; 1 (2): 117-123

  Abstract

  Worldwide, over 35 million people suffer from Alzheimer's disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.

  View details for PubMedID 26146610

• Is there a link between gynecologic surgeries and Alzheimer disease? Neurology Rocca, W. A., Henderson, V. W. 2014; 82 (3): 196-197

  Abstract

  In 2001, an Institute of Medicine report concluded that "being male or female is an important fundamental variable that should be considered when designing and analyzing basic and clinical research."(1) The extent to which gender- and sex-specific factors influence the risk of Alzheimer disease (AD) is a matter of profound importance.(2) Sex refers to biological characteristics of men and women such as chromosomal differences (e.g., XX vs XY chromosomes), hormonal differences (e.g., effects of estrogen), or reproductive differences (e.g., pregnancy or breastfeeding). By contrast, gender refers to social, political, and cultural differences (e.g., access to education or to certain jobs). The burden of AD is particularly great in women, and gender-associated differences in educational attainment may explain part of the differences in AD risk. In addition, exposures to gonadal steroids are linked to differences in Alzheimer-related pathology in animal models, although implications for human disease remain controversial.(3.)

  View details for DOI 10.1212/WNL.0000000000000043

  View details for PubMedID 24336139

• Components of air pollution and cognitive function in middle-aged and older adults in Los Angeles NEUROTOXICOLOGY Gatto, N. M., Henderson, V. W., Hodis, H. N., St John, J. A., Lurmann, F., Chen, J., Mack, W. J. 2014; 40: 1-7

  Abstract

  While experiments in animals demonstrate neurotoxic effects of particulate matter (PM) and ozone (O3), epidemiologic evidence is sparse regarding the relationship between different constituencies of air pollution mixtures and cognitive function in adults. We examined cross-sectional associations between various ambient air pollutants [O3, PM2.5 and nitrogen dioxide (NO2)] and six measures of cognitive function and global cognition among healthy, cognitively intact individuals (n=1496, mean age 60.5 years) residing in the Los Angeles Basin. Air pollution exposures were assigned to each residential address in 2000-06 using a geographic information system that included monitoring data. A neuropsychological battery was used to assess cognitive function; a principal components analysis defined six domain-specific functions and a measure of global cognitive function was created. Regression models estimated effects of air pollutants on cognitive function, adjusting for age, gender, race, education, income, study and mood. Increasing exposure to PM2.5 was associated with lower verbal learning (β=-0.32 per 10μg/m(3) PM2.5, 95% CI=-0.63, 0.00; p=0.05). Ambient exposure to NO2 >20ppb tended to be associated with lower logical memory. Compared to the lowest level of exposure to ambient O3, exposure above 49ppb was associated with lower executive function. Including carotid artery intima-media thickness, a measure of subclinical atherosclerosis, in models as a possible mediator did not attenuate effect estimates. This study provides support for cross-sectional associations between increasing levels of ambient O3, PM2.5 and NO2 and measures of domain-specific cognitive abilities.

  View details for DOI 10.1016/j.neuro.2013.09.004

  View details for PubMedID 24148924

• Alexia Encyclopedia of the Neurological Sciences Henderson, V. W. Elsevier. 2014; 2: 110–112

  View details for DOI doi:10.1016/B978-0-12-385157-4.00467-X

• Marie, Pierre Encyclopedia of the Neurological Sciences Henderson, V. W. Elsevier. 2014; 2: 1003–1004

  View details for DOI doi:10.1016/B978-0-12-385157-4.00953-2

• Dax, Marc Encyclopedia of the Neurological Sciences Henderson, V. W. Elsevier. 2014; 2: 943

  View details for DOI doi:10.1016/B978-0-12-385157-4.00866-6

• Broca, Paul Encyclopedia of the Neurological Sciences Henderson, V. W. Elsevier. 2014; 2: 540–543

  View details for DOI doi:10.1016/B978-0-12-385157-4.00832-0

• Agraphia Encyclopedia of the Neurological Sciences Henderson, V. W. Elsevier. 2014; 2: 86–88

  View details for DOI doi:10.1016/B978-0-12-385157-4.00466-8

• Alzheimer's disease Encyclopedia of Human Biology Henderson, V. W., Kerchner, G. A. edited by Simon, M., Abelson, J. Elsevier. 2014; 3

  View details for DOI doi.org/10.1016/B978-0-12-801238-3.00017-9

• Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Henderson, V. W., St John, J. A., Hodis, H. N., McCleary, C. A., Stanczyk, F. Z., Karim, R., Shoupe, D., Kono, N., Dustin, L., Allayee, H., Mack, W. J. 2013; 110 (50): 20290-20295

  Abstract

  Variations in the hormonal milieu after menopause may influence neural processes concerned with cognition, cognitive aging, and mood, but findings are inconsistent. In particular, cognitive effects of estradiol may vary with time since menopause, but this prediction has not been assessed directly using serum hormone concentrations. We studied 643 healthy postmenopausal women not using hormone therapy who were recruited into early (<6 y after menopause) and late (10+ y after menopause) groups. Women were administered a comprehensive neuropsychological battery and assessed with the Center for Epidemiologic Studies Depression Scale. They provided serum for free estradiol, estrone, progesterone, free testosterone, and sex hormone binding globulin measurements. Cognitive outcomes were standardized composite measures of verbal episodic memory, executive functions, and global cognition. Covariate-adjusted linear regression analyses were conducted for each hormone separately and after adjustment for other hormone levels. Endogenous sex steroid levels were unassociated with cognitive composites, but sex hormone binding globulin was positively associated with verbal memory. Results for early and late groups did not differ significantly, although progesterone concentrations were significantly positively associated with verbal memory and global cognition in early group women. Hormone concentrations were not significantly related to mood. Results fail to support the hypothesis that temporal proximity to menopause modifies the relation between endogenous serum levels of estradiol and verbal memory, executive functions, or global cognition. Physiological variations in endogenous postmenopausal levels of sex steroid hormones are not substantially related to these aspects of cognition or mood; positive associations for progesterone and sex hormone binding globulin merit additional study.

  View details for DOI 10.1073/pnas.1312353110

  View details for Web of Science ID 000328061700074

  View details for PubMedID 24277815

  View details for PubMedCentralID PMC3864289

• Information and misinformation on hormone therapy and meningiomas CLIMACTERIC Henderson, V. W. 2013; 16 (6): 721-722

  View details for Web of Science ID 000327351200017

  View details for PubMedID 24383092

• Strategies for Healthy Brain Aging Henderson, V. W. LIPPINCOTT WILLIAMS & WILKINS. 2013: 1314

  View details for Web of Science ID 000330465700028

• Reproductive History Correlates with Late-Life Cognitive Function in Postmenopausal Women Dang, H., Mack, W. J., Hodis, H., St John, J., Henderson, V. W., Rettberg, J., Brinton, R. D., Karim, R. LIPPINCOTT WILLIAMS & WILKINS. 2013: 1335–36

  View details for Web of Science ID 000330465700108

• Normative Data for the Tower of London Performance in Australian Midlife Women AUSTRALIAN PSYCHOLOGIST Lee, Y. C., Anderson, J. F., Dennerstein, L., Henderson, V. W., Szoeke, C. 2013; 48 (6): 402-407

  View details for DOI 10.1111/ap.12033

  View details for Web of Science ID 000327017900003

• Supply and demand analysis of the current and future US neurology workforce NEUROLOGY Dall, T. M., Storm, M. V., Chakrabarti, R., Drogan, O., Keran, C. M., Donofrio, P. D., Henderson, V. W., Kaminski, H. J., Stevens, J. C., Vidic, T. R. 2013; 81 (5): 470-478

  Abstract

  OBJECTIVE: This study estimates current and projects future neurologist supply and demand under alternative scenarios nationally and by state from 2012 through 2025. METHODS: A microsimulation supply model simulates likely career choices of individual neurologists, taking into account the number of new neurologists trained each year and changing demographics of the neurology workforce. A microsimulation demand model simulates utilization of neurology services for each individual in a representative sample of the population in each state and for the United States as a whole. Demand projections reflect increased prevalence of neurologic conditions associated with population growth and aging, and expanded coverage under health care reform. RESULTS: The estimated active supply of 16,366 neurologists in 2012 is projected to increase to 18,060 by 2025. Long wait times for patients to see a neurologist, difficulty hiring new neurologists, and large numbers of neurologists who do not accept new Medicaid patients are consistent with a current national shortfall of neurologists. Demand for neurologists is projected to increase from ∼18,180 in 2012 (11% shortfall) to 21,440 by 2025 (19% shortfall). This includes an increased demand of 520 full-time equivalent neurologists starting in 2014 from expanded medical insurance coverage associated with the Patient Protection and Affordable Care Act. CONCLUSIONS: In the absence of efforts to increase the number of neurology professionals and retain the existing workforce, current national and geographic shortfalls of neurologists are likely to worsen, exacerbating long wait times and reducing access to care for Medicaid beneficiaries. Current geographic differences in adequacy of supply likely will persist into the future.

  View details for Web of Science ID 000330741800017

  View details for PubMedID 23596071

• Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health CLIMACTERIC De Villiers, T. J., Pines, A., Panay, N., Gambacciani, M., Archer, D. F., Baber, R. J., Davis, S. R., Gompel, A. A., Henderson, V. W., Langer, R., Lobo, R. A., Plu-Bureau, G., Sturdee, D. W. 2013; 16 (3): 316-337

  View details for DOI 10.3109/13697137.2013.795683

  View details for Web of Science ID 000318937600004

  View details for PubMedID 23672656

• The Effect of Soy Isoflavones on Menopausal Vasomotor Flushing. Mucowski, S. J., Shoupe, D., Dang, H., Henderson, V., Kono, N., Hodis, H. N., Mack, W. J. ELSEVIER SCIENCE INC. 2013: S35

  View details for DOI 10.1016/j.fertnstert.2013.01.080

  View details for Web of Science ID 000315281800076

• Memantine is Associated with Longer Survival than Donepezil in a Veterans Affairs Prescription Database, 1997 to 2008 JOURNAL OF ALZHEIMERS DISEASE Lazzeroni, L. C., Halbauer, J. D., Ashford, J. W., Noda, A., Hernandez, B., Azor, V., Hozack, N., Hasson, N., Henderson, V. W., Yesavage, J. A., Tinklenberg, J. R. 2013; 36 (4): 791-798

  Abstract

  Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer (median survival 8.9 years) than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

  View details for DOI 10.3233/JAD-130662

  View details for Web of Science ID 000322738000016

  View details for PubMedID 23703151

• Memory symptoms during the menopausal transition CLIMACTERIC Henderson, V. W. 2012; 15 (5): 508-509

  View details for Web of Science ID 000308942500022

  View details for PubMedID 23145448

• Estrogens and Alzheimer disease risk Is there a window of opportunity? NEUROLOGY Henderson, V. W., Rocca, W. A. 2012; 79 (18): 1840-1841

  View details for DOI 10.1212/WNL.0b013e318271f88f

  View details for Web of Science ID 000310579900006

  View details for PubMedID 23100400

• Effects of physical activity on vasomotor symptoms: examination using objective and subjective measures MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Elavsky, S., Gonzales, J. U., Proctor, D. N., Williams, N., Henderson, V. W. 2012; 19 (10): 1095-1103

  Abstract

  Physical activity (PA) is essential for successful aging and for the prevention and management of common chronic diseases. The empirical support for the beneficial effects of PA on vasomotor symptoms has, however, been mixed. The purpose of this study was to assess the effects of acute aerobic exercise and daily PA on menopausal vasomotor symptoms.Community-dwelling midlife women (N = 121; age range, 40-60 y) not using hormone therapy were recruited for a 15-day daily diary study. Women completed psychological, cardiorespiratory fitness, body composition, and hormonal status screening followed by a 15-day prospective assessment in a "real-life" setting using a personal digital assistant. Participants also completed a 30-minute moderate-intensity aerobic exercise bout on a treadmill between days 5 and 8. Daily PA was assessed objectively through accelerometry, and all symptomatic women (n = 92) completed two 24-hour Biolog sternal skin conductance recordings of hot flashes (HFs)-one at baseline and one immediately after treadmill exercise.Both total objective (P = 0.054) and total subjective (P < 0.05) HFs decreased after the acute exercise bout. At the between-person level, daily PA was not associated with self-reported HFs. However, at the within-person level, performing more moderate physical activity than usual was associated with more self-reported HFs in women with lower fitness levels.Moderate aerobic exercise decreases objective and subjective HFs 24 hours after exercise; however, in women with lower fitness levels, more daily moderate PA leads to more self-reported symptoms.

  View details for DOI 10.1097/gme.0b013e31824f8fb8

  View details for Web of Science ID 000309558800011

  View details for PubMedID 22735162

  View details for PubMedCentralID PMC3460032

• Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk GENOME MEDICINE Huang, Y., Ballinger, D. G., Stokowski, R., Beilharz, E., Robinson, J. G., Liu, S., Robinson, R. D., Henderson, V. W., Rossouw, J. E., Prentice, R. L. 2012; 4

  Abstract

  ABSTRACT: BACKGROUND: Genome-wide association studies have identified several genomic regions that are associated with stroke risk, but these provide an explanation for only a small fraction of familial stroke aggregation. Genotype by environment interactions may contribute further to such an explanation. The Women's Health Initiative (WHI) clinical trial found increased stroke risk with postmenopausal hormone therapy (HT) and provides an efficient setting for evaluating genotype-HT interaction on stroke risk. METHODS: We examined HT by genotype interactions for 392 SNPs selected from candidate gene studies, and 2,371 SNPs associated with changes in blood protein concentrations after hormone therapy, in analyses that included 2,045 postmenopausal women who developed stroke during WHI clinical trial and observational study follow-up and one-to-one matched controls. A two-stage procedure was implemented where SNPs passing the first stage screening based on marginal association with stroke risk were tested in the second stage for interaction with HT using case-only analysis. RESULTS: The two-stage procedure identified two SNPs, rs2154299 and rs12194855, in the coagulation factor XIII subunit A (F13A1) region and two SNPs, rs630431 and rs560892, in the proprotein convertase subtilisin kexin 9 (PCSK9) region, with an estimated false discovery rate <0.05 based on interaction tests. Further analyses showed significant stroke risk interaction between these F13A1 SNPs and estrogen plus progestin (E+P) treatment for ischemic stroke and for ischemic and hemorrhagic stroke combined, and suggested interactions between PCSK9 SNPs with either E+P or estrogen-alone treatment. CONCLUSIONS: Genotype by environment interaction information may help to define genomic regions relevant to stroke risk. Two-stage analysis among postmenopausal women generates novel hypotheses concerning the F13A1 and PCSK9 genomic regions and the effects of hormonal exposures on postmenopausal stroke risk for subsequent independent validation.

  View details for DOI 10.1186/gm358

  View details for Web of Science ID 000314574100001

  View details for PubMedCentralID PMC3580413

• Paying attention to memory MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Henderson, V. W. 2012; 19 (7): 713-714

  View details for DOI 10.1097/gme.0b013e31825b213d

  View details for Web of Science ID 000305900100001

  View details for PubMedID 22735094

• Hormone levels and cognitive function in postmenopausal midlife women. Neurobiology of aging Ryan, J., Stanczyk, F. Z., Dennerstein, L., Mack, W. J., Clark, M. S., Szoeke, C., Kildea, D., Henderson, V. W. 2012; 33 (7): 1138-1147

  Abstract

  Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities.

  View details for DOI 10.1016/j.neurobiolaging.2012.04.011

  View details for PubMedID 22607736

• Hormone therapy and the risk of stroke: perspectives 10 years after the Women's Health Initiative trials CLIMACTERIC Henderson, V. W., Lobo, R. A. 2012; 15 (3): 229-234

  Abstract

  Principal findings on stroke from the Women's Health Initiative (WHI) clinical trials of hormone therapy indicate that estrogen, alone or with a progestogen, increases a woman's risk of stroke. These results were not unexpected, and research during the past decade has tended to support these findings. Consistent evidence from clinical trials and observational research indicates that standard-dose hormone therapy increases stroke risk for postmenopausal women by about one-third; increased risk may be limited to ischemic stroke. Risk is not modified by age of hormone initiation or use, or by temporal proximity to menopause, and risk is similar for estrogen plus progestogen and for unopposed estrogen. Limited evidence implies that lower doses of transdermal estradiol (≤50 μg/day) may not alter stroke risk. For women less than 60 years of age, the absolute risk of stroke from standard-dose hormone therapy is rare, about two additional strokes per 10 000 person-years of use; the absolute risk is considerably greater for older women. Other hormonally active compounds - including raloxifene, tamoxifen, and tibolone - can also affect stroke risk.

  View details for DOI 10.3109/13697137.2012.656254

  View details for Web of Science ID 000304310100005

  View details for PubMedID 22612608

  View details for PubMedCentralID PMC3675220

• Long-term soy isoflavone supplementation and cognition in women A randomized, controlled trial NEUROLOGY Henderson, V. W., St John, J. A., Hodis, H. N., Kono, N., McCleary, C. A., Franke, A. A., Mack, W. J. 2012; 78 (23): 1841-1848

  Abstract

  To determine the cognitive effects of long-term dietary soy isoflavones in a daily dose comparable to that of traditional Asian diets.In the double-blind Women's Isoflavone Soy Health trial, healthy postmenopausal women were randomly allocated to receive daily 25 g of isoflavone-rich soy protein (91 mg of aglycone weight of isoflavones: 52 mg of genistein, 36 mg of daidzein, and 3 mg glycitein) or milk protein-matched placebo. The primary cognitive endpoint compared between groups at 2.5 years was change from baseline on global cognition, a composite of the weighted sum of 14 neuropsychological test score changes. Secondary outcomes compared changes in cognitive factors and individual tests.A total of 350 healthy postmenopausal women aged 45-92 years enrolled in this trial; 313 women with baseline and endpoint cognitive test data were included in intention-to-treat analyses. Adherence in both groups was nearly 90%. There was no significant between-group difference on change from baseline in global cognition (mean standardized improvement of 0.42 in the isoflavone group and 0.31 in the placebo group; mean standardized difference 0.11, 95% confidence interval [CI] -0.13 to 0.35). Secondary analyses indicated greater improvement on a visual memory factor in the isoflavone group (mean standardized difference 0.33, 95% CI 0.06-0.60) but no significant between-group differences on 3 other cognitive factors or individual test scores, and no significant difference within a subgroup of younger postmenopausal women.For healthy postmenopausal women, long-term dietary soy isoflavone supplementation in a dose comparable to that of traditional Asian diets has no effect on global cognition but may improve visual memory. Classification of evidence: This study provides Class I evidence that long-term dietary supplementation with isoflavone-rich soy protein does not improve global cognition of healthy postmenopausal women.

  View details for DOI 10.1212/WNL.0b013e318258f822

  View details for PubMedID 22665144

• Hormone therapy, dementia, and cognition: the Women's Health Initiative 10 years on CLIMACTERIC Maki, P. M., Henderson, V. W. 2012; 15 (3): 256-262

  Abstract

  Principal findings on dementia from the Women's Health Initiative Memory Study (WHIMS) showed that conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA) increase dementia risk in women aged 65 years and above, but not risk of mild cognitive impairment. The dementia finding was unexpected, given consistent observational evidence that associates use of estrogen-containing hormone therapy with reduced risk of Alzheimer's disease. It remains controversial whether hormone use by younger postmenopausal women near the time of menopause reduces dementia risk or whether WHIMS findings should be generalized to younger women. Given the challenges of conducting a primary prevention trial to address that question, it is helpful to consider the impact of hormone therapy on cognitive test performance, particularly verbal memory, for its own sake and as a proxy for dementia risk. The WHI Study of Cognitive Aging (WHISCA) showed that CEE/MPA worsened verbal memory, whereas CEE alone had no influence on cognition. These findings have been replicated in several randomized, clinical trials. The apparent negative effect of CEE/MPA on verbal memory does not appear to be age-dependent. Additional investigations are needed to understand the impact of other hormonally active compounds on dementia and cognitive outcomes.

  View details for DOI 10.3109/13697137.2012.660613

  View details for Web of Science ID 000304310100009

  View details for PubMedID 22612612

  View details for PubMedCentralID PMC3667708

• H. Charlton Bastian on Kinaesthetic Centers and Concepts of Aphasia Henderson, V. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000303204803209

• Isoflavone-Rich Soy Protein and Cognition in Midlife and Late-Life Women: Randomized, Double-Blind, Placebo-Controlled Trial Henderson, V., John, J., Hodis, H., Kono, N., McCleary, C., Franke, A., Mack, W. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000303204802129

• Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk. Genome medicine Huang, Y., Ballinger, D. G., Stokowski, R., Beilharz, E., Robinson, J. G., Liu, S., Robinson, R. D., Henderson, V. W., Rossouw, J. E., Prentice, R. L. 2012; 4 (7): 57

  Abstract

  ABSTRACT: BACKGROUND: Genome-wide association studies have identified several genomic regions that are associated with stroke risk, but these provide an explanation for only a small fraction of familial stroke aggregation. Genotype by environment interactions may contribute further to such an explanation. The Women's Health Initiative (WHI) clinical trial found increased stroke risk with postmenopausal hormone therapy (HT) and provides an efficient setting for evaluating genotype-HT interaction on stroke risk. METHODS: We examined HT by genotype interactions for 392 SNPs selected from candidate gene studies, and 2,371 SNPs associated with changes in blood protein concentrations after hormone therapy, in analyses that included 2,045 postmenopausal women who developed stroke during WHI clinical trial and observational study follow-up and one-to-one matched controls. A two-stage procedure was implemented where SNPs passing the first stage screening based on marginal association with stroke risk were tested in the second stage for interaction with HT using case-only analysis. RESULTS: The two-stage procedure identified two SNPs, rs2154299 and rs12194855, in the coagulation factor XIII subunit A (F13A1) region and two SNPs, rs630431 and rs560892, in the proprotein convertase subtilisin kexin 9 (PCSK9) region, with an estimated false discovery rate <0.05 based on interaction tests. Further analyses showed significant stroke risk interaction between these F13A1 SNPs and estrogen plus progestin (E+P) treatment for ischemic stroke and for ischemic and hemorrhagic stroke combined, and suggested interactions between PCSK9 SNPs with either E+P or estrogen-alone treatment. CONCLUSIONS: Genotype by environment interaction information may help to define genomic regions relevant to stroke risk. Two-stage analysis among postmenopausal women generates novel hypotheses concerning the F13A1 and PCSK9 genomic regions and the effects of hormonal exposures on postmenopausal stroke risk for subsequent independent validation.

  View details for DOI 10.1186/gm358

  View details for PubMedID 22794791

  View details for PubMedCentralID PMC3580413

• Oestrogen Alpha-Receptor Variant and Two-Year Memory Decline in Mid life Australian Women NEUROPSYCHOBIOLOGY Bousman, C. A., Szoeke, C., Chen, K., Dennerstein, L., Henderson, V. W., Everall, I. P. 2012; 66 (4): 259-265

  Abstract

  To prospectively examine the influence of the oestrogen-α receptor (ESR1)PvuII polymorphism on changes in memory performance over a 2-year period among 80 midlife postmenopausal Australian women.Healthy women aged 56-67 years were administered a battery of four memory (verbal and non-verbal) tasks at baseline and 2 years later.Carriers of the ESR1 p allele had significantly greater declines in logical memory compared to participants with the PP genotype, independent of demographic characteristics (e.g. age), chronic illness (e.g. hypertension), sleep aid usage, hormone levels, apolipoprotein E e4 status and prospective changes in mood, smoking and alcohol consumption.These findings provide preliminary evidence for larger and longer prospective trials that will be able to determine if the p allele of the ESR1PvuII polymorphism is a potential biomarker of logical memory decline among aging women.

  View details for DOI 10.1159/000341879

  View details for Web of Science ID 000311601100008

  View details for PubMedID 23128795

• Isoflavone Soy Protein Supplementation and Atherosclerosis Progression in Healthy Postmenopausal Women A Randomized Controlled Trial STROKE Hodis, H. N., Mack, W. J., Kono, N., Azen, S. P., Shoupe, D., Hwang-Levine, J., Petitti, D., Whitfield-Maxwell, L., Yan, M., Franke, A. A., Selzer, R. H. 2011; 42 (11): 3168-U389

  Abstract

  Although epidemiological and experimental studies suggest that dietary intake of soy may be cardioprotective, use of isoflavone soy protein (ISP) supplementation as a primary preventive therapy remains unexplored. We determined whether ISP reduces subclinical atherosclerosis assessed as carotid artery intima-media thickness progression.In a double-blind, placebo-controlled trial, 350 postmenopausal women 45 to 92 years of age without diabetes and cardiovascular disease were randomized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or placebo for 2.7 years.Overall, mean (95% CI) carotid artery intima-media thickness progression rate was 4.77 (3.39-6.16) μm/year in the ISP group and 5.68 (4.30-7.06) μm/year in the placebo group. Although carotid artery intima-media thickness progression was reduced on average by 16% in the ISP group relative to the placebo group, this treatment effect was not statistically significant (P=0.36). Among the subgroup of women who were randomized within 5 years of menopause, ISP participants had on average a 68% lower carotid artery intima-media thickness progression rate than placebo participants 2.16 (-1.10 to 5.43) versus 6.79 (3.56-10.01) μm/year (P=0.05). ISP supplementation had a null effect on women who were >5 years beyond menopause when randomized. There were no major adverse events from ISP supplementation.ISP supplementation did not significantly reduce subclinical atherosclerosis progression in postmenopausal women. Subgroup analysis suggests that ISP supplementation may reduce subclinical atherosclerosis in healthy young (median age, 53 years) women at low-risk for cardiovascular disease who were <5 years postmenopausal. These first trial results of their kind warrant further investigation.

  View details for DOI 10.1161/STROKEAHA.111.620831

  View details for Web of Science ID 000296574500266

  View details for PubMedID 21903957

  View details for PubMedCentralID PMC3202054

• The practice of neurology, 2000-2010 Report of the AAN Member Research Subcommittee NEUROLOGY Adornato, B. T., Drogan, O., Thoresen, P., Coleman, M., Henderson, V. W., Henry, K. A., Liu, L., Mortimer, J. A., Schneck, M. J., Borenstein, A. R. 2011; 77 (21): 1921-1928

  Abstract

  To present an analysis of American Academy of Neurology (AAN) membership demographics and practice trends over the past decade.Data from the 2009 AAN Census and 2010 Practice Profile Form (PPF) surveys were compared to results from 2004 and 2000 surveys. The Census was sent to all AAN members, and the PPF was sent to a random sample of US practicing neurologists.Since 2000, AAN membership increased by 31%, and the number of US neurologist-members increased by 14%. Mean age of US neurologists increased from 48.6 to 53.3 years, and 23.9% of neurologists are women. There was a 15% increase in the proportion of neurologists relative to the US population, from 3.41 neurologists per 100,000 population in 2000 to 3.92 neurologists in 2009. In 2009, 24.1% of US neurologists were in solo practice, 27.8% were in a neurology group, and 35.6% were in multispecialty/university settings, with little change in practice arrangements over time. The top 5 practice interest areas were unchanged since 2004 as were the number of hours devoted to patient care (42.3) or total work hours per week (57.1). Little change was observed in performed procedures, except increased use of botulinum toxin and nerve blocks and a decline in lumbar punctures. Neurologists rely more on physician assistants to see follow-up and new patients independently (p < 0.001).Despite advances in neurologic diagnosis and therapy, there has been little change in practice characteristics of US neurologists.

  View details for DOI 10.1212/WNL.0b013e318238ee13

  View details for Web of Science ID 000297322600020

  View details for PubMedID 22031533

• EFFECTS OF ENDOGENOUS AND EXOGENOUS ESTROGEN EXPOSURES IN MIDLIFE AND LATE-LIFE WOMEN ON EPISODIC MEMORY AND EXECUTIVE FUNCTIONS NEUROSCIENCE Henderson, V. W., Popat, R. A. 2011; 191: 129-138

  Abstract

  Cognitive aging affects episodic memory and executive functions, and these vulnerable domains are postulated to be modulated by endogenous and exogenous estrogen exposures. In midlife and late-life women without dementia, estrogen effects on cognition can be examined through associations with concentrations of serum estrone and estradiol and through clinical trials of estrogen-containing hormone therapy. To this end, we reviewed published studies including at least 100 women (larger studies are less prone to publication bias) addressing associations between estrogen levels and performance on neuropsychological tests of episodic memory or executive functions (including working memory; seven studies), or that reported results of placebo-controlled clinical trials of hormone therapy with objective measures within these cognitive domains (eight studies). Results were considered separately for midlife and late-life (age≥65 years) women. There were no consistent associations between endogenous serum estrogen concentrations and episodic memory or executive functions in naturally menopausal midlife women or in older postmenopausal women. Clinical trial findings suggested no substantial impact of exogenous estrogens on episodic memory or executive functions over time frames of up to several years. A quantitative synthesis of clinical trial results supported the inference of absence of effect. This overall conclusion of no substantial effect on episodic memory or executive functions might reassure women concerned by potential adverse cognitive consequences of menopause or of relatively short-term midlife hormone therapy. There was no apparent window of opportunity during which exogenous hormones might benefit near-term cognition, but included studies provided limited power to identify such a window. Conclusions are tempered by small numbers of studies, imprecise estimates of long-term estrogen exposures, and narrow range of neuropsychological tests. Long-term (late-life) cognitive consequence of midlife estrogen exposures are poorly addressed by current data, as are cognitive consequences of surgical menopause and cognitive consequences of exogenous estrogens during the menopause transition. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

  View details for DOI 10.1016/j.neuroscience.2011.05.059

  View details for Web of Science ID 000295749300013

  View details for PubMedID 21664950

• Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health CLIMACTERIC Sturdee, D. W., Pines, A. 2011; 14 (3): 302-320

  View details for DOI 10.3109/13697137.2011.570590

  View details for Web of Science ID 000290584700002

  View details for PubMedID 21563996

• Executive functions in recently postmenopausal women: Absence of strong association with serum gonadal steroids Workshop on Window of Opportunity Ryan, J., Stanczyk, F. Z., Dennerstein, L., Mack, W. J., Clark, M. S., Szoeke, C., Henderson, V. W. ELSEVIER SCIENCE BV. 2011: 199–205

  Abstract

  It is controversial to what extent endogenous gonadal hormone exposures influence executive functions in midlife women. Participants in the population-based Melbourne Women's Midlife Health Project were administered a battery of neuropsychological tests on two occasions 2 years apart. Tests of executive functions were the Trail Making Test (Part B), Tower of London (administered at baseline only), Symbol Digit Modalities Test, Digit Span Backward, and Letter-Number Sequencing. Estrone, free estradiol, and free testosterone levels were measured at the time of the first testing, and analyses were restricted to 147 women aged 56-64 years who had recently undergone natural menopause (mean age of menopause 53 years) and were not using hormone therapy. In multiple linear regression analyses, 2 of 20 baseline associations were significant at an alpha level of 0.05. Estrone concentrations were positively associated with Tower of London performance (p=0.02), and the ratio of free testosterone to free estradiol was positively associated with scores on the Symbol Digit Modalities Test score (p=0.04). No hormone measure was significantly predictive of 2-year change in executive functions performance. Significance levels in these exploratory analyses were unadjusted for multiple comparisons, and observed associations could be due to unique psychometric properties of these particular tasks or due to chance. Sex hormone binding globulin concentrations were unrelated to executive function scores. In recently postmenopausal women not receiving hormone therapy, serum concentrations of estrone, estradiol and testosterone, and the testosterone/estradiol ratio are not strongly associated with executive functions.

  View details for DOI 10.1016/j.brainres.2010.10.093

  View details for Web of Science ID 000288844300019

  View details for PubMedID 21050841

• Perimenopausal use of hormone therapy is associated with enhanced memory and hippocampal function later in life Workshop on Window of Opportunity Maki, P. M., Dennerstein, L., Clark, M., Guthrie, J., LaMontagne, P., Fornelli, D., Little, D., Henderson, V. W., Resnick, S. M. ELSEVIER SCIENCE BV. 2011: 232–243

  Abstract

  Evidence suggests that initiation of some forms of hormone therapy (HT) early in the perimenopausal or postmenopausal stage might confer benefit to verbal memory and the neural systems underlying memory, whereas late-life initiation confers no benefit or harm. This "critical window hypothesis" remains a topic of debate. Using functional magnetic resonance imaging (fMRI), we examined the long-term impact of perimenopausal HT use on brain function during performance of verbal and figural memory tasks. Participants were 34 postmenopausal women (mean age 60 years) from the Melbourne Women's Midlife Health Project and included 17 early (perimenopausal) and continuous users of HT and 17 never users matched on age, education, and verbal knowledge. Continuous HT use from the perimenopausal stage versus no use was validated with prospective daily diary records and study visit data. The primary outcome was patterns of brain activation in an a priori region of interest in the medial temporal lobe during verbal encoding and recognition of words. Results indicated that perimenopausal HT users performed better than nonusers on the imaging verbal memory task (p<.05). During verbal recognition, perimenopausal HT users showed increased activation in the left hippocampus and decreased activation in the parahippocampal gyrus bilaterally compared with never users. Each of these patterns of activation was associated with better memory performance on the imaging memory task. These results suggest that perimenopausal use of HT might confer long-term benefits to verbal memory and the brain systems underlying verbal memory. More generally, the results support the critical window hypothesis.

  View details for DOI 10.1016/j.brainres.2010.11.030

  View details for Web of Science ID 000288844300023

  View details for PubMedID 21078303

  View details for PubMedCentralID PMC3046212

• Timing Matters: Menopause and Brain Effects of Ovarian Steroids Introduction BRAIN RESEARCH Rasgon, N. L., Henderson, V. W., Brinton, R., Milner, T. A. 2011; 1379: 1

  View details for DOI 10.1016/j.brainres.2011.02.019

  View details for Web of Science ID 000288844300001

• Gonadal hormones and cognitive aging: a midlife perspective. Women's health (London, England) Henderson, V. W. 2011; 7 (1): 81-93

  Abstract

  Gonadal steroids affect a variety of brain processes. Cognitive consequences of hormonal changes associated with menopause are of scientific interest and of relevance to public health. Natural menopause is a normal physiological process that can only be directly studied through observational research. Similarly, surgical menopause in humans is rarely directly amenable to experimental research. Causality with respect to cognitive outcomes is, therefore, difficult to infer. Cross-sectional and longitudinal findings from the Melbourne Women's Midlife Health Project, the Study of Women's Health Across the Nation and other midlife cohorts suggest that cognitive consequences of the natural menopausal transition are probably small, at least during midlife and at least for episodic memory, which is a key cognitive domain. The data for episodic memory are the most robust. Midlife episodic memory performance is similar both shortly before and after natural menopause, and serum estradiol concentration in midlife is not associated with episodic memory performance. Effects of natural menopause on other cognitive domains, cognitive consequences of surgical menopause and late-life cognitive consequences of midlife hormonal exposures are less well understood and merit continued study.

  View details for DOI 10.2217/whe.10.87

  View details for PubMedID 21175393

  View details for PubMedCentralID PMC3675221

• Action of estrogens in the aging brain: Dementia and cognitive aging BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS Henderson, V. W. 2010; 1800 (10): 1077-1083

  Abstract

  Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging.Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk.Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings.Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause.

  View details for DOI 10.1016/j.bbagen.2009.11.005

  View details for Web of Science ID 000281932800006

  View details for PubMedID 19913598

• Age of menopause and impact of climacteric symptoms by geographical region CLIMACTERIC Palacios, S., Henderson, V. W., Siseles, N., Tan, D., Villaseca, P. 2010; 13 (5): 419-428

  Abstract

  To describe differences in the age of onset of menopause and in the prevalence of climacteric symptoms in different geographical areas.Systematic review of published data on onset of menopause and symptoms in Europe, North America, Latin America and Asia.We identified publications by searching electronic databases, including MEDLINE (1966-October 2009) and EMBASE (1975-October 2009). Primary search criteria were age of menopause and climacteric symptoms. A sensitive analysis that excluded papers without full data was performed.The median age at menopause in Europe ranges from 50.1 to 52.8 years, in North America from 50.5 to 51.4 years, in Latin America from 43.8 to 53 years, and in Asia from 42.1 to 49.5 years. The frequency of vasomotor symptoms varies widely depending on the geographical region, selection of criteria, and method of symptom identification. The prevalence of such symptoms ranges from 74% of women in Europe, 36-50% in North America, 45-69% in Latin America and 22-63% in Asia, as reported in different, large, epidemiological studies.There are wide geographical differences in the prevalence of menopausal symptomatology and some differences in the age of onset of menopause. Both in Asia and Latin America, women of poorer socioeconomic status have significantly earlier onset of menopause. Within a geographical region, there are ethnic differences in menopause symptoms. Given differences in study methodologies, firm conclusions are not possible. However, regional differences in age at menopause and in climacteric symptoms are important to acknowledge and lay the foundation for an informed approach to the management of menopause and an understanding of its impact on women's health in the different regions of the world.

  View details for DOI 10.3109/13697137.2010.507886

  View details for Web of Science ID 000282657500003

  View details for PubMedID 20690868

• Summary of the National Institute on Aging-sponsored conference on depressive symptoms and cognitive complaints in the menopausal transition MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Maki, P. M., Freeman, E. W., Greendale, G. A., Henderson, V. W., Newhouse, P. A., Schmidt, P. J., Scott, N. F., Shively, C. A., Soares, C. N. 2010; 17 (4): 815-822

  Abstract

  The National Institutes of Health and The North American Menopause Society sponsored a symposium to understand the impact of the menopausal transition on mood symptoms and cognitive disorders and to identify research priorities for further investigation.The symposium was divided into a morning session on depressive symptoms and an afternoon session on cognitive function. There were four speakers per session, and each session covered four methodological approaches, including longitudinal cohort studies, randomized intervention trials, pharmacological challenge studies, and clinical diagnosis. Interactive panel discussions focused on translating research findings to clinical practice.Most women do not experience serious depressive symptoms during the menopausal transition, but a subgroup of women is at increased risk. Slight changes in memory function and processing speed are evident during the menopausal transition, and physiological factors associated with hot flashes may contribute to memory problems. Clinical trial evidence indicates that estradiol therapy can be effective in treating perimenopausal depression. There is some limited evidence of a cognitive benefit with estrogen-alone therapy in younger postmenopausal women and stronger evidence that certain forms of combination hormone therapy produce modest deficits in verbal memory in younger postmenopausal women.Routine evaluation of depressive symptoms in perimenopausal women is warranted by the literature. Quick and valid screening tools for assessing depression in the clinic are available online and free of charge. Identifying a cognitively neutral or beneficial combination therapy for the treatment of menopausal symptoms in naturally postmenopausal women is an important goal for future research.

  View details for DOI 10.1097/gme.0b013e3181d763d2

  View details for Web of Science ID 000279799300026

  View details for PubMedID 20616668

  View details for PubMedCentralID PMC2901893

• Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Santen, R. J., Allred, D. C., Ardoin, S. P., Archer, D. F., Boyd, N., Braunstein, G. D., Burger, H. G., Colditz, G. A., Davis, S. R., Gambacciani, M., Gower, B. A., Henderson, V. W., Jarjour, W. N., Karas, R. H., Kleerekoper, M., Lobo, R. A., Manson, J. E., Marsden, J., Martin, K. A., Martin, L., Pinkerton, J. V., Rubinow, D. R., Teede, H., Thiboutot, D. M., Utian, W. H. 2010; 95 (7): S7-?

  Abstract

  Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement.Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence.A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors.The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

  View details for DOI 10.1210/jc.2009-2509

  View details for Web of Science ID 000279976400001

• Subtypes of Mild Cognitive Impairment in Older Postmenopausal Women The Women's Health Initiative Memory Study ALZHEIMER DISEASE & ASSOCIATED DISORDERS Rapp, S. R., Legault, C., Henderson, V. W., Brunner, R. L., Masaki, K., Jones, B., Absher, J., Thal, L. 2010; 24 (3): 248-255

  Abstract

  Mild cognitive impairment (MCI) is a transitional state between normal cognitive functioning and dementia. A proposed MCI typology classifies individuals by the type and extent of cognitive impairment, yet few studies have characterized or compared these subtypes. Four hundred forty-seven women 65 years of age and older from the Women's Health Initiative Memory Study were classified into the 4 MCI subgroups and a "no impairment" group and compared on clinical, sociodemographic, and health variables. A cognitive deficit in at least 1 domain was present in 82.1% of participants, with most (74.3%) having deficits in multiple cognitive domains. Only 4.3% had an isolated memory deficit, whereas 21.3% had an isolated nonmemory deficit. Of the 112 women who met all MCI criteria examined, the most common subtype was amnestic multidomain MCI (42.8%), followed by nonamnestic multiple domain MCI (26.7%), nonamnestic single domain (24.1%), and amnestic single domain MCI (6.3%). Subtypes were similar with respect to education, health status, smoking, depression, and prestudy and onstudy use of hormone therapy. Despite the attention it receives in the literature, amnestic MCI is the least common type highlighting the importance of identifying and characterizing other nonamnestic and multidomain subtypes. Further research is needed on the epidemiology of MCI subtypes, clinical and biologic differences between them, and rates for conversion to dementia.

  View details for DOI 10.1097/WAD.0b013e3181d715d5

  View details for Web of Science ID 000281310200006

  View details for PubMedID 20473134

  View details for PubMedCentralID PMC2929315

• Functional magnetic resonance imaging and estrogen effects on the brain: cautious interpretation of a BOLD finding MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Henderson, V. W., Greicius, M. D. 2010; 17 (4): 669-671

  View details for DOI 10.1097/gme.0b013e3181e3a50e

  View details for Web of Science ID 000279799300002

  View details for PubMedID 20944455

• Postmenopausal hormone therapy: an Endocrine Society scientific statement. journal of clinical endocrinology and metabolism Santen, R. J., Allred, D. C., Ardoin, S. P., Archer, D. F., Boyd, N., Braunstein, G. D., Burger, H. G., Colditz, G. A., Davis, S. R., Gambacciani, M., Gower, B. A., Henderson, V. W., Jarjour, W. N., Karas, R. H., Kleerekoper, M., Lobo, R. A., Manson, J. E., Marsden, J., Martin, K. A., Martin, L., Pinkerton, J. V., Rubinow, D. R., Teede, H., Thiboutot, D. M., Utian, W. H. 2010; 95 (7): s1-s66

  Abstract

  Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement.Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence.A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors.The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

  View details for DOI 10.1210/jc.2009-2509

  View details for PubMedID 20566620

• The Relationship Between Cognitive Function and Physical Performance in Older Women: Results From the Women's Health Initiative Memory Study JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Atkinson, H. H., Rapp, S. R., Williamson, J. D., Lovato, J., Absher, J. R., Gass, M., Henderson, V. W., Johnson, K. C., Kostis, J. B., Sink, K. M., Mouton, C. P., Ockene, J. K., Stefanick, M. L., Lane, D. S., Espeland, M. A. 2010; 65 (3): 300-306

  Abstract

  Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear.In the Women's Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change.Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS-gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p

  View details for DOI 10.1093/gerona/glp149

  View details for Web of Science ID 000275420800014

  View details for PubMedID 19789197

  View details for PubMedCentralID PMC2822281

• Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Utian, W. H., Bachmann, G. A., Cahill, E. B., Gallagher, J. C., Grodstein, F., Heiman, J. R., Henderson, V. W., Hodis, H. N., Karas, R. H., Manson, J. E., Morfin-Martin, J. H., Reid, R. L., Santen, R. J., Schmidt, P. J., Stuenkel, C. A., Waxman, N. J., Wysocki, S. 2010; 17 (2): 242-255

  Abstract

  To update for both clinicians and the lay public the evidence-based position statement published by The North American Menopause Society (NAMS) in July 2008 regarding its recommendations for menopausal hormone therapy (HT) for postmenopausal women, with consideration for the therapeutic benefit-risk ratio at various times through menopause and beyond.An Advisory Panel of clinicians and researchers expert in the field of women's health was enlisted to review the July 2008 NAMS position statement, evaluate new evidence through an evidence-based analysis, and reach consensus on recommendations. The Panel' s recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement. Also participating in the review process were other interested organizations who then endorsed the document.Current evidence supports a consensus regarding the role of HT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered. This paper lists all these areas along with explanatory comments. Areas that vary from the 2008 position statement are noted. A suggested reading list of key references published since the last statement is also provided.Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable for women who initiate HT close to menopause but decreases in older women and with time since menopause in previously untreated women.

  View details for DOI 10.1097/gme.0b013e3181d0f6b9

  View details for Web of Science ID 000275485200009

  View details for PubMedID 20154637

• Chapter 37: alexia and agraphia. Handbook of clinical neurology Henderson, V. W. 2010; 95: 583-601

  Abstract

  Studies of alexia and agraphia have played important roles in understanding how complex cognitive functions are related to brain structure and activity. Modern interests in brain-behavior relations began during the second half of the 19th century as an outgrowth of flawed correlative studies by neuroanatomist Franz Gall and subsequent clinical-pathological analyses by Jean-Baptiste Boulliaud on speech and the frontal lobes. In 1856, Louis Victor Marcé drew attention to writing disorders and postulated a cerebral faculty for writing. Following Paul Broca's epochal reports on aphemia, many European physicians investigated reading and writing impairments after brain injury. Albert Pitres published the first detailed description of isolated agraphia, and Adolf Kussmaul identified alexia as an isolated symptom of brain disease. Jules Dejerine in 1892 provided the first clinical-pathological descriptions of pure alexia, and he suggested a key role for the left parietal lobe in reading and writing. In the 20th century, varieties of agraphia or alexia were linked to apraxia (Hugo Liepmann), impaired body image (Josef Gerstmann), spatial misperception, and interhemispheric disconnection. Other analyses focused on error types that defined new clinical syndromes (e.g. deep dyslexia) and provided evidence for cognitive modularity.

  View details for DOI 10.1016/S0072-9752(08)02137-4

  View details for PubMedID 19892140

• Menopause and mitochondria: Windows into Estrogen effects on Alzheimer's disease risk and therapy NEUROENDOCRINOLOGY: PATHOLOGICAL SITUATIONS AND DISEASES Henderson, V. W., Brinton, R. D. 2010; 182: 77-96

  Abstract

  Metabolic derangements and oxidative stress are early events in Alzheimer's disease pathogenesis. Multi-faceted effects of estrogens include improved cerebral metabolic profile and reduced oxidative stress through actions on mitochondria, suggesting that a woman's endogenous and exogenous estrogen exposures during midlife and in the late post-menopause might favourably influence Alzheimer risk and symptoms. This prediction finds partial support in the clinical literature. As expected, early menopause induced by oophorectomy may increase cognitive vulnerability; however, there is no clear link between age at menopause and Alzheimer risk in other settings, or between natural menopause and memory loss. Further, among older post-menopausal women, initiating estrogen-containing hormone therapy increases dementia risk and probably does not improve Alzheimer's disease symptoms. As suggested by the 'critical window' or 'healthy cell' hypothesis, better outcomes might be expected from earlier estrogen exposures. Some observational results imply that effects of hormone therapy on Alzheimer risk are indeed modified by age at initiation, temporal proximity to menopause, or a woman's health. However, potential methodological biases warrant caution in interpreting observational findings. Anticipated results from large, ongoing clinical trials [Early Versus Late Intervention Trial with Estradiol (ELITE), Kronos Early Estrogen Prevention Study (KEEPS)] will help settle whether midlife estrogen therapy improves midlife cognitive skills but not whether midlife estrogen exposures modify late-life Alzheimer risk. Estrogen effects on mitochondria adumbrate the potential relevance of estrogens to Alzheimer's disease. However, laboratory models are inexact embodiments of Alzheimer pathogenesis and progression, making it difficult to surmise net effects of estrogen exposures. Research needs include better predictors of adverse cognitive outcomes, biomarkers for risks associated with hormone therapy, and tools for monitoring brain function and disease progression.

  View details for DOI 10.1016/S0079-6123(10)82003-5

  View details for Web of Science ID 000287858500003

  View details for PubMedID 20541661

• Chapter 17: cognitive assessment in neurology. Handbook of clinical neurology Henderson, V. W. 2010; 95: 235-256

  Abstract

  Modern interests in cognitive assessment began with Franz Gall's early 19th century theory of mental organology and Paul Broca's reports in the 1860s on patients with focal brain injury and aphemia. These workers spurred interest in assessing delimited mental abilities in relation to discrete cerebral areas. With roots in experimental and educational psychology, the intelligence testing movement added assessment tools that could be applied to neurological patients. Early- to mid-20th-century landmarks were Alfred Binet and Theodore Simon's intelligence scale, Howard Knox's nonverbal performance tests, and the intelligence quotient conceived by Lewis Terman and refined by David Wechsler. Also developed during this era were Henry Head's Serial Tests for aphasic patients and Kurt Goldstein's tests for brain-injured patients with impairments in "abstract attitude" and concept formation. Other investigators have contributed procedures for the evaluation of language functions, memory, visuospatial and visuoconstructive skills, praxis, and executive functions. A further milestone was the development of short standardized cognitive instruments for dementia assessment. Within a neurological arena, the historical emphasis has been on a flexible, process-driven approach to the service of neurological diagnosis and syndrome identification. Advances in clinical psychology, neurology, and the cognate clinical neurosciences continue to enrich assessment options.

  View details for DOI 10.1016/S0072-9752(08)02117-9

  View details for PubMedID 19892120

• Aging, Estrogens, and Episodic Memory in Women COGNITIVE AND BEHAVIORAL NEUROLOGY Henderson, V. W. 2009; 22 (4): 205-214

  Abstract

  To review the relation in midlife and beyond between estrogen exposures and episodic memory in women.Episodic memory performance declines with usual aging, and impairments in episodic memory often portend the development of Alzheimer disease. In the laboratory, estradiol influences hippocampal function and animal learning. However, it is controversial whether estrogens affect memory after a woman's reproductive years.Focused literature review, including a summary of a systematic search of clinical trials of estrogens in which outcomes included an objective measure of episodic memory.The natural menopause transition is not associated with the objective changes in episodic memory. Strong clinical trial evidence indicates that initiating estrogen-containing hormone therapy after the age of about 60 years does not benefit episodic memory. Clinical trial findings in middle-aged women before the age of 60 years are limited by smaller sample sizes and shorter treatment durations, but these also do not indicate substantial memory effects. Limited short-term evidence, however, suggests that estrogens may improve verbal memory after surgical menopause. Although hormone therapy initiation in old age increases dementia risk, observational studies raise the question of an early critical window during which midlife estrogen therapy reduces late-life Alzheimer disease. However, almost no data address whether midlife estrogen therapy affects episodic memory in old age.Episodic memory is not substantially impacted by the natural menopause transition or improved by the use of estrogen-containing hormone therapy after the age of 60 years. Further research is needed to determine whether outcomes differ after surgical menopause or whether episodic memory later in life is modified by midlife estrogenic exposures.

  View details for Web of Science ID 000272940200001

  View details for PubMedID 19996872

• Frontiers proposal. National Institute on Aging "bench to bedside: estrogen as a case study" AGE Asthana, S., Brinton, R. D., Henderson, V. W., McEwen, B. S., Morrison, J. H., Schmidt, P. J. 2009; 31 (3): 199-210

  Abstract

  On 28-29 September 2004, the National Institute on Aging (NIA) convened scientists for a workshop on the aging female brain focused on translating into clinical practice discoveries concerning estrogens and progestogens. Workshop objectives were to examine effects of estrogen and progestogen on brain and cognitive function in relation to aging, to examine consistencies and apparent discrepancies between Women's Health Initiative Memory Study findings and other research on cognitive function, to determine whether additional hormone interventions could be developed in this area, and to offer advice on design of clinical trials for other interventions that might ameliorate cognitive aging. Following the workshop, participants joined by other interested scientists organized into regional work groups to continue the dialogue begun in Bethesda and to propose recommendations for NIA. The resulting recommendations, referred to as the "Frontiers Proposal for Estrogen and Cognitive Aging", acknowledge the persistence of critical gaps in our understanding of how decline in ovarian steroid secretion during reproductive aging and use of ovarian steroid hormone therapy affect normal brain function and risk for late-life neurodegenerative disorders such as Alzheimer's disease. There is a pressing need for preclinical, human, and integrated studies on the relationship between the menopausal transition and midlife exposures to estrogens, progestogens and related compounds, and risks for age-associated cognitive disorders. Research is also needed on better predictors of adverse cognitive outcomes, valid biomarkers for risks associated with hormone therapy use, enhanced tools for monitoring brain function and disease progression, and novel forms of therapy for improving long-term cognitive outcomes.

  View details for DOI 10.1007/s11357-009-9087-2

  View details for Web of Science ID 000269417600005

  View details for PubMedID 19277902

  View details for PubMedCentralID PMC2734241

• Memory at midlife: perception and misperception MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Henderson, V. W. 2009; 16 (4): 635-636

  View details for DOI 10.1097/gme.0b013e3181a72622

  View details for Web of Science ID 000267837300007

  View details for PubMedID 19390462

• Estrogens, Episodic Memory and Alzheimer's Disease: A Critical Update SEMINARS IN REPRODUCTIVE MEDICINE Henderson, V. W. 2009; 27 (3): 283-293

  Abstract

  Estrogen-containing hormone therapy initiated during late postmenopause does not improve episodic memory (an important early symptom of Alzheimer's disease), and it increases dementia risk. Cognitive consequences of exogenous estrogen exposures during midlife are less certain. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce risk of Alzheimer's disease later in life. However, there are concerns that observational findings may be systematically biased. Partial insight on this critical issue may be gleaned from results of ongoing clinical trials involving midlife postmenopausal women (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study). The effects of exogenous midlife estrogen exposures and Alzheimer risk can also be approached through better animal models, through carefully designed cohort studies, and through use of surrogate outcomes in randomized controlled trials in midlife women. Selective estrogen receptor modulators have the potential to affect cognitive outcomes and also merit additional study.

  View details for DOI 10.1055/s-0029-1216281

  View details for Web of Science ID 000265486600009

  View details for PubMedID 19401959

  View details for PubMedCentralID PMC3683552

• A prospective study of the association between endogenous hormones and depressive symptoms in postmenopausal women MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Ryan, J., Burger, H. G., Szoeke, C., Lehert, P., Ancelin, M., Henderson, V. W., Dennerstein, L. 2009; 16 (3): 509-517

  Abstract

  Across a woman's lifetime, variations in hormone levels are known to influence mood and well-being. Whether absolute or changes in hormone levels over time are associated with depression among postmenopausal women remains unclear.The Melbourne Women's Midlife Health Project is a longitudinal population-based study of women who were followed through the menopausal transition. This analysis is based on data collected from 138 postmenopausal women in years 11 and 13 of the study, who were assessed for the presence of depressive symptoms using the Center for Epidemiological Studies Depression Scale. Logistic regression models were developed to determine whether absolute or changes in hormone levels were associated with depression.No significant associations were found between depressive symptoms and the absolute levels of sex hormone-binding globulin, testosterone, free androgen index, estradiol, free estradiol, or follicle-stimulating hormone (FSH). On the other hand, women with a decline in total serum estradiol over the 2-year period had a more than threefold increased risk of depressive symptoms (odds ratio, 3.5; 95% CI, 1.2-9.9). A large increase in FSH levels over this period was also associated with depressive symptoms (odds ratio, 2.6; 95% CI, 1.0-6.7). These associations remained even after adjustment for initial depression score, as well as a range of potential confounding factors.Changes in estradiol and, to a lesser extent, in FSH levels are associated with an increased risk of depressive symptoms in postmenopausal women. These results further support a role for fluctuating rather than absolute hormone levels in depression in later life.

  View details for DOI 10.1097/gme.0b013e31818d635f

  View details for Web of Science ID 000265905400017

  View details for PubMedID 19169164

  View details for PubMedCentralID PMC2814239

• Subclinical atherosclerosis is weakly associated with lower cognitive function in healthy hyperhomocysteinemic adults without clinical cardiovascular disease INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Gatto, N. M., Henderson, V. W., John, J. A., McCleary, C., Detrano, R., Hodis, H. N., Mack, W. J. 2009; 24 (4): 390-399

  Abstract

  Atherosclerosis is the most common pathologic process underlying cardiovascular disease (CVD). It is not well known whether subclinical atherosclerosis is an independent risk factor for lower cognitive function among individuals without clinically evident CVD.We examined cross-sectional associations between subclinical atherosclerosis and cognitive function in a community-based sample of otherwise healthy adults with plasma homocysteine >or=8.5 micromol/L enrolled in the BVAIT study (n = 504, mean age 61 years). Carotid artery intima-media thickness (CIMT), coronary artery calcium (CAC) and abdominal aortic calcium (AAC) were used to measure subclinical atherosclerosis. Cognitive function was assessed with a battery of neuropsychological tests. A principal components analysis was used to extract five uncorrelated cognitive factors from scores on individual tests, and a measure of global cognition was derived. Multivariable linear regression was used to examine the association between subclinical atherosclerosis and cognitive function, adjusting for other correlates of cognition.Increasing thickness of CIMT was associated with significantly lower scores on the verbal learning factor (beta = -0.07 per 0.1 mm increase CIMT [SE(beta) = 0.03], p = 0.01). CAC and AAC were not individually associated with any of the cognitive factors.This study provides evidence that increasing CIMT is weakly associated with lower verbal learning abilities but not global cognition in a population of otherwise healthy middle-to-older aged adults with elevated plasma homocysteine levels but without clinically evident CVD. The association between CIMT and poor verbal learning may pertain particularly to men.

  View details for DOI 10.1002/gps.2134

  View details for Web of Science ID 000264959800010

  View details for PubMedID 18836986

  View details for PubMedCentralID PMC2661006

• Menopause, cognitive ageing and dementia: practice implications. Menopause international Henderson, V. W. 2009; 15 (1): 41-44

  Abstract

  Episodic memory is affected by cognitive ageing, and memory impairment beyond that expected on the basis of usual ageing may be an early indicator of Alzheimer's disease. Although memory complaints are common in midlife, it is reassuring that the natural menopausal transition is unaccompanied by objective memory loss. Less is known about memory after surgical menopause. Estrogen-containing hormone therapy initiated during the late postmenopause increases dementia risk and does not improve memory. It is unclear whether hormone use during the menopausal transition or early postmenopause affects Alzheimer risk. Observational studies imply a protective association consistent with the so-called critical window hypothesis, but these findings could be biased. Clinical practice implications are presented.

  View details for DOI 10.1258/mi.2009.009003

  View details for PubMedID 19237622

• Mildly Elevated TSH and Cognition in Middle-Aged and Older Adults THYROID John, J. A., Henderson, V. W., Gatto, N. M., McCleary, C. A., Spencer, C. A., Hodis, H. N., Mack, W. J. 2009; 19 (2): 111-117

  Abstract

  It is accepted that markedly elevated thyroid-stimulating hormone (TSH) levels are associated with impaired cognitive function. However, the findings regarding the association between mildly elevated TSH levels and cognition are equivocal. The objective of this study was to assess the relation between TSH levels in the normal to mildly elevated range (0.3-10.0 mIU/L) and several domains of cognitive function.A healthy, community-based sample of 489 men and women (40-88 years old, mean = 60.5 years) enrolled in the B-Vitamin Atherosclerosis Intervention Trial were studied. A neuropsychological test battery was used to assess a broad array of cognitive functions. Four uncorrelated neuropsychological factors were extracted by principal component analysis. Using multivariable linear regression, performance on each factor was examined in relation to TSH levels, controlling for age, gender, race-ethnicity, education, homocysteine levels, low-density lipoprotein cholesterol levels, and smoking status.TSH levels were not associated with any of the four factor scores in the total sample or in younger (age < 60) or older (age >or= 60) subjects, although there was a trend for older subjects with higher levels of TSH to do more poorly on paragraph recall (p = 0.06). Gender-stratified analyses showed that TSH was positively associated with scores on word list learning for females only (p = 0.003).In this community-based sample of middle-aged to older individuals, increasing TSH levels were not associated with significantly reduced cognitive performance in any domain. Further exploration of the effects of gender on the association between TSH and cognition is warranted.

  View details for DOI 10.1089/thy.2008.0226

  View details for Web of Science ID 000263057200003

  View details for PubMedID 19191743

  View details for PubMedCentralID PMC2715222

• Hormones, Cognition and Dementia Hogervorst E, Henderson VW, Gibbs RB, Brinton RD (eds.) 2009
• Presidential Lecture. Estrogens and Alzheimer's Disease: A Critical ReAppraisal Henderson, V. W. LIPPINCOTT WILLIAMS & WILKINS. 2008: 1197

  View details for Web of Science ID 000260858500034

• Cognitive changes after menopause: Influence of estrogen CLINICAL OBSTETRICS AND GYNECOLOGY Henderson, V. W. 2008; 51 (3): 618-626

  Abstract

  The natural menopause is not associated with substantial cognitive change. Limited clinical trial evidence suggests that estrogen-containing hormone therapy has little effect on cognition during midlife, but prompt initiation after surgical menopause may improve aspects of memory. Among older postmenopausal women, strong clinical trial evidence demonstrates that hormone initiation does not improve cognition. More limited clinical trial evidence indicates no improvement in Alzheimer symptoms, and the Women's Health Initiative Memory Study found an increase in dementia risk among older women. Observational findings of reduced Alzheimer risk may reflect early hormone use in younger women, or findings may be biased. Cognitive effects of selective estrogen receptor modulators are not yet well studied.

  View details for Web of Science ID 000257937600016

  View details for PubMedID 18677155

• Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Utian, W. H., Archer, D. F., Bachmann, G. A., Gallaher, J. C., Grodstein, F., Heiman, J. R., Henderson, V. W., Hodis, H. N., Karas, R. H., Lobo, R. A., Manson, J. E., Reid, R. L., Schmidt, P. J., Stuenkel, C. A. 2008; 15 (4): 584-602

  Abstract

  : To update for both clinicians and the lay public the evidence-based position statement published by The North American Menopause Society (NAMS) in March 2007 regarding its recommendations for menopausal hormone therapy (HT) for postmenopausal women, with consideration for the therapeutic benefit-risk ratio at various times through menopause and beyond.: An Advisory Panel of clinicians and researchers expert in the field of women's health was enlisted to review the March 2007 NAMS position statement, evaluate new evidence through an evidence-based analysis, and reach consensus on recommendations. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement. The document was provided to other interested organizations to seek their endorsement.: Current evidence supports a consensus regarding the role of HT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered. This paper lists all these areas along with explanatory comments. Conclusions that vary from the 2007 position statement are highlighted. Addenda include a discussion of risk concepts, a new component not included in the 2007 paper, and a recommended list of areas for future HT research. A suggested reading list of key references is also provided.: Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women.

  View details for DOI 10.1097/gme.0b013e31817b076a

  View details for Web of Science ID 000257501000004

  View details for PubMedID 18580541

  View details for PubMedCentralID PMC2756246

• Alexia and agraphia - Contrasting perspectives of J.-M. Charcot and J. Hughlings Jackson NEUROLOGY Henderson, V. W. 2008; 70 (5): 391-400

  Abstract

  To evaluate 19th-century concepts of cerebral localization for complex mental activities, focusing on alexia and agraphia in published writings of Jean-Martin Charcot (1825-1893) and John Hughlings Jackson (1835-1911).In the early 1860 s, Broca's reports on a special role for the left frontal lobe in articulate language ignited frenetic interest in cerebral localization. Disorders of written language (alexia and agraphia) were enmeshed in ensuing discussions of how the brain was organized for language and other complex behaviors.Focused review and analysis of Charcot's and Hughlings Jackson's publications on aphasia, alexia, and agraphia.In the wake of Broca's observations, the extent to which language functions in general--or such specialized functions as reading and writing--might involve focal cerebral representation was controversial. Based on his clinical-pathologic approach to "regional diagnosis," Charcot came to value insights provided by "partial isolated aphasias." He described patients with isolated alexia and agraphia, and he proposed a functional-anatomic framework to accommodate these disorders. Adopting a hierarchical model of nervous system organization, Hughlings Jackson argued that reading and writing could not be dissociated from other aspects of "intellectual language." Charcot's reductionism was typical of his era, but Hughlings Jackson's more holistic approach was to gain ascendancy in early decades of the 20th century.Charcot's and Hughlings Jackson's positions on alexia and agraphia reflected contrasting philosophical approaches to the study of brain disorders. Their views informed the opinions of their contemporaries and neurologic heirs in important debates on cerebral organization.

  View details for Web of Science ID 000252719500011

  View details for PubMedID 18227421

• Metabolic syndrome and cognitive function in healthy middle-aged and older adults without diabetes AGING NEUROPSYCHOLOGY AND COGNITION Gatto, N. M., Henderson, V. W., John, J. A., McCleary, C., Hodis, H. N., Mack, W. J. 2008; 15 (5): 627-641

  Abstract

  Few studies have addressed whether the metabolic syndrome (MetS) and its individual components are associated with cognitive function in middle-aged and older populations, as well as whether specific areas of cognition are more affected than others. We examined the cross-sectional association between MetS and six areas of cognitive function in healthy cognitively intact adults without diabetes (n = 853, mean age 61 years) randomized in two intervention trials.The National Cholesterol Education Program (NCEP) criteria were used to identify subjects with MetS. Cognitive function was assessed with a neuropsychological battery. A principal components analysis was used to extract five uncorrelated factors interpreted to represent five areas of cognition, and a measure of global cognition was calculated.MetS was weakly but non-significantly associated with lower verbal learning (beta = -.14 [SE(beta) = 0.09], p = .15). As the number of MetS criteria increased, scores on global cognition (p trend = .01), verbal learning (p trend = .06) and semantic memory (p trend = .04) decreased. Hypertension was the only MetS risk factor that was independently correlated with lower verbal learning (beta = -.17 [SE(beta) = 0.08], p = .04), semantic memory (beta = -.26 [SE(beta) = 0.08], p = .001) and global cognition (beta = -.15 [SE(beta) = 0.07], p = .04).This study adds to the evidence of an association between MetS and lower cognitive function among healthy middle-aged and older adults without CVD and diabetes, as well as confirms the correlation between hypertension and lower cognition.

  View details for DOI 10.1080/13825580802036936

  View details for Web of Science ID 000258498900004

  View details for PubMedID 18608045

  View details for PubMedCentralID PMC2742696

• Cognition and cognitive aging 7th Workshop of the International-Menopause-Society Henderson, V. W. TAYLOR & FRANCIS LTD. 2007: 88–91

  Abstract

  Cognitive effects of estrogen have been considered in a number of large, randomized, double-blind, placebo-controlled trials. Most have involved older, postmenopausal women, and results of these provide little support for the view that estrogen-containing hormone therapy initiated after age 60 substantially affects mean cognitive performance over periods of time ranging up to 5 years. This conclusion appears particularly true for episodic memory, a cognitive domain in which impairments are associated with increased risk of Alzheimer's disease. Other domains have been less thoroughly assessed. For women undergoing surgical menopause, limited clinical trial evidence suggests that prompt initiation of estrogen therapy may benefit verbal episodic memory, at least over a period of several months. Among middle-aged women, observational studies indicate no important deleterious effect of the natural menopause transition on cognitive performance. Similarly, limited clinical trial evidence from middle-aged postmenopausal women implies no substantial effect of hormone therapy on episodic memory, at least over the short term. Unfortunately, no randomized clinical trials have addressed long-term cognitive outcomes of hormone therapy started during the menopausal transition or early postmenopause, a time hypothesized to represent a 'critical window' of opportunity. There is urgent need for research in this area, and at least two clinical trials now underway may eventually provide partial answers.

  View details for Web of Science ID 000250230800017

  View details for PubMedID 17882681

• Alzheimer's disease and other neurological disorders 7th Workshop of the International-Menopause-Society Henderson, V. W. TAYLOR & FRANCIS LTD. 2007: 92–96

  Abstract

  Menopausal status and estrogen-containing hormone therapy may influence several neurological disorders, including Alzheimer's disease, epilepsy, migraine headache, multiple sclerosis, Parkinson's disease, sleep disorders, and stroke. For most of these illnesses, evidence on hormone therapy is insufficient to guide practice decisions. For stroke, clinical trial evidence indicates that hormone therapy increases risk of cerebral infarction. For women with Alzheimer's disease, estrogen treatment trials have tended to be small and of short duration. Most suggest that estrogen started after the onset of dementia symptoms does not meaningfully improve cognition or slow disease progression. Hormone therapy initiated after age 64 increased all-cause dementia in the Women's Health Initiative Memory Study. Many observational studies, however, report protective associations between hormone use and Alzheimer risk. Apparent risk reduction may represent a bias toward hormone therapy, since hormones are more often prescribed to healthier women. However, when compared to the Women's Health Initiative Memory Study, estrogen exposures in many observational studies reflect hormone initiation at a younger age, closer to the time of menopause. One intriguing hypothesis is that hormone therapy initiated or used during an early critical window may reduce later Alzheimer incidence. Public health implications of this hypothesis are important, but current data are inadequate to decide the issue.

  View details for Web of Science ID 000250230800018

  View details for PubMedID 17882682

• Surgical versus natural menopause: cognitive issues MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Henderson, V. W., Sherwin, B. B. 2007; 14 (3): 572-579

  Abstract

  Women who undergo both natural and surgical menopause experience the loss of cyclic ovarian production of estrogen, but hormonal and demographic differences distinguish these two groups of women. Our objective was to review published evidence on whether the premature cessation of endogenous estrogen production in women who underwent a surgical menopause has deleterious consequences for cognitive aging and to determine whether consequences differ for women if they undergo natural menopause. Studies of estrogen-containing hormone therapy are relevant to this issue.We reviewed evidence-based research, including the systematic identification of randomized clinical trials of hormone therapy with cognitive outcomes that included an objective measure of episodic memory.As inferred from very small, short-term, randomized, controlled trials of high-dose estrogen treatment, surgical menopause may be accompanied by cognitive impairment that primarily affects verbal episodic memory. Observational evidence suggests that the natural menopausal transition is not accompanied by substantial changes in cognitive abilities. For initiation of hormone therapy during perimenopause or early postmenopause when the ovaries are intact, limited clinical trial data provide no consistent evidence of short-term benefit or harm. There is stronger clinical trial evidence that initiation of hormone therapy in late postmenopause does not benefit episodic memory or other cognitive skills.Further research is needed on the long-term cognitive consequences of surgical menopause and long-term cognitive consequences of hormone therapy initiated near the time of surgical or natural menopause. A potential short-term cognitive benefit might be weighed when a premenopausal woman considers initiation of estrogen therapy at the time of, or soon after, hysterectomy and oophorectomy for benign conditions, although data are still quite limited and estrogen is not approved for this indication. Older postmenopausal women should not initiate hormone therapy to improve or maintain cognitive skills.

  View details for DOI 10.1097/gme.0b013e31803df49c

  View details for Web of Science ID 000246374700005

  View details for PubMedID 17476147

• The Semantic Object Retrieval Test (SORT) in amnestic mild cognitive impairment COGNITIVE AND BEHAVIORAL NEUROLOGY Kraut, M. A., Cherry, B., Pitcock, J. A., Anand, R., Li, J., Vestal, L., Henderson, V. W., Hart, J. 2007; 20 (1): 62-67

  Abstract

  Between 10% and 15% of patients with the amnestic variety of Mild Cognitive Impairment (MCI) convert to Alzheimer disease (AD) per year.Characterize cognitive markers that may herald conversion from MCI to AD and directly assess semantic memory in patients meeting criteria for amnestic MCI.Thirty-five amnestic MCI patients and 121 healthy aging controls enrolled at an Alzheimer Disease Center received a battery of standard neuropsychologic tests, and the Semantic Object Retrieval Test (SORT), a test that we have developed for the assessment of semantic memory and subsequent name production, and that has been shown to be able to differentiate between normals and patients with AD.On the basis of normative data from the SORT, the MCI subjects could be divided into 2 groups: 10 patients (29%) with a significant semantic impairment (SI+) and 25 without a semantic memory deficit (SI-). There was a significant correlation between all SORT variables and performance on the Boston Naming Test. In this MCI population, significantly impaired SORT performance was associated with a relative decrease in performance on tests of frontal lobe functions, although disruption of thalamic-related processes cannot be excluded as an etiology for semantic memory impairment.The SORT is a specific test of semantic memory, and is a sensitive measure of semantic memory deficits in patients who otherwise meet criteria for amnestic MCI. Using this specific assessment tool, a significant number of MCI patients were found to have semantic memory deficits. As these patients may be early in the course of possible progression toward dementia, the SORT or other tests of semantic memory may provide important diagnostic or prognostic information in patients with MCI.

  View details for Web of Science ID 000245377000011

  View details for PubMedID 17356346

• Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Utian, W. H., Archer, D. F., Bachmann, G. A., Gallagher, J. C., Grodstein, F., Heiman, J. R., Henderson, V. W., Hodis, H. N., Karas, R. H., Lobo, R. A., Manson, J. E., Reid, R. L., Schmidt, P. J., Stuenkel, C. A. 2007; 14 (2): 168-182

  Abstract

  To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2004 regarding recommendations for estrogen and progestogen use in peri- and postmenopausal women.NAMS followed the general principles established for evidence-based guidelines to create this updated document. An Advisory Panel of clinicians and researchers expert in the field of women's health was enlisted to review the 2004 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees. The position statements published by NAMS do not represent "practice standards" that would be codified and held up as standards by regulating bodies and insurance agencies. Rather, they are prevailing opinion pieces in a best effort attempt to incorporate current evidence into practical clinical recommendations.With the primary goal being to evaluate the risk-benefit ratio of peri- and postmenopausal estrogen therapy (ET) and estrogen-progestogen therapy (EPT) for both disease prevention and treatment of menopause-related symptoms, current evidence allowed for a clear distinction between areas of consensus and areas for which the Panel determined that there was inadequate evidence for any conclusion to be reached. The document lists all of these areas along with clear explanatory comments. A comprehensive list of key references is provided. The absence of evidence is also recognized in the list of needs for further research recommended by the Panel.Current evidence supports the use of ET or EPT for menopause-related symptoms and disease prevention in appropriate populations of peri- and postmenopausal women.

  View details for DOI 10.1097/gme.0b013e31803167ab

  View details for Web of Science ID 000244873800004

  View details for PubMedID 17259911

• Comparison of performance on the CERAD neuropsychological battery of Hispanic patients and cognitively normal controls at two sites Clinical Gerontologist Fillenbaum GG, Kuchibhatla M, Henderson VW, Clark CM, Taussig, IM 2007; 30(3): 1-22
• Preventing cognitive decline in usual aging ARCHIVES OF INTERNAL MEDICINE Espeland, M. A., Henderson, V. W. 2006; 166 (22): 2433-2434

  View details for Web of Science ID 000242732500002

  View details for PubMedID 17159007

• The Semantic Object Retrieval Test (SORT) in normal aging and Alzheimer disease COGNITIVE AND BEHAVIORAL NEUROLOGY Kraut, M. A., Cherry, B., Pitcock, J. A., Vestal, L., Henderson, V. W., Hart, J. 2006; 19 (4): 177-184

  Abstract

  To characterize performance on a test of semantic object retrieval (Semantic Object Retrieval Test-SORT) in healthy, elderly subjects and patients with Alzheimer disease (AD).Although the initial presentation of patients with AD often reflects impairment in delayed recall for verbally encoded memory, common complaints of patients with early AD are actually related to semantic memory impairment.Thirty-eight AD patients and 121 healthy aging controls enrolled in an Alzheimer's Disease Center received a battery of standard neuropsychologic tests including the SORT.Compared with normal controls, AD patients had SORT memory impairments with significantly more false positive memory errors, fewer correctly produced names, and more substitutions in the name production aspect of the test. SORT had robust test-retest reliability in normals.The SORT task provides a direct, specific assessment of semantic memory, and has now been administered to 121 healthy, aging controls for normative ranges of performance, and to AD patients. The task detected semantic memory deficits in approximately half of patients with mild-moderate AD, which is comparable to other studies assessing semantic deficits in AD with less specific measures.

  View details for Web of Science ID 000243054900002

  View details for PubMedID 17159612

• The menopausal transition and cognitive function Henderson, V. W. LIPPINCOTT WILLIAMS & WILKINS. 2006: 982

  View details for Web of Science ID 000242255000026

• Subclinical atherosclerosis explains differences in cognitive function Gatto, N. M., Henderson, V. W., John, J., Hodis, H. N., McCleary, C., Mack, W. J. LIPPINCOTT WILLIAMS & WILKINS. 2006: 825

  View details for Web of Science ID 000241792805327

• Spring cleaning at NAMS: the amended and restated code of regulations MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Henderson, V. W., Gass, M. L., Richardson, M. K. 2006; 13 (5): 713-715

  View details for DOI 10.1097/01.gme.0000235361.65276.d9

  View details for Web of Science ID 000240689300001

  View details for PubMedID 16946689

• The neurology of menopause NEUROLOGIST Henderson, V. W. 2006; 12 (3): 149-159

  Abstract

  Menopause is a normal milestone experienced annually by 2 million American women each year, and many women are concerned about the relation between menopause and health. Associated hormonal changes have the potential to influence neurologic disease, as do hormonal therapies prescribed for menopausal symptoms or other conditions. The objective of this article is to increase neurologists' awareness of the relation between menopause and neurologic illness.This was a focused review of 4 common neurologic disorders potentially influenced by menopause or by estrogen-containing hormone therapy: stroke, epilepsy, Parkinson disease, and Alzheimer disease. Hormonal effects are germane to each illness, although clinical implications are clearer for stroke and Alzheimer disease than for epilepsy and Parkinson disease. For women with epilepsy, few clinical data directly address the role of menopause or estrogen-containing hormone therapy on seizure frequency. Relevant clinical research findings on Parkinson disease are inconsistent and provide an inadequate basis for practice guidelines. There is clinical trial evidence that hormone therapy does not reduce stroke incidence and may increase risk of ischemic stroke; hormone therapy cannot be recommended for stroke prevention. The natural menopausal transition is not characterized by objective memory loss. There is clinical trial evidence that hormone therapy should not be used for the postmenopausal woman age 65 years or older for the preservation of cognitive skills, prevention of dementia, or treatment of dementia due to Alzheimer disease. Long-term cognitive consequences of short-term hormone therapy used by younger women for menopausal symptoms remains an important area of uncertainty.Increased awareness of hormonal influences on neurologic illness is important for the practicing neurologist.

  View details for DOI 10.1097/01.nrl.0000215750.52786.b1

  View details for Web of Science ID 000237691400004

  View details for PubMedID 16688016

• Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Ettinger, B., Harris, S. T., Kendler, D., Kessel, B., McClung, M. R., Gorodeski, G. I., Rothert, M. L., Henderson, V. W., Richardson, M. K., Freedman, R. R., Gallagher, J. C., Goldstein, S. R., Kessel, B., Pinkerton, J. V., Reame, N. K., Speroff, L., Stuenkel, C. A., Schiff, I., Utian, W. H., Graham, I. D., Lammers, P. K., Boggs, P. P. 2006; 13 (3): 340-367

  Abstract

  To update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2002 regarding the management of osteoporosis in postmenopausal women.NAMS followed the general principles established for evidence-based guidelines to create this updated document. A panel of clinicians and researchers expert in the field of metabolic bone diseases and/or women's health were enlisted to review the 2002 NAMS position statement, compile supporting statements, and reach consensus on recommendations. The panel's recommendations were reviewed and approved by the NAMS Board of Trustees.Osteoporosis, whose prevalence is especially high among elderly postmenopausal women, increases the risk of fractures. Hip and spine fractures are associated with particularly high morbidity and mortality in this population. Given the health implications of osteoporotic fractures, the primary goal of osteoporosis therapy is to prevent fractures, which is accomplished by slowing or stopping bone loss, maintaining bone strength, and minimizing or eliminating factors that may contribute to fractures. The evaluation of postmenopausal women for osteoporosis risk requires a medical history, physical examination, and diagnostic tests. Major risk factors for postmenopausal osteoporosis (as defined by bone mineral density) include advanced age, genetics, lifestyle factors (such as low calcium and vitamin D intake, smoking), thinness, and menopause status. The most common risk factors for osteoporotic fracture are advanced age, low bone mineral density, and previous fracture as an adult. Management focuses first on nonpharmacologic measures, such as a balanced diet, adequate calcium and vitamin D intake, adequate exercise, smoking cessation, avoidance of excessive alcohol intake, and fall prevention. If pharmacologic therapy is indicated, government-approved options are bisphosphonates, a selective estrogen-receptor modulator, parathyroid hormone, estrogens, and calcitonin.Management strategies for postmenopausal women involve identifying those at risk of low bone density and fracture, followed by instituting measures that focus on reducing modifiable risk factors through lifestyle changes and, if indicated, pharmacologic therapy.

  View details for DOI 10.1097/01.gme.0000222475.93345.b3

  View details for Web of Science ID 000238116100006

  View details for PubMedID 16735931

• Normative visuospatial performance in Australian midlife women AUSTRALIAN PSYCHOLOGIST Elkadi, S., Clark, M. S., Dennerstein, L., Guthrie, J. R., Bowden, S. C., Henderson, V. W. 2006; 41 (1): 43-47

  View details for DOI 10.1080/00050060500421642

  View details for Web of Science ID 000236408100007

• Normative data for Australian midlife women on category fluency and a short form of the Boston Naming Test AUSTRALIAN PSYCHOLOGIST Elkadi, S., Clark, M. S., Dennerstein, L., Guthrie, J. R., Bowden, S. C., Henderson, V. W. 2006; 41 (1): 37-42

  View details for DOI 10.1080/00050060500421634

  View details for Web of Science ID 000236408100006

• Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY MacLennan, A. H., Henderson, V. W., Paine, B. J., Mathias, J., Ramsay, E. N., Ryan, P., Stocks, N. P., Taylor, A. W. 2006; 13 (1): 28-36

  Abstract

  The aim of this pilot study was to assess any trends related to the timing of initiation, and duration, of hormone therapy (HT) use on cognitive function to facilitate the design and power calculations for a future large cohort study entitled Research into Memory, Brain function and Estrogen Replacement (REMEMBER).A total of 428 women aged older than 60 years were recruited from a computer-generated random selection of Adelaide households. Demographic and lifestyle characteristics, and HT use history were recorded and confirmed. The Center for Epidemiological Studies-Depression score was used to assess mood. Cognitive tests were administered measuring global cognition (Mini-Mental State Examination), attention and concentration (Trail Making Test Parts A and B), verbal learning and memory (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] word list immediate and delayed recall), and verbal expression (letter fluency [FAS], category fluency [Animals], and the Boston Naming Test [short form]). Analyses were adjusted for age, education, mood, body mass index, smoking, alcohol intake, and history of cerebrovascular disease. HT use was defined as the use of systemic HT for at least 1 year. Early initiation of HT use was defined as commencement of HT before age 56 years for women with a uterus and ovaries, or within 5 years of a hysterectomy and bilateral oophorectomy. Late initiation of HT use was defined as HT commencing after these times.Early initiators of HT performed better than late initiators on the Mini-Mental State Examination (P = 0.04) and were faster than never users on the Trail Making Test Part A (P = 0.02). Women aged 70-79 years who initiated HT early performed better on the FAS test than never users (P = 0.0008). Late initiators performed worse than never users on the Mini-Mental State Examination (P = 0.09), and on the FAS test in the 60-69 year (P = 0.06) and 80 years and older (P = 0.095) age groups. However, late initiators performed better than never users on the FAS test in the 70-79 year age group (P = 0.015). HT users of less than 11 years (P = 0.09), HT users of more than 11 years (P = 0.04), and estrogen-only users (P = 0.024) performed faster than never users on the Trail Making Test Part A. Combined estrogen plus progestin users performed better than never users on the Boston Naming Test short form (P = 0.07).For some cognitive domains, early initiation of HT from around menopause may be beneficial, and initiation of HT in late menopause may be detrimental. The timing of the initiation of HT seems critical. To fully test these hypotheses and to further examine these trends by route and type of HT regimen in this population, a study size of 2,500 women would be required.

  View details for DOI 10.1097/01.gme.0000191204.38664.61

  View details for Web of Science ID 000234688900008

  View details for PubMedID 16607096

• Estrogen-containing hormon therapy and Alzheimer's disease risk: Understanding discrepant inferences from observational and experimental research NEUROSCIENCE Henderson, V. W. 2006; 138 (3): 1031-1039

  Abstract

  Estrogen has the potential to influence brain processes implicated in Alzheimer's disease pathogenesis. With the loss of ovarian estrogen production after menopause, estrogen-containing hormone therapy might be expected to influence the risk of Alzheimer's disease. Observational data link use of hormone therapy to reductions in Alzheimer risk, but experimental evidence from the Women's Health Initiative Memory Study trial demonstrates that oral estrogen, with or without a progestin, increases the incidence of dementia for postmenopausal women age 65 years or older. Mechanisms of harm in this setting are unknown. Bias and unrecognized confounding in observational research are leading candidates for discrepant results between observational studies and the Women's Health Initiative Memory Study trial. Studies are also distinguished by differences in outcome measures, hormone therapy formulations, prevalence of menopausal symptoms among study participants, and participant age. Finally, Women's Health Initiative Memory Study findings may not generalize to estrogen use by relatively young women during the menopausal transition or early postmenopause, a class of women who were ineligible for the Women's Health Initiative Memory Study trial. In observational studies, hormone therapy exposure often included use by younger women for menopausal vasomotor symptoms. Although there is no clinical trial evidence that hormone therapy at any age protects against Alzheimer's disease, it remains to be determined whether the age at which hormone exposure occurs or the timing of hormone therapy initiation in relation to the menopause (the critical window hypothesis) modifies treatment outcomes on dementia risk.

  View details for DOI 10.1016/j.neuroscience.2005.06.017

  View details for Web of Science ID 000236498500035

  View details for PubMedID 16310963

• Normative data for Australian midlife women on category fluency and a short form of the Boston Naming Test Australian Psychologist Elkadi S, Clark MS, Dennerstein L, Guthrie JR, Bowden SC, Henderson VW 2006; 41 (1): 37-42
• Normative visuospatial performance in Australian midlife women Australian Psychologist Elkadi S, Clark MS, Dennerstein L, Guthrie JR, Bowden SC, Henderson VW 2006; 41 (1): 43-47
• Menopause and disorders of the central nervous system. Minerva ginecologica Henderson, V. W. 2005; 57 (6): 579-592

  Abstract

  The cessation of ovarian estrogen production occurring around the time of menopause has the potential to influence central nervous system function, as well as a number of neurological disorders that affect women during midlife and old age, including memory loss and mild cognitive impairment, ischemic stroke, Parkinson's disease, and Alzheimer's disease. During midlife, there is observational evidence that episodic memory is not substantially affected by natural menopause or by use of estrogen-containing hormone therapy, but short-term clinical trial evidence suggests hormone therapy might benefit verbal memory after surgical menopause. Clinical trial data indicate that hormone therapy does not reduce, and may increase, stroke incidence. Parkinson's disease and Alzheimer's disease are the 2 most common neurodegenerative illnesses. Estrogen influences dopaminergic pathways within the central nervous system. However, available observational evidence is limited and inconclusive regarding any role of hormone therapy in influencing risk or symptoms of Parkinson's disease, a disorder of dopaminergic neurons. Finally, clinical trial data indicate that hormone therapy should not be initiated in the late postmenopause with the goal of improving memory, preventing cognitive decline, reducing dementia risk, or improving Alzheimer's disease symptoms. An important priority for clinical investigation is to determine whether hormone therapy used during the menopausal transition and early postmenopause has long-term effects on cognition or dementia risk. The critical window hypothesis as applied to Alzheimer's disease conjectures that effects of early hormone therapy might differ from those of hormone therapy initiated in the late postmenopause, but convincing evidence is yet to be obtained.

  View details for PubMedID 16306863

• Estrogen and cognition, with a focus on Alzheimer's disease SEMINARS IN REPRODUCTIVE MEDICINE Pinkerton, J. V., Henderson, V. W. 2005; 23 (2): 172-179

  Abstract

  Cognitive aging is associated with decreases in memory, attention, and visual/motor performance and skills. Dementia consists of loss of memory and other cognitive abilities, associated with social or occupational impairment. Potential neuroprotective effects of estrogen include lowering beta-amyloid, enhancing cholinergic function, promoting synaptic plasticity and nerve process growth, reducing oxidative stress, and enhancing brain glucose transport. Observational and longitudinal studies suggest that hormone therapy may attenuate age-associated cognitive impairment or decrease Alzheimer's disease but this has not been confirmed by randomized clinical trials. A critical window of time may exist around the menopause when hormone therapy may delay or decrease cognitive changes; however, hormone therapy initiated in the late postmenopause does not improve global cognition and may increase dementia risk.

  View details for Web of Science ID 000228852900009

  View details for PubMedID 15852203

• Effect of raloxifene on prevention of dementia and cognitive impairment in older women: The multiple outcomes of raloxifene evaluation (MORE) randomized trial AMERICAN JOURNAL OF PSYCHIATRY Yaffe, K., Krueger, K., Cummings, S. R., Blackwell, T., Henderson, V. W., Sarkar, S., Ensrud, K., Grady, D. 2005; 162 (4): 683-690

  Abstract

  This investigation examined whether raloxifene, a selective estrogen receptor modulator, affects the risk for Alzheimer's disease.The Multiple Outcomes of Raloxifene Evaluation was a randomized, placebo-controlled trial among postmenopausal women with osteoporosis. The effect of raloxifene (60 or 120 mg/day) on vertebral fractures was the primary outcome. Development of mild cognitive impairment and dementia was a secondary outcome. Women were given clinical and cognitive evaluations at baseline and annually. After 3 years, among the 5,386 women enrolled at participating sites, those who had clinical symptoms of dementia or scored in the lowest 10th percentile on cognitive screening were evaluated by a blinded dementia specialist and had brain scans and laboratory tests to evaluate dementia etiology. Dementia was diagnosed by a blinded adjudication committee.Of the 5,386 women, 5,153 (95.7%) were classified as cognitively normal, 181 (3.4%) had mild cognitive impairment, and 52 (1.0%) had dementia, 36 with Alzheimer's disease. Compared to those taking placebo, women receiving 120 mg/day of raloxifene had a 33% lower risk of mild cognitive impairment (relative risk, 0.67; 95% confidence interval [CI], 0.46-0.98) and somewhat lower risks of Alzheimer's disease (relative risk=0.52, 95% CI=0.22-1.21) and any cognitive impairment (relative risk=0.73, 95% CI=0.53-1.01). Risks of mild cognitive impairment, Alzheimer's disease, and any impairment were not significantly different in the group taking 60 mg/day of raloxifene.Raloxifene at a dose of 120 mg/day, but not 60 mg/day, resulted in reduced risk of cognitive impairment in postmenopausal women.

  View details for Web of Science ID 000228040600009

  View details for PubMedID 15800139

• Only a matter of time? Hormone therapy and cognition MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Henderson, V. W. 2005; 12 (1): 1-3

  View details for DOI 10.1097/01.GME.0000151280.69688.45

  View details for Web of Science ID 000226370800001

  View details for PubMedID 15668592

• Postmenopausal hormone therapy and Alzheimer's disease risk: interaction with age JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Henderson, V. W., Benke, K. S., Green, R. C., Cupples, L. A., Farrer, L. A. 2005; 76 (1): 103-105

  Abstract

  We examined the relation between oestrogen containing hormone therapy (HT) used for more than 6 months and Alzheimer's disease (AD) risk in 971 postmenopausal women (426 AD patients, 545 relatives without dementia). There was a significant interaction between age and HT use on AD risk (p = 0.03). In stratified analyses, a significant protective association was seen only in the youngest age tertile (50-63 years; odds ratio = 0.35, 95% confidence interval = 0.19 to 0.66). Results must be considered cautiously in light of recent clinical trial evidence that oestrogen plus progestin increases dementia incidence in older postmenopausal women. However, our observational findings are consistent with the view that HT may protect younger women from AD or reduce the risk of early onset forms of AD, or that HT used during the early postmenopause may reduce AD risk.

  View details for DOI 10.1136/jnnp.2003.024927

  View details for Web of Science ID 000225777400021

  View details for PubMedID 15608005

  View details for PubMedCentralID PMC1739309

• Diagnosis and treatment of Alzheimer's disease Journal of Clinical Outcomes Management Edwards-Lee T, Henderson VW 2005; 12 (1): 49-59
• Normative data for tasks of executive function and working memory for Australian-born women aged 56-67 AUSTRALIAN PSYCHOLOGIST Clark, M. S., Dennerstein, L., Elkadi, S., Guthrie, J. R., Bowden, S. C., Henderson, V. W. 2004; 39 (3): 244-250

  View details for DOI 10.1080/0050060412331295126

  View details for Web of Science ID 000225559500010

• Telephone word-list recall tested in the Rural Aging and Memory Study: two parallel versions for the TICS-M INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Hogervorst, E., Bandelow, S., Hart, J., Henderson, V. W. 2004; 19 (9): 875-880

  Abstract

  Parallel versions of memory tasks are useful in clinical and research settings to reduce practice effects engendered by multiple administrations. We aimed to investigate the usefulness of three parallel versions of ten-item word list recall tasks administered by telephone.A population based telephone survey of middle-aged and elderly residents of Bradley County, Arkansas was carried out as part of the Rural Aging and Memory Study (RAMS). Participants in the study were 1845 persons aged 40 to 95 years. Word lists included that used in the telephone interview of cognitive status (TICS) as a criterion standard and two newly developed lists.The mean age of participants was 61.05 (SD 12.44) years; 39.5% were over age 65. 78% of the participants had completed high school, 66% were women and 21% were African-American. There was no difference in demographic characteristics between groups receiving different word list versions, and performances on the three versions were equivalent for both immediate (mean 4.22, SD 1.53) and delayed (mean 2.35 SD 1.75) recall trials. The total memory score (immediate+delayed recall) was negatively associated with older age (beta = -0.41, 95%CI=-0.11 to -0.04), lower education (beta = 0.24, 95%CI = 0.36 to 0.51), male gender (beta = -0.18, 95%CI = -1.39 to -0.90) and African-American race (beta = -0.15, 95%CI = -1.41 to -0.82).The two RAMS word recall lists and the TICS word recall list can be used interchangeably in telephone assessment of memory of middle-aged and elderly persons. This finding is important for future studies where parallel versions of a word-list memory task are needed. (250 words).

  View details for DOI 10.1002/gps.1170

  View details for Web of Science ID 000223870500009

  View details for PubMedID 15352146

• A population-based study of depressed mood in middle-aged, Australian-born women MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Dennerstein, L., Guthrie, J. R., Clark, M., Lehert, P., Henderson, V. W. 2004; 11 (5): 563-568

  Abstract

  There has been controversy about the relationship between menopause and depression. This study utilizes a unique prospective population-based data set of middle-aged, Australian-born women to identify determinants of depressed mood.The Melbourne Women's Midlife Health Project sample consisted of 438 women aged 45 to 55 at baseline; they were followed annually for 11 years. Of this group, 314 (72%) completed the Center for Epidemiologic Studies Depression Scale (CES-D) scale in year 11 to measure depressed mood. Variables measured at baseline and annually included negative mood (measured with Affectometer) and psychosocial, hormonal, health, and lifestyle factors.Women who had the highest CES-D scores were those who by year 11 were still in the menopause transition stage (had not reached final menstrual period) or had experienced surgical menopause. CES-D correlated with negative mood measured concurrently (r = 0.63) and baseline negative mood (r = 0.37). There was a significant reduction in negative mood for all menopause status groups, but those who experienced surgical menopause showed less reduction than other women. Ever-use or number of years of use of hormone therapy made no difference to CES-D outcome. CES-D was associated with baseline negative attitudes toward aging, mood, and premenstrual complaint experience and annual mood, poor self-rated health, number of bothersome symptoms, and daily hassles.Women most likely to have higher depressed mood in the age group 57 to 67 are those who have undergone surgical menopause or have menstruated within the last 12 months. Prior negative mood, history of premenstrual complaints, negative attitudes toward aging or menopause, poor health, and daily hassles predict depressed mood.

  View details for Web of Science ID 000223830600011

  View details for PubMedID 15356410

• Normative verbal and non-verbal memory test scores for Australian women aged 56-67 AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Clark, M. S., Dennerstein, L., Elkadi, S., Guthrie, J. R., Bowden, S. C., Henderson, V. W. 2004; 38 (7): 532-540

  Abstract

  To establish normative data for tests of verbal and non-verbal memory for midlife Australian-born women, and in so doing investigate factors which contribute to variation in test performance.Two hundred and fifty-seven healthy women aged 56-67 years (mean age 60), who are participating in the Melbourne Women's Midlife Longitudinal Health Project, were administered two word list learning tasks, a story recall task (the East Boston Memory Test) and the Faces subtest from the Wechsler Memory Scale III as part of a larger neuropsychological battery. Word list learning tasks consisted of either 16 semantically related words, derived from the California Verbal Learning Test II, or a list of 10 unrelated words. Mood was assessed by the Center for Epidemiological Studies Depression questionnaire.Education was significantly related to memory performance and there was a non-significant trend for test scores to decline with age. Mood was unrelated to test performance. A confirmatory factor analysis indicated a clear distinction between verbal and non-verbal memory performances. Mean scores were stratified by education (less than 12 years vs. 12 or more years) and age (56-59 vs. 60-67 years), and scaled normative data were constructed for all the tests.This study provides education-based normative data for tests of verbal and non-verbal memory for midlife Australian women. The establishment of population-based normative data will facilitate future investigations of ageing and dementia in Australian women.

  View details for Web of Science ID 000222705700008

  View details for PubMedID 15255826

• Detecting dementia in just 12 minutes: the seven minute screen JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Henderson, V. W. 2004; 75 (5): 666-667

  View details for DOI 10.1136/jnnp.2003.032359

  View details for Web of Science ID 000220886700002

  View details for PubMedID 15090555

• Hormone therapy and Alzheimer's disease: benefit or harm? EXPERT OPINION ON PHARMACOTHERAPY Henderson, V. W. 2004; 5 (2): 389-406

  Abstract

  Alzheimer's disease (AD) is the most common cause of dementia. After menopause, circulating levels of oestrogens decline markedly and oestrogen influences several brain processes predicted to modify AD risk. For example, oestrogen reduces the formation of beta-amyloid, a biochemical hallmark of AD. Oestrogen effects on oxidative stress and some effects on inflammation and the cerebral vasculature might also be expected to ameliorate risk. However, AD pathogenesis is incompletely understood and other oestrogen actions could be deleterious. Limited clinical trial evidence suggests that oestrogen therapy, begun after the onset of AD symptoms, is without substantial benefit or harm. Observational studies have associated oestrogen-containing hormone therapy with reduced AD risk. However, in the Women's Health Initiative Memory Study - a randomised, placebo-controlled trial of women 65 - 79 years of age - oral oestrogen plus progestin doubled the rate of dementia, with heightened risk appearing soon after treatment was initiated. Based on current evidence, hormone therapy is thus not indicated for the prevention of AD. Discrepancies between observational studies and the Women's Health Initiative clinical trial may reflect biases and unrecognised confounding factors in observational reports. Other explanations for divergent findings should be considered in future research, including effects of unopposed oestrogen or different hormone therapy preparations and the intriguing theoretical possibility that effects of hormone therapy on AD risk may be modified by the timing of use (e.g., initiation during the menopausal transition or early postmenopause versus initiation during the late postmenopause).

  View details for Web of Science ID 000188837000017

  View details for PubMedID 14996635

• Testosterone and Alzheimer disease - Is it men's turn now? NEUROLOGY Henderson, V. W., Hogervorst, E. 2004; 62 (2): 170-171

  View details for Web of Science ID 000188439300002

  View details for PubMedID 14745046

• Hormone therapy and Alzheimer disease: an evidence based approach to clinical management. Female Patient Henderson VW 2004; 29 (12): 17-22
• Serum lipids and memory in a population based cohort of middle age women JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Henderson, V. W., Guthrie, J. R., Dennerstein, L. 2003; 74 (11): 1530-1535

  Abstract

  To assess the relation between serum lipids and memory in a healthy middle age cohort of women.For 326 women in the Melbourne Women's Midlife Health Project aged 52-63 years, serum lipids were measured annually, and memory was assessed during the eighth annual visit.There was a small but significant association between current low density lipoprotein cholesterol (LDL-C) concentrations and memory; for total cholesterol (TC) the association approached significance. Better memory was associated with positive changes in TC and LDL-C based on lipid measurements three years, but not six years, earlier. Memory performance was lowest among women in the lowest quartile of current LDL-C values and among women whose LDL-C levels declined over the previous three years. High density lipoprotein cholesterol (HDL-C) and triglyceride concentrations were unassociated with memory. The association between memory and TC and LDL-C was primarily related to immediate recall and not delayed recall performance on the word list task. Low cholesterol has been linked with depression, but lipid measures and self-rated mood were unrelated.Higher serum concentrations of LDL-C, and relatively recent increases in TC and LDL-C concentrations, are associated with better memory in healthy middle age women. Possible cognitive effects of cholesterol reduction should be considered in future studies of lipid lowering agents.

  View details for Web of Science ID 000186773600013

  View details for PubMedID 14617710

• Effect of estrogen plus progestin on global cognitive function in postmenopausal women - The Women's Health Initiative Memory Study: A randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Rapp, S. R., Espeland, M. A., Shumaker, S. A., Henderson, V. W., Brunner, R. L., Manson, J. E., Gass, M. L., Stefanick, M. L., Lane, D. S., Hays, J., Johnson, K. C., Coker, L. H., Dailey, M., Bowen, D. 2003; 289 (20): 2663-2672

  Abstract

  Observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. The Women's Health Initiative Memory Study (WHIMS) is an ancillary study of the Women's Health Initiative (WHI) hormone therapy trials. On July 8, 2002, the estrogen plus progestin therapy in the WHI trial was discontinued because of certain increased health risks for women.To determine whether estrogen plus progestin therapy protects global cognitive function in older postmenopausal women.A randomized, double-blind, placebo-controlled clinical trial, WHIMS is an ancillary study of geographically diverse, community-dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus progestin trial that started in June 1995. Of 4894 eligible postmenopausal women aged 65 years or older and free of probable dementia at baseline, 4532 (92.6%) were enrolled in the estrogen plus progestin component of WHIMS. A total of 4381 participants (96.7%) provided at least 1 valid cognitive function score between June 1995 and July 8, 2002.Participants received either 1 daily tablet containing 0.625 mg of conjugated equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236).Global cognitive function measured annually with the Modified Mini-Mental State Examination.The Modified Mini-Mental State Examination mean total scores in both groups increased slightly over time (mean follow-up of 4.2 years). Women in the estrogen plus progestin group had smaller average increases in total scores compared with women receiving placebo (P =.03), but these differences were not clinically important. Removing women by censoring them after adjudicated dementia, mild cognitive impairment, or stroke, and nonadherence to study protocol, did not alter the findings. Prior hormone therapy use and duration of prior use did not affect the interpretation of the results, nor did timing of prior hormone therapy initiation with respect to the final menstrual period. More women in the estrogen plus progestin group had a substantial and clinically important decline (> or =2 SDs) in Modified Mini-Mental State Examination total score (6.7%) compared with the placebo group (4.8%) (P =.008).Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo. While most women receiving estrogen plus progestin did not experience clinically relevant adverse effects on cognition compared with placebo, a small increased risk of clinically meaningful cognitive decline occurred in the estrogen plus progestin group.

  View details for Web of Science ID 000183075600025

  View details for PubMedID 12771113

• Isoflavones: food for thoughtful consideration MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Henderson, V. W. 2003; 10 (3): 189-190

  View details for DOI 10.1097/01.GME.0000067642.38349.65

  View details for Web of Science ID 000182908100001

  View details for PubMedID 12792286

• Estrogen exposures and memory at midlife - A population-based study of women 54th Annual Meeting of the American-Academy-of-Neurology Henderson, V. W., Guthrie, J. R., Dudley, E. C., BURGER, H. G., Dennerstein, L. LIPPINCOTT WILLIAMS & WILKINS. 2003: 1369–71

  Abstract

  Estrogen loss after natural menopause is hypothesized to impair episodic memory. A total of 326 women aged 52 to 63 years participating in the Melbourne Women's Midlife Health Project completed a word list memory task. Estrogen exposures were inferred from menopausal status, time from final menstrual period, use of hormone therapy, serum estradiol concentration, and other indices. Memory did not vary significantly with most exposures. The authors conclude that episodic verbal memory assessed by word list learning is not substantially affected during the menopausal transition or in the years immediately after natural menopause.

  View details for Web of Science ID 000182489600032

  View details for PubMedID 12707448

• DHEA for Alzheimer's disease - A modest showing by a superhormone NEUROLOGY Knopman, D., Henderson, V. W. 2003; 60 (7): 1060-1061

  View details for Web of Science ID 000182680300001

  View details for PubMedID 12682305

• White matter structural integrity in healthy aging adults and patients with Alzheimer disease - A magnetic resonance imaging study ARCHIVES OF NEUROLOGY Bartzokis, G., Cummings, J. L., Sultzer, D., Henderson, V. W., Nuechterlein, K. H., Mintz, J. 2003; 60 (3): 393-398

  Abstract

  Imaging and postmortem studies suggest that frontal lobe white matter (FLWM) volume expands until about the age of 44.6 years and then declines. Postmortem evidence indicates that the structural integrity of myelin sheaths deteriorates during normal aging, especially in late myelinating regions such as the frontal lobes.To assess the integrity of FLWM by magnetic resonance imaging and, thus, to provide an important index of brain aging and its relationship to Alzheimer disease (AD).Cross-sectional study.Two metropolitan university hospitals and AD research centers.Two hundred fifty-two healthy adults (127 men and 125 women), aged 19 to 82 years, and 34 subjects with AD (16 men and 18 women), aged 59 to 85 years.Calculated transverse relaxation rate (R( 2)) of the FLWM (an indirect measure of the structural integrity of white matter).As expected from prior imaging data on FLWM volume, the quadratic function best represented the relationship between age and the FLWM R(2) (P<.001). In healthy individuals, the FLWM R(2) increased until the age of 38 years and then declined markedly with age. The R( 2) of subjects with AD was significantly lower than that of a group of healthy control subjects who were of similar age and sex (P<.001).The R(2) changes in white matter suggest that the healthy adult brain is in a constant state of change, roughly defined as periods of maturation continuing into middle age followed by progressive loss of myelin integrity. Clinically diagnosed AD is associated with more severe myelin breakdown. Noninvasive measures, such as the determination of the R(2), may have the potential to track prospectively the trajectory of deteriorating white matter integrity during normal aging and the development of AD and, thus, may be a useful marker for medication development aimed at the prevention of AD.

  View details for Web of Science ID 000181561500011

  View details for PubMedID 12633151

• Hormone therapy and risk of Alzheimer disease: a critical time. JAMA-the journal of the American Medical Association Resnick, S. M., Henderson, V. W. 2002; 288 (17): 2170-2172

  View details for PubMedID 12413378

• Dementia, butterfly ballots, and voter competence NEUROLOGY Henderson, V. W., Drachman, D. A. 2002; 58 (7): 995-996

  View details for Web of Science ID 000174865900001

  View details for PubMedID 11940678

• Better preservation of memory span relative to supraspan immediate recall in Alzheimer's disease NEUROPSYCHOLOGIA Cherry, B. J., Buckwalter, J. G., Henderson, V. W. 2002; 40 (7): 846-852

  Abstract

  It is suggested that Alzheimer's disease (AD) patients are able to recall more items on the digit span task than on immediate free recall from a supraspan word list. Two experiments were undertaken to verify this assertion and to understand the basis of the putative span/supraspan discrepancy. The first experiment, involving 35 mildly or moderately demented AD patients, confirmed that digit span significantly exceeded immediate recall from a 10-item supraspan word list. Although digit span also exceeded supraspan recall in 38 elderly non-demented control subjects, the discrepancy was significantly greater within the AD group. In a second experiment, 19 AD cases and 20 controls were assessed with a word span task that used nouns matched by frequency and word length to nouns on the supraspan task. The magnitude of the span/supraspan discrepancy was reduced, indicating that part of the initial discrepancy was due to differences in stimulus items (digits versus common nouns). As before, AD subjects recalled more words on the span task than the supraspan task. However, in striking contrast, NC subjects recalled more words on the supraspan task, further indicating that AD patients are particularly impaired on supraspan recall. Using combined data from 106 subjects in both experiments, digit span performance correlated significantly with supraspan recall for NC but not AD subjects. Moreover, within the AD group the magnitude of the discrepancy was inversely related to a working memory measure derived from the backward digit span. The magnitude of the span/supraspan discrepancy correctly classified 88% of patients with mild dementia and 74% of controls. Results indicate that AD patients are specifically vulnerable to information overload inherent in the supraspan task, a view consistent with the perspective that AD is characterized by prominent disturbances in working memory.

  View details for Web of Science ID 000174826900015

  View details for PubMedID 11900735

• Menopause and disorders of neurological function and mental health 4th International Symposium on Womens Health and Menopause Henderson, V. W., Resnick, S. M. SPRINGER. 2002: 323–327

  View details for Web of Science ID 000179729400038

• Clock drawing: Analysis in a retirement community JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Paganini-Hill, A., Clark, L. J., Henderson, V. W., Birge, S. J. 2001; 49 (7): 941-947

  Abstract

  To test the hypothesis that performance on a clock-drawing test in a mailed survey to an older cohort is associated with known and potential risk and protective factors for Alzheimer's disease.The Leisure World Cohort Study is an ongoing study, begun in 1981, of nearly 14,000 older adults. In November 1992, the 8,406 living cohort members were mailed a follow-up questionnaire.Leisure World Laguna Hills, a southern California retirement community.The study population is a predominantly white, well-educated, upper-middle-class community; approximately two-thirds are women. Data from 4,843 cohort members (mean age 80 years; range 52-101) were analyzed.The questionnaire included a clock-drawing task: a predrawn circle 3 1/4 inches (8.3 cm) in diameter was provided with instructions "In the circle below, draw in the numbers as on a clock face. Make no erasures." Clocks were scored on 7 items: all numbers 1-12 present without adding extra or omitting numbers, sequencing of numbers, position of numbers, orientation of numbers to circle, consistent number style (either Arabic or Roman), tilt of numbers, and superfluous marks. A total clock score was calculated by summing the number of correct individual items (0-7). We also classified individuals as cognitively impaired by a previously suggested method: individuals were affected if they did not have three numbers drawn in the upper left quadrant of the clock face.Ninety percent or more of the participants across all ages placed the numbers 1 to 12 on their clocks without omissions or additions; 35% completed the clock drawing without error. The mean total clock scores decreased with each successive 5-year age group in both men and women. Regression analysis indicated a significant effect for age (b = -0.15, P <.0001), education (b = 0.05, P =.0001), smoking (b = 0.13, P =.03), and female gender (b = -0.05, P =.05) and a marginally significant effect of nonrheumatoid arthritis (b = 0.05, P =.07) on total clock score. No other measured variable had a significant effect. Cognitively impaired individuals were more likely to be female and older. After adjusting for age and gender, they were also more likely to be hypertensive and to have taken blood pressure medication and less likely to be college graduates, have glaucoma or arthritis, and to have taken vitamin supplements.The clock-drawing task is an appealing measure of cognitive function for large epidemiological studies because it is a simple, self-administered test that is easily adapted to mail surveys and correlates with more-detailed and more-time-consuming cognitive screens. Although it is relatively free of influence by language, cultural, or ethnic factors, our study shows that even in a highly educated population, clock drawing is influenced by educational level and other known risk factors for Alzheimer's disease. Thus a clock-drawing task may help predict cognitive frailty and future disability in older people. Such determination can direct high-risk individuals to earlier diagnosis, potential therapies, and better management.

  View details for Web of Science ID 000170332700013

  View details for PubMedID 11527486

• Assessing working memory and language comprehension in Alzheimer's disease BRAIN AND LANGUAGE MacDonald, M. C., Almor, A., Henderson, V. W., Kempler, D., Andersen, E. S. 2001; 78 (1): 17-42

  Abstract

  Studies of language impairments in patients with Alzheimer's disease have often assumed that impairments in linguistic working memory underlie comprehension deficits. Assessment of this hypothesis has been hindered both by vagueness of key terms such as "working memory" and by limitations of available working memory tasks, in that many such tasks either seem to have little relationship to language comprehension or are too confusing or difficult for Alzheimer's patients. Four experiments investigated the usefulness of digit ordering, a new task assessing linguistic working memory and/or language processing skill, in normal adults and patients with probable Alzheimer's disease. The digit ordering task was shown to be strongly correlated with the degree of dementia in Alzheimer's patients. The task correlated with measures of language processing on which patients and normal controls performed differently. The results are interpreted as indicating that linguistic representations, linguistic processing, and linguistic working memory are intertwined, such that a deficit of one (e.g., working memory) cannot be said to "cause" a deficit in the other. The implications of this approach are explored in terms of task demands in comprehension and memory measures, and interpretation of previous results in the literature.

  View details for DOI 10.1006/brln.2000.2436

  View details for Web of Science ID 000169481000002

  View details for PubMedID 11412013

• Hormones, Gender and the Aging Brain: The Endocrine Basis of Geriatric Psychiatry. Edited by MF Morrison. Quarterly Review of Biology Henderson VW 2001; 76: 534-535
• Associations between circulating sex steroid hormones and cognition in normal elderly women NEUROLOGY Drake, E. B., Henderson, V. W., Stanczyk, F. Z., McCleary, C. A., Brown, W. S., Smith, C. A., Rizzo, A. A., Murdock, G. A., Buckwalter, J. G. 2000; 54 (3): 599-603

  Abstract

  To provide exploratory analyses of associations between levels of several sex hormones and cognitive performance in elderly women.Sex steroid hormones are implicated in the cognitive processes of the adult brain. Comparing cognitive performance across or between conditions associated with different hormone levels, such as phases of the menstrual cycle, surgical menopause, and estrogen replacement therapy suggests conditions with higher levels of estrogen are associated with better verbal memory and possibly worse visuospatial ability.The authors measured circulating sex hormone levels in 39 highly educated, nondemented, predominantly white elderly women. Levels were correlated with neuropsychological performance, controlling for age, education, frequency of prior testing, use of estrogen replacement, and depression.High estradiol levels were associated with better delayed verbal memory and retrieval efficiency, whereas low levels were associated with better immediate and delayed visual memory. Levels of testosterone were related positively to verbal fluency. Levels of progesterone and androstenedione were unrelated to cognitive performance.Both estrogen and testosterone showed associations with cognitive performance. Estrogen may enhance, and depress, specific cognitive skills.

  View details for Web of Science ID 000085160300011

  View details for PubMedID 10680789

• Estrogen for Alzheimer's disease in women - Randomized, double-blind, placebo-controlled trial NEUROLOGY Henderson, V. W., Paganini-Hill, A., Miller, B. L., Elble, R. J., Reyes, P. F., Shoupe, D., McCleary, C. A., Klein, R. A., Hake, A. M., Farlow, M. R. 2000; 54 (2): 295-301

  Abstract

  AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder.Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks.Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences.Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

  View details for Web of Science ID 000085043800006

  View details for PubMedID 10668686

• Anosognosia and Alzheimer's disease: The role of depressive symptoms in mediating impaired insight JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Smith, C. A., Henderson, V. W., McCleary, C. A., Murdock, G. A., Buckwalter, J. G. 2000; 22 (4): 437-444

  Abstract

  The relation between anosognosia and dementia severity in Alzheimer's disease (AD) has been unclear. We constructed a measure that quantified the difference between the perceptions of deficits of patients with AD (n = 23) and ratings from a knowledgeable informant as a measure of anosognosia. There was no correlation between dementia severity and anosognosia. However, dementia severity was positively correlated with the degree of anosognosia after controlling for depressive symptomatology (p =.03). Post-hoc analyses, also controlling for depressive symptoms, indicated that higher levels of anosognosia were associated with lower performance on specific cognitive tasks. These results suggest depressive symptoms may confound the relationship between anosognosia and dementia severity.

  View details for Web of Science ID 000088550400001

  View details for PubMedID 10923053

• Hormone Therapy and the Brain Henderson VW 2000
• Estrogen and neural plasticity. Curr Direct Psychol Sci Foy MR, Henderson VW, Berger TW, Thompson RF 2000; 9 (5): 148-152
• Oestrogens and dementia. Novartis Foundation symposium Henderson, V. W. 2000; 230: 254-265

  Abstract

  The decline in circulating oestrogen concentrations that occurs after the menopause has the potential to impact Alzheimer's disease and other forms of dementia. Relevant actions include neurotrophic and neuroprotective effects; effects on acetylcholine and other neurotransmitters; and effects on proteins implicated in Alzheimer's disease pathogenesis. Since 1990, 14 case-control and cohort studies have considered the relation between postmenopausal oestrogen therapy and Alzheimer's disease. Most, but not all, report that oestrogen therapy is associated with a reduced Alzheimer risk of approximately one-half. Almost no epidemiological data address the potential link between oestrogen and other forms of dementia. Several small interventional trials have considered whether oestrogen might improve cognitive function of women with Alzheimer's disease. Data, however, are limited, and there is no compelling evidence that the short-term use of oestrogen monotherapy has a substantial impact on dementia symptoms. In summary, the use of oestrogen to reduce Alzheimer risk is biologically credible, and the preponderance of epidemiological evidence suggests that oestrogen therapy is indeed protective. This potentially important role of oestrogens for the primary prevention of Alzheimer's disease remains to be verified through well-designed randomized controlled trials.

  View details for PubMedID 10965513

• In vivo evaluation of brain iron in Alzheimer disease using magnetic resonance imaging ARCHIVES OF GENERAL PSYCHIATRY Bartzokis, G., Sultzer, D., Cummings, J., Holt, L. E., Hance, D. B., Henderson, V. W., Mintz, J. 2000; 57 (1): 47-53

  Abstract

  The basal ganglia contain the highest levels of iron in the brain, and postmortem studies indicate a disruption of iron metabolism in the basal ganglia of patients with Alzheimer disease (AD). Iron can catalyze free radical reactions and may contribute to oxidative damage observed in AD brains. Treatments aimed at reducing oxidative damage have offered novel ways to delay the rate of progression and could possibly defer the onset of AD. Brain iron levels were quantified in vivo using a new magnetic resonance imaging method.Thirty-one patients with AD and 68 control subjects participated in this study. A magnetic resonance imaging method was employed that quantifies the iron content of ferritin molecules (ferritin iron) with specificity through the combined use of high and low field-strength magnetic resonance imaging instruments. Three basal ganglia structures (caudate, putamen, and globus pallidus) and one comparison region (frontal lobe white matter) were evaluated.Basal ganglia ferritin iron levels were significantly increased in the caudate (P = .007; effect size, 0.69) and putamen (P = .008; effect size, 0.67) of AD subjects, with a trend toward an increase in the globus pallidus (P = .13). The increased basal ganglia ferritin iron levels were not a generalized phenomenon; white matter ferritin iron levels were unchanged in patients with AD (P = .50).The data replicate and extend prior results and suggest that basal ganglia ferritin iron levels are increased in AD. Prospective studies are needed to evaluate whether premorbid iron levels are increased in individuals who develop AD.

  View details for Web of Science ID 000084560000005

  View details for PubMedID 10632232

• Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease ALZHEIMER DISEASE & ASSOCIATED DISORDERS Bretsky, P. M., Buckwalter, J. G., Seeman, T. E., Miller, C. A., Poirier, J., Schellenberg, G. D., Finch, C. E., Henderson, V. W. 1999; 13 (4): 216-221

  Abstract

  Carriers of the apolipoprotein E (APOE) epsilon4 allele show significantly higher risk of Alzheimer disease (AD). The aim of this present study was to test the hypothesis that a significant interaction exists between APOE genotype and gender on AD. Interactions of epsilon4 by gender, although indicated in the literature, require further verification. A total of 195 past or current control or AD participants in an ongoing longitudinal study of aging and dementia were genotyped. All subjects were at least 60 years old; demented subjects met clinical or pathologic criteria for late-onset AD. Logistic regression analysis and proportional hazard models were used to evaluate joint effects of APOE and gender. A significant statistical interaction between APOE and gender was shown (p = 0.04) in logistic regression analysis. Women carrying one or more APOE-epsilon4 allele were more likely to develop AD [odds ratio (OR) = 7.8, 95% confidence interval (CI) = 3.2-19. 1]. For men, the presence of the APOE-epsilon4 allele was not associated with a statistically significant increased risk (OR = 1.6, 95% CI = 0.5-5.3). The interaction term in the proportional hazards model neared (p = 0.07) statistical significance, and a similar but reduced gender effect was shown. The analysis suggests that the presence of one or more APOE-epsilon4 allele confers a substantially greater risk of AD to women than to men. These findings in part may account for reports of increased risk of AD faced by women.

  View details for Web of Science ID 000084423200006

  View details for PubMedID 10609670

• Does estrogen therapy enhance memory? Climacteric Henderson, V. W. 1999; 2 (3): 162-163

  View details for PubMedID 11910592

• Sex steroids and Alzheimer?s disease: therapeutic considerations. Menopause Review Henderson VW 1998; 3: 67-73
• Estrogen in the treatment and prevention of Alzheimer's disease. International journal of pharmaceutical compounding Paganini-Hill, A., Henderson, V. W. 1998; 2 (1): 24-29

  View details for PubMedID 23989480

• Hormonothérapie substitutive et maladie d?Alzheimer. Reproduction Humaine et Hormones Henderson VW 1998; 11 (3): 241-246
• Alzheimer?s disease and other dementias in the older woman. Female Patient Henderson VW, Benton D, Paganini-Hill A 1998; 23 (10): 27-34
• Principles of Neurology, 6th ed. By RD Adams, M Victor, and AH Ropper. Neurosurgery Henderson VW 1998; 42: 424-425
• Estrogen replacement therapy and Alzheimer's disease Intern J Pharm Compound Paganini-Hill A, Henderson VW 1998; 2: 24-29
• Lifetime estrogen exposure and cognitive performance in elderly women BRAIN AND COGNITION Smith, C. A., Buckwalter, J. G., Murdock, G. A., McCleary, C. A., Henderson, V. M. 1997; 35 (3): 332-335

  View details for Web of Science ID 000071763600024

• Estrogen, cognition, and a woman's risk of Alzheimer's disease. American journal of medicine Henderson, V. W. 1997; 103 (3A): 11S-18S

  Abstract

  Alzheimer's disease affects women more often than men, and women with this form of dementia show greater naming (semantic memory) deficits during the course of their illness. Gonadal steroids exert organizational and activational effects on central nervous system neurons and influence brain function in other important ways. Several estrogenic actions are potentially relevant to Alzheimer's disease, and it is hypothesized that one consequence of estrogen deprivation after the menopause is a higher risk of this dementing disorder. In healthy women without dementia, estrogen may enhance cognitive performance, especially in the domain of verbal memory, although the magnitude of such effects is small. Several small treatment trials of estrogen replacement in women with Alzheimer's disease, however, suggest that estrogen's effects on cognition could be larger in this population and may be most apparent on tasks of semantic memory. Analyses in voluntary cohorts associate postmenopausal estrogen replacement therapy with a lower risk of subsequent Alzheimer's disease. In 3 recent epidemiologic studies, information on postmenopausal estrogen use was collected prospectively; while inconclusive, findings raise the possibility that postmenopausal estrogen replacement reduces a woman's risk of subsequent dementia. New information from basic research and from large randomized treatment studies, cohort studies, and case-control studies is needed to resolve important unanswered clinical issues.

  View details for PubMedID 9344402

• The relationship between extrapyramidal signs and cognitive performance in patients with Alzheimer's disease enrolled in the CERAD study NEUROLOGY Clark, C. M., Ewbank, D., LERNER, A., Doody, R., Henderson, V. W., Panisset, M., Morris, J. C., Fillenbaum, G. G., Heyman, A. 1997; 49 (1): 70-75

  Abstract

  The objective of this study was to determine the relationship between the presence of extrapyramidal signs and the severity of cognitive and functional impairment in patients with Alzheimer's disease (AD). Eleven university medical centers in the United States and France participated in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) study of extrapyramidal signs in AD. Forty-seven patients with probable AD who had extrapyramidal signs were matched by sex, race, education, and age with 132 probable AD patients without extrapyramidal signs. The main outcome measures were the Clinical Dementia Rating, Blessed Dementia Scale, and the CERAD Neuropsychology Battery (verbal fluency, naming, Mini-Mental State Examination, word list learning, word list recall, savings ratio, word list recognition, and constructional praxis). AD patients with extrapyramidal signs performed more poorly than AD patients without parkinsonism on various neuropsychological tests, even after controlling for the Clinical Dementia Rating and reported duration of cognitive impairment. The severity of the extrapyramidal manifestations was related to the degree of cognitive and functional impairment. Muscular rigidity and bradykinesia were the most frequent extrapyramidal signs associated with AD. Patients with AD associated with extrapyramidal signs have greater cognitive and functional impairment than AD patients without clinical evidence of parkinsonism.

  View details for Web of Science ID A1997XK35300012

  View details for PubMedID 9222172

• Body weight, estrogen and cognitive functioning in Alzheimer's disease: An analysis of the Tacrine Study Group data ARCHIVES OF GERONTOLOGY AND GERIATRICS Buckwalter, J. G., SCHNEIDER, L. S., Wilshire, T. W., Dunn, M. E., Henderson, V. W. 1997; 24 (3): 261-267

  Abstract

  We conducted a retrospective analysis of clinically ascertained Alzheimer's disease subjects, hypothesizing that weight, given its positive relationship to endogenous estrogen levels, would correlate with better cognitive performance among women, but not necessarily men, with this disorder. Baseline (pretreatment) data, collected by the Tacrine Study Group were available from 347 women and 316 men. After controlling for age, duration of dementia, height, and education, we found weight to have a significant, positive relationship with two measures of global cognitive functioning among women. For men, this relationship was smaller and did not reach statistical significance. Post hoc analyses among women found the effect of weight to be independent of concurrent use of estrogen replacement medication. The use of estrogen replacement was independently related to better cognitive performance. Results support the contention that higher body weight - putatively as a reflection of higher levels of endogenous estrogens - has a positive effect on cognitive performance among women with Alzheimer's disease.

  View details for Web of Science ID A1997WU63900004

  View details for PubMedID 15374113

• The epidemiology of estrogen replacement therapy and Alzheimer's disease 10th World Congress of Psychiatry Henderson, V. W. LIPPINCOTT WILLIAMS & WILKINS. 1997: S27–S35

  Abstract

  The burden of Alzheimer's disease (AD) falls more heavily on women than men. It is hypothesized that plummeting levels of circulating estrogens after the menopause increase a woman's risk for this disorder and, conversely, that estrogen replacement therapy may lower the risk for dementia due to AD. A number of estrogenic properties support the biological credibility of this hypothesis. Estrogen interacts with neurotrophins and neurotransmitter systems relevant to AD and in some model systems estrogen modulates synaptic plasticity. Effects on beta-amyloid and apolipoprotein E may be especially germane to putative effects. Estrogen also may blunt neurotoxic consequences of the stress response mediated by the hypothalamic-pituitary-adrenal axis, augment cerebral glucose utilization, and enhance cerebral blood flow. Clinical studies of postmenopausal women suggest beneficial estrogen effects on specific cognitive skills, and small preliminary trials of estrogen replacement in women with AD support claims of clinical meaningful efficacy. Consistent with the estrogen hypothesis, cross-sectional studies imply that postmenopausal estrogen use could be associated with a lower risk for AD. Several recent epidemiologic studies in which information on estrogen replacement therapy was collected prospectively further support this contention, with a dose-response relation evident in some reports. Because estrogen users tend to differ from nonusers in a number of lifestyle characteristics, convincing demonstration of putative protective effects could best some from randomized, placebo-controlled, primary intervention trials. For the present, however, the issue of estrogen efficacy in lowering a woman's risk for AD remains unsettled.

  View details for Web of Science ID A1997XA09700006

  View details for PubMedID 9153164

• Ageing, oestrogen and the brain J Brit Menopause Soc Henderson VW 1997; 3 (3): 15-21
• Estrogen across the lifespan and Alzheimer's disease 2nd International Symposium on Womens Health in Menopause - Risk Reduction Strategies Buckwalter, J. G., Henderson, V. W. KLUWER ACADEMIC PUBL. 1997: 185–190

  View details for Web of Science ID A1997BJ79C00028

• Estrogen and Alzheimer's disease J Soc Obstetr Gynaecol Canada Henderson VW, Paganini-Hill A 1997; 19 [suppl]: 21-28
• Estrogen replacement therapy for the prevention and treatment of Alzheimer?s disease CNS Drugs Henderson VW 1997; 8 (5): 343-351
• A comparative analysis of Spanish- and English-speaking Alzheimer?s disease patients: eligibility and interest in clinical drug trials J Clin Geropsychol Olin JT, Pawluczyk S, Kaufman GT, Taussig IM, Henderson VW, Schneider LS 1997; 3 (3): 183-190
• Estrogen replacement therapy and risk of Alzheimer disease ARCHIVES OF INTERNAL MEDICINE PAGANINIHILL, A., Henderson, V. W. 1996; 156 (19): 2213-2217

  Abstract

  With Alzheimer disease emerging as a major public health problem, the identification of factors that might prevent this disease are important. Estrogen loss associated with menopause may contribute to the development of Alzheimer disease.To evaluate the effects of different estrogen preparations, varying dosages of estrogen, and duration of estrogen replacement therapy on the risk of Alzheimer disease in postmenopausal women.A case-control study nested within a prospective cohort study of residents of Leisure World Laguna Hills, a retirement community in Southern California. The cohort comprised 8877 women who were first mailed a health survey in 1981. Of the 3760 female cohort members who died between 1981 and 1995, 248 women with Alzheimer disease or other dementia diagnoses likely to represent Alzheimer disease (senile dementia, dementia, or senility) mentioned on the death certificate were identified. Five controls were individually matched to each case according to year of death and year of birth (+/- 1 year).The risk of Alzheimer disease and related dementia was significantly reduced in estrogen users compared with nonusers (odds ratio, 0.65; 95% confidence interval, 0.49-0.88). The risk was reduced for both oral and nonoral (i.e., injections and/or creams) routes of administration. The risk decreased significantly with both increasing dosages (P = .01) and increasing duration (P = .01) of oral therapy with conjugated equine estrogen, the most commonly used estrogen preparation. Within each dose category, the risk decreased with increasing duration of therapy, with the lowest observed risk in long-term users who received high doses (odds ratio, 0.48; 95% confidence interval, 0.19-1.17).This study suggests that estrogen replacement therapy may be useful for preventing or delaying the onset of Alzheimer disease in postmenopausal women.

  View details for Web of Science ID A1996VN93900008

  View details for PubMedID 8885820

• Introduction. The investigation of lexical semantic representation in Alzheimer's disease. Brain and language Henderson, V. W. 1996; 54 (2): 179-183

  Abstract

  The study of lexical semantic representation is central to an understanding of brain and language. In Alzheimer's disease, neuropathological alterations consistently involve neocortical areas in which lexical semantic information is represented, and patients with this common dementing disorder evince priminent lexical semantic disturbances. General issues concern the establishment of new semantic memories, the manner in which meaning is represented within the lexicon, the retrieval of semantic information from the lexicon, and the relation between lexical semantics and nonlinguistic cognitive processes. Studies of lexical semantic representation in patients with Alzheimer's disease are especially informative in considering all but the first of these key issues.

  View details for PubMedID 8811951

• Spouses of demented patients with low cobalamin levels: A new risk group for cobalamin deficiency EUROPEAN JOURNAL OF HAEMATOLOGY CARMEL, R., CAIRO, K., Bondareff, W., Gott, P. S., Cummings, J. L., Henderson, V. W. 1996; 57 (1): 62-67

  Abstract

  Low serum cobalamin levels are common in conditions such as dementia and often represent mild deficiency. We surveyed serum cobalamin levels prospectively in spouses and blood relatives of demented patients to determine if any familial predisposition exists for the low levels. Cobalamin status in most of the relatives found to have low levels was assessed further by means of blood counts, metabolic tests, neurologic evaluation, absorption studies and response to cobalamin therapy. Serum cobalamin levels in 36 spouses correlated with those of the 36 demented patients related to them (r = 0.46, p = 0.004). A significant association was not seen in 34 blood relatives of 34 demented patients (r = 0.27). Most importantly, 67% of the spouses of demented patients with low serum cobalamin had low values themselves, compared with only 3% of the spouses of patients with normal levels (p = 0.001). Detailed study of 4 of the 5 spouses (and 3 blood relatives) with low cobalamin levels showed no anemia in any case. Nevertheless, 4 of the subjects had metabolic evidence of deficiency and one had electrophysiological abnormalities; all these defects improved with cobalamin therapy. These observations identify a hitherto unsuspected group of people at high risk for cobalamin deficiency and suggest that spouses of demented patients with low cobalamin levels should also have their cobalamin levels measured. The increased frequency of low serum cobalamin levels in spouses of demented patients with low levels represents in most cases a true, mild cobalamin deficiency that responds to treatment.

  View details for Web of Science ID A1996UZ41300009

  View details for PubMedID 8698133

• The effects of hormone replacement therapy, lipoprotein cholesterol levels, and other factors on a clock drawing task in older women JOURNAL OF THE AMERICAN GERIATRICS SOCIETY PAGANINIHILL, A., Henderson, V. W. 1996; 44 (7): 818-822

  Abstract

  To assess the associations of a clock drawing task with hormone replacement therapy and other factors in older women.Group comparisons.Leisure World Laguna Hills, retirement community in southern California.Two hundred ninety-two postmenopausal women who were analyzed for lipoprotein levels in 1987-88 were contacted by postal survey, which included a clock drawing task, in 1992; 168 women who drew normal clocks were compared with 46 who drew abnormal or blank clocks.Clock drawings; lipoprotein cholesterol levels; serum progesterone, estrone, estradiol, and steroid hormone binding globin levels; self-reported data on smoking, alcohol intake, prior medical diagnoses, and use of certain medications including hormone replacement therapy and analgesics.Women with normal clocks had significantly lower total cholesterol (P = .01), LDL cholesterol (P = .03), and serum progesterone levels (P = .03). They weighed, on average, 5 more pounds at the time of last menstrual period (P = .05), were more likely to use combined hormonal replacement therapy (P = .06), and were less likely to use acetaminophen daily (P = .02) than women with abnormal clocks. Serum estrone and estradiol levels did not differ significantly between women with normal and abnormal clocks.The associations found here suggest that high serum cholesterol and progesterone levels might have a negative effect on clock drawing performance. Acetaminophen may also be related to worse performance on this task.

  View details for Web of Science ID A1996UV34100012

  View details for PubMedID 8675931

• Concurrent validity of Spanish-language versions of the Mini-Mental State Examination, Mental Status Questionnaire, Information-Memory-Concentration test, and Orientation-Memory-Concentration test: Alzheimer's disease patients and nondemented elderly comparison subjects. Journal of the International Neuropsychological Society Taussig, I. M., Mack, W. J., Henderson, V. W. 1996; 2 (4): 286-298

  Abstract

  One-hundred fifty-eight elderly Spanish-speaking U.S. residents (81 patients diagnosed with Alzheimer's disease and 77 subjects without dementia) were tested with Spanish-language versions of four brief cognitive assessment instruments: the Mini-Mental State Examination (S-MMSE), the Mental Status Questionnaire (S-MSQ), the Information-Memory-Concentration test (S-IMC), and the Orientation-Memory-Concentration test (S-OMC). Within-group performances were highly correlated for all four instruments. All tests distinguished between the demented and nondemented groups, but best discrimination was achieved with the S-IMC, which correctly classified 98% of subjects. This version was also the best predictor of functional disability, as measured by impairments in instrumental activities of daily living. Within the normal comparison group, neither gender nor a subject's monolingual/bilingual status affected test performance. These four Spanish-language cognitive screening tasks may aid in the evaluation of dementia among Spanish-speaking patients.

  View details for PubMedID 9375177

• Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer's disease NEUROLOGY SCHNEIDER, L. S., Farlow, M. R., Henderson, V. W., Pogoda, J. M. 1996; 46 (6): 1580-1584

  Abstract

  To examine whether estrogen replacement therapy (ERT) affects clinical and cognitive responses to tacrine in women with Alzheimer's disease (AD).A 30-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial of tacrine in which a subgroup of women were receiving ERT prior to randomization.Women with mild to moderate-stage AD, at least 50 years of age, who were enrolled in the previously reported trial.Randomized assignment to placebo or to one of three ascending-dosage regimens of tacrine: maximum dosages of 80 mg/d, 120 mg/d or 160 mg/d.Alzheimer's Disease Assessment Scale-Cognitive Scale (ADASc), Clinician Interview-Based Impression of change (CIBI), Mini-Mental State Examination (MMSE), Caregiver's Impression of Change (CIC).Of 318 women with evaluable data 14.5% were receiving ERT. Women completing the trial taking ERT and tacrine improved more than women not receiving ERT who were randomly assigned to tacrine or to placebo as assessed by the ADASc (p < 0.01), the CIBI (p = 0.02), the CIC (p = 0.006), and the MMSE (p = 0.07). They improved significantly on the ADASc (p = 0.01) using an intent-to-treat analysis.Prior and continuing ERT may enhance response to tacrine in women with AD. Randomized trials are needed.

  View details for Web of Science ID A1996UQ77700016

  View details for PubMedID 8649552

• Gender comparisons of cognitive performances among vascular dementia, Alzheimer disease, and older adults without dementia ARCHIVES OF NEUROLOGY Buckwalter, J. G., Rizzo, A. A., McCleary, R., SHANKLE, R., Dick, M., Henderson, V. W. 1996; 53 (5): 436-439

  Abstract

  We hypothesized that women with Alzheimer disease (AD) would perform worse on a test of semantic memory but not on tests of other cognitive domains. We did not expect that women without dementia would perform more poorly than men without dementia on the same task.To explore the specificity of a semantic memory deficit among women with AD by exploring gender differences among a group of subjects with vascular dementia (VD).A case-control study in which differences between men and women were explored using regression models to control for the potentially confounding effects of age, education, duration of dementia, and severity of dementia.Alzheimer's Disease Research Center Consortium of Los Angeles and Orange Counties, California.Volunteers, recruited from the community or clinic referrals, who met clinical criteria for AD (n = 159) or VD (n = 117) or met criteria for control status without dementia (n = 134).Five neuropsychological measures, commonly used in the diagnosis and assessment of dementia.Women with VD scored lower than men with VD on 3 tests. However, when controlling for potential confounds, the gender difference was maintained only for the semantic memory task. Women with AD showed a strong trend to perform worse than men with AD on the test of semantic memory only. No gender differences were found among subjects without dementia.Findings support the existence of a semantic memory deficit for women with AD and suggest that a similar deficit may exist among women with VD.

  View details for Web of Science ID A1996UJ82100016

  View details for PubMedID 8624219

• Cognitive skills associated with estrogen replacement in women with Alzheimer's disease PSYCHONEUROENDOCRINOLOGY Henderson, V. W., Watt, L., Buckwalter, J. G. 1996; 21 (4): 421-430

  Abstract

  To delineate putative cognitive effects of estrogen in women with Alzheimer's disease, we compared neuropsychological performances in three groups of patients with clinically diagnosed Alzheimer's disease: women receiving estrogen replacement therapy (n = 9), women not receiving replacement therapy (n = 27), and men (n = 26). Untreated women and men were matched by age, education, and duration of dementia symptoms to women receiving estrogen replacement. We hypothesized that treated women would have better scores on neuropsychological tasks. Results showed that women receiving hormonal therapy performed significantly better than other women on some, but not all, tasks; on no task did women receiving estrogen score significantly worse. The largest group difference was on the Boston Naming Test, a semantic memory task previously shown to be more impaired in women with Alzheimer's disease than in men with this diagnosis. Of tests considered in a discriminant analysis, the naming task was the only neuropsychological variable to distinguish between the two women's groups. Mean differences between estrogen-treated women and men were small and were not statistically significant. Findings support the hypothesis that estrogen therapy for women with Alzheimer's disease is associated with better cognitive skills and that previously noted gender-associated differences in Alzheimer's disease may reflect a state of acquired estrogen deficiency among women with this disorder.

  View details for Web of Science ID A1996VC37700006

  View details for PubMedID 8844880

• Memory span procedures in Alzheimer's disease NEUROPSYCHOLOGY Cherry, B. J., Buckwalter, J. G., Henderson, V. W. 1996; 10 (2): 286-293

  View details for Web of Science ID A1996UD70400014

• The consortium to establish a registry for Alzheimer's disease (CERAD) .13. Obtaining autopsy in Alzheimer's disease NEUROLOGY Fillenbaum, G. G., Huber, M. S., Beekly, D., Henderson, V. W., MORTIMER, J., Morris, J. C., Harrell, L. E. 1996; 46 (1): 142-145

  Abstract

  Although autopsy rates in the United States have been decreasing steadily, the necessity for brain autopsy to confirm Alzheimer's disease (AD) remains. Of 308 consecutively deceased AD patients at 24 CERAD (Consortium to Establish a Registry for Alzheimer's Disease) sites, 167 (54%) were autopsied; 141 (46%) were not. The autopsied and nonautopsied groups were comparable in gender (men, 57.5% versus 49.7%), marital status (married, 69.3% versus 67.1%), age at entry (73 versus 74 years), age at death (76 versus 77 years), and stage of disease at entry (mild, 46% versus 43%). However, the autopsied patients were significantly more likely to be white (94.5% versus 82.1%), to be better educated (13.1 versus 11.3 years), to have been in the study longer (mean, 3.3 versus 2.6 years), and to have had longer total duration of AD (8.1 versus 6.7 years). Of the 24 CERAD sites, 13 stressed the importance of autopsy by dedicating a staff member to seek autopsy and by providing free autopsy and transportation; 11 did not. Logistic regression analysis showed that white race (odds ratio [OR] = 2.74; 95% confidence interval [CI] = 1.10-6.83), increased education (OR = 1.12; 95% CI = 1.04-1.21), and emphasis on autopsy (OR = 4.69; 95% CI = 2.67-8.25) were the only significant factors. Although race and education were important, autopsy was more likely to be obtained when sites dedicated resources to this endeavor.

  View details for Web of Science ID A1996TR67100030

  View details for PubMedID 8559363

• Full-information models for multiple psychometric tests: Annualized rates of change in normal aging and dementia ALZHEIMER DISEASE & ASSOCIATED DISORDERS McCleary, R., Dick, M. B., Buckwalter, G., Henderson, V., Shankle, W. R. 1996; 10 (4): 216-223

  Abstract

  The rates of change for five widely used psychometric tests were analyzed to compare how much more variance reduction can be achieved using full-information methods relative to the single-equation methods previously used in dementia research. Nondemented controls and subjects with Alzheimer disease (AD), probable/ possible vascular dementia (VD), or mixed dementia (MD) were evaluated. A cohort design was followed, with follow-up of three demented groups and one normal control group; data were analyzed in a multiple-equation regression model estimated with full-information methods. The study was conducted at Alzheimer's Disease Research Center sites at the University of California, Irvine, and at the University of Southern California. In all, 226 patients and controls who had completed initial assessment and at least one annual reassessment were included in the study. Dependent variables were annualized rates of change in the Mini-Mental State Examination (MMSE), the Short-Blessed Dementia Rating Scale (DRS), the Consortium to Establish a Registry for Alzheimer's Disease drawings test (CD), the WAIS-R Block Design test (WRB), and the Boston Naming Test (BNT). Independent variables were dementia severity, diagnosis (AD, VD, MD, or control), sex, age, marital status, education, and age at onset. Full-information methods reduced the variance in the change scores by > or = 25% compared with previous studies. The model's prediction of a test's rate of change was almost entirely due to dementia stage and diagnosis. The effects of other explanatory variables (sex, marital status, age, and education) were weak and statistically insignificant. When the effects of other independent variables were controlled, AD and MD patients were found to decline at significantly faster rates than VD patients. Full-information methods, relative to single-equation methods, substantially reduce the variance of rates of change for multiple psychometric tests. They do so by simultaneously considering the correlated error terms in the regression for each dependent psychometric change score variable. The robustness of these results to minor variations in follow-up time suggests that annualization is a reasonably valid procedure for making change scores comparable. This study's results suggest that change scores in psychometric tests provide information that can be used to aid differential diagnosis. However, the large variances of change scores preclude many other uses. Finally, since standardization of psychometric change scores translates all tests to the same scale (0-100%), standardized change scores are easier to interpret. The analysis of standardized change scores deserves further investigation.

  View details for Web of Science ID A1996VV13200006

  View details for PubMedID 8939281

• OCCUPATIONS WITH EXPOSURE TO ELECTROMAGNETIC-FIELDS - A POSSIBLE RISK FACTOR FOR ALZHEIMERS-DISEASE AMERICAN JOURNAL OF EPIDEMIOLOGY Sobel, E., Davanipour, Z., Sulkava, R., Erkinjuntti, T., Wikstrom, J., Henderson, V. W., Buckwalter, G., Bowman, J. D., Lee, P. J. 1995; 142 (5): 515-524

  Abstract

  The authors present analyses of data from three independent clinical series and controls indicating an association between working in occupations with probable medium to high exposure to extremely low frequency (< 300 Hz) electromagnetic fields and sporadic Alzheimer's disease. Case-control analyses were carried out using data from patients examined at the following locations: the Department of Neurology, University of Helsinki, Helsinki, Finland, 1982-1985; the Koskela Hospital in Helsinki, 1977-1978; and the University of Southern California site of the Alzheimer's Disease Research Center of Los Angeles and Orange Counties, 1984-1993. The predominant occupations among medium (2-10 mG or > 10 mG intermittently) to high (> 10 mG or > 100 mG intermittently) exposed cases were seamstress, dressmaker, and tailor. The results appear to be independent of education, and the sex-combined odds ratios for the three series are quite homogeneous: 2.9, 3.1, and 3.0. The odds ratio for the three series analyzed together is 3.0 (p < 0.001), with a 95% confidence interval of 1.6-5.4. The odds ratio for women is 3.8 (p < 0.001), with a 95% confidence interval of 1.7-8.6. The most obvious, possibly etiologically relevant exposure is that of electromagnetic fields, which may have biologic plausibility because they may adversely influence calcium homeostasis and/or inappropriately activate immune system cells such as microglial cells, initiating events that result in neuronal degeneration.

  View details for Web of Science ID A1995RR79000011

  View details for PubMedID 7677130

• THE BEHAVIOR RATING-SCALE FOR DEMENTIA OF THE CONSORTIUM TO ESTABLISH A REGISTRY FOR ALZHEIMERS-DISEASE AMERICAN JOURNAL OF PSYCHIATRY Tariot, P. N., MACK, J. L., PATTERSON, M. B., Edland, S. D., Weiner, M. F., Fillenbaum, G., BLAZINA, L., Teri, L., Rubin, E., Mortimer, J. A., Stern, Y., Doody, R., Nelson, N., Blass, J., Nolan, K., Heyman, A., VANBELLE, G., BEEKLEY, D., Devanand, D. P., Karp, H., Clark, C., Rabins, P., Mohs, R., Mellow, A., Sunderland, T., Reisberg, B., Kluger, A., Ganguli, M., ROSEN, J., Evans, D., Henderson, V., Schneider, L., Morris, J., Larson, E., Raskind, M. 1995; 152 (9): 1349-1357

  View details for Web of Science ID A1995RT23100020

• P300 TOPOGRAPHY IN ALZHEIMERS-DISEASE PSYCHOPHYSIOLOGY Holt, L. E., Raine, A., PA, G., SCHNEIDER, L. S., Henderson, V. W., POLLOCK, V. E. 1995; 32 (3): 257-265

  Abstract

  This study assessed whether P300 scalp topography distinguished subjects with Alzheimer's disease (AD) from controls. Specifically, it was predicted that the AD group would show maximum P300 amplitude over frontal areas and the largest P300 reduction over parietal and left hemisphere areas. These hypotheses were tested using a standard auditory oddball paradigm to compare 26 AD subjects and 26 controls matched on age, sex, handedness, and education. P300 was measured at frontal, central, parietal, and occipital sites over left and right hemispheres and along the midline. Results revealed that the distribution of P300 was different for the two groups such that the controls manifested a maximum over parietal areas, whereas the AD subjects showed a maximum at frontal sites with the largest reductions in P300 over parietal areas. No hemispheric differences in P300 were found. These results are consistent with the hypothesis that P300 represents the activity of multiple neural generators that are differentially disrupted by the disease process.

  View details for Web of Science ID A1995QV89100007

  View details for PubMedID 7784534

• THE FREQUENTLY LOW COBALAMIN LEVELS IN DEMENTIA USUALLY SIGNIFY TREATABLE METABOLIC, NEUROLOGIC AND ELECTROPHYSIOLOGIC ABNORMALITIES EUROPEAN JOURNAL OF HAEMATOLOGY CARMEL, R., Gott, P. S., Waters, C. H., CAIRO, K., Green, R., Bondareff, W., DeGiorgio, C. M., Cummings, J. L., Jacobsen, D. W., Buckwalter, G., Henderson, V. W. 1995; 54 (4): 245-253

  Abstract

  Cobalamin levels are frequently low in patients with dementia, but it is unclear if they represent definable deficiency and what the mechanisms are. Therefore, patients being evaluated for dementia who had low cobalamin levels but no obvious evidence of deficiency were studied hematologically, neurologically and with metabolic tests and were re-evaluated after cobalamin treatment. Abnormalities suggestive of or diagnostic for deficiency were documented in most of the 16 demented and nondemented patients. Metabolic results: 50% of patients tested had abnormal deoxyuridine suppression and 44% had increased serum methylmalonic acid and/or homocysteine levels; these test results correlated with each other. Neurologic results: 73% of patients had clinical abnormalities, primarily mild neuropathies, not attributable to other causes, 75% had electroencephalographic abnormalities, 77% had abnormal visual evoked potentials and 33% had abnormal somatosensory potentials. Metabolic and neurologic dysfunction were present together or absent together in all but 2 cases. Cobalamin therapy improved 50-100% of the various types of abnormalities, although it did not improve cognitive function in the 13 demented patients. Food-cobalamin malabsorption was found in 60% of the patients. Despite the absence of megaloblastic anemia and rarity of traditional malabsorption of free cobalamin, low cobalamin levels in demented patients frequently represent mild cobalamin deficiency and are often associated with food-cobalamin malabsorption. Perhaps most importantly, this is accompanied not only by metabolic changes but by evidence of mild neurologic dysfunction. Their frequent reversibility by cobalamin confirms that these defects indeed arise from cobalamin deficiency. Although the long-standing dementia does not improve, treating such patients with cobalamin has other concrete benefits.

  View details for Web of Science ID A1995RD18800006

  View details for PubMedID 7789470

• Henderson VW. The Mental Status Examination in Neurology, 3rd. ed. By RL Strub and FW Black Alzheimer Disease and Associated Disorders Henderson VW 1995; 9: 247-248
• RELATIONSHIP BETWEEN LEVEL OF INSIGHT AND SEVERITY OF DEMENTIA IN ALZHEIMER-DISEASE ALZHEIMER DISEASE & ASSOCIATED DISORDERS MCDANIEL, K. D., Edland, S. D., Heyman, A., Harrell, L., Henderson, V., Wiederholt, W. C., Karp, H., Evans, D. A., Bennett, D. A., Clark, D. B., Brandt, J., Growdon, J., Foster, N. L., MORTIMER, J., Morris, J., Blass, J., Mayeux, R., Mohs, R., Ferris, S., Tariot, P., Earl, N. L., Friedland, R., Clark, C., Dekosky, S. T., Doody, R., Weiner, M., Larson, E., Raskind, M., Berg, L., VANBELLE, G., Fillenbaum, G. 1995; 9 (2): 101-104

  View details for Web of Science ID A1995RB47300007

• LINGUISTIC AND ATTENTIONAL CONTRIBUTIONS TO ANOMIA IN ALZHEIMERS-DISEASE NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY Kempler, D., Andersen, E. S., Henderson, V. W. 1995; 8 (1): 33-37

  View details for Web of Science ID A1995PY81900006

• Occupational exposure to electromagnetic fields: A possible risk factor for Alzheimer's disease 4th International Conference on Alzheimers Disease and Related Disorders Sobel, E., Davanipour, Z., Sulkava, R., Erkinjuntti, T., Wikstrom, J., Henderson, V. W., Buckwalter, G., Bowman, J. D. JOHN WILEY & SONS LTD. 1995: 43–52

  View details for Web of Science ID A1995BD06G00005

• ESTROGEN REPLACEMENT THERAPY IN OLDER WOMEN - COMPARISONS BETWEEN ALZHEIMERS-DISEASE CASES AND NONDEMENTED CONTROL SUBJECTS ARCHIVES OF NEUROLOGY Henderson, V. W., PAGANINIHILL, A., EMANUEL, C. K., Dunn, M. E., Buckwalter, J. G. 1994; 51 (9): 896-900

  Abstract

  We hypothesized that oral estrogen replacement therapy would be less common among elderly women meeting criteria for Alzheimer's disease (AD) than among nondemented elderly women. For women with AD, we hypothesized that estrogen users would perform better on a cognitive task than would nonusers.A case-control study of estrogen replacement therapy, in which hierarchical procedures were used to control for potentially confounding effects of age and education. When cognitive performances were compared between estrogen users and nonusers with AD, the duration of dementia symptoms was an additional control variable.Alzheimer's Disease Research Center at the University of Southern California, Los Angeles.Subjects were a volunteer sample of consecutively enrolled elderly women, recruited primarily from the community, who met clinical criteria for probable AD (n = 143) or met criteria for nondemented control status (n = 92). Seventy case patients who have subsequently died met histopathologic criteria for AD; one other demented woman who did not meet the autopsy criteria for AD was excluded from all analyses.Current use of estrogen replacement at the time of enrollment as reported by control subjects or by the primary caregivers of AD case patients. Among cases, performances on a brief cognitive screening instrument were compared between estrogen users (n = 10) and nonusers (n = 128) for whom this information was available.Alzheimer's disease case patients were significantly less likely than control subjects to use estrogen replacement (7% vs 18%), but groups did not differ with regard to the total number of prescription medications or to the most frequently prescribed class of drug (thyroid medication). Demented case patients using estrogen did not differ significantly from those not using estrogen in terms of age, education, or symptom duration, but their mean performance on a cognitive screening instrument was significantly better (Mini-Mental State examination scores of 14.9 vs 6.5).Findings are consistent with contentions that postmenopausal estrogen replacement therapy may be associated with a decreased risk of AD and that estrogen replacement may improve cognitive performance of women with this illness.

  View details for Web of Science ID A1994PG22500010

  View details for PubMedID 8080389

• ESTROGEN DEFICIENCY AND RISK OF ALZHEIMERS-DISEASE IN WOMEN AMERICAN JOURNAL OF EPIDEMIOLOGY PAGANINIHILL, A., Henderson, V. W. 1994; 140 (3): 256-261

  Abstract

  The authors explored the possibility that estrogen loss associated with menopause may contribute to the development of Alzheimer's disease by using a case-control study nested within a prospective cohort study. The Leisure World Cohort includes 8,877 female residents of Leisure World Laguna Hills, a retirement community in southern California, who were first mailed a health survey in 1981. From the 2,529 female cohort members who died between 1981 and 1992, the authors identified 138 with Alzheimer's disease or other dementia diagnoses likely to represent Alzheimer's disease (senile dementia, dementia, or senility) mentioned on the death certificate. Four controls were individually matched by birth date (+/- 1 year) and death date (+1 year) to each case. The risk of Alzheimer's disease and related dementia was less in estrogen users relative to nonusers (odds ratio = 0.69, 95 percent confidence interval 0.46-1.03). The risk decreased significantly with increasing estrogen dose and with increasing duration of estrogen use. Risk was also associated with variables related to endogenous estrogen levels; it increased with increasing age at menarche and (although not statistically significant) decreased with increasing weight. This study suggests that the increased incidence of Alzheimer's disease in older women may be due to estrogen deficiency and that estrogen replacement therapy may be useful for preventing or delaying the onset of this dementia.

  View details for Web of Science ID A1994NZ03900006

  View details for PubMedID 8030628

• COGNITIVE DEFICITS OF MEN AND WOMEN WITH ALZHEIMERS-DISEASE NEUROLOGY Henderson, V. W., Buckwalter, J. G. 1994; 44 (1): 90-96

  Abstract

  We performed two studies of cognitive abilities among men and women who met clinical criteria for Alzheimer's disease (AD). Among 46 AD patients, performance of women on a composite neuropsychological battery was more impaired than that of men when the potentially confounding effects of demographic variables were controlled; the largest group differences were due to significantly worse performance by women with AD on a naming task. Based on these initial findings, we next analyzed an independent data set of 647 demented subjects enrolled in the multicenter Consortium to Establish a Registry for Alzheimer's Disease, hypothesizing that the naming performance of women with AD would be significantly worse than that of men with this illness. Analyses controlling for demographic variables, or separately controlling for dementia severity, confirmed that women with AD performed significantly less well on the naming task and on verbal fluency. Women also performed less well on delayed recall, but there were no significant differences on other tasks. Factor analysis confirmed significant differences on a language factor, implying that men retain verbal skills better than women do during the initial stages of AD. Elderly nondemented women performed as well as or better than nondemented men on all comparisons. We conclude that there are modest differences in how men and women with AD perform on cognitive tasks and that differences may be discrete rather than global in nature.

  View details for Web of Science ID A1994MR37100020

  View details for PubMedID 8290098

• GENDER DIFFERENCES ON A BRIEF MEASURE OF COGNITIVE-FUNCTIONING IN ALZHEIMERS-DISEASE ARCHIVES OF NEUROLOGY Buckwalter, J. G., Sobel, E., Dunn, M. E., DIZ, M. M., Henderson, V. W. 1993; 50 (7): 757-760

  Abstract

  We evaluated scores on a brief psychometric screening instrument--the Mini-Mental State Examination (MMSE)--for possible effects of gender, hypothesizing that women with Alzheimer's disease (AD) would perform more poorly than men. A significant gender difference was to be explored with post hoc item analyses.Case-study design. A hierarchical regression procedure controlled for the possible influence on MMSE performance of demographic variables (eg, age, duration of dementia symptoms, education, and family history of dementia) before the effect of gender was analyzed.Data were gathered by trained neuropsychological examiners from subjects enrolled in the Alzheimer's Disease Research Center at the University of Southern California, Los Angeles.One hundred forty-two subjects who met strict criteria for probable AD and 121 nondemented elderly subjects were included in the study. All subjects underwent periodic neuropsychological testing. We extracted MMSE scores and demographic data to test the hypothesis that women would perform more poorly than men on the MMSE. CRITERION MEASURE: The MMSE was chosen because of its wide use in clinical and research settings to screen for the presence or severity of dementia.After controlling for the demographic variables for subjects with AD, we observed a significant difference in the predicted direction for total MMSE score, but there was no significant gender effect on the MMSE for the nondemented elderly sample. Among subjects with AD, gender-associated differences were limited to only a subset of MMSE items.Results imply that MMSE performance may differ between men and women with AD and that differences might pertain only to discrete areas of cognitive functioning. Although gender effects were relatively small, findings indicate the relevance of gender to studies of AD.

  View details for Web of Science ID A1993LL11600015

  View details for PubMedID 8323481

• Sigmund Freud and the diagram-maker school of aphasiology. Brain and language Henderson, V. W. 1992; 43 (1): 19-41

  Abstract

  Published 100 years ago, Freud's monograph on aphasia, Zur Auffassung der Aphasien, is an incisive analysis of the so-called diagram-makers, those aphasiologists who would reduce brain and language to simple schemes of circumscribed cortical centers linked by unidirectional subcortical pathways. Chief architects of the diagram-maker school were Wernicke and Lichtheim, and their formulations of conduction aphasia and the transcortical aphasias were particular targets of Freud's trenchant criticism. Freud argued against functional differentiation within left hemisphere perisylvian language regions, and he suggested that traditional aphasic syndromes were artifacts of lesions that included cortical language regions and deeper white matter pathways not directly involved with language. He provided an innovative classification of aphasia based on types of associations presumed to be affected. Freud, however, failed to adduce new clinical or pathological observations; he was perhaps unnecessarily harsh in challenging authorities in the field of aphasia; and his theory had to compete with a straightforward and already entrenched anatomical view of language representation. Despite Freud's lucid argumentation, his carefully crafted monograph was never widely noted.

  View details for PubMedID 1643510

• BOSTON NAMING TEST - SHORTENED VERSIONS FOR USE IN ALZHEIMERS-DISEASE JOURNALS OF GERONTOLOGY Mack, W. J., Freed, D. M., Williams, B. W., Henderson, V. W. 1992; 47 (3): P154-P158

  Abstract

  Four new 15-item versions of the Boston Naming Test (BNT), a 15-item version used by the Consortium To Establish a Registry for Alzheimer's Disease (CERAD), and three 30-item BNT versions were studied in 26 subjects with Alzheimer's disease (AD) and 26 nondemented, neurologically normal controls. The four 15-item versions were statistically equivalent. On each version, controls performed significantly better than AD subjects, and scores on each could be extrapolated to a complete 60-item BNT score. The CERAD version also differentiated between AD and control subjects, but it was not equivalent to our four versions and could not be as easily extrapolated to a 60-item score. Even and Odd 30-item BNT versions were confirmed to be equivalent, and we further validated a 30-item Empirical Version designed to maximally discriminate between AD and normal subjects. Equivalent 15- or 30-item versions of the BNT will be useful in repeated assessments requiring independent forms of a naming task, as well as in situations where administration of the complete BNT is not practical.

  View details for Web of Science ID A1992HT69100013

  View details for PubMedID 1573197

• The agraphia of Alzheimer's disease. Neurology Henderson, V. W., Buckwalter, J. G., Sobel, E., Freed, D. M., DIZ, M. M. 1992; 42 (4): 777-784

  Abstract

  Hypothesizing that agraphia in Alzheimer's disease (AD) reflects disturbances in multiple cognitive domains, we evaluated writing samples from 33 patients meeting strict criteria for probable AD. We found agraphia to be common on a standard narrative writing task. When compared with 41 education- and age-matched normal control subjects, AD patients had significantly lower writing scores, wrote significantly fewer words, mentioned significantly fewer categories of information, and were significantly more likely to make writing errors. On stepwise regression procedures, neuropsychological measures of visuoperceptual impairment and disease severity were the strongest predictors of agraphia, but other analyses indicated that measures of language, praxis, and attention could also contribute significantly to agraphia. On two writing tasks, we failed to confirm the previous contention that agraphia is a marker for familial AD. However, there was a highly significant interaction between family history, oral naming, and writing: patients with nonfamilial AD, but not those with a family history of dementia, showed a strong correlation between naming and writing performance. We conclude that agraphia in AD can be variously determined and that agraphia is not a reliable marker for familial disease.

  View details for PubMedID 1565231

• NEUROMAGNETIC LOCALIZATION USING MAGNETIC-RESONANCE IMAGES IEEE TRANSACTIONS ON MEDICAL IMAGING Singh, M., BRECHNER, R. R., Henderson, V. W. 1992; 11 (1): 129-134

  Abstract

  Ionic flow associated with neural activation of the brain produces a magnetic field, called the neuromagnetic field, that can be measured outside the head using a highly sensitive superconducting quantum interference device (SQUID)-based neuromagnetometer. Under certain conditions, the sources producing the neuromagnetic field can be localized from a sampling of the neuromagnetic field. Neuromagnetic measurements alone, however, do not contain sufficient information to visualize brain structure. Thus, it is necessary to combine neuromagnetic localization with an anatomical imaging technique such as magnetic resonance imaging (MRI) to visualize both function and anatomy in vivo. Using experimentally measured human neuromagnetic fields and magnetic resonance images, the authors have developed a technique to register accurately these two modalities and have applied the registration procedure to portray the spatiotemporal distribution of neural activity evoked by auditory stimulation.

  View details for Web of Science ID A1992HL33500017

  View details for PubMedID 18218366

• Spanish translation and validation of a neuropsychological battery: performance of Spanish? and English?speaking Alzheimer's disease patients and normal comparison subjects Clinical Gerontologist Taussig IM, Henderson VW, Mack W 1992; 11: 95-108
• Early concepts of conduction aphasia. Conduction Aphasia Henderson VW 1992: 23-38
• SEVERITY OF DEMENTIA IN ALZHEIMER-DISEASE AND NEUROFIBRILLARY TANGLES IN MULTIPLE BRAIN-REGIONS ALZHEIMER DISEASE & ASSOCIATED DISORDERS SAMUEL, W. A., Henderson, V. W., Miller, C. A. 1991; 5 (1): 1-11

  Abstract

  We studied the relationship of numbers of neurofibrillary tangles (NFTs) in selected cortical and subcortical sites to the duration of clinical disease and severity of dementia. Sixteen patients with a clinical diagnosis of "probable" Alzheimer disease were screened with standardized neuropsychological instruments to estimate the severity of dementia. Tissues were obtained at autopsy from the subiculum, four neocortical areas, and the nucleus basalis of Meynert: NFT counts were assessed with the thioflavin S stain. Overall, the subiculum showed the most NFTs, followed by visual association and premotor cortices, primary cortex (motor and visual), and the nucleus basalis. NFT counts were significantly positively correlated with the duration of disease in the nucleus basalis and less strongly in the motor cortex. Neuropsychological impairment was significantly correlated with NFT counts only in the nucleus basalis. In turn, counts in the nucleus basalis were reliably correlated with those in all other brain regions except the subiculum. Counts in the subiculum showed no correlation with any other area. Numbers of NFTs within functionally related sites, the primary motor and premotor cortices or primary and visual association cortices, were significantly or near-significantly correlated, whereas motor and visual cortical counts showed no intercorrelation. Our results indicate that although there is less NFT accumulation in the nucleus basalis than in many other brain regions, counts in this structure bear a close relationship to disease severity and duration and to NFT accumulation in other regions.

  View details for Web of Science ID A1991GU42700001

  View details for PubMedID 2025419

• Stimulant drug treatment of the attention deficit disorder. Southern California Law Review Henderson VW 1991; 65 (1): 397-409
• NEUROMAGNETIC LOCALIZATION OF HIGHER-ORDER BRAIN PROCESSING 1991 IEEE NUCLEAR SCIENCE SYMP AND MEDICAL IMAGING CONF Singh, M., BRECHNER, R. R., Henderson, V. W. I E E E. 1991: 1558–1560

  View details for Web of Science ID A1991BW12R00154

• Diagnosis of Alzheimer Disease and Other Dementias Henderson VW, Sobel E, Davanipour Z 1991
• Studies in Disorders of Communication. By Y Lebrun Archives of Neurology Henderson VW 1991; 48: 129
• NAMING CONSISTENCY IN ALZHEIMERS-DISEASE BRAIN AND LANGUAGE Henderson, V. W., Mack, W., Freed, D. M., Kempler, D., Andersen, E. S. 1990; 39 (4): 530-538

  Abstract

  Although lexical semantic deficits are postulated to play a prominent role in the anomia of Alzheimer's disease, it is unclear whether the primary disturbance is one of lexical access or one of lexical semantic loss. Response consistency on a naming task is one means of evaluating the underlying source of naming impairment. Access dysfunction usually implies variable word-finding difficulty, while a theory of lexical loss predicts that many word names would be consistently unavailable. Nineteen Alzheimer's disease patients were administered a visual confrontation naming task (the Boston Naming Test) on two occasions 6 months apart. Eighty percent of errors occurred consistently at both times; only 20% of errors occurred on only one occasion. Response consistency occurred significantly more often than expected under the assumption of no response consistency. Findings support the hypothesis that anomia in Alzheimer's disease is in part due to a loss of lexical semantic information.

  View details for Web of Science ID A1990ER19400004

  View details for PubMedID 2076494

• LIPOMAS OF THE MESENCEPHALIC TECTUM AND ROSTRAL PONS ASSOCIATED WITH SLEEP-APNEA SYNDROME CLINICAL NEUROPATHOLOGY Sheridan, F., Scharf, D., Henderson, V. W., Miller, C. A. 1990; 9 (3): 152-156

  Abstract

  Two patients with mixed sleep apnea and autopsy-documented lipomas of the mesencephalic tectum and rostral pons are presented. Microscopically, the locus ceruleus was unilaterally invaded by a tumor in one case and may have been compressed in the other. Adipocytes and fibrous tissue were present adjacent to pial surfaces and around small blood vessels within the parenchyma. There was prominent astrogliosis in the adjacent neuropil. Although respiratory control is a complex, multifocal phenomena, these findings raise the possibility that the locus ceruleus or adjacent brain stem regions may be affected in some instances of sleep apnea.

  View details for Web of Science ID A1990DL00200009

  View details for PubMedID 2364596

• ALALIA, APHEMIA, AND APHASIA ARCHIVES OF NEUROLOGY Henderson, V. W. 1990; 47 (1): 85-88

  Abstract

  In the 1860s, vigorous debate followed Paul Broca's seminal aphasiological observations. Scientific, philosophical, and personal disagreements affected ensuing nosological disputes. Competing terms to designate disorders of speech and language were alalia (used by Jacques Lordat), aphemia (coined by Broca), and the ultimately triumphant aphasia (introduced by Armand Trousseau). How these designations came into being, how they were used, and how they were received by the scientific community reflected controversies surrounding the birth of modern aphasiology.

  View details for Web of Science ID A1990CG72800026

  View details for PubMedID 2403787

• SQUID NEUROMAGNETOMETRIC RECONSTRUCTION OF BRAIN ACTIVITY CONF ON DIGITAL IMAGE SYNTHESIS AND INVERSE OPTICS Singh, M., BRECHNER, R. R., Oshio, K., Leahy, R., Henderson, V. W. SPIE - INT SOC OPTICAL ENGINEERING. 1990: 417–426

  View details for Web of Science ID A1990BS46E00039

• NEUROMAGNETIC LOCALIZATION USING MAGNETIC-RESONANCE IMAGES 1990 NUCLEAR SCIENCE SYMP OF THE IEEE Singh, M., BRECHNER, R. R., Oshio, K., Henderson, V. W., Shibata, T. I E E E. 1990: 1402–1409

  View details for Web of Science ID A1990BT11E00225

• ALZHEIMERS DEMENTIA - PERFORMANCE ON PARALLEL FORMS OF THE DEMENTIA ASSESSMENT BATTERY JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Teng, E. L., Wimer, C., Roberts, E., DAMASIO, A. R., ESLINGER, P. J., Folstein, M. F., Tune, L. E., Whitehouse, P. J., BARDOLPH, E. L., Chui, H. C., Henderson, V. W. 1989; 11 (6): 899-912

  Abstract

  Fifty-four patients with Alzheimer's disease performed on the Dementia Assessment Battery that comprised of finger tapping, forward digit span, naming, verbal memory, visual memory, Token Test, digit cancellation, word-list generation, symbol-digit substitution, and copying geometric designs. Four forms of the battery were administered at weekly intervals. The equivalence of the forms, the relative difficulty of the tests, retest reliability, and factorial composition of the battery are presented. Performance improved with repetition. Impairments in visuo-spatial and verbal abilities were independent of each other. The fragility of the patients' working memory was identified as a main cause for their poor recall. The importance of "component analysis" in individual assessment is illustrated.

  View details for Web of Science ID A1989CC21500009

  View details for PubMedID 2687312

• VISUAL EVOKED-POTENTIALS IN DEMENTIA - A META-ANALYSIS AND EMPIRICAL-STUDY OF ALZHEIMERS-DISEASE PATIENTS BIOLOGICAL PSYCHIATRY POLLOCK, V. E., SCHNEIDER, L. S., Chui, H. C., Henderson, V., ZEMANSKY, M., SLOANE, R. B. 1989; 25 (8): 1003-1013

  Abstract

  A meta-analytic review of flash and pattern reversal visual evoked potential research indicates that elderly demented patients have longer P100 latencies than age-matched control subjects. In the present empirical research, patients with research diagnoses of probable Alzheimer's disease were compared with sex- and age-matched control subjects using P100 latencies of visual evoked potentials (VEP) elicited by flash and pattern reversal. As compared to control subjects, Alzheimer's disease patients showed significantly longer P100 latencies of the VEP elicited by pattern reversal; the flash P100 only marginally distinguished them. These findings are discussed within the context of VEP recording practices, patient selection, sex and age matching of control subjects, and the visual system.

  View details for Web of Science ID A1989U554100002

  View details for PubMedID 2720014

• MULTICENTER TRIAL OF NALOXONE IN ALZHEIMERS-DISEASE ANNALS OF NEUROLOGY Henderson, V. W., Roberts, E., Wimer, C., BARDOLPH, E. L., Chui, H. C., DAMASIO, A. R., ESLINGER, P. J., Folstein, M. F., SCHNEIDER, L. S., Teng, E. L., Tune, L. E., Weiner, L. P., Whitehouse, P. J. 1989; 25 (4): 404-406

  Abstract

  In a double-blind, placebo-controlled, crossover study of intravenously administered naloxone hydrochloride, 54 subjects with clinically ascertained Alzheimer's disease tested at three university centers showed no significant improvement in neuropsychological performance after 1-mg or 10-mg doses; 15 patients at 1 center were similarly unimproved after receiving 30 mg naloxone (single blind). Findings fail to support claims that naloxone monotherapy ameliorates cognitive impairments of Alzheimer's disease.

  View details for Web of Science ID A1989U068400012

  View details for PubMedID 2653175

• SPATIAL DISORIENTATION IN ALZHEIMERS-DISEASE ARCHIVES OF NEUROLOGY Henderson, V. W., Mack, W., Williams, B. W. 1989; 46 (4): 391-394

  Abstract

  Spatial disorientation was investigated in 28 ambulatory patients meeting the National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria for "probable" Alzheimer's disease. Based on caregivers' reports, 39% of subjects engaged in at least three of four behavioral measures of spatial disorientation three or more times a week; these patients did not significantly differ from other Alzheimer's disease subjects with regard to age, sex, education, or symptom duration. Using stepwise regression analysis, we found that neuropsychologic measures of memory and visuoconstructive functions, but not disease severity, attention, or language impairment, emerged as significant predictors of spatial disorientation. In the setting of impaired memory, the tendency of some patients with Alzheimer's disease to wander or to get lost may implicate particularly severe dysfunction of right hemisphere neocortical areas concerned with visuospatial processes.

  View details for Web of Science ID A1989T987100015

  View details for PubMedID 2705898

• THE NEUROBIOLOGY OF ALZHEIMERS-DISEASE JOURNAL OF NEUROSURGERY Henderson, V. W., Finch, C. E. 1989; 70 (3): 335-353

  Abstract

  The defining histological characteristics of Alzheimer's disease (AD) are neurofibrillary tangles and neuritic plaques, although neither is pathognomonic for this disorder. The distribution of AD histopathology suggests selective neuronal vulnerability, with specific cell populations affected within discrete regions of the cerebral hemispheres and within certain subcortical and brain-stem nuclear areas. At the ultrastructural level, tangles and plaque neurites contain paired helical filaments whose composition is unknown but may include altered cytoskeletal elements. Amyloid, deposited in plaque cores and often focally present within the cerebral vasculature, contains a polypeptide ("beta-protein," or "beta-amyloid") encoded by a chromosome 21 gene. At least in occasional families, AD has been linked to a separate chromosome 21 locus, but different underlying genetic factors may operate in other cases. Inorganic substances, including aluminum and silicon, are reported to co-localize within tangle-bearing neurons and plaque cores. Specific environmental agents have not been confirmed to be pathogenetically important, however, but may eventually prove to exert a permissive, facilitatory, or even causative role in many AD patients.

  View details for Web of Science ID A1989T391200001

  View details for PubMedID 2464674

• Jacques Lordat's contributions to aphasiology. Neuroscience Across the Centuries Henderson VW 1989: 177-184
• Alzheimer's dementia: performance on parallel forms of the Dementia Assessment Battery J Clin Exp Neuropsychol Teng EL, Wimer C, Roberts E, Damasio AR, Eslinger PJ, Folstein MF, Tune LE, Whitehouse PJ, Bardolph EL, Chui 1989; 11: 899-912
• Profound mixed transcortical aphasia: implications for language representation within the brain. Bull Clin Neurosci Henderson VW 1989; 54: 158-162
• BOSTON NAMING TEST IN ALZHEIMERS-DISEASE NEUROPSYCHOLOGIA Williams, B. W., Mack, W., Henderson, V. W. 1989; 27 (8): 1073-1079

  Abstract

  The 60-item Boston Naming Test (BNT) was administered to 55 subjects: 15 mildly-to-moderately demented patients meeting NINCDS-ADRDA criteria for "probable" Alzheimer's disease (AD), 15 age-equivalent normal control (NC) subjects, and--for purposes of validation--25 additional subjects with other forms of dementia (OD). A cutting score of 51 correctly classified 80% of AD patients and 86% of NC subjects. To facilitate rapid screening of confrontation-naming performance in these populations, three 30-item shortened versions of the BNT were constructed. Even and Odd Versions were equivalent for AD, NC, and OD subjects; high correlations between these two and the 60-item BNT permit easy extrapolation to a total BNT score. A new Empirical Version, derived from performance of our AD and NC reference groups, maintained most of the intergroup discrimination of the full BNT.

  View details for Web of Science ID A1989AQ30200004

  View details for PubMedID 2797414

• MONOCLONAL-ANTIBODIES REACT WITH NEURONAL SUBPOPULATIONS IN THE HUMAN NERVOUS-SYSTEM JOURNAL OF COMPARATIVE NEUROLOGY Hinton, D. R., Henderson, V. W., Blanks, J. C., Rudnicka, M., Miller, C. A. 1988; 267 (3): 398-408

  Abstract

  Monoclonal antibody probes were used to identify antigenic cross reactivities among neuronal subpopulations and to dissect the human nervous system at several levels of organization. Six monoclonal antibodies, prepared with immunogens from Drosophila melanogaster or human nervous tissue, were used to localize antigens immunocytochemically in normal adult human neocortex, hippocampus, cerebellum, spinal cord, and retina. Four of the six antibodies were neural specific in their reactivity and each stained a unique combination of neurons. The antibodies reacted with at least three subpopulations of cerebral cortical neurons, including discrete populations of pyramidal and nonpyramidal cells. Components of a widely distributed functional system within the spinal cord and cerebellum were labelled by one antibody, which reacted with neurons in the nucleus dorsalis of Clarke, deep cerebellar nuclei, and Purkinje cells. At the single-cell level, three of the monoclonals differentially labelled the photoreceptor cell outer segment, inner segment, and perikaryon. Three of the six antibodies were reactive with specific protein bands on immunoblots of tissue homogenates. This monoclonal antibody panel provides a novel and potentially useful method of analysis of the organization of the normal and diseased human nervous system.

  View details for Web of Science ID A1988L650300008

  View details for PubMedID 3343408

• Topics in Behavioral Neurology and Neuropsychology. By DB Hier, PB Gorelick, and AG Schindler Epilepsia Henderson VW 1988; 29: 714-715
• Alzheimer disease: high intensity periventricular white matter alterations on magnetic resonance imaging. Bull Clin Neurosci Henderson VW, Kortman KE, Chui HC, Mack W, Bardolph EL, Bradley WG Jr 1988; 53: 137-147
• Outcome prediction after severe closed head injury in adults. Bulletin of clinical neurosciences Henderson, V. W. 1987; 52: 47-63

  Abstract

  Disability after severe closed head injury (CHI) differs from that of penetrating trauma or other causes of more focal cerebral damage, but its symptoms can be understood in terms of the pathophysiology and the usual pathology of CHI. Outcome can be quantified by means of specific, narrowly-defined measures, which may fail to reflect other serious sequelae, or by means of functional rating scales, which bear little logical relation to CHI pathophysiology and lump together patients with diverse deficits. The choice of appropriate intake measures of CHI severity in turn depends on which aspects of outcome are to be determined. As the cardinal symptom of CHI is altered consciousness, logical intake measures of CHI severity include measures of the depth and the duration of the abnormal state of consciousness. Confounding factors in outcome prediction include secondary complications of CHI, premorbid characteristics, and effects of acute and rehabilitative therapy. Most research has focused on functional outcome predictions based on simple intake measures obtained shortly after injury, but intake measures that permit accurate prediction of rehabilitation potential or of specific cognitive and behavioral outcomes are also needed.

  View details for PubMedID 3509361

• Language disorders: clinical classification and neurovascular substrate. Bulletin of clinical neurosciences Henderson, V. W. 1987; 52: 70-88

  Abstract

  The most prevalent cause of focal brain disease is stroke, Neuroanatomic localization in aphasia--and by inference, the identification of brain regions associated with language functions--is largely determined by, and confounded with, left cerebral hemisphere vascular territories. Traditional nosology of the aphasias, alexias, and agraphias is not always logically coherent and ignores major neurolinguistic boundries, yet it retains the clinical utility of permitting reliable and valid anatomic inferences concerning the underlying neuropathologic substrate.

  View details for PubMedID 3334549

• ANATOMY OF POSTERIOR PATHWAYS IN READING - A REASSESSMENT BRAIN AND LANGUAGE Henderson, V. W. 1986; 29 (1): 119-133

  Abstract

  Contemporary accounts of the neurology of reading stem from Dejerine's original visual-verbal disconnection hypothesis of pure alexia. Reassessment of Dejerine's traditional formulations for posterior left hemisphere pathways in reading suggests that the occipital cortex-left angular gyrus-Wernicke's area scheme is undoubtedly oversimplified. The role of left angular gyrus cortex in reading is unsettled, and although clinically undefined, more inferior portions of the left temporal lobe may also contribute to the reading process. Nevertheless, to a surprising extent, the neuroanatomic edifice erected by Dejerine remains largely intact.

  View details for Web of Science ID A1986D825200008

  View details for PubMedID 3092988

• BROCA,PAUL LESS HERALDED CONTRIBUTIONS TO APHASIA RESEARCH - HISTORICAL-PERSPECTIVE AND CONTEMPORARY RELEVANCE ARCHIVES OF NEUROLOGY Henderson, V. W. 1986; 43 (6): 609-612

  Abstract

  In addition to discovering the dominant role of the left hemisphere for language and describing what is now known as Broca's aphasia, Paul Broca made other insightful, but less well-recalled, aphasiologic observations. He distinguished symptoms of Wernicke's aphasia five years before Carl Wernicke's famous monograph, and he was the first to exploit the surgical relevance of language localization. Broca investigated the anatomic substrate of language laterality by comparing the relative weights of the two hemispheres and the two frontal lobes. He considered language lateralization from a developmental point of view and in relation to handedness. A relatively small portion of Broca's prodigious scientific career was devoted to the study of aphasia, but his seminal work encompasses a number of issues of contemporary concern.

  View details for Web of Science ID A1986C526900017

  View details for PubMedID 3521554

• Principles of Neurologic Diagnosis Montgomery EB Jr, Wall M, Henderson VW 1986
• Non-genetic factors in Alzheimer's disease pathogenesis. Neurobiol Aging Henderson VW 1986; 7 (6): 585-587
• Ambiguities in Alzheimer's disease diagnosis: implications for genetic research. Neurobiol Aging Henderson VW 1986; 7 (6): 469-471
• Graduate training in neurology: implications of the current manpower debate. Bulletin of clinical neurosciences Henderson, V. W. 1986; 51: 33-41

  Abstract

  Despite a rapid increase in the number of neurology residents, the need for physicians who provide neurologic care will continue to exceed the number of available neurologists. Whether there will be a surplus of neurologists will depend more on the extent to which neurologists--and not other medical practitioners--will provide such care than on the degree to which entry into neurology residency programs can be restricted. Other manpower concerns for graduate training in neurology are that the quality of residency applicants may be declining, that some training programs may need substantial improvement, and that more teachers of clinical neurology are needed.

  View details for PubMedID 3455241

• LESION LOCALIZATION IN BROCAS APHASIA - IMPLICATIONS FROM BROCAS APHASIA WITHOUT HEMIPARESIS ARCHIVES OF NEUROLOGY Henderson, V. W. 1985; 42 (12): 1210-1212

  Abstract

  The recent hypothesis that injury of the left precentral gyrus (PCG) is critical in causing Broca's aphasia implies that right hemiparesis is an inevitable accompaniment of Broca's aphasia and not merely a coincidental neighborhood sign of PCG damage. A right-handed man was evaluated for posttraumatic Broca's aphasia. The absence in this case of limb or central facial weakness strongly suggests that language impairments of Broca's aphasia need not be associated with PCG damage.

  View details for Web of Science ID A1985AVP1500023

  View details for PubMedID 4062622

• CLINICAL SUBTYPES OF DEMENTIA OF THE ALZHEIMER TYPE NEUROLOGY Chui, H. C., Teng, E. L., Henderson, V. W., MOY, A. C. 1985; 35 (11): 1544-1550

  Abstract

  Clinical subtypes of dementia of the Alzheimer type were evaluated by comparing age at onset, aphasia, family history, and motor disorder in 146 individuals with progressive dementia. Early onset was significantly associated with more prevalent and more severe language disorder. Forty-five percent of all probands had familial history of dementia, but we could not differentiate relative familial risk based on age at onset or aphasia. Independent of duration of illness, myoclonus and noniatrogenic extrapyramidal disorder were associated with greater severity of dementia.

  View details for Web of Science ID A1985AUQ8000002

  View details for PubMedID 4058744

• LEFT HEMISPHERE PATHWAYS IN READING - INFERENCES FROM PURE ALEXIA WITHOUT HEMIANOPIA NEUROLOGY Henderson, V. W., Friedman, R. B., Teng, E. L., Weiner, J. M. 1985; 35 (7): 962-968

  Abstract

  In pure alexia, reading is impaired despite almost normal speech, spelling, and writing. We studied a right-handed man with pure alexia, but no hemianopia. He had more difficulty reading longer words (word-length effect), but had no selective reading impairment in phonologic or semantic analysis. Clinical-CT correlation suggests that (1) left hemisphere visual pathways crucial for reading arise from or pass close to the left occipitotemporal or inferior temporal gyrus, and (2) relevant transcallosal fibers from the right hemisphere course inferior to the posterior horn of the left lateral ventricle before ascending to left hemisphere language areas.

  View details for Web of Science ID A1985ALE6000004

  View details for PubMedID 4010962

• Jules Dejerine and the third alexia. Archives of neurology Henderson, V. W. 1984; 41 (4): 430-432

  Abstract

  Modern concepts of pure alexia and alexia with agraphia are derived from Dejerine's eloquent clinicopathologic studies of the late 19th century. More recently, a third variety of alexia has been described in association with left frontal lesions causing Broca's aphasia. Dejerine also recognized this "third alexia." For Dejerine, alexia with Broca's aphasia was indispensible to his view of a left-hemisphere language zone in which cortical lesions disrupt all language modalities (speech, reading, and writing). Viewed in light of modern neurolinguistic advances, Dejerine's descriptions of the third alexia are surprisingly prescient.

  View details for PubMedID 6367721

• CT CRITERIA OF HEMISPHERE ASYMMETRY FAIL TO PREDICT LANGUAGE LATERALITY NEUROLOGY Henderson, V. W., Naeser, M. A., Weiner, J. M., PIENIADZ, J. M., Chui, H. C. 1984; 34 (8): 1086-1089

  Abstract

  We compared CT measures of the left and right cerebral hemispheres for two groups of right-handed aphasic adults: those who were left-hemisphere language dominant (n = 89) and those who were right-hemisphere language dominant (n = 15). The distribution of linear CT measures of anterior and posterior widths and lengths did not differ significantly in the two groups. These findings fail to support the hypothesis that CT criteria of hemisphere asymmetry predict language laterality.

  View details for Web of Science ID A1984TC80400017

  View details for PubMedID 6540386

• RECONSTRUCTION OF IMAGES FROM NEUROMAGNETIC FIELDS IEEE TRANSACTIONS ON NUCLEAR SCIENCE Singh, M., Doria, D., Henderson, V. W., HUTH, G. C., Beatty, J. 1984; 31 (1): 585-589

  View details for Web of Science ID A1984SC57700126

• The role of occupational therapy in neurologic rehabilitation. Seminars in Neurology Henderson VW 1983; 3 (2): 195-200
• SPEECH FLUENCY IN CROSSED APHASIA BRAIN Henderson, V. W. 1983; 106 (DEC): 837-857

  Abstract

  Three strongly right-handed patients developed fluent aphasia after right hemisphere infarction documented by computerized tomography. For these patients and for other reported cases of crossed aphasia suitable for analysis, the correlation between fluency and infarct localization was similar to that of right-handed aphasics with left-sided lesions. Right hemisphere language representation in most crossed aphasics probably mirrors that normally present in the language-dominant left hemisphere. Two of these patients showed concomitant hemispatial inattention and visuoconstructive impairment. Right hemisphere language dominance therefore does not preclude ipsilateral specialization for visuospatial functions.

  View details for Web of Science ID A1983RW13000004

  View details for PubMedID 6652465

• IMPAIRED HUE DISCRIMINATION IN HOMONYMOUS VISUAL-FIELDS ARCHIVES OF NEUROLOGY Henderson, V. W. 1982; 39 (7): 418-419

  View details for Web of Science ID A1982NY09200011

  View details for PubMedID 7103773

• RIGHT THALAMIC INJURY, IMPAIRED VISUOSPATIAL PERCEPTION, AND ALEXIA NEUROLOGY Henderson, V. W., Alexander, M. P., Naeser, M. A. 1982; 32 (3): 235-240

  Abstract

  In pure alexia, acquired inability to read contrasts with normal speech and handwriting. Rare cases of right hemisphere lesions causing this syndrome are usually attributed to right hemisphere dominance for language. After infarction of the right occipital lobe and thalamus, a fully right-handed man became alexia, but language and spontaneous and dictated writing were intact. Left hemispatial neglect and constructional disturbances were marked, and we suggest that pure alexia was mimicked by the impairment in visuospatial perception. Injury of the nondominant hemisphere and thalamus together may have been important in causing these deficits.

  View details for Web of Science ID A1982NE38300003

  View details for PubMedID 7199632

• NEUROLEPTIC MALIGNANT SYNDROME - A PATHOGENETIC ROLE FOR DOPAMINE RECEPTOR BLOCKADE NEUROLOGY Henderson, V. W., Wooten, G. F. 1981; 31 (2): 132-137

  Abstract

  The neuroleptic malignant syndrome (NMS) of extrapyramidal signs and hyperthermia is an uncommon complication of therapy with the major tranquilizers. Other manifestations are pallor, diaphoresis, blood pressure fluctuation, tachycardia, and tachypneic hypoventilation, which may necessitate respirator support. Death often occurs, but full recovery can result with prompt recognition and proper management. In a patient with Parkinson disease and a chronic psychiatric disorder treated with haloperidol, typical features of NMS appeared upon cessation of dopaminergic antiparkinsonian drugs. Manifestations of NMS are attributed to dopamine receptor blockade in the striatum, increasing thermogenesis, and in the hypothalamus, impairing heat dissipation.

  View details for Web of Science ID A1981LD49300003

  View details for PubMedID 6110195

• FLUENT CROSSED APHASIA WITH CROSSED GERSTMANNS SYNDROME IN A RIGHT-HANDED MAN TRANSACTIONS OF THE AMERICAN NEUROLOGICAL ASSOCIATION Henderson, V. W., Oken, B., Alexander, M. P. 1981; 106: 326-328

  View details for Web of Science ID A1981PN29200118