Victor W. Henderson

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

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

View details for Web of Science ID 000327351200017

View details for PubMedID 24383092

View details for DOI 10.1111/ap.12033

View details for Web of Science ID 000327017900003

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 PubMedID 23596071

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 PubMedID 23727128

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

View details for Web of Science ID 000308942500022

View details for PubMedID 23145448

View details for DOI 10.1212/WNL.0b013e318271f88f

View details for Web of Science ID 000310579900006

View details for PubMedID 23100400

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 DOI 10.1097/gme.0b013e31825b213d

View details for Web of Science ID 000305900100001

View details for PubMedID 22735094

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

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 ?g/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

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

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 PubMedID 22794791

Abstract

To prospectively examine the influence of the oestrogen-? 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

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

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

View details for DOI 10.3109/13697137.2011.570590

View details for Web of Science ID 000290584700002

View details for PubMedID 21563996

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

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

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

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

View details for DOI 10.1210/jc.2009-2509

View details for Web of Science ID 000279976400001

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

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 DOI 10.1097/gme.0b013e3181e3a50e

View details for Web of Science ID 000279799300002

View details for PubMedID 20944455

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

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

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

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

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

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

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 DOI 10.1097/gme.0b013e3181a72622

View details for Web of Science ID 000267837300007

View details for PubMedID 19390462

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

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

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

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

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

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

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

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

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

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 DOI 10.1080/13697130701537363

View details for Web of Science ID 000250230800017

View details for PubMedID 17882681

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 DOI 10.1080/13697130701534097

View details for Web of Science ID 000250230800018

View details for PubMedID 17882682

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

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

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

View details for Web of Science ID 000242732500002

View details for PubMedID 17159007

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

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

View details for Web of Science ID 000240689300001

View details for PubMedID 16946689

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

View details for DOI 10.1080/00050060500421642

View details for Web of Science ID 000236408100007

View details for DOI 10.1080/00050060500421634

View details for Web of Science ID 000236408100006

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

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

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

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

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

View details for DOI 10.1097/01.GME.0000151280.69688.45

View details for Web of Science ID 000226370800001

View details for PubMedID 15668592

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 DOI 10.1080/0050060412331295126

View details for Web of Science ID 000225559500010

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

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

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

View details for DOI 10.1136/jnnp.2003.032359

View details for Web of Science ID 000220886700002

View details for PubMedID 15090555

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

View details for Web of Science ID 000188439300002

View details for PubMedID 14745046

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

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

View details for DOI 10.1097/01.GME.0000067642.38349.65

View details for Web of Science ID 000182908100001

View details for PubMedID 12792286

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

View details for Web of Science ID 000182680300001

View details for PubMedID 12682305

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

View details for PubMedID 12413378

View details for Web of Science ID 000174865900001

View details for PubMedID 11940678

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

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

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

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

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

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

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

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

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

View details for PubMedID 11910592

View details for Web of Science ID 000071763600024

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

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

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

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

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

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

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

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

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

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

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

View details for Web of Science ID A1996UD70400014

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

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

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

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

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

View details for Web of Science ID A1995BD06G00005

View details for Web of Science ID A1995PY81900006

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

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

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

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

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

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

View details for Web of Science ID A1992HP85500013

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

View details for Web of Science ID A1982NY09200011

View details for PubMedID 7103773

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

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