Associate Professor, Psychiatry and Behavioral Sciences - Child and Adolescent Psychiatry
Member, Child Health Research Institute
Dr. OHaras research aims to identify the physiological markers of neurocognitive impairment in a broad range of late-life disorders, including Mild Cognitive Impairment, Alzheimers disease (AD), Late-Life Depression, and Late-Life Anxiety disorders. Using neuroimaging and genetic approaches to investigating the impact of psychological and physiological stress, and more recently sleep disorders, her research aims to: (1) more fully characterize the genetic risk factors and physiological mechanisms underlying normal and pathological cognitive impairment; (2) assist with early identification of those at greatest risk for cognitive decline, and dementia; (3) increase our understanding of the role of cognitive impairment in exacerbating late-life psychiatric disorders; and (4) develop interventions aimed at reducing this impairment.
To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil.Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity.The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data.Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.
View details for DOI 10.1016/j.jagp.2014.09.007
View details for PubMedID 25747405
Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.
View details for DOI 10.1038/npp.2014.259
View details for PubMedID 25292261
This study examined the extent to which cognitive-behavioural therapy (CBT) for geriatric depression promoted meaning made of stress.Fifty-one participants received CBT and were assessed at pre- and post-treatment.The primary outcome was the Integration of Stressful Life Experiences Scale (ISLES) and demographic factors were examined as moderators of changes over time.Those with more education showed improvement in their ability to regain positive values, worldviews, and purpose in life after a stressor.It appears that CBT promotes some forms of meaning made of stress for those with higher education.Cognitive-behavioural therapy as it is routinely practiced may help highly educated older adults regain their Footing in the World (e.g., maintain positive values, worldviews, and purpose in life) in the aftermath of a stressful life event. Cognitive-behavioural therapy appears to offer fewer gains for less educated older adults (in terms of Footing in the World) as well as for other aspects of meaning-making, such as the ability to 'make sense' of a significant stressor. Although more empirical work is necessary, meaning-oriented interventions (e.g., 're-authoring' a fragmented self-narrative; Neimeyer, 2009, p. 97) hold promise as useful adjuncts to routine therapy that could augment outcomes.
View details for DOI 10.1111/papt.12030
View details for PubMedID 24839175
To identify cognitive predictors of geriatric depression treatment outcome.Older participants completed baseline measures of memory and executive function, health, and baseline and post-treatment Hamilton Depression Scales (HAM-D) in a 12-week trial comparing psychotherapies (problem-solving vs. supportive; N = 46). We examined cognitive predictors to identify treatment responders (i.e., HAM-D scores reduced by ≥50%) and remitters (i.e., post-treatment HAM-D score ≤10).Empirically derived decision trees identified poorer performance on switching (i.e., Trails B), with a cut-score of ≥82 predicting psychotherapy responders. No other cognitive or health variables predicted psychotherapy outcomes in the decision trees.Psychotherapies that support or improve the executive skill of switching may augment treatment response for older patients exhibiting executive dysfunction in depression. If replicated, Trails B has potential as a brief cognitive tool for clinical decision-making in geriatric depression.
View details for DOI 10.1016/j.jagp.2014.09.003
View details for PubMedID 25441055
To test our hypothesis that pre-treatment executive function and brain regional activation during executive function would discriminate between responders and non-responders to cognitive behavioral therapy (CBT) in elderly depressed outpatients.Clinical cohort study.University-affiliated hospital.Sixty outpatients (age 59 years and older) completed 12 weeks of CBT between July 2010 and December 2011. Forty-four completed fMRI procedures.The main outcome consisted of a conversion from a clinical diagnosis (Mini-International Neuropsychiatric Interview) of depression to no clinical diagnosis of depression or a significant improvement in diagnostic criteria. Brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting task (WCST) was the primary predictor variable.67% of patients had a positive response to CBT. Decreased activation in the left inferior frontal triangle and right superior frontal gyrus as well as increased activity in the right middle frontal gyrus and left superior frontal gyrus predicted a positive response to CBT. Demographic and neurocognitive measures of WCST performance were not significant predictors of a positive CBT outcome, whereas the measure of WCST-induced activity in the prefrontal cortex was a significant predictor.These data are among the first to suggest that measures of prefrontal brain activation during executive functioning predict response to CBT in older adults. Further exploration of the specific underlying processes that these prefrontal cortical regions are engaging that contributes to better CBT outcomes is warranted in larger, randomized studies.
View details for DOI 10.1016/j.jagp.2014.02.001
View details for Web of Science ID 000346204400003
View details for PubMedID 24656506
The serotonin transporter polymorphism short (s) allele is associated with heightened emotional reactivity and reduced emotion regulation, which increases vulnerability to depression and anxiety disorders. We investigated behavioral and neural markers of emotion regulation in community-dwelling older adults, contrasting s allele carriers and long allele homozygotes.Participants (N = 26) completed a face-word emotion conflict task during functional magnetic resonance imaging, in which facilitated regulation of emotion conflict was observed on face-word incongruent trials following another incongruent trial (i.e., emotional conflict adaptation).There were no differences between genetic groups in behavioral task performance or neural activation in postincongruent versus postcongruent trials. By contrast, connectivity between dorsal anterior cingulate cortex (ACC) and pregenual ACC, regions previously implicated in emotion conflict regulation, was impaired in s carriers for emotional conflict adaptation.This is the first demonstration of an association between serotonin transporter polymorphism and functional connectivity in older adults. Poor dorsal ACC-pregenual ACC connectivity in s carriers may be one route by which these individuals experience greater difficulty in implementing effective emotional regulation, which may contribute to their vulnerability for affective disorders.
View details for DOI 10.1016/j.jagp.2013.08.004
View details for PubMedID 24119861
Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently.Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed.Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74).Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.
View details for DOI 10.1016/j.jpsychires.2014.03.019
View details for Web of Science ID 000337649300013
View details for PubMedID 24726638
RATIONALE: A functional polymorphism of the serotonin transporter gene (5-HTTLPR) has previously been related to upper airway pathology, but its contribution to obstructive sleep apnea (OSA), a highly prevalent sleep disorder in older adults, remains unclear. OBJECTIVES: We aimed to investigate the relationship between apnea-hypopnea index (AHI) and genetic variations in the promoter region of the 5-HTTLPR in older adults. METHODS: DNA samples from 94 community-dwelling older adults (57% female, mean age 72 ± 8) were genotyped for the 5-HTTLPR polymorphism. All participants were assessed in their homes with full ambulatory polysomnography in order to determine AHI and related parameters such as hypoxia, sleep fragmentation, and self-reported daytime sleepiness. RESULTS: The 5-HTT l allele was significantly associated with AHI (p = 0.019), with l allele carriers displaying a higher AHI than s allele homozygotes. A single allele change in 5-HTTLPR genotype from s to l resulted in an increase of AHI by 4.46 per hour of sleep (95% CI, 0.75-8.17). The l allele was also associated with increased time during sleep spent at oxygen saturation levels below 90% (p = 0.014). CONCLUSIONS: The observed significant association between the 5-HTTLPR l allele and severity of OSA in older adults suggests that the l allele may be important to consider when assessing for OSA in this age group. This association may also explain some of the observed variability among serotonergic pharmacological treatment studies for OSA, and 5-HTT genotype status may have to be taken into account in future therapeutic trials involving serotonergic agents. Copyright © 2013 John Wiley & Sons, Ltd.
View details for DOI 10.1002/gps.3994
View details for Web of Science ID 000330907600002
View details for PubMedID 23754303
This study expands on previous research by examining the effects of prolonged grief disorder (PGD) symptoms and bereavement on diurnal cortisol patterns above and beyond depressive symptomatology.Drawing on information from 56 depressed older adults, 3 groups were compared: (1) a depressed nonbereaved group, (2) a depressed bereaved without elevated PGD symptoms group, and (3) a depressed bereaved with elevated PGD symptoms group. Multilevel modeling was used to examine differences in diurnal cortisol profiles between these 3 groups, controlling for demographic factors and depressive symptoms.Results revealed that those who were bereaved had more dysregulated cortisol patterns, but PGD symptomatology seemed to have little effect. Subsidiary analysis with just the bereaved participants suggests that those who were recently widowed may have had greater cortisol dysregulation compared with other bereaved individuals in the sample.These findings suggest that the circumstance of being bereaved may be associated with more dysregulated cortisol, regardless of PGD symptomatology. This pattern of results might reflect greater disturbance in daily routines among bereaved individuals and acute stress in the case of those experiencing the recent loss of a spouse, which leads to disruption in circadian rhythms and the diurnal cycle of cortisol.
View details for DOI 10.1093/geronb/gbt051
View details for Web of Science ID 000338007300003
Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.
View details for DOI 10.3389/fnagi.2014.00153
View details for PubMedID 25071562
Well-known risk factors for cognitive impairment are also associated with obesity. Research has highlighted genetic risk factors for obesity, yet the relationship of those risk factors with cognitive impairment is unknown. The objective of this study was to determine the associations between cognition, hypertension, diabetes, sleep-disordered breathing, and obesity. Genetic risk factors of obesity were also examined.The sample consisted of 369 nondemented individuals aged 50 years or older from four community cohorts. Primary outcome measures included auditory verbal memory, as measured by the Rey Auditory Verbal Learning Test, and executive functioning, as measured by the Color-Word Interference Test of the Delis-Kaplan Executive Function System battery. Apnea-hypopnea index indicators were determined during standard overnight polysomnography. Statistical analyses included Pearson correlations and linear regressions.Poor executive function and auditory verbal memory were linked to cardiovascular risk factors, but not directly to obesity. Genetic factors appeared to have a small but measureable association to obesity.A direct linkage between obesity and poor executive function and auditory verbal memory is difficult to discern, possibly because nonobese individuals may show cognitive impairment due to insulin resistance and the "metabolic syndrome".
View details for DOI 10.2147/DMSO.S60294
View details for PubMedID 24855383
Previous studies suggest that individuals with elevated levels of cortisol (the "stress hormone") could be particularly resistant to treatment for depression. However, most of these studies have been conducted in the context of antidepressant medications, and no study has examined pretreatment cortisol levels as a predictor of treatment outcomes among older adults with depression in cognitive-behavioral therapy (CBT), despite the relevance of this population for such a research question. The current study includes 54 older adults with depression who provided salivary cortisol samples at baseline and completed measures of depression at pretreatment and posttreatment, following a 12-week course of CBT. Structural equation modeling results suggest that those with higher daily outputs of cortisol and flatter diurnal slopes were less likely to benefit from CBT-a finding which if replicated could have important implications for clinical practice and future research.
View details for DOI 10.1016/j.psychres.2013.07.033
View details for Web of Science ID 000328518600012
View details for PubMedID 23953171
Breast cancer survivors are at increased risk for cognitive dysfunction, which reduces quality of life. Neuroimaging studies provide critical insights regarding the mechanisms underlying these cognitive deficits as well as potential biologic targets for interventions. We measured several metabolite concentrations using (1)H magnetic resonance spectroscopy as well as cognitive performance in 19 female breast cancer survivors and 17 age-matched female controls. Women with breast cancer were all treated with chemotherapy. Results indicated significantly increased choline (Cho) and myo-inositol (mI) with correspondingly decreased N-acetylaspartate (NAA)/Cho and NAA/mI ratios in the breast cancer group compared to controls. The breast cancer group reported reduced executive function and memory, and subjective memory ability was correlated with mI and Cho levels in both groups. These findings provide preliminary evidence of an altered metabolic profile that increases our understanding of neurobiologic status post-breast cancer and chemotherapy.
View details for DOI 10.1007/s11682-013-9228-1
View details for Web of Science ID 000328853800010
View details for PubMedID 23536015
Deficits in brain networks that support cognitive regulatory functions are prevalent in many psychiatric disorders. Findings across neuropsychology and neuroimaging point to broad-based impairments that cross traditional diagnostic boundaries. These dysfunctions are largely separate from the classical symptoms of the disorders, and manifest in regulatory problems in both traditional cognitive and emotional domains. As such, they relate to the capacity of patients to engage effectively in their daily lives and activity, often persist even in the face of symptomatically effective treatment, and are poorly targeted by current treatments. Advances in cognitive neuroscience now allow us to ground an understanding of these cognitive regulatory deficits in the function and interaction of key brain networks. This emerging neurobiological understanding furthermore points to several promising routes for novel neuroscience-informed treatments targeted more specifically at improving cognitive function in a range of psychiatric disorders.
View details for PubMedID 24459409
Exposure to early life trauma (ELT) is known to have a profound impact on mental development, leading to a higher risk for depression and anxiety. Our aim was to use multiple structural imaging methods to systematically investigate how traumatic stressors early in life impact the emotional brain circuits, typically found impaired with clinical diagnosis of depression and anxiety, across the lifespan in an otherwise healthy cohort. MRI data and self-reported histories of ELT from 352 healthy individuals screened for no psychiatric disorders were analyzed in this study. The volume and cortical thickness of the limbic and cingulate regions were assessed for all participants. A large subset of the cohort also had diffusion tensor imaging data, which was used to quantify white matter structural integrity of these regions. We found a significantly smaller amygdala volume and cortical thickness in the rostral anterior cingulate cortex associated with higher ELT exposure only for the adolescence group. White matter integrity of these regions was not affected. These findings demonstrate that exposure to early life trauma is associated with alterations in the gray matter of cingulate-limbic regions during adolescence in an otherwise healthy sample. These findings are interesting in the context that the affected regions are central neuroanatomical components in the psychopathology of depression, and adolescence is a peak period for risk and onset of the disorder.
View details for DOI 10.1371/journal.pone.0075524
View details for Web of Science ID 000324768000080
View details for PubMedID 24073270
Objective: The primary objective of this study was to examine a variety of potential predictors of response to Cognitive Behavioral Therapy (CBT) in depressed older adults. Method: Sixty older adults with a clinical diagnosis of major or minor depression or dysthymic disorder received 12 individual sessions of CBT over a three- to four-month-period. The BDI-II was administered pre- and post-intervention to assess change in the level of depression. A cutoff score of 13 or less at post was used to determine positive treatment response. A variety of measures (obtained at baseline) were evaluated using hierarchical regression techniques to predict improvement following treatment. Results: Individuals who showed greater improvement were: (a) more open to new experiences; (b) less negatively affected by past stressors; (c) less inclined to have an external locus of control but more likely to cite others as responsible for negative stress in their lives; and (d) were more likely to seek emotional support when symptomatic. Lower education level and reported use of active coping strategies at baseline were associated with less improvement. Other variables (e.g., age, overall physical health, and cognitive status) were not associated with treatment response. Use of logistic regression to predict responders vs. nonresponders yielded a similar pattern. Conclusion: These findings agree with prior research confirming the effectiveness of a brief CBT intervention for older depressed persons and suggest further exploration of several psychosocial factors that may contribute to a stronger response to CBT.
View details for DOI 10.1080/13607863.2013.791661
View details for Web of Science ID 000323476600008
View details for PubMedID 23631698
OBJECTIVE: To examine the relationship of neuropsychiatric symptoms and apolipoprotein E (APOE) ε4 allele status to dementia at baseline and progression to dementia in older adults with and without cognitive impairment, no dementia (CIND). METHODS: Adults (n = 856) 71 years and older (mean age = 79.15 years), 12.8% ethnic minority and 60.6% women, completed neuropsychological tests and APOE genotyping, and a proxy informant completed the Neuropsychiatric Inventory. RESULTS: After adjusting for age and education, neuropsychiatric symptoms and APOE ε4 were independently associated with CIND and dementia status at baseline (compared with cognitively normal). Further, neuropsychiatric symptoms predicted progression to dementia at 16- to 18-month follow-up among participants with CIND at baseline; the presence of these symptoms decreased the risk of progression from normal to CIND or dementia at 36 to 48 months. CONCLUSION: Findings provide cross-sectional and longitudinal support for the role of neuropsychiatric symptoms in the prediction of cognitive impairment, particularly dementia. APOE ε4, although important, may be a less robust predictor. This investigation highlights the importance of behavioral symptoms, such as neuropsychiatric symptom status or frequency/severity, as predictors of future cognitive decline. Copyright © 2012 John Wiley & Sons, Ltd.
View details for DOI 10.1002/gps.3868
View details for PubMedID 22927174
Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically.To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency.Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels.Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level.Short REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%).Among patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.
View details for DOI 10.1001/jamaneurol.2013.1589
View details for PubMedID 23649748
Brain-derived neurotrophic factor (BDNF) is associated with antidepressant response on the cellular level, in animal models, and in clinical studies. A common variant in the BDNF gene results in a substitution of a methionine (Met) for a valine at the amino acid position 66. Previous studies reported that the Met variant results in enhanced response to antidepressant medications. These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF.We examined the effects of BDNF single nucleotide polymorphisms (SNPs) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression, treated in a double-blind, randomized, 8-week clinical trial. We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2, cyclic AMP responsive element binding protein 1 (CREB1), and CREB binding protein. A total of 53 SNPs were genotyped.BDNF genetic variation had a significant effect on the efficacy of paroxetine, with patients carrying the Met allele showing impaired response. SNPs at the CREB1 locus, which encodes a transcription factor important in BDNF signaling, also predicted response to paroxetine. Furthermore, we found a significant gene-gene interaction between BDNF and CREB1 that affected response to paroxetine. Because BDNF has been associated with cognitive function, we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial, but there were no significant effects of genotype on cognition.These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients. The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain. Further, the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1.
View details for DOI 10.1097/FPC.0b013e328360b175
View details for Web of Science ID 000318544100002
View details for PubMedID 23619509
Early adversity is a strong and enduring predictor of psychiatric disorders including mood disorders, anxiety disorders, substance abuse or dependence, and posttraumatic stress disorder. However, the mechanisms of this effect are not well understood. The purpose of this review is to summarize and integrate the current research knowledge pertaining to the long-term effects of early adversity on psychiatric disorders, particularly in late life. We explore definitional considerations including key dimensions of the experience such as type, severity, and timing of adversity relative to development. We then review the potential biological and environmental mediators and moderators of the relationships between early adversity and psychiatric disorders. We conclude with clinical implications, methodological challenges and suggestions for future research.
View details for DOI 10.1007/s11920-013-0352-9
View details for PubMedID 23443532
Many studies have provided strong evidence of a fundamental and complex role for sleep disturbances in adult posttraumatic stress disorder (PTSD). Investigations of adult PTSD using subjective and objective measures document sleep architecture abnormalities and high prevalence of sleep disordered breathing, periodic limb movement disorder, nightmares, and insomnia. PTSD treatment methods do appear to significantly improve sleep disturbance, and also studies suggest that treatments for sleep disorders often result in improvements in PTSD symptoms. Further, the most recent evidence suggests sleep abnormalities may precede the development of PTSD. Given the importance of sleep disorders to the onset, course, and treatment of adult PTSD, examination of sleep disturbances far earlier in the life course is imperative. Here we review the literature on what we know about sleep disturbances and disorders in pediatric PTSD. Our review indicates that the extant, empirical data examining sleep disturbance and disorders in pediatric PTSD is limited. Yet, this literature suggests there are significantly higher reports of sleep disturbances and nightmares in children and adolescents exposed to trauma and/or diagnosed with PTSD than in non-trauma-exposed samples. Sleep questionnaires are predominantly employed to assess sleep disorders in pediatric PTSD, with few studies utilizing objective measures. Given the important, complex relationship being uncovered between adult PTSD and sleep, this review calls for further research of sleep in children with PTSD using more specific subjective measures and also objective measures, such as polysomnography and eventually treatment trial studies. CITATION: Kovachy B; O'Hara R; Hawkins N; Gershon A; Primeau MM; Madej J; Carrion V. Sleep disturbance in pediatric PTSD: current findings and future directions. J Clin Sleep Med 2013;9(5):501-510.
View details for DOI 10.5664/jcsm.2678
View details for PubMedID 23674943
Heterogeneity in clinical outcomes may be caused by factors working at multiple levels, e.g., between groups, between subjects, or within subjects over time. A more nuanced assessment of differences in variation among schizophrenia patients and between patients and healthy comparison subjects can clarify etiology and even facilitate the identification of patient subtypes with common neuropathology and clinical course.We compared trajectories (mean duration of 3.5years) of cognitive impairments in a sample of 201 community-dwelling schizophrenia (SCZ) patients (aged 40-100years) with 67 healthy comparison (HC) subjects. We employed growth mixture models to discover subclasses with more homogenous between-subject variation in cognitive trajectories. Post hoc analyses determined factors associated with class membership and class-specific correlates of cognitive trajectories.Three latent classes were indicated: Class 1 (85% HC and 50% SCZ) exhibited relatively high and stable trajectories of cognition, Class 2 (15% HC and 40% SCZ) exhibited lower, modestly declining trajectories, and Class 3 (10% SCZ) exhibited lower, more rapidly declining trajectories. Within the patient group, membership in Classes 2-3 was associated with worse negative symptoms and living in a board and care facility.These results bridge the gap between schizophrenia studies demonstrating cognitive decline and those demonstrating stability. Moreover, a finer-grained characterization of heterogeneity in cognitive trajectories has practical implications for interventions and for case management of patients who show accelerated cognitive decline. Such a characterization requires study designs and analyses sensitive to between- and within-patient heterogeneity in outcomes.
View details for DOI 10.1016/j.schres.2012.10.033
View details for Web of Science ID 000313118700017
View details for PubMedID 23218560
The present work aimed to extend models suggesting that obstructive sleep apnea (OSA) is associated with worse cognitive performance in community-dwelling older adults. We hypothesized that in addition to indices of OSA severity, hypertension is associated with worse cognitive performance in such adults.The PTSD Apnea Clinical Study recruited 120 community-dwelling, male veterans diagnosed with PTSD, ages 55 and older. The Rey Auditory Verbal Learning Test (RAVLT) and Color-Word Interference Test (CWIT) were measures of auditory verbal memory and executive function, respectively. Apnea-hypopnea index (AHI), minimum and mean pulse oximeter oxygen saturation (min SpO(2), mean SpO(2)) indicators were determined during standard overnight polysomnography. Multivariate linear regression and receiver operating characteristic (ROC) curve analyses were performed.In regression models, AHI (??=?-4.099; p?0.01) and hypertension (??=?-4.500; p?0.05) predicted RAVLT; hypertension alone (??=?9.146; p?0.01) predicted CWIT. ROC analyses selected min SpO(2) cut-points of 85% for RAVLT (??=?0.27; ?²?=?8.23, p?0.01) and 80% for CWIT (??=?0.25; ?²?=?12.65, p?0.01). Min SpO(2) cut-points and hypertension were significant when added simultaneously in a regression model for RAVLT (min SpO(2), ??=?4.452; p?0.05; hypertension, ??=?-4.332; p?0.05), and in separate models for CWIT (min SpO(2), ??=?-8.286; p?0.05; hypertension, ??=?-8.993; p?0.01).OSA severity and presence of self-reported hypertension are associated with poor auditory verbal memory and executive function in older adults.
View details for DOI 10.1007/s11325-011-0632-8
View details for Web of Science ID 000311301700038
View details for PubMedID 22193972
Restless legs syndrome (RLS) has gained considerable attention in the recent years: nearly 50 community-based studies have been published in the last decade around the world. The development of strict diagnostic criteria in 1995 and their revision in 2003 helped to stimulate research interest on this syndrome. In community-based surveys, RLS has been studied as: 1) a symptom only, 2) a set of symptoms meeting minimal diagnostic criteria of the international restless legs syndrome study group (IRLSSG), 3) meeting minimal criteria accompanied with a specific frequency and/or severity, and 4) a differential diagnosis. In the first case, prevalence estimates in the general adult population ranged from 9.4% to 15%. In the second case, prevalence ranged from 3.9% to 14.3%. When frequency/severity is added, prevalence ranged from 2.2% to 7.9% and when differential diagnosis is applied prevalence estimates are between 1.9% and 4.6%. In all instances, RLS prevalence is higher in women than in men. It also increases with age in European and North American countries but not in Asian countries. Symptoms of anxiety and depression have been consistently associated with RLS. Overall, individuals with RLS have a poorer health than non-RLS but evidence for specific disease associations is mixed. Future epidemiological studies should focus on systematically adding frequency and severity in the definition of the syndrome in order to minimize the inclusion of cases mimicking RLS.
View details for DOI 10.1016/j.smrv.2011.05.002
View details for Web of Science ID 000306096700002
View details for PubMedID 21795081
Resilience is proposed as a significant component of successful aging. Young adult carriers of the Serotonin Transporter Polymorphism (5-HTTLPR) short(s) allele appear to have reduced resilience to stress. We examined whether the presence of the short allele was associated with poorer emotional resilience in older adults.In a cross-sectional study of 99 healthy, community-dwelling, older adults, we determined 5-HTTLPR genotype status and administered the Connor-Davidson Resilience Scale and self-reported measures of successful aging, cognition, and health.There was no significant association between the 5-HTTLPR s allele and resilience. S allele carriers had worse cognition and self-report ratings of successful aging.These findings suggest that the impact of the 5-HTTLPR s allele on stress-related outcomes may attenuate with older age. However, s allele status appears to be a biomarker of poorer self-rated successful aging, and cognitive performance in older adults.
View details for DOI 10.1097/JGP.0b013e31823e2d03
View details for Web of Science ID 000303295900010
View details for PubMedID 22233775
The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.
View details for DOI 10.1007/s10803-011-1314-x
View details for Web of Science ID 000302771500017
View details for PubMedID 21713591
: To study the prevalence of sleep-disordered breathing (SDB) in Vietnam- era veterans.: This was an observational study of Vietnam-era veterans using unattended, overnight polysomnography, cognitive testing, and genetic measures.: A sample of 105 Vietnam-era veterans with posttraumatic stress disorder: 69% had an Apnea Hypopnea Index >10. Their mean body mass index was 31, "obese" by Centers for Disease Control and Prevention criteria, and body mass index was significantly associated with Apnea Hypopnea Index (Spearman r = 0.41, N = 97, p < 0.0001). No significant effects of sleep-disordered breathing or apolipoprotein status were found on an extensive battery of cognitive tests.: There is a relatively high prevalence of SDB in these patients which raises the question of to what degree excess cognitive loss in older PTSD patients may be due to a high prevalence of SDB.
View details for DOI 10.1097/JGP.0b013e3181e446ea
View details for Web of Science ID 000300642300002
View details for PubMedID 20808112
To address the growing need for ethnically unbiased cognitive screening, we examined whether the Mini Mental State Exam (MMSE), the abbreviated Fuld Object Memory Evaluation (FOME), or a combination of the two provided optimal detection of dementia in an ethnically diverse group of older adults with no cognitive impairment (normal); cognitive impairment not dementia (CIND); and dementia. Participants included 509 Caucasians, 124 African Americans, and 68 Latinos (>70 years old) from the Aging, Demographics, and Memory Study who completed the MMSE and FOME. Empirically derived decision trees were computed using signal detection software for receiver operator characteristics (ROC). Among the three ethnic groups, ROC analyses revealed that lower scores on both the MMSE and FOME provided better detection of CIND or dementia. Sensitivity and specificity of the MMSE was augmented by the addition of the FOME among Caucasian and African American older adults. The MMSE alone was the best screen in Latino older adults to distinguish any cognitive impairment from normal. When comparing CIND versus dementia, however, the FOME alone was best for detecting dementia among Latinos. The abbreviated FOME is recommended to increase clinical validity and thus minimize ethnic biases when administering the MMSE to Caucasian and African American older adults. The MMSE alone is preferred for older Latinos unless comparing CIND and dementia, in which case the FOME alone would then be recommended. Findings suggest that ethnicity is important in the selection of an appropriate cognitive screen and cut-score to use with older adults.
View details for DOI 10.3233/JAD-2012-112180
View details for Web of Science ID 000307377300013
View details for PubMedID 22555374
Little is known about gender differences in sexuality among community-dwelling heterosexual couples in which one partner has Alzheimer's disease (AD). Few studies have examined gender differences in specific sexual behaviors or their associations with caregiver well-being. This study evaluated the impact of gender differences on intimacy and sexual satisfaction in marital relationships in which one partner has AD.Baseline measures were collected from 162 AD patients and their partners enrolled in a multi-site study between 2001 and 2009 to evaluate gender differences in measures of intimacy, caregiver well-being, and patient sexual behaviors.While over 70% of all patients initiated physically intimate activities (i.e., kissing, hugging, and intercourse), most did not initiate intercourse specifically. Female caregivers reported higher levels of stress and depressive symptoms than male caregivers (p < 0.01). Satisfaction with intimacy was significantly associated with fewer stress and depressive symptoms in female caregivers (r = -0.29, p < 0.01). Caregiver gender, satisfaction with intimacy, and caring for a patient with mild AD were significant predictors of caregiver depressive symptoms (p's < 0.05).The majority of couples dealing with AD reported engaging in intimacy, suggesting its importance in the relationship. Female caregivers who reported less sexual satisfaction reported more frequent stress and depressive symptoms. Caregiver gender, satisfaction with intimacy, and the AD patient's level of cognitive functioning significantly contributed to caregiver well-being. Gender-specific therapies to address patient sexual difficulties and caregiver well-being could potentially maintain or improve the marital relationship.
View details for DOI 10.1080/13607863.2011.609532
View details for Web of Science ID 000301535800009
View details for PubMedID 21999712
To examine differences in prefrontal-executive function between breast cancer (BC) survivors with and without a history of chemotherapy treatment compared with healthy control women and to determine the associations between prefrontal cortex deficits and behavioral impairments, as well as certain demographic and disease variables.Observational study.University-based research facility.Twenty-five women with BC who had received chemotherapy, 19 women with BC who had not received chemotherapy, and 18 healthy female controls, all matched for age and other demographic variables.Women with BC demonstrated significantly reduced activation in the left middle dorsolateral prefrontal cortex and premotor cortex compared with healthy controls. The chemotherapy group also demonstrated significantly reduced left caudal lateral prefrontal cortex activation and increased perseverative errors and reduced processing speed compared with the other 2 groups. Reduced left caudal lateral prefrontal cortex activation was significantly correlated with higher disease severity and elevated subjective executive dysfunction in the chemotherapy-treated women. Older age and lower educational level were associated with increased executive function impairment in the chemotherapy group.These findings provide further evidence of neurological impairment associated with primary BC irrespective of treatment history. The left caudal lateral prefrontal region may be particularly vulnerable to the effects of chemotherapy and/or disease severity and may represent a novel biomarker of subjective executive dysfunction in chemotherapy-treated women. Furthermore, negative effects of chemotherapy on brain function may be exacerbated by such factors as increased age and lower educational level.
View details for Web of Science ID 000297014900013
View details for PubMedID 22084128
Characterization of developmental trajectories across the lifespan is integral to understanding the prodromal course of many neuropsychiatric illnesses and the significant risk factors for disease onset or unfavorable outcomes. However, the standard experimental designs used in psychiatric research are not ideal for this purpose. The authors review the limitations of the most commonly employed designs in studies that make developmental or lifespan inferences in psychiatry: cross-sectional, single-cohort longitudinal, and unstructured multicohort longitudinal designs. Cross-sectional studies completely confound within- and between-subject sources of variation and hence rely on the presence of parallel trajectories and negligible sampling and age cohort differences for making valid developmental inferences. Delineating trajectories of within-individual change over substantial periods of time requires data covering long age spans that often cannot be covered using single-cohort longitudinal designs. Unstructured multicohort longitudinal designs are a commonly used alternative that can cover a longer age span in a shorter interval than necessary for a single-cohort design. However, the impact of cohort and sampling effects is often minimized or ignored in unstructured multicohort longitudinal designs. The authors propose that structured multicohort longitudinal designs are a particularly viable and underutilized class of designs in psychiatry that represents a significant improvement over cross-sectional designs and unstructured multicohort longitudinal designs for making developmental inferences while being more practical to implement than single-cohort longitudinal designs. As an example of this approach, the authors analyze changes in entorhinal cortex thickness in Alzheimer's disease in relation to APOE-?4 genotype.
View details for DOI 10.1176/appi.ajp.2011.10111690
View details for Web of Science ID 000294484100009
View details for PubMedID 21724665
One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.One week of ad libitum ambulatory sleep data collection.At-home collection of sleep data and in-laboratory questionnaire.Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set.Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined.Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.
View details for DOI 10.1097/JGP.0b013e31820d92b2
View details for Web of Science ID 000292031900005
View details for PubMedID 21709609
Magnetic Resonance Spectroscopy (MRS) may provide a precise and reliable assessment of the extent and severity of neural tissue loss caused by various diseases. In particular, the N-Acetyl Aspartate (NAA) and Creatine (Cr) ratio has been found to be an indicator of the degree of neuronal loss in Alzheimer's disease (AD). Memantine is thought to benefit the AD brain by stabilizing the NMDA receptors on neurons in turn reducing excitotoxicity. Despite its effectiveness in treating moderate to severe AD, memantine has not had similar success in the treatment of mildly demented AD patients. The objective of this study was to test whether memantine would slow or prevent the loss of neurons in mild to moderate AD patients.A double-blind placebo-controlled study was designed to measure the effect of a year-long course of memantine in patients with a probable AD diagnosis with mild to moderate dementia. The primary outcome measure was stipulated to be change in MRS NAA/Cr ratio in inferior parietal cortex in memantine relative to the placebo treatment condition. The secondary outcome measures were changes in cognitive and function scale scores.This pilot study failed to demonstrate a benefit of memantine on the primary outcome measure, the inferior parietal NAA/Cr ratio, or the secondary outcome measures.More studies are needed to determine the effect of memantine on regions of the brain significantly affected by AD pathology.
View details for DOI 10.3233/JAD-2011-0021
View details for Web of Science ID 000297842800025
View details for PubMedID 21971472
Sleep and wake in Alzheimer's disease (AD) are often fragmented as manifested by bouts of wakefulness at night and napping during the day. Management of sleep disturbances in AD is important because of their negative impact on both patients and caregivers. Pharmacological treatments, mainly sedative-hypnotics and antipsychotics, are often used but can be associated with significant adverse effects. Non-pharmacological treatments represent a beneficial alternative approach to the management of sleep disturbances in AD since they are associated with fewer adverse effects and their efficacy can be sustained after treatment has been completed. The aim of this article is to review non-pharmacological treatments, such as sleep hygiene, sleep restriction therapy (SRT), cognitive behavioral therapy (CBT), light therapy, and continuous positive airway pressure (CPAP), for the management of sleep/wake disturbances in AD.
View details for DOI 10.1007/s12603-010-0050-9
View details for Web of Science ID 000276527000006
View details for PubMedID 20191254
This report highlights the use of multisite training for psychiatry and psychology postdoctoral fellows developing careers in academic clinical research in the field of mental health. The objective is to describe a model of training for young investigators to establish independent academic clinical research careers, including (1) program structure and eligibility, (2) program goals and development of a multisite curriculum, (3) use of technology for implementing the program across multiple sites, and (4) advantages and challenges of this multisite approach. In 2000, in collaboration with the Veterans Affairs (VA) Mental Illness Research, Education and Clinical Centers (MIRECCs), the VA Office of Academic Affiliations launched the Special Fellowship Program in Advanced Psychiatry and Psychology. Each of the 10 currently participating VA sites across the United States is affiliated with a MIRECC and an academic medical institution. In the first five years of this fellowship program, 83 fellows (34 psychiatrists and 49 psychologists) have participated. The success of this multisite approach is evidenced by the 58 fellows who have already graduated from the program: 70% have entered academic clinical research positions, and over 25 have obtained independent extramural grant support from the VA or the National Institutes of Health. Multisite training results in a greater transfer of knowledge and capitalizes on the nationwide availability of experts, creating unique networking and learning opportunities for trainees. The VA's multisite fellowship program plays a valuable role in preparing substantial numbers of psychiatry and psychology trainees for a range of academic clinical research and leadership positions in the field of mental health.
View details for DOI 10.1097/ACM.0b013e3181c47c51
View details for Web of Science ID 000276131300015
View details for PubMedID 20042819
The Research Career Development Institute for Psychiatry is a collaboration between the University of Pittsburgh and Stanford University to recruit and train a broad-based group of promising junior physicians by providing the necessary skills and support for successful research careers in academic psychiatry.Participants whose interests span the spectrum of clinical and intervention research attend a multiday career development institute workshop and follow-up annual booster sessions conducted with the American College of Neuropsychopharmacology. The program identifies and trains 20 new physician-researchers each year, with particular emphasis on women, minorities, and those from less research-intensive psychiatry departments, and provides booster sessions for all trainees. An annual evaluation is used to renew and update the content of the institutes and to measure the long-term value in research and career success.This report is based on the results of 77 participants from the first four Career Development Institute classes. Qualitative assessment of the program content and process led to improvements in each successive year's workshop. Preliminary quantitative follow-up assessment of participants indicated successful career progress toward individual objectives.By providing early career investigators with skills to cope with local and national forces in academic medical centers, the Career Development Institute is significantly contributing to the development of the next generation of leading academic clinical researchers in mental health and can serve as a model for other biomedical research arenas.
View details for Web of Science ID 000269055600010
View details for PubMedID 19690113
The authors examined the association of anxiety, depressive symptoms, and their co-occurrence on cognitive processes in 102 community-dwelling older adults. Participants completed anxiety and depression questionnaires as well as measures of episodic and semantic memory, word fluency, processing speed/shifting attention, and inhibition. Participants with only increased anxiety had poorer processing speed/shifting attention and inhibition, but depressive symptoms alone were not associated with any cognitive deficits. Although coexisting anxiety and depressive symptoms were associated with deficits in 3 cognitive domains, reductions in inhibition were solely attributed to anxiety. Findings suggest an excess cognitive load on inhibitory ability in normal older adults reporting mild anxiety.
View details for DOI 10.1037/a0016035
View details for Web of Science ID 000266580700022
View details for PubMedID 19485667
Sleep apnea is prevalent among patients with traumatic brain injuries (TBIs), and initial studies suggest it is associated with cognitive impairments in these patients. Recent studies found that the apolipoprotein epsilon 4 (APOE epsilon 4) allele increases the risk for sleep disordered breathing, particularly sleep apnea. The APOE epsilon 4 allele is associated with cognitive decline and the development of dementia in the general population as well as in patients with TBI. These findings raise the question of whether patients with TBI who are APOE epsilon 4 allele carriers are more vulnerable to the negative effects of sleep apnea on their cognitive functioning. While few treatments are available for cognitive impairment, highly effective treatments are available for sleep apnea. Here we review these different lines of evidence, making a case that the interactive effects of sleep apnea and the APOE epsilon 4 allele represent an important mechanism by which patients with TBI may develop a range of cognitive and neurobehavioral impairments. Increased understanding of the relationships among sleep apnea, the APOE epsilon 4 allele, and cognition could improve our ability to ameliorate one significant source of cognitive impairment and risk for dementia associated with TBI.
View details for DOI 10.1682/JRRD.2008.10.0140
View details for Web of Science ID 000272638100015
View details for PubMedID 20104407
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in the United States. One of the most common comorbidities of TBI is the disruption of normal sleep. While often viewed as a nuisance symptom, sleep disruption can delay TBI recovery and negatively affect many of the psychological (e.g., anxiety, depression) and neuromuscular (e.g., pain) sequelae of TBI, decreasing quality of life. Treatment of sleep disruption in the context of TBI is complicated by issues of an altered neuronal milieu, polypharmacy, and the complex relationship between the various comorbidities often found in patients with TBI. Given the growing number of veterans returning from combat with TBI and the elevated risk of comorbid disrupted sleep, both caused by and independent of TBI, a comprehensive review of sleep disruption and its treatment is of great relevance to the Department of Veterans Affairs.
View details for DOI 10.1682/JRRD.2008.08.0099
View details for Web of Science ID 000272638100014
View details for PubMedID 20104406
Emerging research implicates a consistent reciprocal relationship between late-life anxiety and cognition. Understanding this relationship may clarify pathophysiological substrates of cognitive impairment and why co-occurring anxiety and cognitive impairment relates to poorer treatment prognosis for both conditions. This article critically reviews evidence of more prevalent anxiety in cognitively impaired older adults, elevated anxiety related to poorer cognitive performance, and more severe anxiety symptoms predicting future cognitive decline. It considers pathophysiologic mediators and moderators, and the influence of comorbid depression or medical illness in anxiety. Identified directions for future research includes use of in-depth anxiety assessment comparing normal and mild cognitively impaired older adults and use of challenging neuropsychological tests to determine if specific cognitive domains suffer in anxious older adults.
View details for Web of Science ID 000259703400002
View details for PubMedID 18827225
Detection of preclinical cognitive deficits is important for identifying those at greatest risk for such disorders as Alzheimer's disease. However, available neuropsychological measures may not be sufficiently sensitive to preclinical cognitive impairment, particularly in high functioning or younger older adults. This study utilizes a battery of computerized cognitive tests (Cognometer) designed to provide a more sensitive measure of age-related cognitive performance by incorporating speed-of-processing components. Fifty-one community-dwelling older adults were administered the Cognometer battery, which incorporates speed-of-processing components into measures of verbal, spatial and working memory, attention, and visuo-spatial ability. Performance of 18 subjects with the epsilon4 allele was compared to that of 33 subjects without the epsilon4 allele. A brief battery of standard neuropsychological measures was also administered. No significant differences were observed between the two groups with respect to performance on any of the neuropsychological measures. However, with respect to the Cognometer battery, individuals with the epsilon4 allele were significantly slower in performing all the cognitive tasks, with the exception of the visuo-spatial task. With respect to performance, the two genotype groups did not differ significantly except on immediate memory, with the epsilon4 group exhibiting increased errors. Overall, the epsilon4 group was significantly slower in performing all of the Cognometer memory tasks. These findings provide continued support for the negative impact of the epsilon4 allele on cognition and further suggest that speed-of-processing during memory tasks may have the potential to detect subtle cognitive deficits.
View details for DOI 10.1016/j.jpsychires.2006.12.001
View details for Web of Science ID 000253397900004
View details for PubMedID 17250852
To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior.This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist.Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors.Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders.
View details for DOI 10.1002/ana.21243
View details for Web of Science ID 000253008700007
View details for PubMedID 17932962
The purpose of our study was to investigate the long-term effect of mnemonic training on memory performance in older adults. Five years after participation in a mnemonic training study, we followed-up 112 community-dwelling older adults, 60 years of age and over. Delayed recall of a word list was assessed prior to, and immediately following mnemonic training, and at the 5-year follow-up. Overall, there was no significant difference between word recall prior to training and that exhibited at follow-up. However, pre-training performance, gain scores in performance immediately post-training and use of the mnemonic predicted performance at follow-up. Individuals who self-reported using the mnemonic exhibited the highest performance overall, with scores significantly higher than at pre-training. Our findings suggest that mnemonic training has long-term benefits for some older adults, particularly those who continue to employ the mnemonic.
View details for DOI 10.1016/j.jpsychires.2006.04.010
View details for Web of Science ID 000245426800006
View details for PubMedID 16780878
View details for PubMedID 17521511
In this article, we review current research regarding diagnosis of cognitive impairment in nondemented adults and discuss why medications and cognitive training together may be more beneficial than either alone. We also review potential cognitive enhancers and future research challenges. There are major reasons for such research: (a) Large numbers of older adults without dementia but with cognitive problems are not treatable with current cognitive training techniques; (b) some medications offer a rationale (i.e., cognitive enhancement) and some evidence that they might be a useful adjunct; and (c) there are unanswered questions about which population to target, which medications to use, how to administer them, and issues regarding tolerance and use of appropriate (active) placebo controls. As the number of cognitively impaired older adults grows, it is likely that there will be pressure to treat more broadly with both medications and cognitive training.
View details for Web of Science ID 000253836500002
View details for PubMedID 17565161
The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic-pituitary-adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.
View details for DOI 10.1038/sj.mp.4001978
View details for Web of Science ID 000246906200003
View details for PubMedID 17353910
Multiple arguments for considering routine dementia screening have been presented. Furthermore, dementia diagnoses are widely unrecognized. As a result, persons with dementia are missing important clinical care and treatment interventions. By distinction, the problems of defining, diagnosing, and treating mild cognitive impairment (MCI) are not yet resolved, and MCI is not ready for a screening recommendation. Dementia screening approaches, including cognitive testing and functional assessment, must be evaluated on their scientific merits, including sensitivity and specificity for recognizing affected individuals in at-risk populations. Screening tests must be "cost-worthy", with the benefits of true-positive test results justifying the costs of testing and resolving false-positive cases, with due consideration for proper diagnostic evaluation and potential harms. With the tremendous number of new cases projected in the near future and the expected emergence of beneficial therapies, considerably more research is needed to develop more efficient screening systems.
View details for DOI 10.1016/j.jalz.2007.03.005
View details for Web of Science ID 000249579900002
View details for PubMedID 19595920
A common polymorphism (Val158Met) in the gene encoding for the catechol-O-methyltransferase (COMT) enzyme has been associated with differences in prefrontal cognitive function in schizophrenic patients and healthy adults. While several studies indicate that the Met allele is associated with better performance on measures of executive function, working memory and verbal fluency, results have been inconsistent. Furthermore, fewer studies have investigated this relationship in older adults, a group known to experience impairments in prefrontal cognitive functions. Additionally, findings vary according to the gender distribution of study participants. We examined whether COMT genotype interacted with gender to impact cognition in a cohort of 163 healthy, older adults. Memory, verbal ability and areas of prefrontal cognitive function, including attention, speed-of-processing, and executive function, were assessed. We found no significant association between COMT genotype and any cognitive measure. However, gender interacted with COMT genotype to impact cognitive performance. Males homozygous for the Val allele performed better than both the Val/Met and Met/Met groups on measures of delayed recall. Heterozygous women performed better than their homozygous counterparts on the measure of verbal ability. These findings suggest that gender may be an important variable in consideration of the impact of COMT on cognition. Further, when gender is taken into consideration, any negative impact of COMT genotype may extend to cognitive domains other than those associated with prefrontal regions.
View details for DOI 10.1016/j.neulet.2006.09.047
View details for Web of Science ID 000242448500010
View details for PubMedID 17029783
The daytime log-cortisol slope appears to be of growing importance in studying the relationship between stress and health. How best to estimate that slope with minimal burden to the participants and the cost of the study is a decision often made without empiric foundation.In 50 older participants, the authors examined cortisol assay comparability across laboratories, assay reliability, test-retest reliability of slopes, and comparability of slope estimates for two, three, and four samples per day.The authors demonstrate in an older sample that 1) assay reliability is a relatively minor issue, that one assay per saliva sample suffices; 2) the use of a sample obtained at wake time for each participant appears to be a preferred anchor for the slope estimate in comparison to a sample 30 minutes postwake time; 3) self-reported times appear preferable to automatic time recording; and 4) test-retest reliability of slopes, however, is not sufficiently high to base a slope estimate on one day; minimally two days and preferably three should be required.Whether these conclusions apply to other populations, or using other protocols, is not assured, but the study itself provides a model that can be used to check research decisions. Unnecessarily imposing a burdensome protocol has both ethical and scientific ramifications and should be carefully avoided.
View details for Web of Science ID 000236540800005
View details for PubMedID 16582041
The question of whether to screen for dementia and Alzheimer's disease (AD) has been discussed in many forums throughout the world. Generally, medical advisory groups and policy-making groups have recognized the importance of early diagnosis but have uniformly avoided making recommendations to screen at-risk populations. This presentation reflects the support for reconsidering the importance of screening individuals at risk or above a certain age. In this statement, the majority of the authors support the consideration of dementia risk factors in individuals at age 50, with routine yearly screening after 75. Other authors remain concerned that the benefits of treatments of early disease do not yet support a general screening recommendation. These statements are made to encourage progress toward the development of a consensus regarding the widespread institution of screening policy. Accordingly, members of the worldwide scientific community are invited to add their perspective by contributing short commentaries (1500 words) on this subject.
View details for DOI 10.1016/j.jalz.2006.02.005
View details for PubMedID 19595860
The current study used Department of Veteran's Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson's disease patients, and pesticide applications to determine if there was evidence for "blow-in" of pesticides as a factor in explaining the prevalence of Central Valley Parkinson's disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.
View details for DOI 10.1177/0891988705284707
View details for Web of Science ID 000235366800006
View details for PubMedID 16449758
Off-label prescribing of medications, polypharmacy, and other questionable prescribing practices have led investigators to examine a large VA pharmacy database to determine if physician prescribing decisions appear reasonable.The current study addresses the question of physician prescribing of atypical antipsychotics in 34,925 veterans with schizophrenia, using a series of signal detection analyses.These results suggest that only three factors (hospital size, age, and secondary diagnosis) allow classification of patients prescribed atypicals into three groups with frequencies of use of atypicals ranging from 43% to 79%, and that these results are consistent with reasonable clinical practice.Results of two-stage signal detection analyses are readily interpretable by clinicians and administrators who are faced with the task of evaluating how physicians prescribe medications in clinical practice. Physicians' decisions to prescribe atypical antipsychotics are based on both patient and fiscal considerations. This likely reflects a combination of clinical judgment and institutional guidelines.
View details for DOI 10.1016/j.jpsychires.2005.06.004
View details for Web of Science ID 000235641200009
View details for PubMedID 16150458
The authors examined the impact of hormone replacement therapy (HRT) on longitudinal cognitive performance (controlling for mood state) in 69 community-dwelling, postmenopausal women.The authors conducted a 5-year follow-up of cognitive performance in 37 postmenopausal HRT users and 32 non-users. The groups did not differ with respect to age, years of education, or inter-test interval.No main effect of HRT was observed on any of the cognitive measures, and depressive symptomatology did not affect the relationship between HRT and cognition.Overall, our findings do not suggest that HRT affects longitudinal cognitive performance in postmenopausal, community-dwelling older women.
View details for Web of Science ID 000233614500011
View details for PubMedID 16319304
The authors investigated the relationship between obstructive sleep apnea/hypopnea (OSAH) and cognition in 36 older adults, 18 APOE epsilon4 carriers, and 18 non-carriers. Greater numbers of respiratory events negatively impacted memory function in epsilon4 carriers only. This is the first study to provide preliminary evidence for a negative interaction of APOE epsilon4 and OSAH on memory in older adults, which may have important implications for treating cognitive decline and delaying dementia onset.
View details for Web of Science ID 000231371600035
View details for PubMedID 16116137
This descriptive study examined reports of behavioral problems among older patients hospitalized in acute care medical settings. Greater numbers of behavioral problems were reported by nursing staff on the Neuropsychiatric Inventory-Questionnaire than were documented in medical charts over the same time period. Such underreporting may have clinical and administrative implications.
View details for Web of Science ID 000230872100012
View details for PubMedID 16051916
Neuroimaging research on the brain basis of memory decline in older adults typically has examined age-related changes either in structure or in function. Structural imaging studies have found that smaller medial temporal lobe (MTL) volumes are associated with lower memory performance. Functional imaging studies have found that older adults often exhibit bilateral frontal-lobe activation under conditions where young adults exhibit unilateral frontal activation. As yet, no one has examined whether these MTL structural and frontal-lobe functional findings are associated. In this study, we tested whether these findings were correlated in a population of healthy older adults in whom we previously demonstrated verbal memory performance was positively associated with left entorhinal cortex volume in the MTL (Rosen et al., 2003) and right frontal lobe activation during memory encoding (Rosen et al., 2002). Thirteen, non-demented, community-dwelling older adults participated both in a functional MRI (fMRI) study of verbal memory encoding and structural imaging. MRI-derived left entorhinal volume was measured on structural images and entered as a regressor against fMRI activation during verbal memory encoding. Right frontal activation (Brodmann's Area 47/insula) was positively correlated with left entorhinal cortex volume. These findings indicate a positive association between MTL volume and right frontal-lobe function that may underlie variability in memory performance among the elderly, and also suggest a two-stage model of memory decline in aging.
View details for Web of Science ID 000230574200015
View details for PubMedID 16042035
For over two decades clinical studies have been conducted which suggest the existence of a relationship between depression and Obstructive Sleep Apnea (OSA). Recently, Ohayon underscored the evidence for a link between these two disorders in the general population, showing that 800 out of 100,000 individuals had both, a breathing-related sleep disorder and a major depressive disorder, with up to 20% of the subjects presenting with one of these disorders also having the other. In some populations, depending on age, gender and other demographic and health characteristics, the prevalence of both disorders may be even higher: OSA may affect more than 50% of individuals over the age of 65, and significant depressive symptoms may be present in as many as 26% of a community-dwelling population of older adults. In clinical practice, the presence of depressive symptomatology is often considered in patients with OSA, and may be accounted for and followed-up when considering treatment approaches and response to treatment. On the other hand, sleep problems and specifically OSA are rarely assessed on a regular basis in patients with a depressive disorder. However, OSA might not only be associated with a depressive syndrome, but its presence may also be responsible for failure to respond to appropriate pharmacological treatment. Furthermore, an undiagnosed OSA might be exacerbated by adjunct treatments to antidepressant medications, such as benzodiazepines. Increased awareness of the relationship between depression and OSA might significantly improve diagnostic accuracy as well as treatment outcome for both disorders. In this review, we will summarize important findings in the current literature regarding the association between depression and OSA, and the possible mechanisms by which both disorders interact. Implications for clinical practice will be discussed.
View details for PubMedID 15982424
Oxybutynin is a powerful anticholinergic drug already known to impair cognition in the elderly. The impact of this drug on cognitive functioning in the pediatric population is unknown. We report the results of a study designed to assess the effect of oxybutynin on cognitive function in children.A total of 25 patients presenting with the primary symptom of daytime enuresis were recruited for this nonrandomized trial. All subjects initially received 4 weeks of behavior modification, followed by an additional 4 weeks of behavior modification either alone or with oxybutynin for continued treatment of enuresis. Neuropsychological testing was performed at baseline (4 weeks) and after additional therapy (8 weeks).Patient demographics included a male-to-female ratio of 11:14 and a mean age of 7.2 +/- 1.8 years. A total of 10 patients were assigned to the control group receiving behavior modification, and 15 patients were assigned to the treatment group receiving behavior modification plus oxybutynin. The oxybutynin treated patients had a lower overall performance at baseline pretreatment testing. However, performance in this group improved following treatment with oxybutynin.Oxybutynin, a commonly used pharmacological agent in pediatric urology, was not associated with cognitive impairment following treatment. However, we observed lower baseline cognitive functioning in patients whose parents chose oxybutynin over behavior modification alone. This finding may represent a selection bias. However, it also supports the need for a multidisciplinary approach to the treatment of patients with dysfunctional voiding, as some may have cognitive difficulties that have not previously been explored.
View details for Web of Science ID 000229051700055
View details for PubMedID 15879864
Differences in cognitive ability and domain-specific expertise may help explain age differences in pilot performance. Pilots heard air-traffic controller messages and then executed them while "flying" in a simulator. Messages varied in length and speech rate. Age was associated with lower accuracy, but the expected Age x Message Difficulty interactions were not obtained. Expertise, as indexed by pilot ratings, was associated with higher accuracy; yet expertise did not reduce age differences in accuracy. The effect of age on communication task accuracy was largely explainable as an age-associated decrease in working memory span, which in turn was explainable as decreases in both speed and interference control. Results are discussed within frameworks of deliberate practice and cognitive mediation of age differences.
View details for DOI 10.1037/0882-79126.96.36.199
View details for Web of Science ID 000227731300009
View details for PubMedID 15769218
The purpose of this study was to assess whether pharmacy database information from US Department of Veterans Affairs (VA) medical centers could be used to screen for areas of higher Parkinson's disease prevalence in patients exposed to pesticides. The authors used pharmacy data sets and compared the use of antiparkinsonian medications at 2 VA medical centers in California: one in Palo Alto, near the ocean, and one in Fresno, downwind from extensively farmed parts of the Central Valley. They found that patients at Fresno had higher odds ratios (1.5-1.8) for the use of Parkinson's disease medications than patients at Palo Alto. These data are consistent with the observations of prior epidemiologic studies and suggest that VA pharmacy databases can prioritize locations for further epidemiologic research. However, a thorough exploration of alternative explanations is needed to reach definitive conclusions regarding the findings suggested by this method.
View details for DOI 10.1117/0891988703258672
View details for Web of Science ID 000223474900007
View details for PubMedID 15018696
Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele.
View details for DOI 10.1117/0891988703261994
View details for Web of Science ID 000223474900004
View details for PubMedID 15018693
The arguments pitting categorical versus dimensional approaches to psychiatric diagnosis have been long ongoing with little sign of imminent resolution. We argue that categorical and dimensional approaches are fundamentally equivalent, but that one or other approach is more appropriate depending on the clinical circumstances and research questions being addressed. This paper aims to demonstrate (a) how these two approaches necessarily interdigitate, (b) to clarify the conditions under which one should utilize one approach over the other, and (c) to alert psychiatric clinicians and researchers to issues in the methodology literature that might facilitate their considerations. Using an example from the Infant Health and Development Program (IHDP), we illustrate the importance of using dimensional approaches for hypothesis testing, identify the problems with power and with interpretation that arise from employing a categorical approach, and underscore the importance of identifying the appropriate cutpoints when a categorical approach is necessitated. We argue that failure to utilize the correct approach under the appropriate circumstances can result in impaired clinical and research decision-making.
View details for DOI 10.1016/S0022-3956(03)00097-9
View details for Web of Science ID 000220190700003
View details for PubMedID 14690767
Magnetic resonance imaging-derived entorhinal and hippocampal volumes were measured in 14 nondemented, community-dwelling older adults. Participants were selected so that memory scores from 2 years prior to scanning varied widely but were not deficient relative to age-appropriate norms. A median split of these memory scores defined high-memory and low-memory groups. Verbal memory scores at the time of imaging were lower, and entorhinal and hippocampal volumes were smaller, in the low-memory group than in the high-memory group. Left entorhinal cortex volume showed the strongest correlation (r= .79) with immediate recall of word lists. Left hippocampal volume showed the strongest correlation (r= .57) with delayed paragraph recall. These results suggest that entorhinal and hippocampal volumes are related to individual differences in dissociable kinds of memory performance among healthy older adults.
View details for DOI 10.1037/0735-7044.117.6.1150
View details for Web of Science ID 000187402300004
View details for PubMedID 14674836
We used a novel application of a signal detection technique, receiver operator characteristics (ROC), to describe factors entering a physician's decision to switch a patient from a typical high potency neuroleptic to a particular atypical, olanzapine (OLA) or risperidone (RIS).ROC analyses were performed on pharmacy records of 476 VA patients who had been treated on a high potency neuroleptic then changed to either OLA or RIS.Overall 68% patients switched to OLA and 32% to RIS. The best predictor of neuroleptic choice was age at switch, with 78% of patients aged less than 55 years receiving OLA and 51% of those aged greater than or equal to 55 years receiving OLA (chi(2)=38.2, P<0.001). Further analysis of the former group indicated that adding the predictor of one or more inpatient days to age increased the likelihood of an OLA switch from 78% to 85% (chi(2)=7.3, P<0.01) while further analysis of the latter group indicated that adding the predictor of less than 10 inpatients days to age decreased the likelihood of an OLA switch from 51% to 45% (chi(2)=7.0, P<0.01).ROC analyses have the advantage over other analyses, such as regression techniques, insofar as their "cut-points" are readily interpretable, their sequential use forms an intuitive "decision tree" and allows the potential identification of clinically relevant "subgroups". The software used in this analysis is in the public domain (http://mirecc.stanford.edu).
View details for DOI 10.1016/S0022-3956(03)00053-0
View details for Web of Science ID 000186239700010
View details for PubMedID 14563385
The cholinergic system plays a major role in cognitive abilities that are essential to piloting an aircraft: attention, learning, and memory. In previous studies, drugs that enhance the cholinergic system through different pharmacologic mechanisms have shown beneficial effects on cognition; but dissimilar cognitive measures were used and samples were not comparable. A comparison within the same cognitive tasks, within comparable samples appears desirable. Toward this aim, we compared effect sizes (ES) of performance-enhancing doses of nicotine (a nicotinic receptor agonist) and donepezil (an acetylcholinesterase inhibitor) as found in our prior work on pilot performance. We also compared cholinergic ES to those of performance-impairing doses of alcohol. In three randomized, placebo-controlled trials, we assessed the flight performance of aircraft pilots in a Frasca 141 simulator, testing I: the acute effects of nicotine gum 2 mg; II: the effects of administration of 5 mg donepezil/day for 30 days; and III: the acute and 8 h-carryover effects of alcohol after a target peak BAC of 0.10%. We calculated the ES of nicotine, donepezil, and alcohol on a flight summary score and on four flight component scores. Compared to placebo, nicotine and donepezil significantly improved, while alcohol significantly impaired overall flight performance: ES (nicotine)=0.80; ES (donepezil)=1.02; ES (alcohol acute)=-3.66; ES (alcohol 8 h)=-0.82. Both cholinergic drugs showed the largest effects on flight tasks requiring sustained visual attention. Although the two tested cholinergic drugs have different pharmacologic mechanisms, their effects on flight performance were similar in kind and size. The beneficial effects of the cholinergic drugs on overall flight performance were large and the absolute (ie nondirectional) sizes were about one-fourth of the absolute ES of acute alcohol intoxication and roughly the same as the absolute 8 h-carryover ES of alcohol.
View details for DOI 10.1038/sj.npp.1300202
View details for Web of Science ID 000183773000018
View details for PubMedID 12784106
Declarative memory declines with age, but there is profound variation in the severity of this decline. Healthy elderly adults with high or low memory scores and young adults viewed words under semantic or non-semantic encoding conditions while undergoing fMRI. Young adults had superior memory for the words, and elderly adults with high memory scores had better memory for the words than those with low memory scores. The elderly with high scores had left lateral and medial prefrontal activations for semantic encoding equal to the young, and greater right prefrontal activation than the young. The elderly with low scores had reduced activations in all three regions relative to the elderly with high memory scores. Thus, successful aging was characterized by preserved left prefrontal and enhanced right prefrontal activation that may have provided compensatory encoding resources.
View details for DOI 10.1097/01.wnr.0000048001.96487.05
View details for Web of Science ID 000180673200010
View details for PubMedID 12499842
A number of systems have been proposed for classifying older adults who suffer from cognitive impairment or decline but do not yet meet criteria for Alzheimer's disease (AD). The classification, Mild Cognitive Impairment (MCI), has attracted much attention. It uses relatively specific diagnostic criteria and individuals who meet these criteria appear to be at substantial risk for the development of AD. However, little data is available to define the prevalence of MCI in any age group. We propose a simple mathematical model for the progression of patients from Non-Affected (NA) to MCI to AD. This first-order Markov model defines the likely prevalence of MCI at specific ages. Primary assumptions of the model include an AD prevalence of 1% at age 60 increasing to 25% at age 85 and a conversion rate from MCI to AD of 10% constant across all ages considered. We used the best available information for our model and found (1) that the MCI prevalence increased from 1% at age 60 to 42% at age 85 and (2) that the conversion rate from NA to MCI increased from 1% per year at age 60 to 11% at age 85. In conclusion, this model allows estimation of prevalence of MCI and conversion from NA to MCI based upon known prevalences of AD, conversion rates of MCI to AD, and death rates. Due to its substantial prevalence, MCI may be an important target for screening and possible intervention.
View details for Web of Science ID 000178254700002
View details for PubMedID 12127595
We report a randomized, double-blind, parallel group, placebo-controlled study to test the effects of the acetylcholinesterase inhibitor, donepezil (5 mg/d for 30 days), on aircraft pilot performance in 18 licensed pilots with mean age of 52 years. After 30 days of treatment, the donepezil group showed greater ability to retain the capacity to perform a set of complex simulator tasks than the placebo group, p < 0.05. Donepezil appears to have beneficial effects on retention of training on complex aviation tasks in nondemented older adults.
View details for Web of Science ID 000176622600025
View details for PubMedID 12105320
In the current study of 1062 Alzheimer's disease (AD) patients, we employed receiver operating characteristic curve analysis to identify characteristics of patients at increased risk for rapid cognitive decline. The patients are participants at one of the nine Alzheimer's Disease Research Centers of California. Rapid decline was defined as a 3-point or greater loss on the Mini-Mental State Examination (MMSE) per year, post visit. The independent variables were age at clinic visit, age at symptom onset of AD, MMSE at patient visit, years of education, gender, ethnicity, living arrangement, presence of aphasia, delusions, hallucinations, and extrapyramidal signs. Receiver operating characteristic curve analysis indicated that AD patients presenting with moderate to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater than 7 were at increased risk for rapid cognitive decline. This information could help clinicians target these patients for pharmacologic interventions, facilitate long-term care planning, and potentially create savings by delaying or stabilizing the course of the disease.
View details for Web of Science ID 000179584400009
View details for PubMedID 12489920
OBJECTIVES: (a) To determine the quantity and quality of behavioral problems in older hospitalized patients on acute care units; (b) to determine the burden of these behaviors on staff; and (c) to identify predictors of behavioral problems. METHODS: Upon admission, patients performed the Mini-Mental State Exam (MMSE), the Geriatric Depression Scale (GDS), and information was obtained on age, ethnicity, level of education, living arrangement, and psychiatric history. Two days post-admission, a clinical staff member caring for each patient, performed the Neuropsychiatric Inventory-Questionnaire (NPI-Q) to assess patients' behavioral problems and staff distress. PARTICIPANTS AND SETTING : Forty-two patients, over 60 years of age, admitted to medical and surgical units of the Veterans Affairs Hospitals in Palo Alto and San Francisco, participated. RESULTS: Twenty-three of 42 (55%) patients exhibited behavioral problems. Anxiety, depression, irritability, and agitation/aggression were the most frequently observed behaviors. The severity of the behavioral problems was significantly correlated with staff distress. Lower performance on the MMSE at admission was significantly associated with higher NPI-Q ratings. Specifically, of those cases with scores less than or equal to 27 on the MMSE, 66% had behavioral problems during hospitalization, compared to only 31% of those with scores greater than 27. CONCLUSION: Behavioral problems in older hospitalized patients appear to occur frequently, are a significant source of distress to staff, and can result in the need for psychiatric consultation. Assessment of the mental status of older adults at admission to hospital may be valuable in identifying individuals at increased risk for behavioral problems during hospitalization.
View details for PubMedID 12537601
We examined the effect of the apolipoprotein E (apo E) epsilon4 allele on the relationship between self-reported stress and mood in caregivers of patients with Alzheimer's disease. Eighty-six female subjects between the ages of 28 and 82 years who were community-dwelling AD patient caregivers participated in the study. A cross-sectional analysis of stress and mood was performed using the Revised Memory and Behavior Problem Checklist and the Geriatric Depression Scale. All subjects were evaluated for normal cognitive function (Mini-Mental Status Examination) and apo E genotype. The results indicated that increased levels of stress were associated with increased levels of depressive symptoms in nondemented caregivers with the epsilon4 allele. This relationship was not observed in caregivers without the epsilon4 allele. These results suggest that carriers of the epsilon4 allele may respond differently to psychological stress than do individuals without the epsilon4 allele.
View details for Web of Science ID 000170894200002
View details for PubMedID 11563433
The United Nations projects that the number of individuals with dementia in developed countries alone will be approximately 36,7 million by the year 2050. International recognition of the significant emotional and economic burden of Alzheimer's disease has been matched by a dramatic increase in the development of pharmacological and nonpharmacological approaches to this illness in the past decade. Changing demographics have underscored the necessity to develop similar approaches for the remediation of the cognitive impairment associated with more benign syndromes, such as mild cognitive impairment (MCI) and age-associated cognitive decline (AACD). The present article aims to provide an overview of the most current therapeutic approaches to age-associated neurocognitive disorders. Additionally, it discusses the conceptual and methodological issues that surround the design, implementation, and interpretation of such approaches.
View details for PubMedID 22033831
Previous studies investigating the influence of the menstrual cycle on cognitive functioning of women after alcohol ingestion have obtained inconsistent results. The present study tested the hypothesis that flight simulator performance during acute alcohol intoxication and 8 hours after drinking differs between the menstrual and the luteal phase of the menstrual cycle.White female pilots (N = 24) were tested during the menstrual and the luteal phases of their menstrual cycles. On each test day they performed a baseline simulator flight, consumed 0.67 g/kg ethanol, and performed an acute-intoxication and an 8-hour-carryover simulator flight.Subjects reached highly significant increases in estradiol (E2) as well as progesterone (P) levels during the luteal test day. Yet, there were no significant differences in overall flight performance after alcohol ingestion between the menstrual and luteal phases during acute intoxication or at 8-hour carryover. We found no correlations between E, or P levels and overall flight performance. However, there was a statistically significant Phase x Order interaction: Pilots who started the experiment with their menstrual day were less susceptible to the effects of alcohol during the second test day than were pilots who started with their luteal day.The tested menstrual cycle phases and varying E2 and P levels did not significantly influence postdrink flight performance. Because the present study included a comparatively large sample size and because it involved complex "real world" tasks (piloting an aircraft), we believe that the present findings are important. We hope that our failure to detect menstrual cycle effects will encourage researchers to include women in their investigations of alcohol effects and human performance.
View details for Web of Science ID 000170348900002
View details for PubMedID 11523532
Studies about whether or not the cognitive performance of women is influenced by changes in levels of sex steroid hormones across the menstrual cycle have produced ambiguous results.This study tested whether flight simulator performance differs significantly between the menstrual and the luteal phase of the menstrual cycle.In a within-subjects design, 24 female pilots were tested twice during their menstrual cycle: once during the menstrual and once during the luteal phase. On both test days they performed a 75-min simulator flight in a Frasca 141, a popular pilot training device.Despite highly significant differences in estradiol (E2) as well as progesterone (P) levels on the 2 test days, and despite excluding subjects with anovulatory cycles from the analyses, there were no significant differences in overall flight performance between the menstrual and luteal phases. We found no significant correlations between E2 or P levels and flight performance.We found no evidence that the tested menstrual cycle phases and their associated E2 and P levels significantly influence flight simulator performance. We consider these negative findings based on 24 subjects meaningful because previous studies on the influence of menstrual cycle on cognitive performance have not involved complex "real world" tasks such as piloting an aircraft and they obtained inconsistent results.
View details for Web of Science ID 000168778000013
View details for PubMedID 11401010
The Apolipoprotein-E (APOE) epsilon 4 allele is a risk factor for Alzheimer's disease (AD) and cognitive decline in older adults. Depression may also be a risk factor for dementia, and depression is important in the differential diagnosis of dementia. The authors performed a 5-year longitudinal study of APOE genotype and change in Geriatric Depression Scale scores in 113 community-dwelling older adults. No association was observed between APOE genotype and change in depressive symptoms. These results do not support the hypothesis that the APOE epsilon 4 allele is associated with depression. Important objections have been raised to APOE genotyping in the diagnosis of AD. However, the specificity of APOE genotyping in AD diagnosis would not appear to be compromised by an association with depression.
View details for Web of Science ID 000088230700003
View details for PubMedID 10910416
We report on the relationship between CogScreen-Aeromedical Edition (AE) factor scores and flight simulator performance in aircraft pilots aged 50-69.Some 100 licensed, civilian aviators (average age 58+/-5.3 yr) performed aviation tasks in a Frasca model 141 flight simulator and the CogScreen-AE battery. The aviation performance indices were: a) staying on course; b) dialing in communication frequencies; c) avoiding conflicting traffic; d) monitoring cockpit instruments; e) executing the approach; and f) a summary score, which was the mean of these scores. The CogScreen predictors were based on a factor structure reported by Kay (11), which comprised 28 CogScreen scores. Through principal components analysis of Kay's nine factors, we reduced the number of predictors to five composite CogScreen scores: Speed/Working Memory (WM), Visual Associative Memory, Motor Coordination, Tracking, and Attribute Identification.Speed/WM scores had the highest correlation with the flight summary score, Spearman r(rho) = 0.57. A stepwise-forward multiple regression analysis indicated that four CogScreen variables could explain 45% of the variance in flight summary scores. Significant predictors, in order of entry, were: Speed/WM, Visual Associative Memory, Motor Coordination, and Tracking (p<0.05). Pilot age was found to significantly improve prediction beyond that which could be predicted by the four cognitive variables. In addition, there was some evidence for specific ability relationships between certain flight component scores and CogScreen scores, such as approach performance and tracking errors.These data support the validity of CogScreen-AE as a cognitive battery that taps skills relevant to piloting.
View details for Web of Science ID 000086061300002
View details for PubMedID 10766461
The Geriatric Depression Scale-15 (GDS-15) is a short, 15-item instrument specifically designed to assess depression in geriatric populations. Its items require a yes/no response. The Geriatric Depression Scale was first introduced by Yesavage et al. in 1983, and the short form (GDS-15) was developed by Sheikh and Yesavage in 1986. The aim of the current study was the standardization of the GDS-15 for use in Greece. Subjects were divided into Group A: 168 control subjects, and Group B: 103 patients suffering from clinically diagnosed depression. All were over 65 years of age. A score of 6/7 on the GDS-15 was found to be the best cut-off point for diagnosing depression in an elderly Greek population, with Sensitivity = 92.23 and Specificity = 95.24. GDS-15 manifests high internal consistency with Cronbach's alpha = 0.94, and all items seem to be equivalent. Factor Analysis of the GDS-15 revealed 4 factors: a cognitive (thought content), an affective, a functional, and a factor that reflects helplessness and fear for the future. The two diagnostic groups differed on all 4 factors scores at p-value <0.001.
View details for Web of Science ID 000085695000004
View details for PubMedID 10738851
To determine the relationship between age and aviator performance on a flight simulator.A cross-sectional observational study.The sample consisted of 100 aviators aged 50 to 69 (mean = 58).Pilots were tested on a Frasca 141 flight simulator (Urbana, IL), linked to a UNIX-based IRIS 4D computer (Silicon Graphics, Mountain View, CA), which both generated graphics of the environment in which the pilots flew and collected data concerning the aircraft's flight conditions.We found that increased age was significantly associated with decreased aviator performance on a flight simulator.Although there was a significant relationship between increased age and decreased aviator performance, age explained 22% or less of the variance of performance on different flight tasks; hence, other factors are also important in explaining the performance of older pilots.
View details for Web of Science ID 000081323400007
View details for PubMedID 10404925
This study investigated the influence of menstrual cycle and female sex steroid levels on ethanol pharmacokinetics. In a within-subjects design, 24 female volunteers each consumed 0.67 g x kg(-1) ethanol during the menstrual and luteal phases of their menstrual cycle. On each test day, we collected blood samples before ethanol administration to determine estradiol (E2) and progesterone (P) levels and to confirm ovulation. We took 20 or more postdrink breath ethanol concentration readings and examined pharmacokinetic differences between the two phases, using classical pharmacokinetic measures, as well as Michaelis-Menten measures. Despite highly significant differences in measured E2 as well as P levels on the 2 test days, and despite excluding subjects with anovulatory cycles from the analysis, there were no significant differences between menstrual and luteal phases for any of the pharmacokinetic variables. We found no correlation between E2 or P levels and any of the pharmacokinetic measures. In summary, we found no evidence that the tested menstrual cycle phases or varying E2 and progesterone levels significantly influence ethanol pharmacokinetics. Because previous studies about the topic have used few subjects and revealed controversial results, we consider our negative findings based on 24 subjects meaningful.
View details for Web of Science ID 000078678700009
View details for PubMedID 10069553
Women appear to become more impaired than men after drinking equivalent amounts of alcohol, achieving higher blood alcohol concentrations even when doses are adjusted for body weight. This finding may be attributable in part to gender differences in total body water content. Men and women appear to eliminate approximately the same total amount of alcohol per unit body weight per hour. However, women seem to eliminate significantly more alcohol per unit of lean body mass per hour than men. Some studies report that women are more susceptible than men to alcohol-related impairment of cognitive performance, especially in tasks involving delayed memory or divided attention functions. Psychomotor performance impairment, however, does not appear to be affected by gender. This article provides an overview of alcohol metabolism (pharmacokinetics) and reviews recent studies on gender differences in alcohol absorption, distribution, elimination, and impairment. Speculation that gender differences in alcohol pharmacokinetics or alcohol-induced performance impairment may be caused by the menstrual cycle and variations in female sex hormones are discussed. It is concluded that the menstrual cycle is unlikely to influence alcohol pharmacokinetics.
View details for Web of Science ID 000084105600008
View details for PubMedID 10890798
This study investigated whether the Apolipoprotein (APOE) epsilon4 allele was associated with cognitive decline in community-dwelling older adults.Longitudinal cognitive performance of older adults with the epsilon3/epsilon4 genotype was compared with that of older adults with the epsilon3/epsilon3 genotype.Aging Clinical Research Center, Stanford University.One hundred community-dwelling older adults were recruited from a pool of 531 individuals who had participated in a memory training study 4 to 5 years earlier. These individuals were concerned about their memory functioning and were recruited through newspaper advertisements and contacts with local senior centers. The 100 individuals who agreed to participate in the follow-up investigation were between 59 and 95 years of age.At both baseline and follow-up, subjects were administered a battery of seven cognitive tests that examined verbal and spatial memory, attention, speed-of-processing, and language abilities. APOE genotype was determined at follow-up.Individuals with the epsilon3/epsilon4 APOE genotype were significantly younger than individuals with the APOE epsilon3/epsilon3 genotype. No significant differences were observed between the two groups on measures of attention, speed-of-processing, vocabulary, immediate verbal memory, and immediate spatial memory. However, those older adults with the epsilon3/epsilon4 genotype exhibited significantly greater decline in performance on delayed recall of verbal material than did those with the epsilon3/epsilon3 APOE genotype.These findings are consistent with previous studies, which suggest that the APOE epsilon4 allele predicts decline on measures of delayed recall.
View details for Web of Science ID 000077358700001
View details for PubMedID 9848808
In a placebo-controlled study, we investigated the influence of nicotine on late-day aviation performance in 15 non-smoking subjects. In a within-subjects design, subjects were tested on 2 days, each lasting 8 h and consisting of three 75-min simulator flights (late-afternoon practice, evening test, night test). Prior to each test, subjects received either nicotine polacrilex 2 mg or placebo gum. As expected, overall performance was significantly better after nicotine, compared to placebo (P < 0.01). Post-hoc analysis of individual flight tasks showed that nicotine improved scores on approach to landing, a task which appears to require sustained attention. We conclude that nicotine may improve late-day flight performance in non-smoking aviators.
View details for Web of Science ID 000077151700005
View details for PubMedID 9862400
View details for Web of Science ID 000222209400569