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ObjectiveMajor depression in older adults increases the statistical likelihood of dementia. It is challenging to translate statistical evidence of cognitive decline at the group level into knowledge of individual cognitive outcomes. The objective of the current study is to investigate 2-year reliable cognitive change in late-life depression (LLD), which will enhance understanding of cognitive changes in LLD and provide a means to assess individual change.MethodsIn a sample of non-depressed cognitively normal older adults or NDCN (n = 113), we used linear regression to predict tests of global cognition, processing speed-executive functioning, and memory administered 1 and 2 years later. Stepwise regression was used to select covariates among demographics and raw test scores (either baseline or year 1) and we cross-validated the final models using the predicted residual error sum of squares (PRESS). We then derived a z-change score from the difference between actual and predicted follow-up scores and investigated the proportion of LLD patients (n = 199) and NDCN adults who experienced reliable “decline” (a z-score +1.645).ResultsA greater proportion LLD compared with NDCN experienced cognitive decline in processing speed/executive functioning and global cognition over 2 years. When compared to NDCN, a greater proportion of LLD also significantly improved on one test of processing speed over 2 years.ConclusionsOlder adults with LLD are at risk of meaningful cognitive decline over a relatively short period, particularly in the domain of executive functioning and processing speed. This study provides a series of reliable change equations for common neuropsychological tests that can be applied clinically.

Objective: This study sought to conduct a comprehensive search for genetic risk of cognitive decline in the context of geriatric depression. Design: A genome-wide association study (GWAS) analysis in the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. Setting: Longitudinal, naturalistic follow-up study. Participants: Older depressed adults, both outpatients and inpatients, receiving care at an academic medical center. Measurements: The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery was administered to the study participants at baseline and a minimum of twice within a subsequent 3-year period in order to measure cognitive decline. A GWAS analysis was conducted to identify genetic variation that is associated with baseline and change in the CERAD Total Score (CERAD-TS) in NCODE. Results: The GWAS of baseline CERAD-TS revealed a significant association with an intergenic single-nucleotide polymorphism (SNP) on chromosome 6, rs17662598, that surpassed adjustment for multiple testing (p = 3.7 × 10−7; false discovery rate q = 0.0371). For each additional G allele, average baseline CERAD-TS decreased by 8.656 points. The most significant SNP that lies within a gene was rs11666579 in SLC27A1 (p = 1.1 × 10−5). Each additional copy of the G allele was associated with an average decrease of baseline CERAD-TS of 4.829 points. SLC27A1 is involved with processing docosahexaenoic acid (DHA), an endogenous neuroprotective compound in the brain. Decreased levels of DHA have been associated with the development of Alzheimer’s disease. The most significant SNP associated with CERAD-TS decline over time was rs73240021 in GRXCR1 (p = 1.1 × 10−6), a gene previously linked with deafness. However, none of the associations within genes survived adjustment for multiple testing. Conclusions: Our GWAS of cognitive function and decline among individuals with late-life depression (LLD) has identified promising candidate genes that, upon replication in other cohorts of LLD, may be potential biomarkers for cognitive decline and suggests DHA supplementation as a possible therapy of interest.

Introduction Alcohol use disorder interferes with antidepressant treatment in older adults with major depression (LLD) and is associated with suicidal ideation. Less is known about the effects of moderate alcohol use in LLD on mood and cognitive outcomes over time. Much of the evidence on alcohol use and cognition and mood stems from epidemiological research and not clinical studies of depressed older adults. The purported benefits of moderate alcohol use on older adults’ cognitive functioning have often been reported. Yet, not all studies report a positive association between moderate alcohol use and cognitive functioning, and there is also other evidence to suggest moderate alcohol use is correlated with markers of poorer brain health in older adults (e.g., atrophy). In respect to mood, epidemiological research suggests little to no association between moderate alcohol use and depression in older adults or even an inverse association with increased social interactions as a mediator. Given the times at conflicting evidence and the lack of longitudinal studies in well-defined clinical samples, we hypothesized that depressed older adults who were moderate drinkers would experience greater cognitive decline compared to depressed non-drinkers. We also hypothesized that moderate alcohol use would have a detrimental effect on depression illness course in older adults with LLD. Methods This study used data from Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. NCODE participants underwent annual neuropsychological evaluations with the Consortium to Establish a Registry of Alzheimer's Disease (CERAD) cognitive battery as well as other tests of executive functioning and processing speed (e.g., Trail Making Test). Participants also underwent annual depression severity ratings with a geriatric psychiatrist using the Montgomery Asberg Depression Rating Scale (MADRS). We used patients self-reported alcohol use at the time of study entry and characterized them as either abstainers (n=81) and moderate drinkers (n=30). We were also able to define a small sample of risky drinkers (n=10) and included this group for exploratory reasons. Alcohol use was based upon NIAAA guidelines for older adult alcohol consumption. Risky alcohol use exceeded NIAAA alcohol consumption guidelines for older adults (meaning >=3 drinks per day or >=8 drinks per week) and moderate alcohol use was defined as Results In terms of cognition, we found that the total CERAD score of moderate and heavy drinkers significantly declined compared to no alcohol use patients (e.g.,moderate alcohol use x time interaction term estimate = -.00410, DF = 898, t = -5.02, p Conclusions Moderate alcohol consumption appears to have a beneficial impact on depression severity and a detrimental impact on cognitive functioning in LLD patients followed for upwards of five years. Larger samples are needed to confirm the findings in this small and exploratory study.

Objective Late-life depression is associated with cognitive deficits and increased risk for cognitive decline. The purpose of the study was to determine whether clinical characteristics could serve as phenotypes informative of subsequent cognitive decline. Age at depression onset and antidepressant remission at 3 months (acute response) and 12 months (chronic response) were examined. Methods In a longitudinal study of late-life depression in an academic center, 273 depressed and 164 never-depressed community-dwelling elders aged 60 years or older were followed on average for over 5 years. Participants completed annual neuropsychological testing. Neuropsychological measures were converted to z-scores derived from the baseline performance of all participants. Cognitive domain scores at each time were then created by averaging z-scores across tests, grouped into domains of episodic memory, attention-working memory, verbal fluency, and executive function. Results Depressed participants exhibited poorer performance at baseline and greater subsequent decline in all domains. Early-onset depressed individuals exhibited a greater decline in all domains than late-onset or nondepressed groups. For remission, remitters and nonremitters at both 3 and 12 month exhibited greater decline in episodic memory and attention-working memory than nondepressed subjects. Three-month remitters also exhibited a greater decline in verbal fluency and executive function, whereas 12-month nonremitters exhibited greater decline in executive function than other groups. Conclusion Consistent with past studies, depressed elders exhibit greater cognitive decline than nondepressed subjects, particularly individuals with early depression onset, supporting the theory that repeated depressive episodes may contribute to decline. Clinical remission is not associated with less cognitive decline.

Objective Exposure to stressful events is associated with both occurrence of depression and also vascular disease. The objective of this study was to determine whether higher levels of stress exposure was related to measures of pathological brain aging, specifically white matter hyperintensity volumes, in older adults with and without depression. Methods The sample included 130 depressed and 110 never-depressed older adults aged 60 years or older enrolled in a longitudinal study at an academic medical center. Participants completed clinical assessments, assessment of stressful event exposure and perceived stress, and magnetic resonance imaging at baseline and after 2 years. Analyses examined both cross-sectional and longitudinal relationships between stress measures and white matter hyperintensity volumes. Results There were no statistically significant relationships observed between cross-sectional baseline stress measures and either baseline hyperintensity volume or 2-year change in hyperintensity volume. However, after controlling for demographic variables and baseline measures, change in stressor exposure was associated with change in hyperintensity volumes. In this analysis, increased stressor exposure was associated with greater increases in white matter hyperintensity volume, while reductions in stressor exposure were associated with less increase in hyperintensity volume. This relationship did not significantly differ based on the presence of either depression or medical comorbidities. Conclusions This work adds to a growing literature associating exposure to stressful events in later life with more rapid pathological brain aging. Work is needed to understand the physiological mechanisms by which stress exposure has this effect and examine whether stress reduction techniques may modify these observed outcomes. Copyright © 2016 John Wiley & Sons, Ltd.

BackgroundChildhood early life stress (ELS) increases risk of adulthood major depressive disorder (MDD) and is associated with altered brain structure and function. It is unclear whether specific ELSs affect depression risk, cognitive function and brain structure.MethodThis cross-sectional study included 64 antidepressant-free depressed and 65 never-depressed individuals. Both groups reported a range of ELSs on the Early Life Stress Questionnaire, completed neuropsychological testing and 3T magnetic resonance imaging (MRI). Neuropsychological testing assessed domains of episodic memory, working memory, processing speed and executive function. MRI measures included cortical thickness and regional gray matter volumes, with a priori focus on the cingulate cortex, orbitofrontal cortex (OFC), amygdala, caudate and hippocampus.ResultsOf 19 ELSs, only emotional abuse, sexual abuse and severe family conflict independently predicted adulthood MDD diagnosis. The effect of total ELS score differed between groups. Greater ELS exposure was associated with slower processing speed and smaller OFC volumes in depressed subjects, but faster speed and larger volumes in non-depressed subjects. In contrast, exposure to ELSs predictive of depression had similar effects in both diagnostic groups. Individuals reporting predictive ELSs exhibited poorer processing speed and working memory performance, smaller volumes of the lateral OFC and caudate, and decreased cortical thickness in multiple areas including the insula bilaterally. Predictive ELS exposure was also associated with smaller left hippocampal volume in depressed subjects.ConclusionsFindings suggest an association between childhood trauma exposure and adulthood cognitive function and brain structure. These relationships appear to differ between individuals who do and do not develop depression.

Background Late-life depression (LLD) is associated with a fragile antidepressant response and high recurrence risk. This study examined what measures predict recurrence in remitted LLD. Methods Individuals of age 60 years or older with a Diagnostic and Statistical Manual - IV (DSM-IV) diagnosis of major depressive disorder were enrolled in the neurocognitive outcomes of depression in the elderly study. Participants received manualized antidepressant treatment and were followed longitudinally for an average of 5 years. Study analyses included participants who remitted. Measures included demographic and clinical measures, medical comorbidity, disability, life stress, social support, and neuropsychological testing. A subset underwent structural magnetic resonance imaging (MRI). Results Of 241 remitted elders, approximately over 4 years, 137 (56.8%) experienced recurrence and 104 (43.2%) maintained remission. In the final model, greater recurrence risk was associated with female sex (hazard ratio [HR] = 1.536; confidence interval [CI] = 1.027-2.297), younger age of onset (HR = 0.990; CI = 0.981-0.999), higher perceived stress (HR = 1.121; CI = 1.022-1.229), disability (HR = 1.060; CI = 1.005-1.119), and less support with activities (HR = 0.885; CI = 0.812-0.963). Recurrence risk was also associated with higher Montgomery-Asberg Depression Rating Scale (MADRS) scores prior to censoring (HR = 1.081; CI = 1.033-1.131) and baseline symptoms of suicidal thoughts by MADRS (HR = 1.175; CI = 1.002-1.377) and sadness by Center for Epidemiologic Studies-Depression (HR = 1.302; CI, 1.080-1.569). Sex, age of onset, and suicidal thoughts were no longer associated with recurrence in a model incorporating report of multiple prior episodes (HR = 2.107; CI = 1.252-3.548). Neither neuropsychological test performance nor MRI measures of aging pathology were associated with recurrence. Conclusions Over half of the depressed elders who remitted experienced recurrence, mostly within 2 years. Multiple clinical and environmental measures predict recurrence risk. Work is needed to develop instruments that stratify risk.

Background Cognitive complaints are common in depression, and cognition may be an important treatment target as cognitive problems often remain during remission and may contribute to recurrence risk. Previous studies of cognitive performance in depression have mainly examined late-life depression, with a focus on older adults, or assessed performance in specific cognitive tasks rather than cognitive domains. Methods This study examined cognitive performance across multiple cognitive domains in antidepressant-free depressed adults with early onset recurrent depression compared to never-depressed controls. Domain scores were calculated for episodic memory, executive function, processing speed, and working memory, and the effect of depression diagnosis, depression severity, and depression duration on each domain score was examined, including interactions with age, sex, and education. Results Currently depressed adults (n = 91) exhibited poorer performance in the processing speed domain compared with never-depressed adults (n = 105). Additionally, there was an interactive effect of depression duration and age on processing speed and executive function domain performance, such that performance was worse with older age and longer duration of depression. There were no effects of depression severity on performance across the cognitive domains. Conclusions These findings support that processing speed deficits appear in young adults with early onset depression that may not be related to current mood. Additionally, the effects of cumulative depressive episodes may interact with aging such that cognitive performance deficits worsen with recurrence over the lifespan.

Introduction It has long been known that major depressive disorder during later life (LDD) is associated with cognitive decline and development of Alzheimer's disease and other dementias. Less is known about the characteristics of LLD that contribute to individual cognitive outcomes, but identifying phenotypes of these outcomes could make important contributions to early detection and treatment. The current study explored clinical and neuroimaging phenotypes associated with normal and non-normal cognitive diagnostic outcomes in LLD. Methods The data were from a prospective study of individuals (N = 240) with acute depression at baseline and followed under treatment for a minimum of five years. Baseline assessment included clinical measures of mood, neuropsychological assessment, and neuroimaging. Mood was assessed during regular treatment over the course of each year, and neuropsychological assessment was obtained annually. A consensus review was held annually to assign clinical diagnoses based on cognitive status, which included categories of normal cognition; cognitive impairment, no dementia (CIND); dementia, with subtypes including Alzheimer's disease (AD). The current study analyzed diagnostic outcomes at five years from study entry, and the clinical characteristics that predict these outcomes. Results We found that 90% of cognitive diagnostic outcomes over five-years of follow-up were in three diagnostic categories: 1) cognitively normal, 2) persistent CIND, and 3) AD. The remaining 10% were non-AD dementias and various medical and neuropsychiatric diagnoses. Individuals with normal cognition were 50% of the sample, and this endpoint was associated with first depression onset before age 60 and indicators of heightened sensitivity to stress. Individuals with persistent CIND (22%) were not associated with age of depression onset, but were associated with clinical characteristics of frailty and indicators of cerebrovascular pathology on neuroimaging. Individuals with AD (18%) were associated with age of depression onset after age 60, depressive symptoms of appetite/weight loss, reduced hippocampal volume, and worse memory performance at study entry. Conclusions The current study found distinct clinical and neuroimaging profiles associated with the three major cognitive endpoints of LLD. Approximately half of individuals with LLD maintained normal cognition over five years, which appeared to be associated with a lifetime predisposition to depression and heightened sensitivity to stress. In contrast, nearly 20% of individuals with LLD converted to AD within five years of follow up, and results suggest a clinically detectable phenotype of prodromal AD based on appetitive disturbance, reduced hippocampal volume, and memory deficits. Individuals with persistent CIND demonstrated a profile consistent with physical decline and cerebrovascular pathology, which did not manifest as dementia over 5 years, but may represent a slower progress toward vascular dementia relative to those with AD. These clinical phenotypes reflect a starting point for mechanistic discovery while also improving current treatment of LLD by identifying individuals on distinct cognitive trajectories who many benefit from differentiated approaches to the treatment of mood and cognition. The current cohort is part of a collaborative project to further detect and characterize linkages between cognitive outcomes of LLD and their clinical and neuroimaging phenotypes. This research was funded by This research was supported by funding from the National Institute of Mental Health (R01MH108560), and the Leo and Anne Albert Charitable Trust. The authors have no industry or other conflicts to report.

Objective The aim of this study was to examine the association between physical frailty and neurocognitive performance in late-life depression (LLD). Methods Cross-sectional design using baseline data from a treatment study of late-life depression was used in this study. Individuals aged 60 years and older were diagnosed with major depressive disorder at time of assessment (N = 173). All participants received clinical assessment of depression and completed neuropsychological testing during a depressive episode. Physical frailty was assessed using an adaptation of the FRAIL scale. Neuropsychological domains were derived from a factor analysis that yielded three factors: (i) speeded executive and fluency, (ii) episodic memory, and (iii) working memory. Associations were examined with bivariate tests and multivariate models. Results Depressed individuals with a FRAIL score >1 had worse performance than nonfrail depressed across all three factors; however, speeded executive and fluency was the only factor that remained significant after controlling for depression symptom severity and demographic characteristics. Conclusions Although physical frailty is associated with broad neurocognitive deficits in LLD, it is most robustly associated with deficits in speeded executive functions and verbal fluency. Causal inferences are limited by the cross-sectional design, and future research would benefit from a comparison group of nondepressed older adults with similar levels of frailty. Research is needed to understand the mechanisms underlying associations among depression symptoms, physical frailty, and executive dysfunction and how they are related to the cognitive and symptomatic course of LLD.

Background:Depression in late life is a risk factor for cognitive decline. Depression is also associated with increased disability and social support deficits; these may precede conversion to dementia and inform risk. In this study, we examined if baseline or one-year change in disability and social support predicted later cognitive deterioration.Methods:299 cognitively intact depressed older adults were followed for an average of approximately seven years. Participants received antidepressant treatment according to a standardized algorithm. Neuropsychological testing and assessment of disability and social support were assessed annually. Cognitive diagnosis was reviewed annually at a consensus conference to determine if participants remained cognitively normal, or if they progressed to either dementia or cognitively impaired, no dementia (CIND).Results:During study participation, 167 individuals remained cognitively normal (56%), 83 progressed to CIND (28%), and 49 progressed to dementia (16%). Greater baseline instrumental activities of daily living (IADL) deficits predicted subsequent conversion to a cognitive diagnosis (CIND or dementia). However, neither baseline measures nor one-year change in basic ADLs (BADLs) and social support predicted cognitive conversion. In post hoc analyses, two IADL measures (managing finances, preparing meals) significantly increased the odds of cognitive conversion.Conclusions:Greater IADL deficits predicted increased risk of cognitive conversion. Assessment of IADL deficits may provide clues about risk of later cognitive decline.

Objectives Smaller hippocampal volumes are observed in depression but it remains unclear how antidepressant response and persistent depression relate to changes in hippocampal volume. We examined the longitudinal relationship between hippocampal atrophy and course of late-life depression. Setting Academic medical center. Participants Depressed and never-depressed cognitively intact subjects age 60 years or older. Measurements Depression severity was measured every three months with the Montgomery-Asberg Depression Rating Scale (MADRS). Participants also completed cranial 1.5-T magnetic resonance imaging every 2 years. We compared 2-year change in hippocampal volume based on remission status, then in expanded analyses examined how hippocampal volumes predicted MADRS score. Results In analyses of 92 depressed and 70 never-depressed subjects, over 2 years the cohort whose depression never remitted exhibited greater hippocampal atrophy than the never-depressed cohort. In expanded analyses of a broader sample of 152 depressed elders, depression severity was significantly predicted by a hippocampus × time interaction where smaller hippocampus volumes over time were associated with greater depression severity. Conclusions Hippocampal atrophy is associated with greater and persistent depression severity. Neuropathological studies are needed to determine if this atrophy is related to the toxic effects of persistent depression or related to underlying Alzheimer disease.

Objective:Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus.Method:The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise l...

Objectives This study aimed to examine the association of appetite loss symptoms to neurocognitive performance in late-life depression (LLD). Methods This study used cross-sectional data from individuals aged 60+ years with major depressive disorder (N = 322). Participants received clinical assessment of depression and neuropsychological testing. Factor analysis was used to characterize depression symptom factors, and composite scales were developed for episodic memory, psychomotor–executive functions, verbal fluency, and working memory span. Results Factor analysis produced a five-factor solution: (1) anhedonia/sadness; (2) suicidality/guilt; (3) appetite/weight loss; (4) sleep disturbance; and (5) anxiety/tension. In separate multivariate models for each neurocognitive domain and including all five depression factors, higher appetite-loss-related symptoms were associated with lower performance in episodic memory, psychomotor–executive functions, and verbal fluency; results were significant with covariates of age, education, race, sex, age of depression onset, and illness burden. No other depression factors were associated with neurocognitive performance in these models. In an additional set of models, the appetite factor mediated the association between global depression severity and neurocognitive performance. Discussion A factor of appetite and weight loss symptoms in LLD was uniquely associated with neurocognitive performance, in contrast to lack of association among other depression symptom factors. Conclusion Cognitive deficits are a major adverse outcome of LLD, and prominent appetite loss during acute depression may be a marker for these deficits, independent of overall depression severity. Research is needed to understand the mechanisms that may explain this association, and how it is related to the cognitive and symptomatic course of LLD. Copyright © 2014 John Wiley & Sons, Ltd.

Background:Memory impairment in geriatric depression is understudied, but may identify individuals at risk for development of dementia and Alzheimer's disease (AD). Using a neuropsychologically based definition of amnestic mild cognitive impairment (aMCI) in patients with geriatric depression, we hypothesized that patients with aMCI, compared with those without it, would have increased incidence of both dementia and AD.Methods:Participants were aged 60 years and older and consisted of depressed participants and non-depressed volunteer controls. The depressed cohort met criteria for unipolar major depression. All participants were free of dementia and other neurological illness at baseline. At study entry, participants were administered a standardized clinical interview, a battery of neurocognitive tests, and provided a blood sample for determination of apolipoprotein E genotype. A cognitive diagnosis was assigned by a panel of experts who convened annually and reviewed available clinical, neuropsychological and laboratory data to achieve a consensus cognitive diagnosis to determine a consensus diagnosis. Survival analysis examined the association between aMCI and later dementia (all-cause) and AD.Results:Among 295 depressed individuals, 63 (21.36%) met criteria for aMCI. Among 161 non-depressed controls, four (2.48%) met aMCI criteria. Participants were followed for 6.28 years on average. Forty-three individuals developed dementia, including 40 (13.6%) depressed and three (1.9%) control participants. Both aMCI and age were associated with incident dementia and AD.Conclusions:The presence of aMCI is a poor prognostic sign among patients with geriatric depression. Clinicians should carefully screen elderly depressed adults for memory impairment.

Recent studies have implicated Ca supplements in vascular risk elevation, and therefore these supplements may also be associated with the occurrence of brain lesions (or hyperintensities) in older adults. These lesions represent damage to brain tissue that is caused by ischaemia. In the present cross-sectional clinical observational study, the association between Ca-containing dietary supplement use and lesion volumes was investigated in a sample of 227 older adults (60 years and above). Food and supplemental Ca intakes were assessed with the Block 1998 FFQ; participants with supplemental Ca intake above zero were categorised as supplement users. Lesion volumes were determined from cranial MRI (1·5 tesla) scans using a semi-automated technique; volumes were log-transformed because they were non-normal. ANCOVA models revealed that supplement users had greater lesion volumes than non-users, even after controlling for food Ca intake, age, sex, race, years of education, energy intake, depression and hypertension (Ca supplement use: β = 0·34, se 0·10, F1,217= 10·98, P= 0·0011). The influence of supplemental Ca use on lesion volume was of a magnitude similar to that of the influence of hypertension, a well-established risk factor for lesions. Among the supplement users, the amount of supplemental Ca was not associated with lesion volume (β = − 0·000035, se 0·00 015, F1,139= 0·06, P= 0·81). The present study demonstrates that the use of Ca-containing dietary supplements, even low-dose supplements, by older adults may be associated with greater lesion volumes. Evaluation of randomised controlled trials is warranted to determine whether this relationship is a causal one.

White matter lesions have detrimental effects upon older adults, while serum calcium levels have been associated with elevated vascular risk and may be associated with these lesions. Depression, a serious mental disorder characterized by disturbances in calcium metabolism, may be an important contributor to any calcium-lesion relationship. This cross-sectional pilot study examined the association between serum ionized calcium (the physiologically active form of calcium) and white matter lesion volumes in a sample of depressed and non-depressed older adults (N = 42, 60 years and older). Serum ionized calcium was determined using an ion-selective electrode technique, while lesion volumes were estimated from magnetic resonance imaging using an automated expectation-maximization segmentation. A linear regression model, controlling for age and group (depression vs. comparison), showed a trend for a positive relationship between serum ionized calcium and white matter lesion volume (β = 4.34, SE = 2.27, t = 1.91, p = 0.063). Subsample analyses with depressed participants showed a significant positive relationship between higher ionic calcium and greater lesion volume (β = 6.41, SE = 2.53, t = 2.53, p = 0.018), but no association was found for non-depressed participants. Sex-specific subsample analyses showed a significant positive relationship between higher calcium and greater lesion volume in men only (β = 7.49, SE = 3.42, t = 2.19, p = 0.041). These preliminary results indicate that serum ionized calcium may be associated with white matter lesions in older adults, particularly among men and individuals with depression. Larger studies are needed to confirm these findings.

Exposure to stressful events is associated with both occurrence of depression and also vascular disease. The objective of this study was to determine whether higher levels of stress exposure was related to measures of pathological brain aging, specifically white matter hyperintensity volumes, in older adults with and without depression.The sample included 130 depressed and 110 never-depressed older adults aged 60 years or older enrolled in a longitudinal study at an academic medical center. Participants completed clinical assessments, assessment of stressful event exposure and perceived stress, and magnetic resonance imaging at baseline and after 2 years. Analyses examined both cross-sectional and longitudinal relationships between stress measures and white matter hyperintensity volumes.There were no statistically significant relationships observed between cross-sectional baseline stress measures and either baseline hyperintensity volume or 2-year change in hyperintensity volume. However, after controlling for demographic variables and baseline measures, change in stressor exposure was associated with change in hyperintensity volumes. In this analysis, increased stressor exposure was associated with greater increases in white matter hyperintensity volume, while reductions in stressor exposure were associated with less increase in hyperintensity volume. This relationship did not significantly differ based on the presence of either depression or medical comorbidities.This work adds to a growing literature associating exposure to stressful events in later life with more rapid pathological brain aging. Work is needed to understand the physiological mechanisms by which stress exposure has this effect and examine whether stress reduction techniques may modify these observed outcomes. Copyright © 2016 John WileySons, Ltd.

The APOE e4 allele is associated with cognitive deficits and brain atrophy in older adults, but studies in younger adults are mixed. We examined APOE genotype effects on cognition and brain structure in younger adults and whether genotype effects differed by age and with presence of depression. 157 adults (32 % e4 carriers, 46 % depressed) between 20 and 50 years of age completed neuropsychological testing, 131 of which also completed 3 T cranial MRI. We did not observe a direct effect of APOE genotype on cognitive performance or structural MRI measures. A significant genotype by age interaction was observed for executive function, where age had less of an effect on executive function in e4 carriers. Similar interactions were observed for the entorhinal cortex, rostral and caudal anterior cingulate cortex and parahippocampal gyrus, where the effect of age on regional volumes was reduced in e4 carriers. There were no significant interactions between APOE genotype and depression diagnosis. The e4 allele benefits younger adults by allowing them to maintain executive function performance and volumes of cingulate and temporal cortex regions with aging, at least through age fifty years.

Background.Obesity and muscle weakness are independently associated with increased risk of physical and functional impairment in older adults. It is unknown whether physical activity (PA) and muscle strength combined provide added protection against functional impairment. This study examines the association between muscle strength, PA, and functional outcomes in older adults with central obesity.Methods.Prevalence and odds of physical (PL), ADL, and IADL limitation were calculated for 6,388 community dwelling adults aged ≥ 60 with central obesity. Individuals were stratified by sex-specific hand grip tertiles and PA. Logistic models were adjusted for age, education, comorbidities, and body-mass index and weighted.Results.Overall prevalence of PL and ADL and IADL limitations were progressively lower by grip category. Within grip categories, prevalence was lower for individuals who were active than those who were inactive. Adjusted models showed significantly lower odds of PL OR 0.42 [0.31, 0.56]; ADL OR 0.60 [0.43, 0.84], and IADL OR 0.46[0.35, 0.61] for those in the highest grip strength category as compared to those in the lowest grip category.Conclusion.Improving grip strength in obese elders who are not able to engage in traditional exercise is important for reducing odds of physical and functional impairment.

The renin–angiotensin system (RAS) is implicated in the response to physiological and psychosocial stressors, but its role in stress-related psychiatric disorders is poorly understood. We examined if variation in AGTR1 , the gene coding for the type 1 angiotensin II receptor (AT 1 R), is associated with a diagnosis of depression and differences in white matter hyperintensities and frontotemporal brain volumes. Participants comprised 257 depressed and 116 nondepressed elderly Caucasian subjects who completed clinical assessments and provided blood samples for genotyping. We used a haplotype-tagging single nucleotide polymorphism (htSNP) analysis to test for variation in AGTR1 . For measurement of hyperintense lesions, 1.5 Tesla magnetic resonance imaging (MRI) data were available on 33 subjects. For measurements of the hippocampus and dorsolateral prefrontal cortex (dlPFC), 3 Tesla MRI data were available on 70 subjects. Two htSNPs exhibited statistically significant frequency differences between diagnostic cohorts: rs10935724 and rs12721331. Although hyperintense lesion volume did not significantly differ by any htSNP, dlPFC and hippocampus volume differed significantly for several htSNPs. Intriguingly, for those htSNPs differing significantly for both dlPFC and hippocampus volume, the variant associated with smaller dlPFC volume was associated with larger hippocampal volume. This supports the idea that genetic variation in AGTR1 is associated with depression and differences in frontotemporal morphology.

Depression is common in the elderly population. Although numerous neuroimaging studies have examined depressed elders, there is limited research examining how amygdala volume may be related to depression.A cross-sectional examination of amygdala volume comparing elders with and without a diagnosis of major depressive disorder, and between depressed subjects with early and later initial depression onset.An academic medical center.Ninety-one elderly patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for major depression (54 early-onset depressed and 37 late-onset depressed) and 31 elderly subjects without any psychiatric diagnoses.Amygdala and cerebral volumes were measured using reliable manual tracing methods.In models controlling for age, sex, and cerebral volume, there was a significant difference between diagnostic cohorts in amygdala volume bilaterally (left: F[2, 116] = 16.28, p0.0001; right: F[2, 116] = 16.28, p0.0001). Using least squares mean group analyses, both early- and late-onset depressed subjects exhibited smaller bilateral amygdala volumes than did the nondepressed cohort (all comparisons p0.0001), but the two depressed cohorts did not exhibit a statistically significant difference.Limitations include missing antidepressant treatment data, recall bias, inability to establish a causal relationship between amygdala size and depression given the cross-sectional nature of the design.Depression in later life is associated with smaller amygdala volumes, regardless of age of initial onset of depression.

Postmortem studies have documented abnormalities in the dorsolateral prefrontal cortex (dlPFC) in depressed subjects. In this study we used magnetic resonance imaging to test for dlPFC volume differences between older depressed and non-depressed individuals. Eighty-eight subjects meeting DSM IV criteria for major depressive disorder and thirty-five control subjects completed clinical evaluations and cranial 3T magnetic resonance imaging. After tissue types were identified using an automated segmentation process, the dlPFC was measured in both hemispheres using manual delineation based on anatomical landmarks. Depressed subjects had significantly lower gray matter in the left and right dorsolateral prefrontal cortex (standardized to cerebral parenchyma) after controlling for age and sex. Our study confirmed the reduction of dorsolateral prefrontal cortex in elderly depressed subjects, especially in the gray matter. These regional abnormalities may be associated with psychopathological changes in late-life depression.

Cognitive impairment in late-life depression is a risk factor for multiple adverse outcomes in physical health, functional independence, and mortality (Mehta et al. 2003). Depression in late life may be a prodromal symptom of Alzheimer’s disease and a risk factor for dementia more broadly (Kessing & Nilsson 2003), while cognitive impairment during depression is also associated with persistent deficits (Lee et al. 2007) and dementia (Alexopoulos et al. 1993). Based on community samples, the prevalence of cognitive impairment and comorbid depression doubles at 5-year intervals after the age of 70, and is estimated to be present in 25% of individuals aged 85 and older (Arve et al. 1999). These rates make it important to understand the factors that contribute to acute and persistent cognitive dysfunction in depressed older adults. While studies of depression have examined neurobiological correlates of cognitive dysfunction in depression, less attention has been devoted to the role of psychosocial factors. The association between greater life stress and higher rates of depression has been well established (Kessler 1997; Mazure et al. 2002), and higher perceived stress is associated with incomplete remission of depression (Hybels et al. 2006). Higher levels of perceived stress and stressful life events also have been associated with greater age-related differences on objective measures of episodic memory and executive functions (VonDras et al. 2005). Evidence supports the idea that stress-related coping requires a certain amount of cognitive attention and therefore the presence of major stress reduces the amount of attention one can devote to other information processing tasks (Kahneman 1973; Stawski et al. 2006), which would be exacerbated in later life (Smith 2003), and presumably more so when stress results in a depressive episode. It has also been posed that stress-related hypercortisolemia during depression may have a progressive toxic effect on the hippocampus and associated cognitive functions, which has some support among non-depressed, but is more mixed in studies of late life depression (Lupien et al. 1999; Steffens & Potter 2007). Social support (both perceived and actual) is another psychosocial factor that may contribute to cognitive dysfunction in late life depression. Low levels of perceived social support are associated with longitudinal depression severity (Steffens et al. 2005). Instrumental social support appears to provide a buffer against functional decline in late-life depression (Hays et al. 2001), but the role in cognitive decline is not well studied in this condition. There is evidence in non-depressed elderly, however, that low satisfaction with social support is associated with 5-year decline in episodic memory (Hughes et al. 1988) and that perceived social isolation (i.e., loneliness) is associated with cognitive decline over a 10-year period (Tilvis et al. 2004). Thus, poor social support, or the perception of poor support, may also contribute to cognitive decline among depressed older adults as well. The purpose of this study was to examine the effects of stress and social support on cognition in depressed and non-depressed older adults. We expected that a change in stress from baseline to one-year (and first year of treatment for patients) would predict a change in cognitive performance in follow-up assessments across both the depressed and non-depressed population. In addition, we hypothesized that changes in the level of social support during the first year of the study would affect changes in cognitive ability the following year for the whole sample. We hypothesized an increase in stress or a decrease in social support would predict a decrease in cognitive ability over the following year. We hypothesized that these associations would be significant after controlling for age, sex, years of education and depression status (depressed/non-depressed) at baseline. A secondary objective was to explore which aspects of cognition might be sensitive to the influence of social factors. Overall, the potential clinical importance of this study is that finding specific associations between stress and social support with cognition could highlight potentially modifiable intervention targets to treat depression and prevent cognitive decline.

Objective: The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been linked to unipolar major depressive disorder (MDD) and magnetic resonance imaging (MRI) hyperintensities. The authors examined the relationship between the MTHFR C677T polymorphism (C677T) and a) geriatric depression, b) MRI hyperintense lesion volume, and c) neurocognitive test performance. Design: Cross-sectional. Setting: Duke University Medical Center. Participants: Depressed (N = 178) and comparison (N = 85) elderly subjects. Measurements: Subjects had blood drawn to assess MTHFR genotype, were imaged by MRI to determine their white matter hyperintense lesion (WML) and gray matter hyperintense lesion (GML) volume, and assessed using a comprehensive neurocognitive battery evaluating multiple domains of function. Linear regression models were fit to test the effect of genotype, a depression by genotype interaction, and an age by genotype interaction on both hyperintense lesion volume measures and neurocognitive task performance. Results: The MTHFR C677T genotype by age interaction term was significantly associated with MRI WML volume (p = 0.0175); however, this relationship was no longer statistically significant when WML volumes underwent a log transformation to produce a more normal distribution. The 677T allele was neither more frequent in depressed subjects nor associated with either gray matter hyperintensity volume or neurocognitive test performance. Conclusions: MTHFR genotype affects the relationship between age and WML volume where individuals who carry the 677T allele exhibit greater WML volume by age, although this relationship should be verified given the failure to replicate the finding using transformed WML volumes. Genotype was not related to GML volume, cognitive function, or presence of depression, although demographic differences could account for this negative finding.

Objective: Catechol-O-Methyltransferase (COMT) and Methylenetetrahydrofolate reductase (MTHFR) had been reported to relate to depression but with inconsistent results. The basal ganglia are also important in the pathophysiology of affective disorder via connections with limbic system and prefrontal cortex. The authors examined the relationship between an interaction of COMT/ MTHFR polymorphisms and volumes of putamen in depressed and nondepressed elders. Methods: Participants included 170 depressed and 83 nondepressed subjects aged 60 years or older. Subjects completed cross-sectional assessments, including clinical evaluation, brain magnetic resonance imaging (MRI) scan, and COMT Val158Met and MTHFR C677T genotyping. Putamen volumes were measured using 1.5-Tesla whole-body MRI system. Statistical models examined the relationship between COMT/MTHFR genotype, proportional volumes of putamen and depression while controlling for age and sex. Results: After controlling for covariates, depressed subjects with MTHFR C/C, both the right and left putamen have smaller volumes as the number of COMT 158Val increase. The left putamen volumes of depressed subjects with COMT Met/Met are smaller as the number of MTHFR 677T increase compared to nondepressed subjects. Conclusions: Our findings do not support a major role for COMT or MTHFR alone. However, an epigenetic interaction of COMT Val158Met and MTHFR C677T polymorphisms may contribute to putamen volumes differences between depressed and nondepressed subjects. Further studies with a larger sample size are necessary to support a genetically based role for basal ganglia structures in the etiopathogenesis of depression.

We examined the frequency and course of cognitive impairment, no dementia among a group of older patients enrolled in a longitudinal study of depression. Among 230 participants, 29 with baseline dementia diagnosis were excluded from further analyses. Among the remaining 201 participants, 69 were classified with cognitive impairment, no dementia—broadly defined (34.3%) and 28 (13.9%) with cognitive impairment, no dementia—narrowly defined. At 2-year follow-up, individuals with cognitive impairment, no dementia either narrowly or broadly defined had varied outcomes including (1) improvement to normal cognition, (2) continued cognitive impairment, and (3) progression to dementia. Patients with cognitive impairment, no dementia were more likely to be assigned a later diagnosis of dementia. Our results characterize the concept of cognitive impairment, no dementia as a risk factor for dementia among older individuals with current and past depression; however, just as with the general population, the course of this condition is heterogeneous.

Objective We examined the relationship between 5HTTLPR genotype and volume of magnetic resonance imaging (MRI) brain lesions. Method We studied 217 older depressed patients and 141 individuals in the comparison group using a standard brain MRI protocol to calculate lesion volumes. Genotype at 5HTTLPR was determined for each subject. Results In age-adjusted models, the l/s genotype was associated with increased volume of total and white-matter lesions among depressed patients. This relationship lost significance in models controlling for reported hypertension. Conclusions The finding that 5HTTLPR heterozygotes have higher vascular lesion volumes may be related to development of hypertension. Copyright © 2007 John Wiley & Sons, Ltd.

Objective The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with cognitive and neuroimaging changes. The authors examined the relationship between this polymorphism and depression in an elderly sample, hypothesizing that the Met66 allele would be associated with late-life depression. Methods A total of 245 elderly depressed white subjects and 94 elderly comparison white subjects completed clinical assessments and provided a blood sample for genotyping. Subjects were dichotomized as either homozygous for the Val66 allele or Met66 allele carriers. Gene frequencies were compared between groups, with separate analyses examining for differences in gene frequencies based on age of depression onset, family history, and depression history. Logistic regression models examined the relationship between genotype and depression after controlling for age, sex, and race. Results Depressed subjects were more likely to be Met66 allele carriers than were comparison subjects (38.8% versus 24.4%; χ 2 = 6.13, 1 df, p=0.0133). This relationship remained significant after controlling for covariates (Wald χ 2 = 5.10, 1 df, p=0.024; odds ratio: 1.92, 95% confidence interval: 1.09–3.38). There were no significant relationships between genotype and age of onset, number of episodes, or family history of depression. Conclusion Met66 allele carriers have almost double the odds of having geriatric depression than do Val66 allele homozygotes. This polymorphism was unrelated to other clinical characteristics of depression in later life.

Objective: Several studies suggest that depression is a risk factor for development of dementia in the elderly. In a study of older depressed individuals, the authors examined both neuroimaging and genetic factors in development of dementia. The authors hypothesized that change in subcortical gray matter and white matter hyperintensity volumes would be associated with development of dementia, as would presence of an apolipoprotein E (APOE) epsilon 4 allele. Methods: The sample consisted of 161 older depressed subjects without dementia who had magnetic resonance imaging scans at baseline and at two years. Blood samples were also taken to determine APOE genotype. All participants were treated with antidepressants using a guidelinebased treatment algorithm. Their cognitive status was evaluated annually. A consensus panel of experts evaluated each case to determine cognitive status and assign a diagnosis. Results: Twenty subjects became demented over the follow-up period (5.4 years on average). Change in white matter hyperintensity volume was significantly associated with development of dementia, especially among non-Alzheimer dementias. There was a trend for change in subcortical gray matter hyperintensity volume to be associated with incident dementia. APOE genotype was not associated with onset of dementia. Conclusion: Worsening cerebrovascular disease in older depressed adults is associated with cognitive decline and dementia, particularly of the non-Alzheimer disease type. The association of change in white matter lesion volume and incident dementia among depressed elders extends the vascular depression hypothesis of geriatric depression to include cognitive outcomes of depression in the elderly. (Am J Geriatr Psychiatry 2007; 15

BackgroundOrbitofrontal cortex (OFC) volumetric differences have been reported in depression, but in relatively small samples. Factors associated with these differences are not well described. We examined OFC volumes in a large sample of elderly depressed and non-depressed subjects, exploring the relationship between OFC volume, 5HTTLPR genotype, apolipoprotein E (APOE) genotype and hyperintense lesion volume. We hypothesized that smaller OFC volume would be associated with depression, greater hyperintense lesion volume and severity, and APOE ε4 or 5HTTLPR short allele carriers.MethodA total of 226 depressed and 144 non-depressed older subjects completed 1·5 T magnetic resonance imaging (MRI) and genotyping. OFC volumes and lesion volumes were measured using standardized methods. Lesion severity was additionally rated using the Coffey rating scale. Differences between groups were compared while controlling for age, sex and total cerebral volume; separate models added lesion measures and genetic polymorphisms.ResultsDepressed subjects exhibited smaller OFC volumes. There was a trend for a negative association between white-matter lesion volume and OFC volume; however, rated white-matter lesion severity was significantly negatively associated with OFC volume. There was no association between gray-matter lesion measures or 5HTTLPR genotype and OFC volume. Contrary to our hypothesis, subjects who were APOE ε4 allele positive exhibited larger OFC volumes; in secondary analyses, this finding was limited to the non-depressed group.ConclusionsReduced OFC volumes are seen in depression and associated with greater severity of white-matter lesions. Healthy subjects who are APOE ε4 allele positive exhibited larger OFC volumes. This finding should be examined in other populations.

Poor task persistence is often observed among depressed individuals, and may be associated with some of the same frontal regions that are involved in depression. The current study explored the association between white-matter lesion volume in prefrontal cortex and noncompletion rates on a complex neurocognitive task among older adults in a treatment study for depression. Older adults in treatment for depression (n=83) and nondepressed (n=47) elders were administered the Stockings of Cambridge subtest (SoC) of the Cambridge Automated Neuropsychological Testing Battery (CANTAB) and completed a brain magnetic resonance imaging scan as part of an ongoing research study. Noncompletion of the SoC occurred in approximately 19% of depressed participants (16/83) and only 2% of nondepressed participants (1/47), which was statistically significant. In multivariate models, failure to complete the SoC was consistently and significantly associated with greater volume of white matter lesions in the anterior-most region of prefrontal cortex, particularly in the left hemisphere, and with greater age. Although SoC completion was not significantly associated with depression severity, noncompletion rates were significantly higher among unremitted individuals and those with comorbid anxiety at study entry. The inability to initiate behavior sufficient to sustain a complex neurocognitive task is a characteristic of geriatric depression which may be associated with integrity of left-prefrontal regions. Future research should investigate whether task impersistence is a construct that generalizes to other neurocognitive tasks, and if it is associated with other adverse outcomes in geriatric depression related to cerebrovascular pathology, such as poor treatment response.

Background Aging-related muscle weakness is associated with increased risk of functional limitations and disability. This study examined the association between varying degrees of hand grip strength on functional ability in community-dwelling older adults. Methods Cross-sectional analysis of 4289 men and 5860 women ≥60 from 2006 and 2008 waves of the population-based Health and Retirement Study (HRS) were stratified by sex-specific grip strength tertiles (low, mid, high). Prevalence and adjusted odds of physical limitations (PL), and ADL/IADL limitation were calculated by sex, race/ethnicity and age group (60–69, 70–79, 80+). Models were weighted, adjusted for age, sex, race/ethnicity, education, smoking status, BMI, comorbidities and participation in physical activity. Results Prevalence of PL, ADL and IADL limitations were significantly lower among adults in the highest grip category as compared to those in the lowest grip category. Adjusted odds for PL OR 0.41[0.33,0.52]; ADL OR.51 [0.39,0.67], and IADL OR 0.47 [0.38–0.59] limitations were significantly lower among adults in the highest grip compared to the lowest grip category. However, notable differences were observed in the strength of these associations by gender, race and age group. Conclusion Demographic characteristics are important factors to consider for risk stratification and the development of effective grip strength training interventions for older adults.

The aim of this study was to examine the association between physical frailty and neurocognitive performance in late-life depression (LLD).Cross-sectional design using baseline data from a treatment study of late-life depression was used in this study. Individuals aged 60 years and older were diagnosed with major depressive disorder at time of assessment (N = 173). All participants received clinical assessment of depression and completed neuropsychological testing during a depressive episode. Physical frailty was assessed using an adaptation of the FRAIL scale. Neuropsychological domains were derived from a factor analysis that yielded three factors: (i) speeded executive and fluency, (ii) episodic memory, and (iii) working memory. Associations were examined with bivariate tests and multivariate models.Depressed individuals with a FRAIL score1 had worse performance than nonfrail depressed across all three factors; however, speeded executive and fluency was the only factor that remained significant after controlling for depression symptom severity and demographic characteristics.Although physical frailty is associated with broad neurocognitive deficits in LLD, it is most robustly associated with deficits in speeded executive functions and verbal fluency. Causal inferences are limited by the cross-sectional design, and future research would benefit from a comparison group of nondepressed older adults with similar levels of frailty. Research is needed to understand the mechanisms underlying associations among depression symptoms, physical frailty, and executive dysfunction and how they are related to the cognitive and symptomatic course of LLD.

Background Past work demonstrates that depressed individuals with suicidal thoughts or behaviors exhibit specific neuroanatomical alterations. This may represent a distinct phenotype characterized by specific findings on neuroimaging, but it is unclear if these findings extend to individuals with milder thoughts of death. We examined this question in outpatients with recurrent Major Depressive Disorder not receiving antidepressant treatment. Methods We examined 165 subjects: 53 depressed without thoughts of death, 21 depressed with thoughts of death, and 91 healthy comparison subjects. Participants completed 3 T cranial MRI, including anatomical and diffusion tensor imaging acquisitions. Automated methods measured regional gray matter volumes in addition to cortical thickness. White matter analyses examined diffusion measures within specific fiber tracts and included voxelwise comparisons. Results After adjustment for multiple comparisons, the depressed group with thoughts of death did not exhibit differences in regional gray matter volume, but did exhibit reduced cortical thickness in frontoparietal regions and the insula. This depressed group with thoughts of death also exhibited widespread white matter differences in fractional anisotropy and radial diffusivity. These differences were observed primarily in posterior parietal white matter regions and central white matter tracts adjacent to the basal ganglia and thalamus. Conclusions Mild thoughts of death are associated with structural alterations in regions of the salience network, default mode network, and thalamocortical circuits. Further work is needed to understand the pathological basis of these findings.

Predicting memory problems in older depressed patients receiving electroconvulsive therapy (ECT) is difficult. In this study, hippocampal volume and acute memory outcomes were examined in 15 patients following an index course of ECT. Smaller hippocampal volume was associated with poorer ECT-related memory outcomes. These results add to a growing literature on memory, ECT, and the hippocampus. Although the findings are significant, the sample size in the study is small, so future studies with more complex modeling of key variables that may influence memory are warranted.

White matter hyperintense lesions on T2-weighted images are associated with late-life depression. Little work has been carried out examining differences in lesion location between elderly individuals with and without depression. In contrast to previous studies examining total brain white matter lesion volume, this study examined lobar differences in white matter lesion volumes derived from brain magnetic resonance imaging. This study examined 49 subjects with a DSM-IV diagnosis of major depression and 50 comparison subjects without depression. All participants were age 60 years or older. White matter lesion volumes were measured in each hemisphere using a semiautomated segmentation process and localized to lobar regions using a lobar atlas created for this sample using the imaging tools provided by the Biomedical Informatics Research Network (BIRN). The lobar lesion volumes were compared against depression status. After controlling for age and hypertension, subjects with depression exhibited significantly greater total white matter lesion volume in both hemispheres and in both frontal lobes than did control subjects. Although a similar trend was observed in the parietal lobes, the difference did not reach a level of statistical significance. Models of the temporal and occipital lobes were not statistically significant. Older individuals with depression have greater white matter disease than healthy controls, predominantly in the frontal lobes. These changes are thought to disrupt neural circuits involved in mood regulation, thus increasing the risk of developing depression.

Objective The authors examined the relationship between hippocampal volume and acute electroconvulsive therapy (ECT) outcomes. Methods Depression was measured by Montgomery-Asberg Depression Rating Scale (MADRS) scores, and hippocampal volume was assessed by magnetic resonance imaging. Results After controlling for baseline MADRS score, larger right-hippocampal volume was associated with higher MADRS scores after an index course of ECT. Conclusion These results are the converse of those obtained in a study assessing the relationship between hippocampal volume and pharmacotherapy. The findings suggest a need for further study in this area.

Hyperintense lesions in both white matter and gray matter on T2-weighted magnetic resonance imaging (MRI) are associated with late-life depression. This large study examined differences in gray and white matter lesion volumes on brain MRI between 253 elderly depressed and 146 control subjects. White matter and gray matter lesion volumes were measured in each hemisphere using a semi-automated segmentation process and compared against depression status. Depressed subjects exhibited significantly greater total white matter (mean 7.22 ml) and gray matter (mean 0.30 ml) lesion volumes in both hemispheres than did control subjects (mean 4.87 ml in white matter and 0.18 ml in gray matter). This difference remained statistically significant even after controlling for confounders such as age, sex, race and reports of hypertension, diabetes and heart disease. Patients with late-life depression have larger white matter lesion and gray matter lesion volumes than do control subjects. Future research should combine similar volumetric techniques with methods of identifying the location of lesions specific to late-life depression.

Objective The authors sought to examine the effect of symptoms of generalized anxiety disorder (GAD) on acute course of depression in a group of older depressed patients. Methods Authors assessed GAD symptoms in a sample of 204 patients age 60 and older with unipolar major depression. Patients were treated naturalistically by study geriatric psychiatrists using a treatment guideline for geriatric depression and assessed with the Montgomery-Asberg Depression Rating Scale. They were dichotomized as meeting or not meeting GAD symptom criteria. The groups were analyzed by Cox proportional-hazards models. Results There were 138 remitters and 66 non-remitters. After analysis controlled for benzodiazepine use, stressful life events, social support, and functional status, having GAD symptoms was associated with longer time-to-remission. Conclusions Older depressed patients with GAD have a worse outcome than those without anxiety. Future studies will need to determine the appropriate role of benzodiazepines and other anxiolytics in the treatment of older depressed patients with symptoms of GAD.

Remission of depressive symptoms is the goal of all antidepressant therapy. Rating scales define remission in clinical trials, but it is unclear how well these definitions predict risk of later relapse. We measured the sensitivity and specificity of a range of Montgomery-Asberg Depression Rating Scale (MADRS) cutoff scores at 3- and 6-months, wherein scores above a given cutoff would predict relapse over an 18-month period. We examined 153 elderly depressed subjects exhibiting a MADRSor = 15 after 3 or 6 months of antidepressant therapy. Subjects who subsequently exhibited a MADRS15 during the 18-month study period were defined as relapsed. Receiver operating characteristic (ROC) curves were developed and area under the curve (AUC) values calculated for the sensitivity and specificity of 3- and 6-month MADRS scores to predict future relapse. The 3-month ROC had an AUC value of 0.63; the 6-month ROC had an AUC value of 0.66. There was no MADRS cutoff found that could predict likelihood of relapse with good sensitivity and specificity. A post hoc analysis where relapse rate was adjusted by controlling for medical comorbidity, disability, and social support showed no change in the ROCs or AUC values. The higher the MADRS score at 3 and 6 months, the greater the likelihood of relapse. With no clean MADRS cutoff score, the goal of antidepressant therapy should be the lowest possible degree of depressive symptomatology to minimize risk of later relapse. Definitions of remission that are better associated with longer-term outcomes are needed.

Statins are investigational therapies for preventing or treating Alzheimer's disease (AD) and mild cognitive impairment (MCI). Hippocampal atrophy is a characteristic feature of MCI and AD. This study analyzed cross-sectional data from 246 nondemented elderly subjects to test the effect of lipid lowering agent (LLA) therapy on cognition and brain magnetic resonance imaging (MRI) measures of white matter lesions and hippocampal volume. The study also compared rates of hippocampal volume change over two and four years in a smaller subset. At baseline, LLA users were younger, better educated, more likely to be male, and had higher cognitive scores. Cognitive performance also varied by age and gender, and MRI measures varied by age. After adjusting for these differences, the effect of LLA use on baseline cognition, baseline hippocampal volume, and baseline white matter lesion scores was not significant. The effect of LLA use on hippocampal volume loss at two-year and four-year follow-ups was also not significant. This study is the first to examine statin effects on brain atrophy measured by MRI. In this cohort, statin use was not associated with rate of change of hippocampal volume. While the study was limited by a relatively small number of statin users, the findings seem consistent with three prior randomized trials that found no cognitive benefits for statins in nondemented subjects. Prospective studies in both nondemented and AD subjects may provide more conclusive answers.

Previous studies have shown a reduction of orbital frontal cortex volume and an increase in magnetic resonance imaging signal hyperintensities in geriatric depression. We aimed to assess the relationship between subcortical gray- and deep white-matter lesions and orbital frontal cortex volume in elderly depressives and controls. The study included 41 elderly depressed patients and 41 age-matched control subjects. The orbital frontal cortex volume was measured in both hemispheres using a standardized MRI procedure. Signal hyperintensities were rated on (T2)-weighted MRI with qualitative lesion analyses performed according to an established hyperintensity classification system. After controlling for total cerebral hemisphere, age and sex, the geriatric depressed subjects had significant reduction in orbital frontal cortex volume and compared with the control group. Multiple linear regression modeling indicated that reduced orbital frontal cortex volumes were significantly associated with increased subcortical gray-matter lesions. Our study confirmed the reduction of OFC volume in geriatric depressed subjects. We also suggest that subcortical lesions may decrease OFC volume. Further studies are needed to understand how subcortical lesions may be related to OFC volume changes.

Changes within the prefrontal cortex (PFC) have been associated with both mood disorders and with specific impairments in cognitive testing. The left PFC has been implicated in relational processing, that is, binding different pieces of information. We hypothesized that among older depressives and elderly controls, lower performance on one test of relational processing would be associated with smaller volume of the orbital frontal cortex (OFC). A total of 30 depressed and 40 control subjects were included in the study. All subjects were administered the Benton Visual Retention Test (BVRT). Subjects received a standardized magnetic resonance imaging, for which volumes of the OFC and total brain were calculated. We found that, controlling for age and education, total correct on BVRT was associated with left OFC volume normalized for total brain volume among the entire sample. For the depressed sample only, the number of perseverative errors was negatively associated with left OFC volume normalized for total brain volume after controlling for age and education. These results add to the literature linking mood and cognitive disturbances to the PFC. Future studies with a larger sample employing functional measures are warranted.

Objective Although geriatric depression generally responds to treatment, patients are often left with residual symptoms after acute treatment. Data are lacking on the eventual outcomes of individuals who are partial responders or poor responders to initial treatment. Methods The authors examined 200 patients initially treated with a treatment-based guideline approach that allowed for physician choice. Results After 3 months, 34.0% of patients were remitted, 37.5% had achieved a partial response, and 28.5% were still highly symptomatic. After 6 months of treatment, 51.1% of patients were remitted, 36.5% were partial responders, and 12.5% were still experiencing significant depressive symptoms. Cumulative remission rates over 18 months of treatment were significantly higher among partial responders than among highly symptomatic patients at 6 months, but not at 3 months. In terms of relapse, defined as a Montgomery-Asberg Depression Rating Scale score greater than 15, 42.0% of the remitted and partial-responder groups had relapsed by 18 months. When compared with remitted patients, partial responders at 6 months were more likely to experience a relapse. There were no differences in relapse rate between the two groups at 3 months. Conclusion These results suggest that during ongoing active treatment of geriatric depression, the level of improvement at 6 months, but not 3 months, is predictive of subsequent course.

OBJECTIVE The authors examined psychosocial and clinical predictors of time-to-remission in a sample of initially clinically depressed elderly patients. METHODS Using a standardized algorithm, a prospective cohort study enrolled 239 patients undergoing treatment. Patients were followed for up to 4.5 years, until death or withdrawal from the study. Baseline predictor variables included psychosocial factors, such as four domains of social support; basic and instrumental activities of daily living; and clinical factors, including use of electroconvulsive therapy (ECT), past history of depression, comorbidities, and antidepressant treatment. RESULTS Only 33% of the sample (n = 79) met our classification for depression remission. A lack of instrumental and subjective social support, poor self-rated health, the use of antipsychotic medication, or use of an antidepressant in the last 7 days were predictors of longer time-to-remission. Use of ECT in the last year was related to shorter time-to-remission. CONCLUSION Baseline psychosocial factors were just as important, as predictors of depression remission, as were clinical and diagnostic variables. Interventions directed toward social support resources, in addition to clinical intervention, including the use of ECT where appropriate, are likely to improve rates of depression remission.