Reliable Cognitive Decline in Late-Life Major Depression.

OBJECTIVE: Major 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. METHODS: In 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), "stability" (z-scores between + - 1.645), and "improvement" (z scores > +1.645). RESULTS: A 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. CONCLUSIONS: Older 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.

Predictors of recurrence in remitted late-life 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.

Cognitive performance in antidepressant-free recurrent major depressive disorder.

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.

Longitudinal Cognitive Outcomes of Clinical Phenotypes of Late-Life Depression.

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.

APOE ε4 associated with preserved executive function performance and maintenance of temporal and cingulate brain volumes in younger adults.

The APOE ε4 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 % ε4 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 ε4 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 ε4 carriers. There were no significant interactions between APOE genotype and depression diagnosis. The ε4 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.

Effects of stressful life events on cerebral white matter hyperintensity progression.

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.

Muscle Strength, Physical Activity, and Functional Limitations in Older Adults with Central Obesity.

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.

Sex, race and age differences in muscle strength and limitations in community dwelling older adults: Data from the Health and Retirement Survey (HRS).

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.

Physical frailty in late-life depression is associated with deficits in speed-dependent executive functions.

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.

Widespread white matter but focal gray matter alterations in depressed individuals with thoughts of death.

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 3T 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.

Appetite loss and neurocognitive deficits in late-life depression.

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.

Disability but not social support predicts cognitive deterioration in late-life depression.

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.

Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age.

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 linkage disequilibrium values and apolipoprotein E (APOE) genotype. RESULTS: Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss. CONCLUSIONS: Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.

Amnestic mild cognitive impairment and incident dementia and Alzheimer's disease in geriatric depression.

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.

Elevated brain lesion volumes in older adults who use calcium supplements: a cross-sectional clinical observational study.

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: ß = 0.34, SE 0.10, F(1,217)= 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 (ß = - 0.000035, SE 0.00 015, F(1,139)= 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.

Hippocampus atrophy and the longitudinal course of late-life depression.

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.

Clinical outcomes of older depressed patients with and without comorbid neuroticism.

BACKGROUND: Neuroticism is a psychological construct that includes tendency to exhibit negative affect (NA), having poor stress tolerance and being at risk for depression and anxiety disorders. The consequences of neuroticism in the elderly adults are understudied. We hypothesized that older depressed patients with comorbid neuroticism at baseline would have worse mood and cognitive outcomes compared with older depressed patients without neuroticism. METHODS: One hundred and ten older depressed adults completed baseline self-reports of depression and the NEO-Personality Inventory as a measure of neuroticism, were administered a battery of cognitive tests annually and were seen by a study psychiatrist who assessed patients using the Montgomery Åsberg Depression Rating Scale (MADRS) and treated patients with antidepressants using an established treatment guideline. Patients were followed as clinically indicated for up to three years. We measured remission (defined as MADRS score ≤ 6) rates at one year as a categorical outcome. In addition, we used Cox proportional hazard models to examine the relationship between neuroticism and change in MADRS and cognitive score over time. RESULTS: Non-remitters (30%) at one year had higher scores in total neuroticism (TN), vulnerability to stress (VS), and NA. Over three years, time to achieve remission was associated with higher TN, higher VS, and greater NA. In analyses controlling for baseline cognitive score, age, sex, and education, VS was associated with baseline to two-year change in cognition. CONCLUSIONS: Presence of neuroticism in older depressed patients treated with medication is associated with poor mood outcomes and may indicate increased risk of cognitive decline.

Serum ionized calcium may be related to white matter lesion volumes in older adults: a pilot study.

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 (ß = 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 (ß = 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 (ß = 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.

Negative life stress and longitudinal hippocampal volume changes in older adults with and without depression.

Major depressive disorder is associated with smaller hippocampal volumes but the mechanisms underlying this relationship are unclear. To examine the effect of environmental influences, we examined the relationship between self-reported stressors and two-year change in hippocampal volume. Seventy elderly nondepressed subjects and eighty-nine elderly depressed subjects were followed for two years. The number of negative stressful life events (nSLE), perceived stress levels, and cranial MRI were obtained at baseline and at the two-year assessment. For secondary analyses, subjects provided blood for 5-HTTLPR polymorphism genotyping. After controlling for covariates including presence or absence of depression, greater numbers of baseline nSLEs were significantly associated with greater baseline hippocampal volumes bilaterally. Greater numbers of baseline nSLEs were also associated with reduction in hippocampal volume over two years in the right but not the left hemisphere. Neither perceived stress levels nor changes in stress measures were significantly associated with hippocampal volume measures. However, in secondary analyses, we found that increases in perceived stress over time was associated with volume reduction of the left hippocampus, but only in 5-HTTLPR L/L homozygotes. Our findings suggest different short- and long-term effects of negative life stressors on hippocampal volumes in older adults. These effects appear independent on the presence or absence of depression. Furthermore, these effects may be moderated by genetic polymorphisms in key neurotransmitter systems. These novel findings have important implications for understanding environmental influences on brain aging.

AGTR1 gene variation: association with depression and frontotemporal morphology.

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.