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.

Late-life Depression Modifies the Association Between Cerebral White Matter Hyperintensities and Functional Decline Among Older Adults.

OBJECTIVE: Vascular lesions seen through brain imaging as hyperintensities are associated with both depression and functional impairment in older adults. Our objective was to determine if the relationship between the volume of cerebral white matter hyperintensities (WMHs) and functional decline differed in the presence of late life depression. DESIGN: Secondary analysis of data collected through the Neurocognitive Outcomes of Depression Study. Analysis techniques included general linear mixed models examining trajectories of functional change predicted by lesion volume at baseline. PARTICIPANTS: 381 participants (244 patients diagnosed with major depression and 137 never depressed comparison participants) ages 60 years and older followed for up to 16 years. MEASUREMENTS: WMH volume was measured through analysis of brain magnetic resonance imaging data. Functional limitations included difficulties with basic activities of daily living tasks, instrumental activities of daily living tasks, and mobility. RESULTS: Those participants who were both depressed and had a higher volume of WMHs at baseline were most at risk for functional decline across all measures of function. Among the never depressed, those with a higher WMH volume at baseline had a more accelerated rate of functional decline than those with lower WMH volume, and those who were depressed with lower volume of WMH started with more limitations than the never depressed but appeared to progress at a rate similar to those who were never depressed with lower WMH. CONCLUSION: Older patients with both cerebrovascular risk factors and depression are at an increased risk for functional decline, and may benefit from the treatment of both conditions.

Posterior structural brain volumes differ in maltreated youth with and without chronic posttraumatic stress disorder.

Magnetic resonance imaging studies of maltreated children with posttraumatic stress disorder (PTSD) suggest that maltreatment-related PTSD is associated with adverse brain development. Maltreated youth resilient to chronic PTSD were not previously investigated and may elucidate neuromechanisms of the stress diathesis that leads to resilience to chronic PTSD. In this cross-sectional study, anatomical volumetric and corpus callosum diffusion tensor imaging measures were examined using magnetic resonance imaging in maltreated youth with chronic PTSD (N = 38), without PTSD (N = 35), and nonmaltreated participants (n = 59). Groups were sociodemographically similar. Participants underwent assessments for strict inclusion/exclusion criteria and psychopathology. Maltreated youth with PTSD were psychobiologically different from maltreated youth without PTSD and nonmaltreated controls. Maltreated youth with PTSD had smaller posterior cerebral and cerebellar gray matter volumes than did maltreated youth without PTSD and nonmaltreated participants. Cerebral and cerebellar gray matter volumes inversely correlated with PTSD symptoms. Posterior corpus callosum microstructure in pediatric maltreatment-related PTSD differed compared to maltreated youth without PTSD and controls. The group differences remained significant when controlling for psychopathology, numbers of Axis I disorders, and trauma load. Alterations of these posterior brain structures may result from a shared trauma-related mechanism or an inherent vulnerability that mediates the pathway from chronic PTSD to comorbidity.

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.

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.

Application of variable threshold intensity to segmentation for white matter hyperintensities in fluid attenuated inversion recovery magnetic resonance images.

INTRODUCTION: White matter hyperintensities (WMHs) are regions of abnormally high intensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Accurate and reproducible automatic segmentation of WMHs is important since WMHs are often seen in the elderly and are associated with various geriatric and psychiatric disorders. METHODS: We developed a fully automated monospectral segmentation method for WMHs using FLAIR MRIs. Through this method, we introduce an optimal threshold intensity (I O ) for segmenting WMHs, which varies with WMHs volume (V WMH), and we establish the I O -V WMH relationship. RESULTS: Our method showed accurate validations in volumetric and spatial agreements of automatically segmented WMHs compared with manually segmented WMHs for 32 confirmatory images. Bland-Altman values of volumetric agreement were 0.96 ± 8.311 ml (bias and 95 % confidence interval), and the similarity index of spatial agreement was 0.762 ± 0.127 (mean ± standard deviation). Furthermore, similar validation accuracies were obtained in the images acquired from different scanners. CONCLUSIONS: The proposed segmentation method uses only FLAIR MRIs, has the potential to be accurate with images obtained from different scanners, and can be implemented with a fully automated procedure. In our study, validation results were obtained with FLAIR MRIs from only two scanner types. The design of the method may allow its use in large multicenter studies with correct efficiency.

Vascular lesions and functional limitations among older adults: does depression make a difference?

ABSTRACT Background: The association between disability and depression is complex, with disability well established as a correlate and consequence of late life depression. Studies in community samples report that greater volumes of cerebral white matter hyperintensities (WMHs) seen on brain imaging are linked with functional impairment. These vascular changes are also associated with late life depression, but it is not known if depression is a modifier in the relationship between cerebrovascular changes and functional impairment. Methods: The study sample was 237 older adults diagnosed with major depression and 140 never depressed comparison adults, with both groups assessed at study enrollment. The dependent variable was the number of limitations in basic activities of daily living (ADL), instrumental ADLs, and mobility tasks. The independent variable was the total volume of cerebral white matter lesions or hyperintensities assessed though magnetic resonance imaging. Results: In analyses controlling for age, sex, race, high blood pressure, and cognitive status, a greater volume of WMH was positively associated with the total number of functional limitations as well as the number of mobility limitations among those older adults with late life depression but not among those never depressed, suggesting the association between WMH volume and functional status differs in the presence of late life depression. Conclusions: These findings suggest older patients with both depression and vascular risk factors may be at an increased risk for functional decline, and may benefit from management of both cerebrovascular risk factors and depression.

Fiber tract-specific white matter lesion severity Findings in late-life depression and by AGTR1 A1166C genotype.

Past work demonstrated that late-life depression is associated with greater severity of ischemic cerebral hyperintense white matter lesions, particularly frontal lesions. However, these lesions are also associated with other neuropsychiatric deficits, so these clinical relationships may depend on which fiber tracts are damaged. We examined the ratio of lesion to nonlesioned white matter tissue within multiple fiber tracts between depressed and nondepressed elders. We also sought to determine if the AGTR1 A1166C and BDNF Val66Met polymorphisms contributed to vulnerability to lesion development in discrete tracts. The 3T structural MR images and blood samples for genetic analyses were acquired on 54 depressed and 37 nondepressed elders. Lesion maps were created through an automated tissue segmentation process and applied to a probabilistic white matter fiber tract atlas allowing for identification of the fraction of the tract occupied by lesion. The depressed cohort exhibited a significantly greater lesion ratio only in the left upper cingulum near the cingulate gyrus (F((1,86)) = 4.62, P = 0.0344), supporting past work implicating cingulate dysfunction in the pathogenesis of depression. In the 62 Caucasian subjects with genetic data, AGTR1 C1166 carriers exhibited greater lesion ratios across multiple tracts including the anterior thalamic radiation and inferior fronto-occipital fasciculus. In contrast, BDNF Met allele carriers exhibited greater lesion ratios only in the frontal corpus callosum. Although these findings did not survive correction for multiple comparisons, this study supports our hypothesis and provides preliminary evidence that genetic differences related to vascular disease may increase lesion vulnerability differentially across fiber tracts.

Association of five-factor model personality domains and facets with presence, onset, and treatment outcomes of major depression in older adults.

OBJECTIVES: To assess the relationship of multiple domains and facets of the five-factor model of personality with presence, onset, and severity of late-life depression. DESIGN: Cross-sectional analysis of depression status, and age of onset. Retrospective analysis of baseline severity. Longitudinal analysis of severity after 3 and 12 months of psychiatric treatment. SETTING: Private university-affiliated medical center in the Southeastern United States. PARTICIPANTS: One hundred twelve psychiatric patients with a current episode of unipolar major depression, and 104 nondepressed comparison subjects, age 60 and older (mean: 70, SD: 6). MEASUREMENTS: Revised NEO Personality Inventory, Diagnostic Interview Schedule, and Montgomery-Åsberg Depression Rating Scale. RESULTS: Binary logistic regression found that depression was related to higher neuroticism (and all its facets) and to lower extraversion (and facets of assertiveness, activity, and positive emotionality) and conscientiousness (and facets of competence, order, dutifulness, and self-discipline). Multinomial logistic regression found some of these relationships held only for depression with onset before age 50 (hostility, self-consciousness, extraversion, assertiveness, positive emotions, order, and dutifulness). Linear regression found that personality was unrelated to depression severity at the beginning of treatment, but improvement after 3 months was related to lower neuroticism (and facets depressiveness and stress-vulnerability) and higher warmth and competence. Improvement after 12 months was related to lower neuroticism, depressiveness, and stress-vulnerability. CONCLUSIONS: Specific personality facets are related with depression and treatment outcomes. Screening for certain personality traits at the start of treatment may help identify patients at risk of worse response to treatment after 3 months.

Folate metabolism genes, dietary folate and response to antidepressant medications in late-life depression.

OBJECTIVE: The primary aims of this study were to (i) determine whether folate metabolism genetic polymorphisms predict age of onset and occurrence of late life depression; and (ii) determine whether folate metabolism genetic polymorphisms predict response to antidepressant medications in late-life depression. METHODS: This study used the Conte Center for the Neuroscience of Depression and the Neurocognitive Outcomes of Depression in the Elderly Study database, which includes individuals aged ≥60. The folate nutrition assessment was determined by the Block Food Frequency Questionnaire. Genotype was evaluated for 15 single nucleotide polymorphisms from 10 folate metabolism genes. Logistic regression models were used to examine genetic polymorphisms and folate estimates with association with depression age of onset and remission status. RESULTS: There were 304 Caucasians in the database, 106 of these were not depressed and 198 had a diagnosis of depression. There were no significant differences between remitters and non-remitters in age, sex or estimated folate intakes. There were no folate estimates or folate metabolism gene single nucleotide polymorphisms that significantly predicted age of onset of depression or occurrence of depression. Methionine synthase reductase (MTRR) A66G (rs1801394) was significantly associated with remission status (p = 0.0077) such that those with the AA genotype were 3.2 times as likely as those with the GG genotype to be in remission (p = 0.0020). Methylenetetrahydrofolate reductase A1298C (rs1801131) achieved a borderline significance for association with remission status (p = 0.0313). CONCLUSION: The major finding from this study is that the MTRR A66G genotype predicts response to selective serotonin reuptake inhibitor antidepressants in late life depression.

Religion and the presence and severity of depression in older adults.

OBJECTIVES: : To examine the associations of dimensions of religiousness with the presence and severity of depression in older adults. DESIGN: : Cross-sectional analysis of clinical and interview data. SETTING: : Private university-affiliated medical center in the Southeastern United States. PARTICIPANTS: : Four hundred seventy-six psychiatric patients with a current episode of unipolar major depression, and 167 nondepressed comparison subjects, ages 58 years or older (mean = 70 years, SD = 7). MEASUREMENTS: : Diagnostic Interview Schedule, Montgomery-Åsberg Depression Rating Scale, and Duke Depression Evaluation Schedule were used in the study. RESULTS: : Presence of depression was related to less frequent worship attendance, more frequent private religious practice, and moderate subjective religiosity. Among the depressed group, less severe depression was related to more frequent worship attendance, less religiousness, and having had a born-again experience. These results were only partially explained by effects of social support and stress buffering. CONCLUSIONS: : Religion is related to depression diagnosis and severity via multiple pathways.

Association of attentional shift and reversal learning to functional deficits in geriatric depression.

OBJECTIVE: The objective of this study is to examine the association between self-reported functional disability in depressed older adults and two types of executive function processes, attentional set shifting and reversal learning. METHODS: Participants (N = 89) were aged 60 or over and enrolled in a naturalistic treatment study of major depressive disorder. Participants provided information on self-reported function in instrumental activities of daily living (IADL) and completed the Intra-Extra Dimensional Set Shift test (IED) from the Cambridge Neuropsychological Testing Automated Battery, which assesses intra-dimensional attentional shifts, extra-dimensional attentional shifts, and reversal learning. Participants were categorized by the presence or absence of IADL difficulties and compared on IED performance using bivariable and multivariable tests. RESULTS: Participants who reported IADL difficulties had more errors in extra-dimensional attentional shifting and reversal learning, but intra-dimensional shift errors were not associated with IADLs. Only extra-dimensional shift errors were significant in multivariable models that controlled for age, sex, and depression severity. CONCLUSIONS: Attentional shifting across categories (i.e., extra-dimensional) was most strongly associated with increased IADL difficulties among depressed older adults, which make interventions to improve flexible problem solving a potential target for reducing instrumental disability in this population.

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.

Change in hippocampal volume on magnetic resonance imaging and cognitive decline among older depressed and nondepressed subjects in the neurocognitive outcomes of depression in the elderly study.

INTRODUCTION: previous studies have linked hippocampal volume change and cognitive decline in older adults with dementia. The authors examined hippocampal volume change and cognitive change in older nondemented adults with and without major depression. METHODS: the sample consisted of 90 depressed individuals and 72 healthy, nondepressed individuals aged 60 years and older who completed at least 2 years of follow-up data. All patients underwent periodic clinical evaluation by a geriatric psychiatrist as well as baseline and 2-year magnetic resonance imaging. RESULTS: over 2 years, the depressed group showed a greater reduction in left hippocampal volume (normalized for total cerebral volume) compared with the nondepressed group (mean difference = 0.013 ± 0.0059, t = 2.18, df = 160, p <0.0305). The difference remained significant after controlling for age, sex, and baseline normalized left hippocampal volume. The authors also found that hippocampal change from baseline to 2 years was associated with subsequent change in Mini-Mental State Examination score from 2 years to 2½ years (left t = 2.81, df = 66, p = 0.0066; right t = 2.40, df = 66, p = 0.0193) among the depressed group. CONCLUSIONS: these findings add to the literature linking hippocampal volume loss and late-life depression. Depressed patients with hippocampal volume loss are at greater risk of cognitive decline.

One-year change in anterior cingulate cortex white matter microstructure: relationship with late-life depression outcomes.

OBJECTIVE: differences in white matter structure measured with diffusion tensor imaging (DTI) are associated with late-life depression, but results examining how these differences relate to antidepressant remission are mixed. To better describe these relationships, the authors examined how 1-year change in DTI measures are related to 1-year course of depression. DESIGN: one-year cross-sectional follow-up to a 12-week clinical trial of sertraline. SETTING: outpatients at an academic medical center. PARTICIPANTS: twenty-nine depressed and 20 never-depressed elderly subjects. Over the 1-year period, 16 depressed subjects achieved and maintained remission, whereas 13 did not. MEASUREMENTS: one-year change in fractional anisotropy (FA) and diffusivity in frontal white matter, as measured by DTI. RESULTS: contrary to our hypotheses, depressed subjects who did not remit over the study interval exhibited significantly less change in anterior cingulate cortex (ACC) white matter FA than did never-depressed or depressed-remitted subjects. There were no group differences in other frontal or central white matter regions. Moreover, there was a significant positive relationship between change in Montgomery-Asberg Depression Rating Scale (MADRS) and change in ACC FA, wherein greater interval decline in FA was associated with greater interval decline in MADRS. CONCLUSION: older depressed individuals who remit exhibit white matter changes comparable with what is observed in never-depressed individuals, whereas nonremitters exhibit significantly less change in ACC FA. Such a finding may be related to either antidepressant effects on brain structure or the effects of chronic stress on brain structure. Further work is needed to better understand this relationship.

Amygdala volume in late-life depression: relationship with age of onset.

OBJECTIVES: 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. DESIGN: 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. SETTING: An academic medical center. PARTICIPANTS: 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. MEASUREMENTS: Amygdala and cerebral volumes were measured using reliable manual tracing methods. RESULTS: 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, p < 0.0001; right: F[2, 116] = 16.28, p < 0.0001). 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 p < 0.0001), but the two depressed cohorts did not exhibit a statistically significant difference. LIMITATIONS: 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. CONCLUSIONS: Depression in later life is associated with smaller amygdala volumes, regardless of age of initial onset of depression.

Reduction of dorsolateral prefrontal cortex gray matter in late-life 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.

Differential patterns of cognitive decline in anterior and posterior white matter hyperintensity progression.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) found on brain MRI in elderly individuals are largely thought to be due to microvascular disease, and its progression has been associated with cognitive decline. The present study sought to determine patterns of cognitive decline associated with anterior and posterior WMH progression. METHODS: Subjects included 110 normal controls, aged >or=60 years, who were participants in the Duke Neurocognitive Outcomes of Depression in the Elderly study. All subjects had comprehensive cognitive evaluations and MRI scans at baseline and after 2 years. Cognitive composites were created in 5 domains: complex processing speed, working memory, general memory, visual-constructional skills, and language. Change in cognition was calculated using standard regression-based models accounting for variables known to impact serial testing. A semiautomated segmentation method was used to measure WMH extent in anterior and posterior brain regions. Hierarchical multiple linear regression models were used to evaluate which of the 5 measured cognitive domains was most strongly associated with regional (anterior and posterior) and total WMH progression after adjusting for demographics (age, sex, and education). RESULTS: Decline in complex processing speed was independently associated with both anterior (r(2)=0.06, P=0.02) and total WMH progression (r(2)=0.05, P=0.04). In contrast, decline in visual-constructional skills was uniquely associated with posterior progression (r(2)=0.05, P<0.05). CONCLUSIONS: Distinct cognitive profiles are associated with anterior and posterior WMH progression among normal elders. These differing profiles need to be considered when evaluating the cognitive correlates of WMHs.

The brain-derived neurotrophic factor Val66Met polymorphism, hippocampal volume, and cognitive function in geriatric depression.

OBJECTIVE: The Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene is associated with geriatric depression. In studies of younger adults without depression, met allele carriers exhibit smaller hippocampal volumes and have poorer performance on neuropsychological tests. The authors examined the relationship between the BDNF gene and hippocampal volumes in depressed and nondepressed older individuals and its relationship with memory functions mediated by the hippocampus. DESIGN: One hundred seventy-six elderly depressed white participants and 88 nondepressed participants completed clinical assessments, neuropsychological testing, and provided blood samples for genotyping. One hundred seventy-three participants also underwent brain magnetic resonance imaging. Statistical modeling tested the relationship between genotype and hippocampal volume and function while controlling for diagnosis and other covariates. RESULTS: BDNF genotype was not associated with a difference in performance on tests mediated by the hippocampus, including word list learning, prose recall, nonverbal memory, or digit span. After controlling for covariates, BDNF genotype was not significantly associated with hippocampal volume (F[1, 171] = 1.10, p = 0.30). CONCLUSION: Despite different findings in younger populations, the BDNF Val66Met polymorphism is not significantly associated with hippocampal volume or function in a geriatric population. The authors hypothesize that other factors may have a stronger effect on hippocampal structure in older individuals and that the association between the Val66Met polymorphism and geriatric depression is mediated through other mechanisms.

APOE related hippocampal shape alteration in geriatric depression.

Late-onset depression often precedes the onset of dementia associated with the hippocampal degeneration. Using large deformation diffeomorphic metric mapping (LDDMM), we evaluated apolipoprotein E epsilon-4 allele (apoE E4) effects on hippocampal volume and shape in 38 depressed patients without the apoE E4, 14 depressed patients with one apoE E4, and 31 healthy comparison subjects without the apoE E4. The hippocampal volumes were manually assessed. We applied a diffeomorphic template generation procedure for creating the hippocampal templates based on a subset of the population. The LDDMM mappings were used to generate the hippocampal shape of each subject and characterize the surface deformation of each hippocampus relative to the template. Such deformation was modeled as random field characterized by the Laplace-Beltrami basis functions in the template coordinates. Linear regression was used to examine group differences in the hippocampal volume and shape. We found that there were significant hippocampal shape alternations in both depressed groups while the groups of depressed patients and the group of healthy subjects did not differ in the hippocampal volume. The depressed patients with one apoE E4 show more pronounced shape inward-compression in the anterior CA1 than the depressed patients without the apoE E4 when compared with the healthy controls without the apoE E4. Thus, hippocampal shape abnormalities in late-onset depressed patients with one apoE E4 may indicate future conversion of this group to AD at higher risk than depressed patients without the apoE E4.