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1.  COGNITION AS A THERAPEUTIC TARGET IN LATE-LIFE DEPRESSION: POTENTIAL FOR NICOTINIC THERAPEUTICS 
Biochemical pharmacology  2013;86(8):10.1016/j.bcp.2013.07.032.
Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs and parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging.
doi:10.1016/j.bcp.2013.07.032
PMCID: PMC3856552  PMID: 23933385
cognition; depression; late-life; nicotinic acetylcholine receptors; aging
2.  Negative life stress and longitudinal hippocampal volume changes in older adults with and without depression 
Journal of psychiatric research  2013;47(6):829-834.
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.
doi:10.1016/j.jpsychires.2013.02.008
PMCID: PMC3622849  PMID: 23478048
depression; geriatric depression; late-life depression; genetic polymorphism; hippocampus; life events; stress; neuroimaging; serotonin transporter; longitudinal
3.  The Vascular Depression Hypothesis: Mechanisms Linking Vascular Disease with Depression 
Molecular psychiatry  2013;18(9):963-974.
The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between late-life depression, vascular risk factors, and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in late-life depression, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression but also provide guidance on the potential repurposing of pharmacological agents that may improve late-life depression outcomes.
doi:10.1038/mp.2013.20
PMCID: PMC3674224  PMID: 23439482
Depression; geriatrics; cerebrovascular; review; neuroimaging; cognition
4.  Fiber Tract-Specific White Matter Lesion Severity: Findings in Late-Life Depression and by AGTR1 A1166C Genotype 
Human brain mapping  2011;34(2):295-303.
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. 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 (F1,86 = 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.
doi:10.1002/hbm.21445
PMCID: PMC3772522  PMID: 22021115
5.  Angiotensin Converting Enzyme Inhibitors and Alzheimer Disease in the Presence of the Apolipoprotein E4 Allele 
Objective
The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD.
Methods
This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined.
Results
A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08–140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education.
Conclusion
The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers.
doi:10.1016/j.jagp.2012.08.017
PMCID: PMC3873370  PMID: 23567418
Alzheimer disease; Apolipoprotein E4 allele (ApoE4); angiotensin converting enzyme (ACE); ACE inhibitor
6.  Association of NEO 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 US.
Participants
One hundred twelve psychiatric patients with a current episode of unipolar major depression, and 104 nondepressed comparison subjects, ages 60 years and older (mean = 70, SD = 6).
Measurements
Revised NEO Personality Inventory, Diagnostic Interview Schedule, 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.
doi:10.1016/j.jagp.2012.11.012
PMCID: PMC3382026  PMID: 23290206
Personality; depression; neuroticism; extraversion; conscientiousness
7.  Association of attentional shift and reversal learning to functional deficits in geriatric depression 
International journal of geriatric psychiatry  2012;27(11):10.1002/gps.3764.
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.
doi:10.1002/gps.3764
PMCID: PMC3866797  PMID: 22271429
depression; older adults; instrumental activities of daily living; disability; CANTAB; executive functions
8.  Treatment Course With Antidepressant Therapy in Late-Life Depression 
The American journal of psychiatry  2012;169(11):1185-1193.
Objective
In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial.
Method
In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antide-pressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time.
Results
Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyperintensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not.
Conclusions
These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.
PMCID: PMC3752387  PMID: 23534057
9.  Cognitive Improvement Following Treatment in Late Life Depression: Relationship to Vascular Risk and Age of Onset 
Objectives
To test the hypothesis that the degree vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late life depression.
Design
Measurement of cognition both prior to and following 12-weeks of treatment with Sertraline.
Setting
University Medical Centers (Washington University and Duke University)
Participants
166 individuals with late life depression.
Intervention
Sertraline treatment.
Measurements
The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2 based white matter hyperintensities using the Fazekas criteria.
Results
Both episodic memory and executive function demonstrated significant improvement among adults with late life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental state exam scores predicted less change in working memory. Further, older age, later age of onset, and higher vascular risk scores predicted less change in executive function.
Conclusions
These results have important clinical implications, in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life.
doi:10.1097/JGP.0b013e318246b6cb
PMCID: PMC3382028  PMID: 22430020
Cognition; Vascular Depression; Treatment; white matter
10.  Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms 
Stress (Amsterdam, Netherlands)  2012;15(4):425-434.
Although the relation between stressful life events (SLEs) and risk of major depressive disorder (MDD) is well-established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were: 1) to examine how baseline stress and change in stress is associated with course of geriatric depression; and 2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. 216 depressed subjects age 60 years or older were categorized by remission status (MADRS ≤ 6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.
doi:10.3109/10253890.2011.634263
PMCID: PMC3319482  PMID: 22044241
COMT Val158Met; gene-environment interactions; geriatric depression; late-life depression; life events; perceived stress; serotonin transporter
11.  AGTR1 gene variation: association with depression and frontotemporal morphology 
Psychiatry Research  2012;202(2):104-109.
The renin-angiotensin system (RAS) is implicated in the response to physiological and psychosocial stressors however 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 (AT1R), is associated with a diagnosis of depression and differences in white matter hyperintensities and frontotemporal brain volumes. 257 depressed and 116 nondepressed elderly Caucasian subjects completed clinical assessments and provided blood samples for genotyping. We utilized a haplotype-tagging single nucleotide polymorphism (htSNP) analysis to test for variation in AGTR1. 1.5T MRI data for measurement of hyperintense lesions were available on 281 subjects, while 70 subjects completed 3T MRI allowing for measurements of the hippocampus and dorsolateral prefrontal cortex (dlPFC). 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 that genetic variation in AGTR1 is associated with depression and differences in frontotemporal morphology.
doi:10.1016/j.pscychresns.2012.03.007
PMCID: PMC3398195  PMID: 22703619
Geriatrics; renin-angiotensin system; MRI; genetic polymorphisms; hippocampus; amygdala; prefrontal cortex
12.  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.
doi:10.1097/JGP.0b013e318211069a
PMCID: PMC3164525  PMID: 21873832
age of onset; amygdala; depression; geriatrics; MRI
13.  Social organization of self-management support of persons with diabetes: A health systems comparison 
Objective
Identify important organizational elements for providing self-management support (SMS).
Design
Semi-structured qualitative interviews conducted in two healthcare systems.
Setting
Kaiser Permanente Northern California and the Danish Health Care System.
Subjects
36 managers and healthcare professionals in the two healthcare systems.
Main outcome measures
Elements important to providing self-management support to persons with diabetes.
Results
Healthcare professionals’ provision of SMS was influenced by healthcare system organization and their perceptions of SMS, the capability and responsibility of healthcare systems, and their roles in the healthcare organization. Enabling factors for providing SMS included: strong leadership; aligned incentives; use of an integrated health information technology (HIT) system; multidisciplinary healthcare provider teams; ongoing training for healthcare professionals; outreach; and quality goals. Barriers to providing SMS included lack of collaboration between providers and skeptical attitudes towards prevention and outreach.
Conclusions and implications
Implementation of SMS can be improved by an understanding of the elements that enhance its provision: (1) initiatives seeking to improve collaboration and integration between providers; (2) implementation of an integrated HIT system; and (3) ongoing training of healthcare professionals.
doi:10.3109/02813432.2012.704810
PMCID: PMC3443944  PMID: 22839353
Denmark; diabetes mellitus; general practice; health system; international comparison; patient education; self-management support
14.  Reduction of dorsolateral prefrontal cortex gray matter in late-life depression 
Psychiatry research  2011;193(1):1-6.
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 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.
doi:10.1016/j.pscychresns.2011.01.003
PMCID: PMC3105213  PMID: 21596532
magnetic resonance imaging; elderly; mood
15.  One-Year Change in Anterior Cingulate Cortex White Matter Microstructure: Relationship with Late-Life Depression Outcomes 
Objectives
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, we examined how one-year change in DTI measures are related to one-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
29 depressed and 20 never-depressed elderly subjects. Over the one-year period, 16 depressed subjects achieved and maintained remission, while 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 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 MADRS and change in anterior cingulate cortex FA, wherein greater interval decline in FA was associated with greater interval decline in MADRS.
Conclusions
Older depressed individuals who remit exhibit white matter changes comparable to what is observed in never-depressed individuals, while nonremitters exhibit significantly less change in anterior cingulate cortex 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.
doi:10.1097/JGP.0b013e3181e70cec
PMCID: PMC3000437  PMID: 20808126
Aging; depression; frontal lobe; anterior cingulate cortex; white matter; diffusion tensor imaging
16.  The BDNF Val66Met Genotype and Six-Month Remission Rates in Late-Life Depression 
The pharmacogenomics journal  2010;11(2):146-154.
Although not observed in younger adult cohorts, in older individuals the BDNF Val66Met polymorphism is associated with Major Depressive Disorder (MDD) risk. It is further associated with subjective social support and MRI hyperintense lesions, clinical features independently related to MDD. We examined the relationship between this polymorphism and antidepressant remission rates in an elderly sample with MDD, while also testing for mediation effects of social support and hyperintensities. 229 elderly Caucasian subjects with MDD completed baseline assessments, 1.5T MRI, and BDNF genotyping. They received antidepressant medication under a structured treatment algorithm and evaluated for remission at 3- and 6-months. At the 3-month evaluation BDNF Val66Met genotype was not associated with remission (Wald χ2 = 2.51, p = 0.1131). When not controlling for multiple comparisons, Met66 allele carriers were more likely to be remitted at 6-months (χ2 = 4.32, p = 0.0377) with an odds ratio of 1.82 (95% CI: 1.04, 3.22). This effect persisted after controlling for lesion volume and social support, neither of which mediated this relationship. Thus in this exploratory analysis, the Met66 allele may be associated with increased odds of remission in older subjects, but also with increased time to remission as there was no 3-month effect.
doi:10.1038/tpj.2010.12
PMCID: PMC2962689  PMID: 20195291
BDNF; geriatrics; Major Depressive Disorder; antidepressant response; genetic polymorphism
17.  Structural Integrity of the Uncinate Fasciculus and Resting State Functional Connectivity of the Ventral Prefrontal Cortex in Late Life Depression 
PLoS ONE  2011;6(7):e22697.
Background
Neuroimaging studies in late life depression have reported decreased structural integrity of white matter tracts in the prefrontal cortex. Functional studies have identified changes in functional connectivity among several key areas involved in mood regulation. Few studies have combined structural and functional imaging. In this study we sought to examine the relationship between the uncinate fasciculus, a key fronto-temporal tract and resting state functional connectivity between the ventral prefrontal cortex ((PFC) and limbic and striatal areas.
Methods
The sample consisted of 24 older patients remitted from unipolar major depression. Each participant had a magnetic resonance imaging brain scan using standardized protocols to obtain both diffusion tensor imaging and resting state functional connectivity data. Our statistical approach compared structural integrity of the uncinate fasciculus and functional connectivity data.
Results
We found positive correlations between left uncinate fasciculus (UF) fractional anisotropy (FA) and resting state functional connectivity (rsFC) between the left ventrolateral PFC and left amygdala and between the left ventrolateral PFC and the left hippocampus. In addition, we found a significant negative correlation between left ventromedial PFC-caudate rsFC and left UF FA. The right UF FA did not correlate with any of the seed region based connectivity.
Conclusions
These results support the notion that resting state functional connectivity reflects structural integrity, since the ventral PFC is structurally connected to temporal regions by the UF. Future studies should include larger samples of patients and healthy comparison subjects in which both resting state and task-based functional connectivity are examined.
doi:10.1371/journal.pone.0022697
PMCID: PMC3142185  PMID: 21799934
18.  The BDNF 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. We examined the relationship between the BDNF gene and hippocampal volumes in depressed and non-depressed older individuals and its relationship with memory functions mediated by the hippocampus.
Design
One hundred seventy-six elderly depressed Caucasian participants and eighty-eight non-depressed participants completed clinical assessments, neuropsychological testing and provided blood samples for genotyping. One hundred seventy-three participants also underwent brain Magnetic Resonance Imaging (MRI). 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, non verbal memory, or digit span. After controlling for covariates, BDNF genotype was not significantly associated with hippocampal volume (F1, 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. We 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.
doi:10.1097/JGP.0b013e3181cabd2b
PMCID: PMC2928477  PMID: 20220593
genetic polymorphism; magnetic resonance imaging; depression; hippocampus
19.  Support for the Vascular Depression Hypothesis in Late Life Depression: Results from a Two Site Prospective Antidepressant Treatment Trial 
Archives of general psychiatry  2010;67(3):277-285.
Context
Research on “vascular depression” has used two approaches to subtype late life depression (LLD) based on executive dysfunction or white matter hyperintensity (WMH) severity.
Objective
Evaluate the relationship of neuropsychological performance and WMH to clinical response in LLD.
Design
2-site prospective nonrandomized controlled trial.
Setting
Outpatient clinics at Washington University and Duke University.
Participants
217 subjects age ≥ 60 met DSM-IV criteria for major depression, scored ≥ 20 (MADRS), received vascular risk factor (VRF) scores, neuropsychological testing and MRI scan; were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade WMH lesions.
Intervention
12 weeks of sertraline treatment, titrated by clinical response.
Outcome
Montgomery-Asberg Depression Rating Scale (MADRS) score over time.
Results
Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (p = 0.002); language (p = 0.007); working memory (p = 0.01); processing speed (p = 0.0001); executive function factor scores (p = 0.002), and categorical Fazekas ratings (p = 0.049) predicted MADRS scores, controlling for age, education, age of onset and race. Controlling for baseline MADRS scores these factors remained significant predictors of decrease in MADRS scores except working memory and Fazekas ratings. 33% of subjects achieved remission (MADRS ≤ 7). Remitters differed from non-remitters in baseline cognitive processing speed, executive function, language, episodic memory and VRF scores.
Discussion
Comprehensive neuropsychological function and WMH severity predicted MADRS scores prospectively over a 12 week SSRI treatment course in LLD. Baseline neuropsychological function differentiated remitters from non-remitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with VRF severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity.
doi:10.1001/archgenpsychiatry.2009.204
PMCID: PMC2838210  PMID: 20194828
late life depression; antidepressant; neuropsychology; WMH; cognitive deficit; age of onset; vascular risk factors; factor scores
20.  ANGIOTENSIN RECEPTOR GENE POLYMORPHISMS AND TWO-YEAR CHANGE IN HYPERINTENSE LESION VOLUME IN MEN 
Molecular psychiatry  2009;15(8):816-822.
This longitudinal study examined the relationship between 2-year change in white matter hyperintense lesion (WML) volume and polymorphisms in genes coding for the angiotensin-II type 1 and type 2 receptors, AGTR1 A1166C and AGTR2 C3123A. 137 depressed and 94 nondepressed subjects age 60 years or older were enrolled. Standard clinical evaluations were performed on all subjects and blood samples obtained for genotyping. 1.5T MRI was obtained at baseline and approximately two years later. These scans were processed using a semi-automated segmentation process which allowed for the calculation of WML volume at each time point. Statistical models tested for the relationship between change in WML volume and genotype, while also controlling for age, sex, diagnostic strata, baseline WML volume, and comorbid cerebrovascular risk factors. In men, AGTR1 1166A allele homozygotes exhibited significantly less change in WML volume than 1166C carriers. We also found that men reporting hypertension with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without hypertension. There were no significant relationships between these polymorphisms and change in WML volume in women. No significant gene-gene or gene-depression interactions were observed. Our results parallel previously observed gender differences of the relationship between other renin-angiotensin system polymorphisms and hypertension. Further work is needed to determine if these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and if antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.
doi:10.1038/mp.2009.26
PMCID: PMC2891956  PMID: 19274051
MRI; Major Depressive Disorder; Volumetric Study; Cerebrovascular Disease; Renin-Angiotensin System; Genetic Polymorphisms
21.  Variability in Frontotemporal Brain Structure: The Importance of Recruitment of African Americans in Neuroscience Research 
PLoS ONE  2010;5(10):e13642.
Background
Variation in brain structure is both genetically and environmentally influenced. The question about potential differences in brain anatomy across populations of differing race and ethnicity remains a controversial issue. There are few studies specifically examining racial or ethnic differences and also few studies that test for race-related differences in context of other neuropsychiatric research, possibly due to the underrepresentation of ethnic minorities in clinical research. It is within this context that we conducted a secondary data analysis examining volumetric MRI data from healthy participants and compared the volumes of the amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebral volume between Caucasian and African-American participants. We discuss the importance of this finding in context of neuroimaging methodology, but also the need for improved recruitment of African Americans in clinical research and its broader implications for a better understanding of the neural basis of neuropsychiatric disorders.
Methodology/Principal Findings
This was a case control study in the setting of an academic medical center outpatient service. Participants consisted of 44 Caucasians and 33 ethnic minorities. The following volumetric data were obtained: amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebrum. Each participant completed a 1.5 T magnetic resonance imaging (MRI). Our primary finding in analyses of brain subregions was that when compared to Caucasians, African Americans exhibited larger left OFC volumes (F 1,68 = 7.50, p = 0.008).
Conclusions
The biological implications of our findings are unclear as we do not know what factors may be contributing to these observed differences. However, this study raises several questions that have important implications for the future of neuropsychiatric research.
doi:10.1371/journal.pone.0013642
PMCID: PMC2964318  PMID: 21049028
22.  Influence of the MTHFR C677T polymorphism on MRI hyperintensity volume and cognition in geriatric depression 
Objective
The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been linked to unipolar major depressive disorder (MDD) and MRI hyperintensities. We 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 (WML) and gray (GML) matter hyperintense lesion 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.
doi:10.1097/JGP.0b013e3181aad5b2
PMCID: PMC2805265  PMID: 19910873
MTHFR polymorphism; depression; white matter lesion; folate; homocysteine; elderly
23.  Association analysis of the COMT/ MTHFR genes and geriatric depression: An MRI study of the putamen 
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.
doi:10.1002/gps.2206
PMCID: PMC2711996  PMID: 19235787
MTHFR; COMT; putamen; genetics; depression
24.  BIOCHEMICAL ABNORMALITIES OF THE MEDIAL TEMPORAL LOBE AND MEDIAL PREFRONTAL CORTEX IN LATE-LIFE DEPRESSION 
Psychiatry research  2009;172(1):49-54.
We utilized single-voxel 1H magnetic resonance spectroscopy (MRS) to examine for biochemical abnormalities related to late-life depression in the medial prefrontal cortex and medial temporal lobe. Fourteen elderly subjects whose depression responded to treatment and 12 nondepressed subjects were enrolled. Subjects were scanned using a GE 3.0 Tesla whole body MR scanner. Metabolite concentrations were quantified using the LC Model software and adjusted for CSF and ratio of gray to white matter. ANCOVA models tested for group differences while controlling for age and sex. Older previously depressed individuals showed significantly reduced concentrations of total N-Acetyl aspartate, choline, and creatine in the prefrontal cortex and significantly elevated left medial temporal lobe concentrations of NAA and myo-inositol. There were no significant group differences in right temporal metabolite concentrations. The prefrontal cortex observations suggest that reduced neuronal, phospolipid, and energy metabolism is present even in clinically improved depression. In contrast, elevated NAA and myo-inositol concentrations in the left medial temporal lobe could be associated with neuronal and glial cell changes in the amygdala.
doi:10.1016/j.pscychresns.2008.07.001
PMCID: PMC2659332  PMID: 19179054
Geriatrics; magnetic resonance spectroscopy; prefrontal cortex; temporal lobe; metabolite concentration
25.  TEMPORAL LOBE VOLUME IN BIPOLAR DISORDER: RELATIONSHIP WITH DIAGNOSIS AND ANTIPSYCHOTIC MEDICATION USE 
Journal of affective disorders  2008;114(1-3):50-57.
Background
We tested for differences in temporal lobe volume in bipolar disorder and the relationship between these volumes and psychotropic medication use.
Methods
125 subjects with bipolar disorder and 87 comparison subjects with no psychiatric illness completed clinical interviews and 1.5T MRI brain scans. Temporal lobe volumes were manually traced and segmented into gray matter and white matter volumes using an automated process. General linear models examined the relationship between these volumes and diagnosis as the primary predictor with age, sex, education, and race as copredictors. Secondary analyses incorporated the use of psychotropic medication into the linear models, and parsimonious models developed through backwards regression.
Results
In initial models, subjects with bipolar disorder exhibited larger temporal lobe white matter bilaterally (left: F1,211 = 2.86, p = 0.0047; right: F1,211 = 3.25, p = 0.0014). Current antipsychotic use was significantly associated with larger bilateral temporal lobe white matter volumes (left: F2,211 = 9.45, p = 0.0001; right: F2,211 = 10.79, p < 0.0001), wherein bipolar subjects taking antipsychotics had larger volumes than bipolar subjects not taking antipsychotics or healthy comparison subjects. Temporal lobe gray matter volume was not significantly associated with diagnosis or medication use.
Limitations
Excluding subjects with substance use disorders may limit the study’s generlizability.
Conclusions
These findings indicate that differences in temporal lobe white matter are associated with bipolar disorder and use of antipsychotic medications.
doi:10.1016/j.jad.2008.07.003
PMCID: PMC2643314  PMID: 18691766

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