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.
Measurement of cognition both prior to and following 12-weeks of treatment with Sertraline.
University Medical Centers (Washington University and Duke University)
166 individuals with late life depression.
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.
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.
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.
Cognition; Vascular Depression; Treatment; white matter
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.
COMT Val158Met; gene-environment interactions; geriatric depression; late-life depression; life events; perceived stress; serotonin transporter
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.
Geriatrics; renin-angiotensin system; MRI; genetic polymorphisms; hippocampus; amygdala; prefrontal cortex
Depression is common in the elderly population. Although numerous neuroimaging studies have examined depressed elders, there is limited research examining how amygdala volume may be related to depression.
A cross-sectional examination of amygdala volume comparing elders with and without a diagnosis of major depressive disorder, and between depressed subjects with early and later initial depression onset.
An academic medical center.
Ninety-one elderly patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for major depression (54 early-onset depressed and 37 late-onset depressed) and 31 elderly subjects without any psychiatric diagnoses.
Amygdala and cerebral volumes were measured using reliable manual tracing methods.
In models controlling for age, sex, and cerebral volume, there was a significant difference between diagnostic cohorts in amygdala volume bilaterally (left: F[2, 116]= 16.28, 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 include missing antidepressant treatment data, recall bias, inability to establish a causal relationship between amygdala size and depression given the cross-sectional nature of the design.
Depression in later life is associated with smaller amygdala volumes, regardless of age of initial onset of depression.
age of onset; amygdala; depression; geriatrics; MRI
Identify important organizational elements for providing self-management support (SMS).
Semi-structured qualitative interviews conducted in two healthcare systems.
Kaiser Permanente Northern California and the Danish Health Care System.
36 managers and healthcare professionals in the two healthcare systems.
Main outcome measures
Elements important to providing self-management support to persons with diabetes.
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.
Denmark; diabetes mellitus; general practice; health system; international comparison; patient education; self-management support
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.
magnetic resonance imaging; elderly; mood
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.
One-year cross-sectional follow-up to a 12-week clinical trial of sertraline.
Outpatients at an academic medical center.
29 depressed and 20 never-depressed elderly subjects. Over the one-year period, 16 depressed subjects achieved and maintained remission, while 13 did not.
One-year change in fractional anisotropy (FA) and diffusivity in frontal white matter, as measured by DTI.
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.
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.
Aging; depression; frontal lobe; anterior cingulate cortex; white matter; diffusion tensor imaging
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.
BDNF; geriatrics; Major Depressive Disorder; antidepressant response; genetic polymorphism
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.
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.
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.
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.
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.
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.
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).
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.
genetic polymorphism; magnetic resonance imaging; depression; hippocampus
Research on “vascular depression” has used two approaches to subtype late life depression (LLD) based on executive dysfunction or white matter hyperintensity (WMH) severity.
Evaluate the relationship of neuropsychological performance and WMH to clinical response in LLD.
2-site prospective nonrandomized controlled trial.
Outpatient clinics at Washington University and Duke University.
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.
12 weeks of sertraline treatment, titrated by clinical response.
Montgomery-Asberg Depression Rating Scale (MADRS) score over time.
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.
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.
late life depression; antidepressant; neuropsychology; WMH; cognitive deficit; age of onset; vascular risk factors; factor scores
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.
MRI; Major Depressive Disorder; Volumetric Study; Cerebrovascular Disease; Renin-Angiotensin System; Genetic Polymorphisms
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.
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).
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.
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.
Duke University Medical Center.
Depressed (N=178) and comparison (N=85) elderly subjects.
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.
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.
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.
MTHFR polymorphism; depression; white matter lesion; folate; homocysteine; elderly
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.
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.
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.
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.
MTHFR; COMT; putamen; genetics; depression
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.
Geriatrics; magnetic resonance spectroscopy; prefrontal cortex; temporal lobe; metabolite concentration
We tested for differences in temporal lobe volume in bipolar disorder and the relationship between these volumes and psychotropic medication use.
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.
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.
Excluding subjects with substance use disorders may limit the study’s generlizability.
These findings indicate that differences in temporal lobe white matter are associated with bipolar disorder and use of antipsychotic medications.
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 hippocampal shapes for 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.
hippocampal shape; geriatric depression; APOE; diffeomorphic mapping
Although often viewed as a purely environmental construct, perception of social support may be influenced by genetic factors. This study examined the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and social support measures in older subjects. The sample consisted of 243 depressed and 115 nondepressed older subjects, age 60 years or older; 233 were Val66 allele homozygotes, while 125 were Met66 allele carriers. All subjects completed clinical assessments, including a self-report questionnaire assessing four social support domains, and provided blood for genotyping. Statistical models examined the relationship between scale scores of social support and BDNF Val66Met genotype, while controlling for presence or absence of major depressive disorder and other demographic factors significantly associated with social support. As social support measures were not normally distributed, log-transformed scores were examined. After controlling for diagnosis and education level, the Met66 allele was associated with lower levels of subjective social support (F1, 357 = 5.33, p = 0.0216) and a trend for fewer social interactions (F1, 357 = 3.66, p = 0.0567). To our knowledge, this is the first report associating a measure of social support with a genetic polymorphism. This supports previous work that genetic factors may influence social support perception. Further work is needed to determine the generalizability of this finding to the broader population, as well as its significance for clinical outcomes.
Geriatrics; depression; aging; polymorphism; single nucleotide
Neuroanatomic features associated with antidepressant treatment outcomes in older depressed individuals are not well established. This study used diffusion tensor imaging to examine frontal white matter structure in depressed subjects undergoing a 12-week trial of sertraline. We hypothesized that remission would be associated with higher frontal anisotropy measures, and failure to remit with lower anisotropy.
74 subjects with Major Depressive Disorder and age 60 years or older were enrolled in a twelve-week open-label trial of sertraline and completed clinical assessments and 1.5T magnetic resonance brain imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the dorsolateral prefrontal cortex, anterior cingulate cortex, and corpus callosum. Differences in ADC and FA values between subjects who did and did not remit to treatment over the study period were assessed using generalized estimating equations, controlling for age, sex, medical comorbidity and baseline depression severity.
Subjects who did not remit to sertraline exhibited higher FA values in the superior frontal gyri and anterior cingulate cortices bilaterally. There were no statistically significant associations between ADC measures and remission.
Failure to remit to sertraline is associated with higher frontal FA values. Functional imaging studies demonstrate that depression is characterized by functional disconnection between frontal and limbic regions. Those individuals where this disconnection is related to structural changes as detected by DTI may be more likely to respond to antidepressants.
Major depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F1,103 = 5.26; p = 0.0240) but not right hippocampus volume (F1,103 = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms.
The uncinate fasciculus connects limbic structures, such as the hippocampus and amygdala, with frontal regions. This study utilized diffusion tensor imaging to examine the structural integrity of the uncinate fasciculus in late-life depression.
18 elderly depressed and 19 elderly nondepressed subjects were matched for age and sex; 8 subjects had mid- to late-onset of depression while 10 subjects had early-onset depression. 3T diffusion tensor imaging-based fiber tract mapping delineated the uncinate fasciculus in each hemisphere, which guided measurement of the fractional anisotropy of the uncinate fasciculus in the temporal stem. After controlling for age and sex, differences between diagnostic groups were assessed.
After controlling for age and sex, individuals with early onset depression exhibited lower anisotropy of the left uncinate fasciculus than did mid- and late-onset or nondepressed subjects (F2,36 = 4.50, p = 0.02). Analyses of the right uncinate fasciculus were not statistically significant.
This provides preliminary evidence that there is a structural connectivity deficit between left frontal and limbic structures in early-onset depression. Further work is needed to determine if this is seen in younger depressed subjects, and if it influences treatment outcomes.
depression; elderly; magnetic resonance imaging; temporal lobe
We examined the relationship between COMT Val158Met genotype and temporal lobe volumes, including the caudate as a control region. 31 healthy subjects completed 1.5T brain MRI and genotyping. After controlling for demographics, Val158 allele homozygotes exhibited significantly smaller temporal lobe and hippocampal volumes, with a trend for smaller amygdala volumes.
Magnetic Resonance Imaging; Genetic Polymorphisms; Hippocampus; Temporal Lobe
The effects of coronary artery bypass graft (CAB) and coronary collaterals (CC) on myocardial blood flow (MBF) were studied in 24 patients undergoing 29 CAB's. MBF after CAB was compared to preexisting MBF by intraoperatively injecting 133xenon via distal CAB with proximal CAB first occluded then open. Pressure gradients across bypassed obstructions were measured. The results were correlated with preoperative coronary arteriograms to determine the effects of CC on MBF and postobstructive perfusion pressures. Mean MBF was increased by CAB from 32±6 (se) ml/min per 100 g (CAB occluded) to 118±13 ml/min per 100 g (CAB open). The 133Xe clearance curves with CAB open were resolved into slow (19±2 ml/min per 100 g) and rapid (133±12 ml/min per 100 g) phases, suggesting that MBF remained heterogeneous after CAB. Vessels with less than 80% stenosis by angiography had pressure gradients less than 20 mm Hg across obstructions, high postobstructive perfusion pressures (75±7 mm Hg), and normal MBF (87±6 ml/min per 100 g) even with CAB occluded. Vessels with greater than 80% stenosis or total occlusion by angiography had significant pressure gradients with marked reduction of postobstructive MBF. No significant difference in postobstructive MBF was found when vessels with CC (21±4 ml/min per 100 g) were compared to those without CC (17±4 ml/min per 100 g) (P > 0.4).
These studies demonstrate that (a) mean MBF increased 268% after CAB, (b) heterogeneous MBF persisted after CAB, (c) CC were not associated with significant increases in MBF, and (d) vessels with less than 80% stenosis had less than 20 mm Hg gradient with minimal effect on resting MBF.
Regional myocardial blood flow before and after sublingual nitroglycerin was measured in 10 patients with coronary artery disease. During thoracotomy, 133Xe was injected directly into the subepicardium in diseased regions of the anterior left ventricular wall, and washout rates were recorded with a scintillation counter. All disappearance curves were closely approximated by two exponential decays analyzed as two parallel flow systems by the compartmental method. The appearance of a double exponential decay pattern in diseased regions suggests that the slow phase was associated with collateral blood flow, although nonhomogeneous myocardium-to-blood partition coefficients for xenon cannot be excluded. Nitroglycerin increased the rapid phase flow in 9 of 10 patients and the slow flow in 7 of 10 patients. Average flow increased in 9 of the 10 patients (P < 0.01). Mean rapid phase flow in the control state was 110 ml/100 g per min and after nitroglycerin increased to 132 ml/100 g per min (P < 0.01); slow phase flow increased from 12 ml/100 g per min to 15 ml/100 g per min (P < 0.05). It is concluded that, under these conditions, nitroglycerin improves perfusion in regions of diseased myocardium in patients with coronary artery disease.