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OBJECTIVE: To examine the bi-directional associations of a weight loss intervention with quality of life and mental health in obese older adults with functional limitations. DESIGN: Combined-group analyses of secondary variables from the MEASUR-UP randomized controlled trial. SETTING: Academic medical center. PARTICIPANTS: Obese community-dwelling men and women (N = 67; age ≥60; BMI ≥30) with functional limitations (Short Physical Performance Battery [SPPB] score of 4–10 out of 12). INTERVENTION: Six-month reduced calorie diet at two protein levels MEASUREMENTS: Weight, height, body composition, physical function, medical history, and mental health and quality of life assessments (Center for Epidemiologic Studies Depression Scale [CES-D]; Profile of Mood States [POMS], Pittsburgh Sleep Quality Index [PSQI]; Perceived Stress Scale [PSS]; Satisfaction with Life Scale [SWLS]; and Short Form Health Survey [SF-36]) were acquired at 0, 3 and 6 months RESULTS: Physical composite quality of life (SF-36) improved significantly at 3 months (β = 6.29, t2,48 = 2.60, p = 0.012) and 6 months (β = 10.03, t2,48 = 4.83, p < 0.001), as did several domains of physical quality of life. Baseline depression symptoms (CES-D and POMS) were found to predict lower amounts of weight loss; higher baseline sleep latency (PSQI) and anger (POMS) predicted less improvement in physical function (SPPB). CONCLUSION: The significant bi-directional associations found between a weight loss intervention and mental health/quality of life, including substantial improvements in physical quality of life with obesity treatment, indicate the importance of considering mental health and quality of life as part of any weight loss intervention for older adults.

Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation.A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model.In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation.CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.

To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors.We conducted a prospective, randomized, double-blind, placebo-controlled trial among Women's Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C).Between September 1993 and October 1998, a total of 68,132 women aged 50-79 years were recruited and randomized to the WHI-Dietary Modification (n=48,835) and WHI-Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI-Hormone Therapy (16,089) and WHI-Dietary Modification (n=25,210) trials were randomized in the WHI-Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was -1.6, (95% confidence interval [CI] -5.5 to 2.2) mg/dL for calcium+vitamin D alone, -9.0 (95% CI -13.0 to -5.1) mg/dL for hormone therapy alone, and -13.8 (95% CI -17.8 to -9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03).Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision.ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.

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.

Objective To estimate trajectories of body mass index (BMI) and determine their association with incident frailty in later life. Methods Data come from the 2004 to 2012 waves of the Health and Retirement Study, a longitudinal survey of older adults. Analysis was restricted to respondents who were not frail at baseline (n = 10,827). BMI (kg/m2) was calculated from self-reported weight and height. Incident frailty was assessed using the Frailty Index. Longitudinal growth mixture modeling was used to estimate the relationship between BMI trajectories and incident frailty over a 10-year period. Results Four trajectory classes were identified: weight gain (n = 162 [1.4%], mean final BMI = 42 kg/m2), weight loss (n = 171 [1.7%], mean final BMI = 25.0 kg/m2), consistent obesity (n = 640 [6.8%], mean final BMI = 34.7 kg/m2), and consistent overweight (n = 9,864 [90.1%] mean final BMI = 26.0 kg/m2). Cumulative incidence of frailty was 19.9%. Relative to the consistent overweight class, the weight gain class had the highest likelihood of incident frailty (odds ratio, OR: 3.61, 95% confidence interval, CI: 2.39–5.46). The consistent obesity (OR: 2.72, 95% CI: 2.06–3.58) and weight loss (OR: 2.81, 95% CI: 1.84–4.30) classes had similarly elevated risk of frailty. Conclusions Weight change and obesity are associated with risk of frailty.

Obesity affects a large proportion of older adults, contributing to poor physical and mental health outcomes. Yet, weight loss (WL) interventions have been under-studied in this population due to concerns about exacerbating age-related reductions in muscle mass, bone density, and physical function. Thus, the potential influence of WL interventions on mental health and quality of life is mostly unknown. We assessed these attributes in a group of community-dwelling, obese (BMI ≥30 kg/m2) older adults (≥60 yr; n = 67) with mild to moderate physical impairment (SPPB score 4–10 out of 12) who were participating in a 6-month WL intervention (-500 kcal/day deficit; 2 diet groups [0.8 g versus 1.2 protein/kg body wt/day]). Significant weight loss and improved SPPB scores (ps < 0.05) were achieved by both groups. Mixed model analysis of the combined groups revealed short-term improvements in mental composite quality of life (SF-36), positive affect (CES-D), and total mood disturbance (POMS) at 3 months and sustained improvement of physical composite quality of life and its subdomains at both 3 and 6 months (ps < 0.05). Conversely, higher baseline depression (CES-D and POMS) and anger (POMS) and longer sleep latency (PSQI) were associated with less successful WL and blunted functional benefit. These findings demonstrate the potential benefits to mental health and quality of life of intentional WL in obese older adults and underscores the need for evaluation of mental health when considering a WL intervention for obese older adults.

Background: Obesity is a significant cause of functional limitations in older adults; yet, concerns that weight reduction could diminish muscle along with fat mass have impeded progress toward an intervention. Meal-based enhancement of protein intake could protect function and/or lean mass but has not been studied during geriatric obesity reduction. Methods: In this 6-month randomized controlled trial, 67 obese (body mass index ≥30 kg/m 2 ) older (≥60 years) adults with a Short Physical Performance Battery score of 4–10 were randomly assigned to a traditional (Control) weight loss regimen or one with higher protein intake (>30 g) at each meal (Protein). All participants were prescribed a hypo-caloric diet, and weighed and provided dietary guidance weekly. Physical function (Short Physical Performance Battery) and lean mass (BOD POD), along with secondary measures, were assessed at 0, 3, and 6 months. Results: At the 6-month endpoint, there was significant (p < .001) weight loss in both the Control (−7.5 ± 6.2 kg) and Protein (−8.7 ± 7.4 kg) groups. Both groups also improved function but the increase in the Protein (+2.4 ± 1.7 units; p < .001) was greater than in the Control (+0.9 ± 1.7 units; p < .01) group (p = .02). Conclusion: Obese, functionally limited older adults undergoing a 6-month weight loss intervention with a meal-based enhancement of protein quantity and quality lost similar amounts of weight but had greater functional improvements relative to the Control group. If confirmed, this dietary approach could have important implications for improving the functional status of this vulnerable population (ClinicalTrials.gov identifier: NCT01715753).

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.

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.

Obese older adults with even modest functional limitations are at a disadvantage for maintaining their independence into late life. However, there is no established intervention for obesity in older individuals. The Measuring Eating, Activity and Strength: Understanding the Response --Using Protein (MEASUR-UP) trial is a randomized controlled pilot study of obese women and men aged ≥60 years with mild to moderate functional impairments. Changes in body composition (lean and fat mass) and function (Short Physical Performance Battery) in an enhanced protein weight reduction (Protein) arm will be compared to those in a traditional weight loss (Control) arm. The Protein intervention is based on evidence that older adults achieve optimal rates of muscle protein synthesis when consuming about 25-30 grams of high quality protein per meal; these participants will consume −30 g of animal protein at each meal via a combination of provided protein (beef) servings and diet counseling. This trial will provide information on the feasibility and efficacy of enhancing protein quantity and quality in the context of a weight reduction regimen and determine the impact of this intervention on body weight, functional status, and lean muscle mass. We hypothesize that the enhancement of protein quantity and quality in the Protein arm will result in better outcomes for function and/or lean muscle mass than in the Control arm. Ultimately, we hope our findings will help identify a safe weight loss approach that can delay or prevent late life disability by changing the trajectory of age-associated functional impairment associated with obesity.

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

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

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

Racial/ethnic differences in obesity prevalence and in responses to weight-loss treatment between Black and White women are well documented. Whether these differences influence responses to weight-loss treatment among older women is unknown. Therefore, we evaluated racial/ethnic differences among participants in a 6-month weight-loss study with traditional versus higher protein intake. Participants were obese (BMI ≥ 30 kg/m2) community-dwelling women, age 45 years or older, who self-identified as either Black or White. Change in body-weight, 6 minute walk test (6MWT), general health (SF-36), and satisfaction with life (SWL) were evaluated at 0, 4 and 6 months. Both racial groups reduced (ps < 0.01) body weight at 4 and 6 months, with a trend toward more weight loss among White women (p = 0.07), relative to Black women. Other racial/ethnic differences included greater improvements in general health (p = 0.05) and 6MWT (p < 0.05) for White versus Black women at 6 months; these differences persisted after adjusting for treatment group, age/education, and comorbidity. Although racial/ethnic differences in SWL were not observed, significant improvement was observed only among White women (p < 0.01). Interestingly, weight loss was associated with improved 6MWT only among Black women (r = -0.66, p < 0.05) and with general health only among White women (r = -0.44, p < 0.05). Overall, White women experienced greater improvements in health and physical function as a result of weight-loss than did Black women. Further research is needed to identify equitable intervention strategies for the treatment of sarcopenic obesity.

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

Background Anemia is associated with poorer sleep in children, and clinically, anemia is linked to insomnia. However, the association between anemia and insomnia in older adults is understudied. Methods We examined the cross-sectional association between anemia and insomnia in 1,053 adults (71.4 ± 10.6 years) in the Baltimore Longitudinal Study of Aging. Participants were classified as nonanemic, non-iron-deficient anemic, or iron-deficient anemic based on hemoglobin, ferritin, transferrin saturation, and mean cell volume. Insomnia symptoms were evaluated by the Women's Health Initiative Insomnia Rating Scale (WHIIRS). A total score (range 0-20) was generated, and participants were also classified as having 0, 1, or 2+ symptoms. Results Overall, 10.5% of participants had non-iron-deficient anemia, 0.9% had iron-deficient anemia, and 88.5% had no anemia. Due to its low prevalence, the iron-deficient anemic group was dropped from analyses. In models adjusted for demographics, number of medical conditions, and Center for Epidemiologic Studies Depression Scale score, non-iron-deficient anemic individuals had significantly higher WHIIRS total scores, indicating greater insomnia severity, compared to those without anemia (predicted adjusted mean WHIIRS of 7.24 [95% confidence interval (CI): 6.40-8.08] vs 5.92 [95% CI: 5.65-6.19]). They also had twice the risk of reporting ≥2 insomnia symptoms (vs 0 symptoms; relative risk ratio = 2.20, 95% CI: 1.25-3.89). Conclusions Results suggest that individuals with non-iron-deficient anemia are more likely to experience insomnia symptoms than those who are nonanemic. These results may have implications for insomnia treatment or the identification of underlying frailty in individuals with sleep problems.

A cross-sectional association between depression and serum low-density lipoprotein cholesterol (LDL-c) has been noted in psychiatric literature, raising the question of temporality: does low LDL-c predict depression, does depression lead to changes in LDL-c levels, or is this relationship bidirectional? In a previous longitudinal analysis of postmenopausal women ages 50–79 who participated in the Women’s Health Initiative (WHI), we detected an association between low LDL-c and the subsequent onset of depressive symptoms (HR=1.25, 95% CI 1.05–1.49, p=0.01). This current study uses the WHI cohort to explore the question of temporality in the opposite direction, examining the influence of depressive symptoms on subsequent changes in LDL-c levels. This study provides no evidence to suggest an association between depression and subsequent changes in LDL-c level (−2.78 mg/dL, 95% CI=−7.49 to 1.92, p=0.25), nor was any association detected for total cholesterol, HDL, or triglyceride changes over time. Further, this study demonstrates that the relationship between depression and serum LDL changes is not mediated by changes in weight, exercise, or energy intake.

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

Objective The primary aims of this study were to 1) determine whether folate metabolism genetic polymorphisms predict age of onset and occurrence of late life depression and 2) determine whether folate metabolism genetic polymorphisms predict response to antidepressant medications in late-life depression.

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.

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-Asberg 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.

Psychiatric patients (age 59+) were assessed before study treatment for major depressive disorder, and again after 3 months. Measures taken before study treatment included facets of religiousness (subjective religiosity, private prayer, worship attendance, and religious media use), social support, and perceived stress. Clinician-rated depression severity was assessed both before and after treatment using the Montgomery-Åsberg Depression Rating Scale (MADRS). Structural equation modeling was used to test a path model of direct and indirect effects of religious factors via psychosocial pathways. Subjective religiousness was directly related to worse initial MADRS, but indirectly related to better posttreatment MADRS via the pathway of more private prayer. Worship attendance was directly related to better initial MADRS, and indirectly related to better post-treatment MADRS via pathways of lower stress, more social support, and more private prayer. Private prayer was directly related to better post-treatment MADRS. Religious media use was related to more private prayer, but had no direct relationship with MADRS.

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.

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

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

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

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

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, respectively. 137 depressed and 94 non-depressed participants aged >or=60 years were enrolled. Standard clinical evaluations were performed on all participants and blood samples obtained for genotyping. 1.5-T MRI (magnetic resonance imaging) data were obtained at baseline and approximately 2 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 were 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 (HTN) with the AGTR2 3123C allele exhibit less change in WML volume than hypertensive men with the 3123A allele, or men without HTN. 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 earlier observed gender differences of the relationship between other renin-angiotensin system polymorphisms and HTN. Further work is needed to determine whether these observed relationships are secondary to polymorphisms affecting response to antihypertensive medication, and whether antihypertensive medications can slow WML progression and lower the risk of morbidity associated with WMLs.

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.

Major predictors of Alzheimer's disease (AD) include apolipoprotein E (APOE)-epsilon4, hippocampal atrophy on magnetic resonance imaging (MRI), and memory dysfunction prior to diagnosis. We examined 159 normal elderly subjects with MRI and the California Verbal Learning Test (CVLT); 84 returned for longitudinal follow-up 5 years later. Analyses at baseline revealed significant variance in hippocampal volume accounted for by cerebral volume and age but not by APOE isoform. However, interactions involving APOE isoform and laterality were observed. As hypothesized, an APOE x time interaction was revealed for CVLT long-delay free recall: APOE-epsilon3/4 subjects had significantly poorer performance than APOE-epsilon3/3 subjects at follow-up. Forward stepwise multiple regression analysis predicting follow-up long-delay free recall selected baseline recall, followed by number of APOE-epsilon4 alleles, followed by left-hippocampal volume. Age and sex did not enter into the model. We conclude that APOE-epsilon4 predicts longitudinal memory decline in healthy controls and that MRI morphometry of hippocampus adds slightly to predictive value.

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

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

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

To estimate trajectories of body mass index (BMI) and determine their association with incident frailty in later life.Data come from the 2004 to 2012 waves of the Health and Retirement Study, a longitudinal survey of older adults. Analysis was restricted to respondents who were not frail at baseline (n = 10,827). BMI (kg/m(2) ) was calculated from self-reported weight and height. Incident frailty was assessed using the Frailty Index. Longitudinal growth mixture modeling was used to estimate the relationship between BMI trajectories and incident frailty over a 10-year period.Four trajectory classes were identified: weight gain (n = 162 [1.4%], mean final BMI = 42 kg/m(2) ), weight loss (n = 171 [1.7%], mean final BMI = 25.0 kg/m(2) ), consistent obesity (n = 640 [6.8%], mean final BMI = 34.7 kg/m(2) ), and consistent overweight (n = 9,864 [90.1%] mean final BMI = 26.0 kg/m(2) ). Cumulative incidence of frailty was 19.9%. Relative to the consistent overweight class, the weight gain class had the highest likelihood of incident frailty (odds ratio, OR: 3.61, 95% confidence interval, CI: 2.39-5.46). The consistent obesity (OR: 2.72, 95% CI: 2.06-3.58) and weight loss (OR: 2.81, 95% CI: 1.84-4.30) classes had similarly elevated risk of frailty.Weight change and obesity are associated with risk of frailty.

Insomnia and anemia can lead to poor health. We determined the cross-sectional association between anemia and insomnia symptoms in 1,066 adults (71.6±10.7 yr) from the Baltimore Longitudinal Study ...

Background The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) are critical for mood regulation. Alterations in the white matter connections of these regions may impair their role in mood regulation and increase the risk of developing depression. This study used diffusion tensor imaging to examine for white matter microstructural abnormalities of these regions and of central white matter structures in late-life depression. Methods One hundred six elderly depressed subjects and eighty-four elderly nondepressed subjects underwent clinical assessment and diffusion tensor imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the DLPFC, ACC, corpus callosum, and internal capsule. Differences between groups were assessed, controlling for age, sex, and total cerebral volume. Results After controlling for covariates, depressed subjects had significantly lower FA values in white matter of the right ACC, bilateral superior frontal gyri, and left middle frontal gyrus. There were no significant differences in ADC values. Conclusions Lower FA, representing lower tissue organization, is observed in depressed elders in the DLPFC and right ACC. These findings support the hypothesis that altered connectivity between brain regions contributes to the risk of depression.

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

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

Objective: In this study, we examined 204 older depressed individuals for up to 64 months to determine factors related to depression outcome. We hypothesized that both presence of vascular brain lesions seen on baseline magnetic resonance imaging (MRI) scans and lower baseline social support measures would be related to worse depression outcome.Method: At study entry, all subjects were at least 59 years old, had a diagnosis of major depression, and were free of other major psychiatric illness and primary neurological illness, including dementia and stroke. Depression was diagnosed via structured interview and clinical assessment by a geriatric psychiatrist who completed a Montgomery Asberg Depression Rating Scale (MADRS) to determine severity of depression. Subjects provided self-report data on social support variables and ability to perform basic and instrumental activities of daily living (ADL, IADL). All subjects agreed to have a baseline standardized MRI brain scan. Ratings of severity of hyperintensities were determined for the periventricular white matter, deep white matter, and subcortical gray matter by two readers who decided by consensus. Treatment was provided by geropsychiatrists following clinical guidelines. Using mixed models to analyze the data, we determined the effect of a variety of demographic, social and imaging variables on the trajectory of MADRS score, the outcome variable of interest.Results: MADRS scores decreased steadily over time. In a final HLM model, in which time since entry, a baseline time indicator, age, gender, education and Mini-mental State Examination score were controlled, subjective social support, instrumental ADL impairment, subcortical gray matter severity, and the interactions of time with social network and with subcortical gray matter lesions remained significantly associated with MADRS score.Conclusions: Both social and biological factors at baseline are associated with longitudinal depression severity in geriatric depression.

Background Several studies have linked geriatric depression with cerebrovascular disease. The apolipoprotein E gene (APOE) e4 allele has been associated with a variety of late-life neuropsychiatric disorders, including Alzheimer’s disease, vascular dementia, and depression. Methods The sample consisted of 145 elderly depressive individuals and 100 nondepressed elderly control subjects. After a standardized clinical assessment, all subjects underwent a magnetic resonance imaging brain scan. Volumes of subcortical white and gray matter lesions were determined using a semi-automated method. Apolipoprotein E genotype was determined on blood sample using a standard protocol. A series of linear regression models were developed to assess the relationships between APOE genotype and white and gray matter lesion volumes. Results Older age, lower Mini-Mental State Examination score, and having any APOE e4 allele were each correlated with gray-matter lesion volume in depressed patients. Apolipoprotein E genotype was not associated with any lesion volume among control subjects. In a subsequent linear regression model, gray matter lesion volume was associated with older age, having at least one APOE e4 allele, and white matter lesion volume among depressed patients. Conclusions These results are consistent with previous reports linking cerebrovascular disease and APOE genotype. Further studies are needed to replicate this finding in elderly depressive individuals and to explain the relationship between the APOE locus and development of central nervous system vascular pathology.

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

Background: Apolipoprotein E has been associated with hippocampal volume loss in Alzheimer's disease and in elderly controls. In this study, we examined the role of apolipoprotein E and hippocampal volume change in 45 older nondemented depressed subjects. All had baseline and 2-year magnetic resonance imaging scans . Methods: Hippocampal volumes were determined using a semiautomated method . Results: Compared with 36 depressed subjects without an apolipoprotein E e4 allele, 9 subjects with at least one APOE e4 allele showed significant decline in hippocampal volume, particularly in the right hippocampus. In a logistic model, percent change in right hippocampal volume remained associated with presence of an APOE e4 allele after controlling for age, gender, Mini-Mental State Examination score, and baseline total cerebral volume . Conclusions: Future studies are needed to explain this association and to determine whether the finding for the right hippocampus has a biological basis, or if it is merely a function of small sample size .

New research on assessing neuropsychiatric manifestations of Alzheimer´s Disease (AD) involves grouping neuropsychiatric symptoms into syndromes. Yet this approach is limited by high inter-subject variability in neuropsychiatric symptoms and a relatively low degree of concordance across studies attempting to cluster neuropsychiatric symptoms into syndromes. An alternative strategy that involves dichotomizing AD subjects into those with few versus multiple neuropsychiatric symptoms is both consonant with real-world clinical practice and can contribute to understanding neurobiological underpinnings of neuropsychiatric symptoms in AD patients. The aim of this study was to address whether the number of neuropsychiatric symptoms (i.e., presence of few [≤2] versus multiple [≥3] symptoms) in AD would be associated with degree of significant gray matter (GM) volume loss. Of particular interest was volume loss in brain regions involved in memory, emotional processing and salience brain networks, including the prefrontal, lateral temporal and parietal cortices, anterior cingulate gyrus, temporo-limbic structures and insula. We recruited 19 AD patients and 13 healthy controls, which underwent an MRI and neuropsychiatric assessment. Regional brain volumes were determined using voxel-based morphometry and other advanced imaging processing methods. Our results indicated the presence of different patterns of GM atrophy in the two AD subgroups relative to healthy controls. AD patients with multiple neuropsychiatric manifestations showed more evident GM atrophy in the left superior temporal gyrus and insula as compared with healthy controls. In contrast, AD subjects with few neuropsychiatric symptoms displayed more GM atrophy in prefrontal regions, as well as in the dorsal anterior cingulate ad post-central gyri, as compared with healthy controls. Our findings suggest that the presence of multiple neuropsychiatric symptoms is more related to the degree of atrophy in specific brain networks rather than dependent on the global severity of widespread neurodegenerative brain changes.

Background: The consumption of sweetened beverages, refined foods, and pastries has been shown to be associated with an increased risk of depression in longitudinal studies. However, any influence that refined carbohydrates has on mood could be commensurate with their proportion in the overall diet; studies are therefore needed that measure overall intakes of carbohydrate and sugar, glycemic index (GI), and glycemic load. Objective: We hypothesized that higher dietary GI and glycemic load would be associated with greater odds of the prevalence and incidence of depression. Design: This was a prospective cohort study to investigate the relations between dietary GI, glycemic load, and other carbohydrate measures (added sugars, total sugars, glucose, sucrose, lactose, fructose, starch, carbohydrate) and depression in postmenopausal women who participated in the Women’s Health Initiative Observational Study at baseline between 1994 and 1998 (n = 87,618) and at the 3-y follow-up (n = 69,954). Results: We found a progressively higher dietary GI to be associated with increasing odds of incident depression in fully adjusted models (OR for the fifth compared with first quintile: 1.22; 95% CI: 1.09, 1.37), with the trend being statistically significant (P = 0.0032). Progressively higher consumption of dietary added sugars was also associated with increasing odds of incident depression (OR for the fifth compared with first quintile: 1.23; 95% CI: 1.07, 1.41; P-trend = 0.0029). Higher consumption of lactose, fiber, nonjuice fruit, and vegetables was significantly associated with lower odds of incident depression, and nonwhole/refined grain consumption was associated with increased odds of depression. Conclusions: The results from this study suggest that high-GI diets could be a risk factor for depression in postmenopausal women. Randomized trials should be undertaken to examine the question of whether diets rich in low-GI foods could serve as treatments and primary preventive measures for depression in postmenopausal women. The Women’s Health Initiative was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00000611","term_id":"NCT00000611"}}NCT00000611.

OBJECTIVE The aim of this study was to characterize the relationship between serum low-density lipoprotein cholesterol (LDL-c) and subsequent depressive symptoms onset in postmenopausal women. We secondarily assessed serum high-density lipoprotein (HDL-c), total cholesterol, and triglycerides. METHOD This population-based prospective cohort study utilizes data from 24,216 women between 50 and 79 years of age who were participants of the Women's Health Initiative, which originally ran from 1993 to 2005 and has since incorporated 2 extension studies, with the most recent culminating in 2015. Fasting lipids were measured for all participants at baseline and for a subset through 6 years of follow-up. Depressive symptoms were characterized using the Burnam 8-item scale for depressive disorders (Center for Epidemiologic Studies-Depression/Diagnostic Interview Schedule short form) at baseline and during follow-up, using a cut point of 0.06 to indicate presence of depressive symptoms. RESULTS The lowest quintile of LDL-c was associated with an increased risk of subsequent depressive symptoms (hazard ratio [HR] = 1.25, 95% CI = 1.05-1.49, P = .01), and follow-up analyses demonstrated that the elevated risk appeared to be confined to the lowest decile (LDL-c < 100 mg/dL). Further, this elevated risk was moderated by lipid-lowering drug treatment. Elevated risk was demonstrated among those who reported no lipid-lowering medication use (HR = 1.23, 95% CI = 1.03-1.47, P = .02), but not among those reporting use (HR = 0.65, 95% CI = 0.18-2.29, P = .50). CONCLUSIONS Among postmenopausal women, untreated serum LDL-c below 100 mg/dL was associated with an increased risk of developing depressive symptoms. No excess risk was observed in those attaining LDL-c < 100 mg/dL with lipid-lowering therapy. These findings have important implications for risk assessment, treatment considerations, and mechanistic insight.

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.

Background: Early studies using magnetic resonance (MR) imaging suggested that subcortical vascular changes are more prevalent in late-life depression and that they may play a role in the pathophysiology of depression. Studying the location of the lesion relative to the occurrence of depression could be critical in delineating the neuroanatomic substrates of depression. Our purpose was to characterize these lesions in terms of location by development of statistical parametric maps of lesions that differentiate patients from control subjects. Methods: Magnetic resonance images were acquired on 88 elderly depressed subjects ("patients," unipolar major depression assessed using the Duke Depression Evaluation Schedule, age range 63–80 years) enrolled in the Duke University Clinical Research Center for the Study of Late-Life Depression and 47 age- and gender-matched nondepressed subjects ("control subjects"). The MR protocol includes a volumetric, dual-contrast fast spin–echo pulse sequence. A statistical parametric map was formed from a two-group t test to test for differences in lesion density between patients and control subjects. Additional testing was performed to evaluate whether there were regions that correlated with the severity of depression using the 17-item Hamilton Depression rating. Results: The statistical parametric mapping analysis between groups showed two major regions of increased lesion density in the patients in the medial orbital prefrontal white matter. Severity of depression among depressed patients was correlated with lesions in the medial orbital region. Conclusions: This study supports recent evidence implicating the medial orbital frontal cortex in depression.