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The neurobiological basis of neuroticism in late-life depression (LLD) is understudied. We hypothesized that older depressed subjects scoring high in measures of neuroticism would have smaller hippocampal and prefrontal volumes compared with non-neurotic older depressed subjects and with nondepressed comparison subjects based on previous research. Non-demented subjects were recruited and were either depressed with high neuroticism (n = 65), depressed with low neuroticism (n = 36), or never depressed (n = 27). For imaging outcomes focused on volumetric analyses, we found no significant between-group differences in hippocampal volume. However, we found several frontal lobe regions for which depressed subjects with high neuroticism scores had smaller volumes compared with non-neurotic older depressed subjects and with nondepressed comparison subjects, controlling for age and gender. These regions included the frontal pole, medial orbitofrontal cortex, and left pars orbitalis. In addition, we found that non-neurotic depressed subjects had a higher volume of non-white matter hypointensities on T1-weighted images (possibly related to cerebrovascular disease) than did neurotic depressed subjects. Our finding that depressed subjects low in neuroticism had higher volumes of non-white matter hypointensities is consistent with prior literature on “vascular depression.” In contrast, the finding that those high in neuroticism had smaller frontal volume than depressed subjects low in neuroticism and never-depressed subjects highlight the importance of frontal circuitry in the subgroup of older depressed individuals with comorbid neuroticism. Together, these results implicate different neural mechanisms in older neurotic and non-neurotic depressed groups and suggest that multiple biological pathologies may lead to different clinical expressions of LLD.
Many academic authors, policy makers, NGOs, and corporations have focused on top-down human rights global norm-making, such as the United Nations Guiding Principles for Business and Human Rights (UNGPs). What is often missing are contextual and substantive analyses that interrogate rights mobilization and linkages between voluntary transnational rules and domestic governance. Deploying a socio-legal approach and using a combination of longitudinal field and archival data, this article investigates how a local, indigenous community in Northern Chile mobilized their rights over a period of almost two decades. We found that rights mobilization was largely shaped by tensions between the different logics of legality and the business organization. In our case, the UNGP implementation process has been ineffective in giving rightsholders access to genuine remedy. On the contrary, it has led to weakened rights mobilization, dividing the local community. We conclude that greater attention to rights mobilization and domestic governance dynamics should be given in the business and human rights debate.
The evidence linking low-carbohydrate diets (LCD) to CVD is controversial, and results from epidemiological studies are inconsistent. We aimed to assess the relationship between LCD patterns and coronary artery Ca (CAC) scores from computed tomography in the Multi-Ethnic Study of Atherosclerosis cohort. Our sample included 5614 men and women free of clinical CVD at baseline (2000–2002), who had a FFQ, a baseline measure and ≥1 measure of CAC during follow-up. We excluded those with implausible energy intake or daily physical activity. The overall, animal-based and plant-based LCD scores were calculated based on intakes of macronutrients. Relative risk regression and robust regression models were used to examine the cross-sectional and longitudinal relationship between LCD score quintile and CAC outcomes, after adjustment for multiple cardiovascular risk factors. The mean age of participants was 63 years. The median intakes of total carbohydrate, fat and protein were 53·7, 30·5 and 15·6 % energy/d, respectively. Among 2892 participants with zero CAC scores at baseline, 264 developed positive scores during 2·4-year follow-up (11–59 months). Among those with positive scores at baseline, the median increase in CAC was 47 units over the course of follow-up. The overall, the animal-based and the plant-based LCD scores were not associated with CAC prevalence, incidence and progression. In conclusion, diets low in carbohydrate and high in fat and/or protein, regardless of the sources of protein and fat, were not associated with higher levels of CAC, a validated predictor of cardiovascular events, in this large multi-ethnic cohort.
Few studies have examined functional connectivity (FC) patterns using functional magnetic resonance imaging (fMRI) to predict outcomes in late-life depression. We hypothesized that FC within and between frontal and limbic regions would be associated with 12-week depression outcome in older depressed adults. Seventy-one subjects with major depression were enrolled in the study. A study geriatric psychiatrist performed a clinical interview and completed a Montgomery-Åsberg Depression Rating Scale (MADRS). All study participants were free of medication at baseline and had a brain fMRI scan. Using a regions of interest (ROI) atlas (including 164 ROIs), we conducted ROI-to-ROI resting-state FC analyses for each participant. In terms of treatment participants were offered sertraline initially, although in this naturalistic study, other medications were also prescribed. Subjects were evaluated every 2 weeks up to 12 weeks by the study psychiatrist, who followed a flexible, clinically based medication dosing schedule. Multivariate regression analysis was used to examine correlation between change of MADRS score over 12 weeks and baseline FC between brain regions, controlling for age, gender, mean head motion, and baseline MADRS. We found greater FC between the left inferior frontal gyrus pars triangularis and the left frontal eye field and FC of these two regions with a number of brain regions related to reward, salience, and sensorimortor function were correlated with change in MADRS score over 12 weeks. Our results highlight the important role of between inner speech-reward, attention-salience, and attention-sensorimotor network synchronization in predicting acute treatment response in late-life depression.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
Complement factor H (CFH) plays a key role in regulating the cascade of the alternative pathway of the complement system. Dysregulation of CFH may be involved in the pathophysiology of various inflammation-mediated diseases including neuropsychiatric illnesses. This study aimed to investigate this relationship by examining determining CFH levels in elderly individuals with and without depression.
A total of 152 elderly individuals (major depressive disorder (MDD) group, n = 76; comparison sample, n = 76) were selected from the Ansan Geriatric study. The plasma level of CFH was measured. MDD was diagnosed with the Mini-International Neuropsychiatric Interview as per DSM-IV criteria. The severity of depression was evaluated with the geriatric depression scale (GDS). Mean CFH levels were compared using the Mann–Whitney U test. After adjusting for possible confounding factors including age, sex, marital status, education, alcohol use, hemoglobin levels, and the Korean version of the Mini-Mental State Examination (MMSE-KC), a multiple regression analysis was conducted. The GDS score and plasma level of CFH were analyzed using Spearman's correlation.
Plasma CFH level was significantly higher in individuals with MDD than in the comparison sample (289.51 ± 21.16 vs. 339.67 ± 66.23, p < 0.001). In a regression model adjusted for possible confounders, CFH was significantly associated with geriatric depression (p < 0.001). CFH levels were not significantly related to GDS scores in the depressed group.
This study revealed an association between high plasma levels of CFH and geriatric depression, thereby suggesting the alternative pathway of the complement system contributing to the development of geriatric depression.
Neuroticism in older adults is common yet understudied, particularly its effects on depression treatment outcomes. We hypothesized that presence of high neuroticism would be associated with lower 12-week remission rates in older depressed sertraline-treated patients. In this longitudinal cohort study, 43 depressed older adults completed the Revised NEO Personality Inventory (NEO PI-R). A study psychiatrist administered the Montgomery Ǻsberg Depression Rating Scale (MADRS), and the Cumulative Illness Rating Scale (CIRS, a measure of medical burden) at baseline, and the MADRS at each clinical visit. All subjects began open-label sertraline treatment and were followed over 12 weeks with clinically indicated flexible dosing and an option to switch antidepressants. We used regression analyses to examine factors related to 12-week remission of depression (MADRS score < 8) and final MADRS score. We found that higher total neuroticism (odds ratio (OR) = 0.963, 95% confidence interval (CI) = 0.928–1.000) and a neuroticism subscale, stress vulnerability (OR = 0.846, 95% CI = 0.728–0.983), were associated with lower likelihood of remission among both the intention-to-treat group and sertraline completers. Findings remained significant after controlling for baseline MADRS and CIRS score. In conclusion, assessment of personality, particularly features of neuroticism, may be important in management of late-life depression. Future studies should determine if depressed patients high in neuroticism may benefit from psychotherapy focusing on emotional regulation and stress management.
Background: The UK Department of Health Improving Access to Psychological Therapies (IAPT) initiative set out to train a large number of therapists in cognitive behaviour therapies (CBT) for depression and anxiety disorders. Little is currently known about the retention of IAPT CBT trainees, or the use of CBT skills acquired on the course in the workplace after training has finished. Aims: This study set out to conduct a follow-up survey of past CBT trainees on the IAPT High Intensity CBT Course at the Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London (KCL), one of the largest IAPT High Intensity courses in the UK. Method: Past trainees (n = 212) across 6 cohorts (2008-2014 intakes) were contacted and invited to participate in a follow-up survey. A response rate of 92.5% (n = 196) was achieved. Results: The vast majority of IAPT trainees continue to work in IAPT services posttraining (79%) and to practise CBT as their main therapy modality (94%); 61% have become CBT supervisors. A minority (23%) have progressed to other senior roles in the services. Shortcomings are reported in the use of out-of-office CBT interventions, the use of disorder-specific outcome measures and therapy recordings to inform therapy and supervision. Conclusions: Past trainees stay working in IAPT services and continue to use CBT methods taught on the course. Some NICE recommended treatment procedures that are likely to facilitate patients’ recovery are not being routinely implemented across IAPT services. The results have implications for the continued roll out of the IAPT programme, and other future large scale training initiatives.
Clinicians have long appreciated the links between depression, cognitive impairment, and development of Alzheimer's disease (AD) and other dementias. More recently, investigators in the fields of epidemiology, genetics, neuroimaging, and neuropathology have sought to quantify the risk and to understand the underlying neurobiology of the relationship between depression and AD.
Previous studies suggest that there is a strong association between depression and cognitive decline, and that concurrent depressive symptoms in MCI patients could contribute to a difference in neurocognitive characteristics compared to MCI patients without depression. The authors tried to compare neurocognitive functions between MCI patients with and without depression by analyzing the results of neuropsychological tests.
Participants included 153 MCI patients. Based on the diagnosis of major depressive disorder, the participants were divided into two groups: depressed MCI (MCI/D+) versus non-depressed MCI (MCI/D−). The general cognitive and functional statuses of participants were evaluated. And a subset of various neuropsychological tests was presented to participants. Demographic and clinical data were analyzed using Student t-test or χ2 test.
A total of 153 participants were divided into two groups: 94 MCI/D+ patients and 59 MCI/D− patients. Age, sex, and years of education were not significantly different between the two groups. There were no significant differences in general cognitive status between MCI/D+ and MCI/D− patients, but MCI/D+ participants showed significantly reduced performance in the six subtests (Contrasting Program, Go-no-go task, Fist-edge-palm task, Constructional Praxis, Memory Recall, TMT-A) compared with MCI/D− patients.
There were significantly greater deficits in neurocognitive functions including verbal memory, executive function, attention/processing speed, and visual memory in MCI/D+ participants compared to MCI/D−. Once the biological mechanism is identified, distinct approaches in treatment or prevention will be determined.
We sought to investigate the relationship between neuroticism and depression in an elderly cohort. In this paper, we describe the methods of an National Institute of Mental Health—NIMH-supported study and present findings among the cohort enrolled to date.
We used the NEO Personality Inventory to assess neuroticism, and we employed several cognitive neuroscience-based measures to examine emotional control.
Compared with a group of 27 non-depressed older control subjects, 33 older depressed subjects scored higher on measures of state and trait anxiety and neuroticism. On our experimental neuroscience-based measures, depressed subjects endorsed more negative words compared with controls on an emotional characterization test. In addition, we found a significant group-by-congruency effect on an emotional interference test where subjects were asked to identify the face's emotional expression while ignoring the words “fear” or “happy” labeled across the face.
Thus, in this preliminary work, we found significant differences in measures of neuroticism and emotional controls among older adults with and without depression.
Depression in late life is a risk factor for cognitive decline. Depression is also associated with increased disability and social support deficits; these may precede conversion to dementia and inform risk. In this study, we examined if baseline or one-year change in disability and social support predicted later cognitive deterioration.
299 cognitively intact depressed older adults were followed for an average of approximately seven years. Participants received antidepressant treatment according to a standardized algorithm. Neuropsychological testing and assessment of disability and social support were assessed annually. Cognitive diagnosis was reviewed annually at a consensus conference to determine if participants remained cognitively normal, or if they progressed to either dementia or cognitively impaired, no dementia (CIND).
During study participation, 167 individuals remained cognitively normal (56%), 83 progressed to CIND (28%), and 49 progressed to dementia (16%). Greater baseline instrumental activities of daily living (IADL) deficits predicted subsequent conversion to a cognitive diagnosis (CIND or dementia). However, neither baseline measures nor one-year change in basic ADLs (BADLs) and social support predicted cognitive conversion. In post hoc analyses, two IADL measures (managing finances, preparing meals) significantly increased the odds of cognitive conversion.
Greater IADL deficits predicted increased risk of cognitive conversion. Assessment of IADL deficits may provide clues about risk of later cognitive decline.
Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs.
The ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process.
Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as “strongly agree” or “somewhat agree” (68–88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications.
A provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment.
The Mediterranean diet has been reported to be inversely associated with incident metabolic syndrome (MetSyn) among older adults; however, this association has not been studied in young African American and white adults. The objective of the present study was to evaluate the association of a modified Mediterranean diet (mMedDiet) score with the 25-year incidence of the MetSyn in 4713 African American and white adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. A diet history questionnaire was used to assess dietary intake at baseline, year 7 and year 20 and a mMedDiet score was created. Cardiovascular risk factors were measured at multiple examinations over 25 years. The MetSyn was defined according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Cox proportional-hazards regression analysis was use to evaluate associations for incident MetSyn across the mMedDiet score categories adjusting for demographic characteristics, lifestyle factors and BMI. Higher mMedDiet scores represented adherence to a dietary pattern rich in fruit, vegetables, whole grains, nuts and fish, but poor in red and processed meat and snack foods. The incidence of MetSyn components (abdominal obesity, elevated TAG concentrations and low HDL-cholesterol concentrations) was lower in those with higher mMedDiet scores than in those with lower scores. Furthermore, the incidence of the MetSyn was lower across the five mMedDiet score categories; the hazard ratios and 95 % CI from category 1 to category 5 were 1·0; 0·94 (0·76, 1·15); 0·84 (0·68, 1·04); 0·73 (0·58, 0·92); and 0·72 (0·54, 0·96), respectively (Ptrend= 0·005). These findings suggest that the risk of developing the MetSyn is lower when consuming a diet rich in fruit, vegetables, whole grains, nuts and fish.
Dietary protein has been shown to increase urinary Ca excretion in randomised controlled trials, and diets high in protein may have detrimental effects on bone health; however, studies examining the relationship between dietary protein and bone health have conflicting results. In the present study, we examined the relationship between dietary protein (total, animal and vegetable protein) and lumbar spine trabecular volumetric bone mineral density (vBMD) among participants enrolled in the Multi-Ethnic Study of Atherosclerosis (n 1658). Protein intake was assessed using a FFQ obtained at baseline examination (2000–2). Lumbar spine vBMD was measured using quantitative computed tomography (2002–5), on average 3 years later. Multivariable linear and robust regression techniques were used to examine the associations between dietary protein and vBMD. Sex and race/ethnicity jointly modified the association of dietary protein with vBMD (P for interaction = 0·03). Among white women, higher vegetable protein intake was associated with higher vBMD (P for trend = 0·03), after adjustment for age, BMI, physical activity, alcohol consumption, current smoking, educational level, hormone therapy use, menopause and additional dietary factors. There were no consistently significant associations for total and animal protein intakes among white women or other sex and racial/ethnic groups. In conclusion, data from the present large, multi-ethnic, population-based study suggest that a higher level of protein intake, when substituted for fat, is not associated with poor bone health. Differences in the relationship between protein source and race/ethnicity of study populations may in part explain the inconsistent findings reported previously.
The Leloir pathway enzyme uridine diphosphate (UDP)-galactose 4′-epimerase from the common liver fluke Fasciola hepatica (FhGALE) was identified and characterized. The enzyme can be expressed in, and purified from, Escherichia coli. The recombinant enzyme is active: the Km (470 μm) is higher than the corresponding human enzyme (HsGALE), whereas the kcat (2·3 s−1) is substantially lower. FhGALE binds NAD+ and has shown to be dimeric by analytical gel filtration. Like the human and yeast GALEs, FhGALE is stabilized by the substrate UDP-galactose. Molecular modelling predicted that FhGALE adopts a similar overall fold to HsGALE and that tyrosine 155 is likely to be the catalytically critical residue in the active site. In silico screening of the National Cancer Institute Developmental Therapeutics Program library identified 40 potential inhibitors of FhGALE which were tested in vitro. Of these, 6 showed concentration-dependent inhibition of FhGALE, some with nanomolar IC50 values. Two inhibitors (5-fluoroorotate and N-[(benzyloxy)carbonyl]leucyltryptophan) demonstrated selectivity for FhGALE over HsGALE. These compounds also thermally destabilized FhGALE in a concentration-dependent manner. Interestingly, the selectivity of 5-fluoroorotate was not shown by orotic acid, which differs in structure by 1 fluorine atom. These results demonstrate that, despite the structural and biochemical similarities of FhGALE and HsGALE, it is possible to discover compounds which preferentially inhibit FhGALE.
Memory impairment in geriatric depression is understudied, but may identify individuals at risk for development of dementia and Alzheimer's disease (AD). Using a neuropsychologically based definition of amnestic mild cognitive impairment (aMCI) in patients with geriatric depression, we hypothesized that patients with aMCI, compared with those without it, would have increased incidence of both dementia and AD.
Participants were aged 60 years and older and consisted of depressed participants and non-depressed volunteer controls. The depressed cohort met criteria for unipolar major depression. All participants were free of dementia and other neurological illness at baseline. At study entry, participants were administered a standardized clinical interview, a battery of neurocognitive tests, and provided a blood sample for determination of apolipoprotein E genotype. A cognitive diagnosis was assigned by a panel of experts who convened annually and reviewed available clinical, neuropsychological and laboratory data to achieve a consensus cognitive diagnosis to determine a consensus diagnosis. Survival analysis examined the association between aMCI and later dementia (all-cause) and AD.
Among 295 depressed individuals, 63 (21.36%) met criteria for aMCI. Among 161 non-depressed controls, four (2.48%) met aMCI criteria. Participants were followed for 6.28 years on average. Forty-three individuals developed dementia, including 40 (13.6%) depressed and three (1.9%) control participants. Both aMCI and age were associated with incident dementia and AD.
The presence of aMCI is a poor prognostic sign among patients with geriatric depression. Clinicians should carefully screen elderly depressed adults for memory impairment.