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Association of cerebral small vessel disease burden with brain structure and cognitive and vascular risk trajectories in mid-to-late life
We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96 SD=5.18, 79% men). We used linear mixed-effects models to investigate associations of SVD burden with up to 25-year retrospective trajectories of vascular risk and cognitive performance. General linear modelling was used to investigate concurrent associations with grey matter (GM) density and white matter (WM) microstructure, and whether these associations were modified by cognitive status (Montreal Cognitive Assessment, MoCA). Severe SVD burden in older age was associated with higher mean arterial pressure throughout midlife (β=3.36, 95% CI [0.42- 6.30]), and faster 25-year cognitive decline in letter fluency (β=-0.07, 95% CI [-0.13–-0.01]), and verbal reasoning (β=-0.05, 95% CI [-0.11–-0.001]). Moreover, SVD burden was related to lower GM volumes in 9.7% of total GM, and widespread WM microstructural decline (FWE-corrected p<0.05). The latter association was most pronounced in individuals with cognitive impairments on MoCA (F3,608=2.14, p=0.007). These findings highlight the importance of managing midlife vascular health to preserve brain structure and cognitive function in old age.
The effects of APOE on the functional architecture of the resting brain.
There is a well-established association between APOE genotype and the risk of developing Alzheimer's disease (AD). Relative to individuals with the common ε3/ε3 genotype, carriers of the ε4 allele are at increased risk of developing AD, while carriers of the ε2 allele appear to be protected against the disease. However, we recently reported that in a sample of cognitively healthy adults, both ε4 and ε2 carriers showed nearly identical changes in the pattern of fMRI activity during memory and non-memory tasks, relative to ε3 homozygotes. These findings suggest that the effects of APOE on brain function are not tightly linked to the effects of this gene on AD risk. Here we test the hypothesis that APOE has an intrinsic effect on the brain's functional networks. Resting-state fMRI was used to compare the pattern of functional connectivity of a variety of resting-state networks between 77 cognitively healthy participants aged 32 to 55 with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 8 ε4/ε4). Differences between genotype groups were found in two hippocampal networks, the auditory network, the left frontal-parietal network, and the lateral visual network. While there was considerable variety in the brain regions affected and the direction of change across networks, the main finding was that changes in functional connectivity were similar in ε4 and ε2 carriers, relative to ε3 homozygotes. APOE appears to have an intrinsic effect on the differentiation of functional networks in the brain. This effect is apparent in cognitively healthy adults and does not manifest in a manner reflective of the link between APOE and AD risk. Rather, the effects of APOE on brain function may relate to the role of this gene in neurodevelopment.
Magnetic resonance imaging in late-life depression: multimodal examination of network disruption.
CONTEXT: Disruption of frontal-subcortical and limbic networks is hypothesized to have a key role in late-life depression (LLD) and can be examined using magnetic resonance imaging (MRI) techniques. Gray matter can be examined using T1-weighted MRI, white matter using T2-weighted MRI and diffusion tensor imaging, and functional connectivity in resting-state networks using functional MRI. Although independent MRI studies have supported gray and white matter abnormalities in frontosubcortical and limbic networks and increased functional connectivity in the default-mode network in depression, no study has concurrently examined gray matter, white matter, and functional connectivity. OBJECTIVE: To examine whether results of different MRI techniques are complementary, multimodal MRI was used to compare gray matter, white matter, and resting-state networks between LLD and control groups. DESIGN: Cross-sectional, case-control, multimodal MRI analysis. SETTING: University research department. PARTICIPANTS: Thirty-six recovered participants with LLD (mean age, 71.8 years) and 25 control participants (mean age, 71.8 years). MAIN OUTCOME MEASURES: Gray matter was examined across the whole brain using voxel-based morphometry. Subcortical gray matter structures were also automatically segmented, and volumetric and shape analyses were performed. For white matter analysis, fractional anisotropy, axial diffusivity, and radial diffusivity values were examined using tract-based spatial statistics. For resting-state network analysis, correlation coefficients were compared using independent components analysis followed by dual regression. RESULTS: White matter integrity was widely reduced in LLD, without significant group differences in gray matter volumes or functional connectivity. CONCLUSIONS: The present work strongly supports the hypothesis that white matter abnormalities in frontal-subcortical and limbic networks play a key role in LLD even in the absence of changes in resting functional connectivity and gray matter. Factors that could contribute to the lack of significant differences in gray matter and functional connectivity measures, including current symptom severity, medication status, and age of participants with LLD, are discussed.
Neuroticism as a predictor of mood change
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Transcranial magnetic stimulation in the management of mood disorders.
BACKGROUND: Many trials of transcranial magnetic stimulation (TMS) have used small samples and, therefore, lack power. Here we present an up-to-date meta-analysis of TMS in the treatment of depression. METHODS: We searched Medline and Embase from 1996 until 2008 for randomized sham-controlled trials, with patients and investigators blinded to treatment, and outcome measured using a version of the Hamilton Depression Rating Scale (or similar). We identified 1,789 studies. Thirty-one were suitable for inclusion, with a cumulative sample of 815 active and 716 sham TMS courses. RESULTS: We found a moderately sized effect in favour of TMS [Random Effects Model Hedges' g = 0.64, 95% confidence interval (95% CI) = 0.50-0.79]. The corresponding Pooled Peto Odds Ratio for treatment response (≤50% reduction in depression scores) was 4.1 (95% CI = 2.9-5.9). There was significant variability between study effect sizes. Meta-regressions with relevant study variables did not reveal any predictors of treatment efficacy. Nine studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up (Hedges' g = -0.02, 95% CI = -0.22 to +0.18) and no heterogeneity in outcome. DISCUSSION: TMS appears to be an effective treatment; however, at 4 weeks' follow-up after TMS, there had been no further change in depression severity. Problems with finding a suitably blind and ineffective placebo condition may have confounded the published effect sizes. If the TMS effect is specific, only further large double-blind randomized controlled designs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen.
Association of trajectories of depressive symptoms with vascular risk, cognitive function and adverse brain outcomes: The Whitehall II MRI sub-study.
BACKGROUND: Trajectories of depressive symptoms over the lifespan vary between people, but it is unclear whether these differences exhibit distinct characteristics in brain structure and function. METHODS: In order to compare indices of white matter microstructure and cognitive characteristics of groups with different trajectories of depressive symptoms, we examined 774 participants of the Whitehall II Imaging Sub-study, who had completed the depressive subscale of the General Health Questionnaire up to nine times over 25 years. Twenty-seven years after the first examination, participants underwent magnetic resonance imaging to characterize white matter hyperintensities (WMH) and microstructure and completed neuropsychological tests to assess cognition. Twenty-nine years after the first examination, participants completed a further cognitive screening test. OUTCOMES: Using K-means cluster modelling, we identified five trajectory groups of depressive symptoms: consistently low scorers ("low"; n = 505, 62·5%), a subgroup with an early peak in depression scores ("early"; n = 123, 15·9%), intermediate scorers ("middle"; n = 89, 11·5%), a late symptom subgroup with an increase in symptoms towards the end of the follow-up period ("late"; n = 29, 3·7%), and consistently high scorers ("high"; n = 28, 3·6%). The late, but not the consistently high scorers, showed higher mean diffusivity, larger volumes of WMH and impaired executive function. In addition, the late subgroup had higher Framingham Stroke Risk scores throughout the follow-up period, indicating a higher load of vascular risk factors. INTERPRETATION: Our findings suggest that tracking depressive symptoms in the community over time may be a useful tool to identify phenotypes that show different etiologies and cognitive and brain outcomes.
Education and Income Show Heterogeneous Relationships to Lifespan Brain and Cognitive Differences Across European and US Cohorts.
Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4-97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES-cognition relationships. SES was more strongly related to ICV than to GM, implying that SES-cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES-ICV associations rather are compatible with SES-brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.
Vascular risk factors and depression in later life: a systematic review and meta-analysis.
Reports of the association between cardiovascular risk factors and depression in later life are inconsistent; to establish the nature of their association seems important for prevention and treatment of late-life depression. We searched MEDLINE, EMBASE, and PsycINFO for relevant cohort or case control studies over the last 22 years; 1097 were retrieved; 26 met inclusion criteria. Separate meta-analyses were performed for Risk Factor Composite Scores (RFCS) combining different subsets of risk factors, Framingham Stroke Risk Score, and single factors. We found a positive association (odds ratio [OR]: 1.49; 95% confidence interval [CI]: 1.27-1.75) between RFCS and late-life depression. There was no association between Framingham Stroke Risk Score (OR: 1.25; 95% CI: .99-1.57), hypertension (OR: 1.14; 95% CI: .94-1.40), or dyslipidemia (OR: 1.08; 95% CI: .91-1.28) and late-life depression. The association with smoking was weak (OR: 1.35; 95% CI: 1.00-1.81), whereas positive associations were found with diabetes (OR: 1.51; 95% CI: 1.30-1.76), cardiovascular disease (OR: 1.76; 95% CI: 1.52-2.04), and stroke (OR: 2.11; 95% CI: 1.61-2.77). Moderate to high heterogeneity was found in the results for RFCS, smoking, hypertension, dyslipidemia, and stroke, whereas publication bias was detected for RFCS and diabetes. We therefore found convincing evidence of a strong relationship between key diseases and depression (cardiovascular disease, diabetes, and stroke) and between composite vascular risk and depression but not between some vascular risk factors (hypertension, smoking, dyslipidemia) and depression. More evidence is needed to be accumulated from large longitudinal epidemiological studies, particularly if complemented by neuroimaging.
Diffusion tensor imaging in parkinsonian syndromes: a systematic review and meta-analysis.
OBJECTIVES: We performed a systematic review to assess alterations in measures of diffusion tensor imaging (DTI) in parkinsonian syndromes, exploring the potential role of DTI in diagnosis and as a candidate biomarker. METHODS: We searched EMBASE and Medline databases for DTI studies comparing parkinsonian syndromes or related dementias with controls or another defined parkinsonian syndrome. Key details for each study regarding participants, imaging methods, and results were extracted. Estimates were pooled, where appropriate, by random-effects meta-analysis. RESULTS: Of 333 results, we identified 43 studies suitable for inclusion (958 patients, 764 controls). DTI measures detected alterations in all parkinsonian syndromes, with distribution varying differentially with disease type. Nine studies were included in a meta-analysis of the substantia nigra in Parkinson disease. A notable effect size was found for lowered fractional anisotropy in the substantia nigra for patients with Parkinson disease vs controls (-0.639, 95% confidence interval -0.860 to -0.417, p < 0.0001). CONCLUSION: DTI may be a promising biomarker in parkinsonian syndromes and have a future role in differential diagnosis. Larger cohort studies are required to investigate some encouraging preliminary findings. Given the complexity of the parkinsonian syndromes, it is likely that any potential DTI biomarker would be used in combination with other relevant biomarkers.
Vascular changes and brain plasticity: a new approach to neurodegenerative diseases.
The world's population is aging, which will result in an increasing prevalence of neurodegenerative diseases, such as dementia. Observations from functional brain imaging that older brains can be more active than their younger counterparts challenge stereotypical ideas of aging. In those aging successfully, brain activation is more anterior, less lateralized and more coordinated than in those at risk of, or suffering from, cognitive impairment. Several theories have been proposed to explain these findings. One of the most enticing is the scaffolding theory, which posits that the older brain is a plastic homeostatic organ, able to compensate for its deteriorating structure. However, with aging also come diffuse vascular changes and the resulting white matter damage. This decreases the compensatory capacity, and dementia can ensue. This and alternative hypotheses will be discussed, along with potential methodological problems of this genre of study and with their clinical implications.
A systematic review and meta-analysis of magnetic resonance imaging studies in late-life depression.
Gray matter abnormalities within frontal-subcortical and limbic networks are hypothesized to play a key role in the pathophysiology of late-life depression. In this work, gray matter abnormalities in late-life depression are examined in a systematic review and meta-analysis of magnetic resonance imaging studies. In the systematic review, 27 articles were identified that compared participants with late-life depression with comparison group participants, and 17 studies were suitable for inclusion in meta-analyses of volumes of the whole brain, orbitofrontal cortex, caudate, hippocampus, putamen, and thalamus. Volume reductions were detected in 7 of 15 comparisons of the hippocampus and a meta-analysis revealed a significant, but small, effect size. Although examined by fewer studies, meta-analyses also revealed significant volume reductions in the orbitofrontal cortex, putamen, and thalamus. A more systematic and comprehensive analysis of the global distribution of gray matter abnormalities, and an examination of subcortical abnormalities were identified as key areas for future research.
Early diagnosis beneficial in Alzheimer's disease.
GPs should consider a diagnosis of dementia when a patient presents with functional impairment in addition to at least two changes in cognitive function e.g. short-term memory, language, reasoning, spatial orientation, or personality change. The patient, friends, family or professional carers should have noticed these changes for at least six months. Patients should be referred to a memory clinic to make a formal diagnosis of probable or possible Alzheimer's disease and to exclude other types of dementia. Key to assessment is a careful history of cognitive and functional changes, medical conditions and past psychiatric history. An objective cognitive assessment is important, and in primary care screening tools such as the General Practitioner Assessment of Cognition provide a useful adjunct to justify referral to specialist services. Patients should have a physical examination and a dementia screen to exclude treatable causes of cognitive impairment. Acetylcholinesterase inhibitors and memantine both slow the progression of cognitive decline and extend independence in activities of daily living. NICE recommends donepezil, rivastigmine or galantamine for mild to moderate Alzheimer's disease, and memantine for severe disease. Primary care is optimally placed to screen for cognitive impairments, to provide essential longitudinal information that will make a diagnosis of dementia safer. Primary care also has a crucial role in primary and, particularly secondary, prevention programmes to tackle excessive weight, lack of activity, smoking, and other lifestyle risk factors for dementia, including Alzheimer's disease, as well as the treatment of medical conditions which increase dementia risk.
Use of self-administered instruments to assess psychiatric disorders in older people: validity of the General Health Questionnaire, the Center for Epidemiologic Studies Depression Scale and the self-completion version of the revised Clinical Interview Schedule.
BACKGROUND: Diagnosis of depressive disorder using interviewer-administered instruments is expensive and frequently impractical in large epidemiological surveys. The aim of this study was to assess the validity of three self-completion measures of depressive disorder and other psychiatric disorders in older people against an interviewer-administered instrument. METHOD: A random sample stratified by sex, age and social position was selected from the Whitehall II study participants. This sample was supplemented by inclusion of depressed Whitehall II participants. Depressive disorder and other mental disorders were assessed by the interviewer-administered structured revised Clinical Interview Schedule (CIS-R) in 277 participants aged 58-80 years. Participants also completed a computerized self-completion version of the CIS-R in addition to the General Health Questionnaire (GHQ) and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: The mean total score was similar for the interviewer-administered (4.43) and self-completion (4.35) versions of the CIS-R [95% confidence interval (CI) for difference -0.31 to 0.16]. Differences were not related to sex, age, social position or presence of chronic physical illness. Sensitivity/specificity of self-completion CIS-R was 74%/98% for any mental disorder and 75%/98% for depressive episode. The corresponding figures were 86%/87% and 78%/83% for GHQ and 77%/89% and 89%/86% for CES-D. CONCLUSIONS: The self-completion computerized version of the CIS-R is feasible and has good validity as a measure of any mental disorder and depression in people aged ≥ 60 years. GHQ and CES-D also have good criterion validity as measures of any mental disorder and depressive disorder respectively.