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CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies.
BACKGROUND: Inflammatory markers are raised in cross-sectional studies of depressed patients and may represent an important mediating factor for behaviour, neural plasticity and brain structure. METHODS: We undertook a systematic review of longitudinal studies, investigating whether raised inflammatory markers indicate an increased risk of subsequent depressive symptoms. We searched three databases (1970-2012) for longitudinal studies with repeat data on CRP or IL-6 levels and subsequent depressive symptoms. We calculated effect sizes using a mixed-effects model, with separate meta-analyses for inflammatory markers and age groups. RESULTS: We identified eight papers for CRP (14,832 participants) and three for IL-6 (3695 participants). There was a significant association between increased CRP and depressive symptoms (weighted-mean effect size 'unadjusted r'=0.069, p<0.0005; 'adjusted r'=0.046, p<0.0005), with moderate heterogeneity between studies (Q=11.21, p=0.08, I(2)=46.5). For IL-6 the weighted-mean effect size was smaller ('unadjusted r'=0.045, p-value=0.007; 'adjusted r'=0.097, p-value=0.06). LIMITATIONS: The meta-analysis was based on a relatively small number of studies (particularly for IL-6) and only two inflammatory markers. There was moderate heterogeneity between studies and some evidence of publication bias. CONCLUSIONS: Raised inflammatory markers have a small but significant association with the subsequent development of depressive symptoms. This is a robust effect which remains significant after adjustment for age and a wide range of factors associated with risk for depression. Our results support the hypothesis that there is a causal pathway from inflammation to depression.
Prescribing selective serotonin reuptake inhibitors in older age.
Apart from commercial reasons, two motivations have led to the introduction of SSRIs to replace the first and second generation antidepressants already available. One was the search for a more rational treatment, based on specific mechanisms, the other the development of effective treatments with fewer side effects, particularly for older patients, who have a greater sensitivity to cardio-vascular and central nervous system effects. The first has been frustrated up to a point, in that SSRIs and other single mechanism drugs do not appear to be more effective than the earliest relatively non-specific antidepressants. The second has been fulfilled, in that SSRIs generally are better tolerated in older patients and in overdose. However, there is a spectrum of other side effects that are particularly relevant in older age and that need attention when treating depression in this particular patient group.
Mind over matter--what do we know about neuroplasticity in adults?
BACKGROUND: An increasing number of studies have examined the effects of training of cognitive and other tasks on brain structure, using magnetic resonance imaging. METHODS: Studies combining cognitive and other tasks training with longitudinal imaging designs were reviewed, with a view to identify paradigms potentially applicable to treatment of cognitive impairment. RESULTS: We identified 36 studies, employing training as variable as juggling, working memory, meditation, learning abstract information, and aerobic exercise. There were training-related structural changes, increases in gray matter volume, decreases, increases and decreases in different regions, or no change at all. There was increased integrity in white matter following training, but other patterns of results were also reported. CONCLUSIONS: Questions still to be answered are: Are changes due to use-dependent effects or are they specific to learning? What are the underlying neural correlates of learning, the temporal dynamics of changes, the relations between structure and function, and the upper limits of improvement? How can gains be maintained? The question whether neuroplasticity will contribute to the treatment of dementia will need to be posed again at that stage.
Cerebral hemodynamics in cerebral small vessel disease
Small vessel disease is an important frontier in neurology; about 25% of strokes are classified as small vessel, and SVD is the most common cause of vascular cognitive impairment. The risk of developing SVD increases with age, making this a growing concern for countries with aging populations. Despite this, there has been a paucity of information about its causes, diagnosis, prevention and treatment. This volume brings together contributions from leading international experts in the field and discusses pathogenesis, pathophysiology, clinical and radiologic manifestations, prevention and treatment modalities, and future directions for research and practice. Genetic forms of SVD are discussed, as well as the rapid development of neuroimaging techniques as tools for screening and treatment. This authoritative book is essential reading for neurologists, stroke physicians, geriatricians, and interventional neuroradiologists, as well as researchers in the fields of aging and dementia.
Parkinson's disease
Parkinson’s disease is a common neurological condition affecting movement, but also mental function. This review provides an introduction to the underlying pathology, clinical symptoms, diagnosis and treatment. More detailed discussion focusses on the use of neuroimaging to support clinical diagnosis, psychiatric co-morbidity and the cognitive changes associated with Parkinson’s disease.
Health benefits of encore careers for baby boomers.
Baby boomers now represent an aging population group at risk of the diseases of older age. Their relatively high education, amongst other attributes, means that they can make a significant contribution to the work force beyond the statutory retirement age. On an individual level, potential health benefits may motivate them to pursue encore careers. We review some of the evidence supporting such a trend.
Subjective Cognitive Complaints Given in Questionnaire: Relationship With Brain Structure, Cognitive Performance and Self-Reported Depressive Symptoms in a 25-Year Retrospective Cohort Study.
BACKGROUND: Subjective cognitive complaints are common but it is unclear whether they indicate an underlying pathological process or reflect affective symptoms. METHOD: 800 community-dwelling older adults were drawn from the Whitehall II cohort. Subjective cognitive complaint inquiry for memory and concentration, a range of neuropsychological tests and multimodal MRI were performed in 2012-2016. Subjective complaints were again elicited after 1 year. Group differences in grey and white matter, between those with and without subjective complaints, were assessed using voxel-based morphometry and tract-based spatial statistics, respectively. Mixed effects models assessed whether cognitive decline or depressive symptoms (over a 25-year period) were associated with later subjective complaints. Analyses were controlled for potential confounders and multiple comparisons. RESULTS: Mean age of the sample at scanning was 69.8 years (±5.1, range: 60.3-84.6). Subjective memory complaints were common (41%) and predicted further similar complaints later (mean 1.4 ± 1.4 years). There were no group differences in grey matter density or white matter integrity. Subjective complaints were not cross-sectionally or longitudinally associated with objectively assessed cognition. However, those with subjective complaints reported higher depressive symptoms ("poor concentration": odds ratio = 1.12, 95% CI 1.07-1.18; "poor memory": odds ratio = 1.18, 1.12-1.24). CONCLUSIONS: In our sample subjective complaints were consistent over time and reflected depressive symptoms but not markers of neurodegenerative brain damage or concurrent or future objective cognitive impairment. Clinicians assessing patients presenting with memory complaints should be vigilant for affective disorders. These results question the rationale for including subjective complaints in a spectrum with Mild Cognitive Impairment diagnostic criteria.
Biomarkers.
BACKGROUND: Cerebrovascular reactivity (CVR) is implicated in the progression of dementia, though the underlying mechanisms is not understood. This study examines the relationships between CVR and brain structure and cognitive decline, moderated by mid-life dementia risk. METHOD: 163 participants from the Whitehall-II cohort underwent neuropsychological testing and MRI, including T1-weighted, FLAIR, and DTI sequences, at two phases (Phase-I: mean age=68.2±4.4; Phase-II: mean age=76.9±4.5). CVR was quantified via BOLD response to 5% CO2 only at Phase-II. Linear regression tested the Phase-II and Phase-I to Phase-II associations between CVR and brain and cognitive outcomes (Table 1), alongside its interaction with dementia risks. Post-hoc analysis clarified the extent of these associations among different risk groups. RESULT: Tables 2 and 3 list significant cross-sectional and longitudinal results, respectively. At Phase-II, global CVR was positively associated with volume of left nucleus accumbens, and temporoparietal junction (p<0.03). Parietal CVR was positively associated with left hippocampus volume (p=0.03). These associations were more pronounced in the low-risk group. Temporal CVR was related to thalamus volume (p<0.05) across all participants, with associations of the right thalamus exclusive to the high-risk group (p=0.03). Longitudinally, lower global and regional CVR at Phase-II was linked to greater reduction in temporoparietal junction volume (p<0.04). In high-risk individuals, lower frontal, parietal, or global CVR was linked to larger volume declines in total grey matter or right thalamus respectively (p<0.05). Across all participants, lower parietal CVR at follow-up was linked to greater FA reductions and RD increases between examinations in the corpus callosum (p=0.02) and to greater declines in FA and increases in MD, RD, and L1 in the cingulum bundle (p<0.04), with these effects being more pronounced in the low-risk group. At Phase-II, lower parietal and temporal CVR was associated with worse fluency and intelligence, respectively, in high-risk individuals (p<0.05). Lower frontal CVR was linked to more executive function decline in the low-risk group over-time (p=0.03). CONCLUSION: This study highlights the differential impacts of global and regional CVR on brain structure and cognitive changes dependent on mid-life dementia risks, which provides evidence for CVR as a potential biomarker for dementia and age-related cognitive change.
Alcohol use and dementia in diverse populations (F96)
Background: The impact of alcohol use on dementia risk remains contentious. Methodological limitations of previous studies have made distinguishing causation from con- founding difficult. Mendelian randomization is a quasi- experimental method that can estimate causal effects via genetics. Methods: We estimated dose-response relationships be- tween alcohol and dementia in observational and genetic analyses. First, we pooled and harmonized individual-level phenotype data from two prospective cohort studies: the US Million Veteran Program (MVP) and UK Biobank (UKB; mean follow-up 4 and 12 years respectively). Associations were examined using Cox regression analysis and results combined using random-effects meta-analysis. We compared these findings with genetic associations between alcohol use and dementia (calculated de novo) using data from 2.4 mil- lion participants using Mendelian randomization. Results: 559,559 participants (247,136 from MVP and 312,423 from UKB) aged 56-72 years old at baseline were included in observational analyses. 14,540 developed dementia and 48,034 died during follow-up. Observational as- sociations between alcohol and dementia were U-shaped, meaning that non-drinkers, heavy (> 40 drinks per week) drinkers (hazard ratio = 1.41 [1.15 to 1.74]) and dependent drinkers (1.51 [1.42-1.60]) were all at higher dementia risk compared with light drinkers. In contrast, genetic analyses revealed a monotonically increasing association between alcohol dose and dementia, with no evidence supporting a protective effect of any level of drinking. A two-fold in- crease in genetically-predicted alcohol use disorder prevalence was associated with a 16 % increase in dementia cases (IVW OR = 1.16 [1.03-1.30]), and a one standard deviation in- crease in log-transformed drinks per week was associated with a 15% increase (IVW OR = 1.15[1.03-1.27]). Discussion: Alcohol consumption has a causal role for dementia. Halving the population prevalence of alcohol use disorder would lead to a 16% reduction in dementia cases.
Association of gout with brain reserve and vulnerability to neurodegenerative disease.
Studies of neurodegenerative disease risk in gout are contradictory. Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. Here we investigated associations between gout, brain structure, and neurodegenerative disease incidence. Gout patients had smaller global and regional brain volumes and markers of higher brain iron, using both observational and genetic approaches. Participants with gout also had higher incidence of all-cause dementia, Parkinson's disease, and probable essential tremor. Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis. These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Motor and cognitive impairments may affect gout patients, particularly in early years after diagnosis.
The maternal brain: Region-specific patterns of brain aging are traceable decades after childbirth.
Pregnancy involves maternal brain adaptations, but little is known about how parity influences women's brain aging trajectories later in life. In this study, we replicated previous findings showing less apparent brain aging in women with a history of childbirths, and identified regional brain aging patterns linked to parity in 19,787 middle- and older-aged women. Using novel applications of brain-age prediction methods, we found that a higher number of previous childbirths were linked to less apparent brain aging in striatal and limbic regions. The strongest effect was found in the accumbens-a key region in the mesolimbic reward system, which plays an important role in maternal behavior. While only prospective longitudinal studies would be conclusive, our findings indicate that subcortical brain modulations during pregnancy and postpartum may be traceable decades after childbirth.
Sex- and age-specific associations between cardiometabolic risk and white matter brain age in the UK Biobank cohort.
Cardiometabolic risk (CMR) factors are associated with accelerated brain aging and increased risk for sex-dimorphic illnesses such as Alzheimer's disease (AD). Yet, it is unknown how CMRs interact with sex and apolipoprotein E-ϵ4 (APOE4), a known genetic risk factor for AD, to influence brain age across different life stages. Using age prediction based on multi-shell diffusion-weighted imaging data in 21,308 UK Biobank participants, we investigated whether associations between white matter Brain Age Gap (BAG) and body mass index (BMI), waist-to-hip ratio (WHR), body fat percentage (BF%), and APOE4 status varied (i) between males and females, (ii) according to age at menopause in females, and (iii) across different age groups in males and females. We report sex differences in associations between BAG and all three CMRs, with stronger positive associations among males compared to females. Independent of APOE4 status, higher BAG (older brain age relative to chronological age) was associated with greater BMI, WHR, and BF% in males, whereas in females, higher BAG was associated with greater WHR, but not BMI and BF%. These divergent associations were most prominent within the oldest group of females (66-81 years), where greater BF% was linked to lower BAG. Earlier menopause transition was associated with higher BAG, but no interactions were found with CMRs. In conclusion, the findings point to sex- and age-specific associations between CMRs and brain age. Incorporating sex as a factor of interest in studies addressing CMR may promote sex-specific precision medicine, consequently improving health care for both males and females.
No significant association between self-reported physical activity and brain volumes in women and men from five European cohorts
Various studies have reported an association between physical activity and grey matter volumes. Some studies have suggested that this relationship may be moderated by sex, yet the direction is still under debate. Focusing on hippocampus and dorsolateral prefrontal cortex (dlPFC), we tested whether the association between regional grey matter volumes and self-reported physical activity differs between women and men. We examined this interaction in five European cohorts from the Lifebrain consortium (n = 1,809; age range: 18 – 88 years). Effect sizes were first determined by linear models run separately for each cohort, then pooled across datasets in a random-effects meta-analysis. Contrary to our hypotheses, there was no evidence of a relationship between physical activity and hippocampal or dlPFC volumes, nor was there a moderation by sex. Our null findings raise the question of whether self-report questionnaires of physical activity, which commonly feature in big datasets, are sufficiently sensitive to capture a – presumably modest – association between physical activity levels and grey matter outcomes. We conclude that the reliance on self-report questionnaires of physical activity is sub-optimal for brain-behaviour analyses.
Nuclei-specific hypothalamus networks predict a dimensional marker of stress in humans.
The hypothalamus is part of the hypothalamic-pituitary-adrenal axis which activates stress responses through release of cortisol. It is a small but heterogeneous structure comprising multiple nuclei. In vivo human neuroimaging has rarely succeeded in recording signals from individual hypothalamus nuclei. Here we use human resting-state fMRI (n = 498) with high spatial resolution to examine relationships between the functional connectivity of specific hypothalamic nuclei and a dimensional marker of prolonged stress. First, we demonstrate that we can parcellate the human hypothalamus into seven nuclei in vivo. Using the functional connectivity between these nuclei and other subcortical structures including the amygdala, we significantly predict stress scores out-of-sample. Predictions use 0.0015% of all possible brain edges, are specific to stress, and improve when using nucleus-specific compared to whole-hypothalamus connectivity. Thus, stress relates to connectivity changes in precise and functionally meaningful subcortical networks, which may be exploited in future studies using interventions in stress disorders.