Peripheral hearing loss at age 70 predicts brain atrophy and associated cognitive change.

BACKGROUND: Hearing loss has been proposed as a modifiable risk factor for dementia. However, the relationship between hearing, neurodegeneration, and cognitive change, and the extent to which pathological processes such as Alzheimer's disease and cerebrovascular disease influence these relationships, is unclear. METHODS: Data from 287 adults born in the same week of 1946 who underwent baseline pure tone audiometry (mean age=70.6 years) and two time point cognitive assessment/multimodal brain imaging (mean interval 2.4 years) were analysed. Hearing impairment at baseline was defined as a pure tone average of greater than 25 decibels in the best hearing ear. Rates of change for whole brain, hippocampal and ventricle volume were estimated from structural MRI using the Boundary Shift Integral. Cognition was assessed using the Pre-clinical Alzheimer's Cognitive Composite. Regression models were performed to evaluate how baseline hearing impairment associated with subsequent brain atrophy and cognitive decline after adjustment for a range of confounders including baseline ß-amyloid deposition and white matter hyperintensity volume. RESULTS: 111 out of 287 participants had hearing impairment. Compared with those with preserved hearing, hearing impaired individuals had faster rates of whole brain atrophy, and worse hearing (higher pure tone average) predicted faster rates of hippocampal atrophy. In participants with hearing impairment, faster rates of whole brain atrophy predicted greater cognitive change. All observed relationships were independent of ß-amyloid deposition and white matter hyperintensity volume. CONCLUSIONS: Hearing loss may influence dementia risk via pathways distinct from those typically implicated in Alzheimer's and cerebrovascular disease in cognitively unimpaired older adults.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

Predictors of primary care psychological therapy outcomes for depression and anxiety in people living with dementia: evidence from national healthcare records in England.

BACKGROUND: Psychological therapies can be effective in reducing symptoms of depression and anxiety in people living with dementia (PLWD). However, factors associated with better therapy outcomes in PLWD are currently unknown. AIMS: To investigate whether dementia-specific and non-dementia-specific factors are associated with therapy outcomes in PLWD. METHOD: National linked healthcare records were used to identify 1522 PLWD who attended psychological therapy services across England. Associations between various factors and therapy outcomes were explored. RESULTS: People with frontotemporal dementia were more likely to experience reliable deterioration in depression/anxiety symptoms compared with people with vascular dementia (odds ratio 2.98, 95% CI 1.08-8.22; P = 0.03) or Alzheimer's disease (odds ratio 2.95, 95% CI 1.15-7.55; P = 0.03). Greater depression severity (reliable recovery: odds ratio 0.95, 95% CI 0.92-0.98, P < 0.001; reliable deterioration: odds ratio 1.73, 95% CI 1.04-2.90, P = 0.04), lower work and social functioning (recovery: odds ratio 0.98, 95% CI 0.96-0.99, P = 0.002), psychotropic medication use (recovery: odds ratio 0.67, 95% CI 0.51-0.90, P = 0.01), being of working age (recovery: odds ratio 2.03, 95% CI 1.10-3.73, P = 0.02) and fewer therapy sessions (recovery: odds ratio 1.12, 95% CI 1.09-1.16, P < 0.001) were associated with worse therapy outcomes in PLWD. CONCLUSIONS: Dementia type was generally not associated with outcomes, whereas clinical factors were consistent with those identified for the general population. Additional support and adaptations may be required to improve therapy outcomes in PLWD, particularly in those who are younger and have more severe depression.

Updating the study protocol: Insight 46 - a longitudinal neuroscience sub-study of the MRC National Survey of Health and Development - phases 2 and 3.

BACKGROUND: Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. METHODS/DESIGN: Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. DISCUSSION: The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

Mendelian randomization identifies blood metabolites previously linked to midlife cognition as causal candidates in Alzheimer's disease.

There are currently no disease-modifying treatments for Alzheimer's disease (AD), and an understanding of preclinical causal biomarkers to help target disease pathogenesis in the earliest phases remains elusive. Here, we investigated whether 19 metabolites previously associated with midlife cognition-a preclinical predictor of AD-translate to later clinical risk, using Mendelian randomization (MR) to tease out AD-specific causal relationships. Summary statistics from the largest genome-wide association studies (GWASs) for AD and metabolites were used to perform bidirectional univariable MR. Bayesian model averaging (BMA) was additionally performed to address high correlation between metabolites and identify metabolite combinations that may be on the AD causal pathway. Univariable MR indicated four extra-large high-density lipoproteins (XL.HDL) on the causal pathway to AD: free cholesterol (XL.HDL.FC: 95% CI = 0.78 to 0.94), total lipids (XL.HDL.L: 95% CI = 0.80 to 0.97), phospholipids (XL.HDL.PL: 95% CI = 0.81 to 0.97), and concentration of XL.HDL particles (95% CI = 0.79 to 0.96), significant at an adjusted P < 0.009. MR-BMA corroborated XL.HDL.FC to be among the top three causal metabolites, in addition to total cholesterol in XL.HDL (XL.HDL.C) and glycoprotein acetyls (GP). Both XL.HDL.C and GP demonstrated suggestive univariable evidence of causality (P < 0.05), and GP successfully replicated within an independent dataset. This study offers insight into the causal relationship between metabolites demonstrating association with midlife cognition and AD. It highlights GP in addition to several XL.HDLs-particularly XL.HDL.FC-as causal candidates warranting further investigation. As AD pathology is thought to develop decades prior to symptom onset, expanding on these findings could inform risk reduction strategies.

Psychological therapies for depression and cardiovascular risk: evidence from national healthcare records in England.

AIMS: People with depression are up to 72% more at risk to develop cardiovascular disease (CVD) in their lifetime. Evidence-based psychotherapies are first-line interventions for the treatment of depression and are delivered nationally in England through the National Health Service via the Improving Access to Psychological Therapy (IAPT) primary care programme. It is currently unknown whether positive therapy outcomes may be associated with cardiovascular risk reduction. This study aimed to examine the association between psychotherapy outcomes for depression and incident CVD. METHODS AND RESULTS: A cohort of 636 955 individuals who have completed a course of psychotherapy was built from linked electronic healthcare record databases of national coverage in England: the national IAPT database, the Hospital Episode Statistics (HES) database, and the HES-ONS (Office of National Statistics) mortality database. Multivariable Cox models adjusting for clinical and demographic covariates were run to estimate the association between reliable improvement from depression and the risk of subsequent incidence of cardiovascular events. After a median follow-up of 3.1 years, reliable improvement from depression symptoms was associated with a lower risk of new onset of any CVD [hazard ratio (HR): 0.88, 95% confidence interval (CI): 0.86, 0.89], coronary heart disease (HR: 0.89, 95% CI: 0.86, 0.92), stroke (HR: 0.88, 95% CI: 0.83, 0.94), and all-cause mortality (HR: 0.81, 95% CI: 0.78, 0.84). This association was stronger in the under 60 compared with the over 60 for all outcomes. Results were confirmed in sensitivity analyses. CONCLUSION: Management of depression through psychological interventions may be associated with reduced risk of CVD. More research is needed to understand the causality of these associations.

Inequalities in accelerated cognitive decline: Resolving observational window bias using nested non-linear regression.

INTRODUCTION: Limited observational windows lead to conflicting results in studies examining educational differences in Alzheimer's disease and related dementias (ADRD) risk, due to observational window bias relative to onset of accelerated cognitive decline. This study tested a novel model to address observational window bias and tested for the presence and sources of disparities in accelerated cognitive declines due to ADRD. METHODS: The sample examined 167,314 cognitive assessments from 32,441 Health and Retirement Study participants. We implemented a parametric non-linear nested longitudinal regression and reported multivariable-adjusted nodal incidence ratios (aNIR). RESULTS: University degrees were associated with lower incidence (aNIR = 0.253, 95% confidence interval [CI] = [0.221 to 0.289], p < 0.001), while black participants had a higher incidence (aNIR = 1.995, [1.858 to 2.141], p < 0.001) of accelerated cognitive decline, adjusting for demographic, sociobehavioral, and medical risk factors. Sex-stratified analyses identified diminished educational returns for women and increased incidence among minoritized women. DISCUSSION: Addressing observational window bias reveals large social inequalities in the onset of accelerated cognitive declines indicative of ADRD. HIGHLIGHTS: This study identifies observational window bias as a source of conflicting results among previous studies of educational achievement in Alzheimer's disease and related dementias (ADRD) disparities. The study locates preclinical accelerated cognitive decline, which is indicative of ADRD while occurring 10+ years prior to symptom onset, as a site to study ADRD disparities that mitigates observational window bias. A novel method, nested non-linear regression, is developed to test for differences in the onset of accelerated cognitive decline. Educational and racial/ethnic disparities are demonstrated in the onset of accelerated cognitive decline, as are their intersecting differences with sex/gender.

Common infections and neuroimaging markers of dementia in three UK cohort studies.

INTRODUCTION: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. METHODS: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain  = 2632; NAPOE-interaction  = 1810). RESULTS: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (ß = -3.89 mL [-5.81, -1.97], Padjusted  < 0.05); these were largely attenuated in fully adjusted models (ß = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. DISCUSSION: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.

Circulating Metabolome and White Matter Hyperintensities in Women and Men.

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

Long-term psychological distress trajectories and the COVID-19 pandemic in three British birth cohorts: A multi-cohort study.

BACKGROUND: Growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until midlife and then falls after midlife in both sexes, is unknown. We aimed to analyse whether long-term pre-pandemic psychological distress trajectories were disrupted during the pandemic, and whether these changes have been different across cohorts and by sex. METHODS AND FINDINGS: We used data from three nationally representative birth cohorts comprising all people born in Great Britain in a single week of 1946 (National Survey of Health and Development, NSHD), 1958 (National Child Development Study, NCDS), or 1970 (British Cohort Study, BCS70). The follow-up data used spanned 39 years in NSHD (1982 to 2021), 40 years in NCDS (1981 to 2001), and 25 years in BCS70 (1996 to 2021). We used psychological distress factor scores, as measured by validated self-reported questionnaires (NSHD: Present State Examination, Psychiatric Symptoms Frequency, and 28- and 12-item versions of General Health Questionnaire; NCDS and BCS70: Malaise Inventory; all: 2-item versions of Generalized Anxiety Disorder scale and Patient Health Questionnaire). We used a multilevel growth curve modelling approach to model the trajectories of distress across cohorts and sexes and obtained estimates of the differences between the distress levels observed during the pandemic and those observed at the most recent pre-pandemic assessment and at the peak in the cohort-specific pre-pandemic distress trajectory, located at midlife. We further analysed whether pre-existing cohort and sex inequalities had changed with the pandemic onset using a difference-in-differences (DiD) approach. The analytic sample included 16,389 participants. By September/October 2020, distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts (standardised mean differences [SMD] and 95% confidence intervals of SMDNSHD,pre-peak = -0.02 [-0.07, 0.04], SMDNCDS,pre-peak = 0.05 [0.02, 0.07], and SMDBCS70,pre-peak = 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively). Increases in distress were larger among women than men, widening pre-existing sex inequalities (DiD and 95% confidence intervals of DiDNSHD,sex,pre-peak = 0.17 [0.06, 0.28], DiDNCDS,sex,pre-peak = 0.11 [0.07, 0.16], and DiDBCS70,sex,pre-peak = 0.11 [0.05, 0.16] when comparing sex inequalities in the pre-pandemic peak in midlife to those observed by September/October 2020). As expected in cohort designs, our study suffered from high proportions of attrition with respect to the original samples. Although we used non-response weights to restore sample representativeness to the target populations (those born in the United Kingdom in 1946, 1958, and 1970, alive and residing in the UK), results may not be generalisable to other sections within the UK population (e.g., migrants and ethnic minority groups) and countries different than the UK. CONCLUSIONS: Pre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems.

Timing of physical activity across adulthood on later-life cognition: 30 years follow-up in the 1946 British birth cohort.

BACKGROUND: To assess how timing, frequency and maintenance of being physically active, spanning over 30 years in adulthood, is associated with later-life cognitive function. METHODS: Participants (n=1417, 53% female) were from the prospective longitudinal cohort study, 1946 British birth cohort. Participation in leisure time physical activity was reported five times between ages 36 and 69, categorised into: not active (no participation in physical activity/month); moderately active (participated 1-4 times/month); most active (participated 5 or more times/month). Cognition at age 69 was assessed by tests of cognitive state (Addenbrooke's Cognitive Examination-III), verbal memory (word learning test) and processing speed (visual search speed). RESULTS: Being physically active, at all assessments in adulthood, was associated with higher cognition at age 69. For cognitive state and verbal memory, the effect sizes were similar across all adult ages, and between those who were moderately and most physically active. The strongest association was between sustained cumulative physical activity and later-life cognitive state, in a dose-response manner. Adjusting for childhood cognition, childhood socioeconomic position and education largely attenuated these associations but results mainly remained significant at the 5% level. CONCLUSIONS: Being physically active at any time in adulthood, and to any extent, is linked with higher later-life cognitive state, but lifelong maintenance of physical activity was most optimal. These relationships were partly explained by childhood cognition and education, but independent of cardiovascular and mental health and APOE-E4, suggestive of the importance of education on the lifelong impacts of physical activity.

Changes in the adult consequences of adolescent mental ill-health: findings from the 1958 and 1970 British birth cohorts.

BACKGROUND: Adolescent mental health difficulties are increasing over time. However, it is not known whether their adulthood health and socio-economic sequelae are changing over time. METHODS: Participants (N = 31 349) are from two prospective national birth cohort studies: 1958 National Child Development Study (n = 16 091) and the 1970 British Cohort Study (n = 15 258). Adolescent mental health was operationalised both as traditional internalising and externalising factors and a hierarchical bi-factor. Associations between adolescent psychopathology and age 42 health and wellbeing (mental health, general health, life satisfaction), social (cohabitation, voting behaviour) and economic (education and employment) outcomes are estimated using linear and logistic multivariable regressions across cohorts, controlling for a wide range of early life potential confounding factors. RESULTS: The prevalence of adolescent mental health difficulties increased and their associations with midlife health, wellbeing, social and economic outcomes became more severe or remained similar between those born in 1958 and 1970. For instance, a stronger association with adolescent mental health difficulties was found for those born in 1970 for midlife psychological distress [odds ratio (OR) 1970 = 1.82 (1.65-1.99), OR 1958 = 1.60 (1.43-1.79)], cohabitation [OR 1970 = 0.64 (0.59-0.70), OR 1958 = 0.79 (0.72-0.87)], and professional occupations [OR 1970 = 0.75 (0.67-0.84), OR 1958 = 1.05 (0.88-1.24)]. The associations of externalising symptoms with later outcomes were mainly explained by their shared variance with internalising symptoms. CONCLUSION: The widening of mental health-based inequalities in midlife outcomes further supports the need to recognise that secular increases in adolescent mental health symptoms is a public health challenge with measurable negative consequences through the life-course. Increased public health efforts to minimise adverse outcomes are needed.

Associations between psychological therapy outcomes for depression and incidence of dementia.

BACKGROUND: Depression is an important, potentially modifiable dementia risk factor. However, it is not known whether effective treatment of depression through psychological therapies is associated with reduced dementia incidence. The aim of this study was to investigate associations between reduction in depressive symptoms following psychological therapy and the subsequent incidence of dementia. METHODS: National psychological therapy data were linked with hospital records of dementia diagnosis for 119808 people aged 65+. Participants received a course of psychological therapy treatment in Improving Access to Psychological Therapies (IAPT) services between 2012 and 2019. Cox proportional hazards models were run to test associations between improvement in depression following psychological therapy and incidence of dementia diagnosis up to eight years later. RESULTS: Improvements in depression following treatment were associated with reduced rates of dementia diagnosis up to 8 years later (HR = 0.88, 95% CI 0.83-0.94), after adjustment for key covariates. Strongest effects were observed for vascular dementia (HR = 0.86, 95% CI 0.77-0.97) compared with Alzheimer's disease (HR = 0.91, 95% CI 0.83-1.00). CONCLUSIONS: Reliable improvement in depression across psychological therapy was associated with reduced incidence of future dementia. Results are consistent with at least two possibilities. Firstly, psychological interventions to improve symptoms of depression may have the potential to contribute to dementia risk reduction efforts. Secondly, psychological therapies may be less effective in people with underlying dementia pathology or they may be more likely to drop out of therapy (reverse causality). Tackling the under-representation of older people in psychological therapies and optimizing therapy outcomes is an important goal for future research.

Social Health and Change in Cognitive Capability among Older Adults: Findings from Four European Longitudinal Studies.

INTRODUCTION: In this study, we examine whether social health markers measured at baseline are associated with differences in cognitive capability and the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies. METHODS: We applied an integrated data analysis approach to 16,858 participants (mean age 65 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Study of Aging (ELSA), the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), and the Rotterdam Study. We used multilevel models to examine social health in relation to cognitive capability and the rate of cognitive decline. RESULTS: Pooled estimates show distinct relationships between markers of social health and cognitive domains, e.g., a large network size (≥6 people vs. none) was associated with higher executive function (0.17 standard deviation [SD] [95% CI: 0.00, 0.34], I2 = 27%) but not with memory (0.08 SD [95% CI: -0.02, 0.18], I2 = 19%). We also observed pooled associations between being married or cohabiting, having a large network size, and participating in social activities with slower decline in cognitive capability. However, estimates were close to zero, e.g., 0.01 SD/year (95% CI: 0.01, 0.02) I2 = 19% for marital status and executive function. There were clear study-specific differences: results for average processing speed were the most homogenous, and results for average memory were the most heterogeneous. CONCLUSION: Overall, markers of good social health have a positive association with cognitive capability. However, we found differential associations between specific markers of social health and cognitive domains and differences between studies. These findings highlight the importance of examining between-study differences and considering the context specificity of findings in developing and deploying interventions.

Area disadvantage and mental health over the life course: a 69-year prospective birth cohort study.

PURPOSE: Existing evidence on the mental health consequences of disadvantaged areas uses cross-sectional or longitudinal studies with short observation periods. The objective of this research was to investigate this association over a 69-year period. METHODS: Data were obtained from the MRC National Survey of Health and Development (NSHD; the British 1946 birth cohort), which consisted of 2125 participants at 69 years. We assessed longitudinal associations between area disadvantage and mental health symptoms at adolescence and adulthood with use of multilevel modelling framework. RESULTS: After adjustment for father's social class, for each one percentage increase in area disadvantage at age 4, there was a 0.02 (95% CI 0.001, 0.04) mean increase in the total score of the neuroticism scale at age 13-15. After adjustment for father's social class, adult socio-economic position, cognitive ability and educational attainment, a one percentage increase in change score of area disadvantage between age 4 and 26 was associated with a mean increase in the total Psychiatric Symptom Frequency score (MD 0.06; 95% CI 0.007, 0.11). Similar associations were observed with change scores between ages 4, 53, 60 and total General Health Questionnaire-28 score at age 53 (MD 0.05; 95% CI 0.01, 0.11) and 60-64 (MD 0.06; 95% CI 0.009, 0.11). CONCLUSIONS: Cohort members who experienced increasing area disadvantage from childhood were at increased risk of poor mental health over the life course. Population-wide interventions aiming at improving social and physical aspects of the early neighbourhood environment could reduce the socio-economic burden of poor mental health.

Effects of mental health status during adolescence on primary care costs in adulthood across three British cohorts.

PURPOSE: This study examines the association between mental health problems in adolescence and general practice (GP) costs during adulthood up to age 50 in the UK. METHODS: We conducted secondary analyses of three British birth cohorts (individuals born in single weeks in 1946, 1958 and 1970). Data for the three cohorts were analysed separately. All respondents who participated in the cohort studies were included. Adolescent mental health status was assessed in each cohort using the Rutter scale (or, for one cohort, a forerunner of that scale) completed in interviews with parents and teachers when cohort members were aged around 16. Presence and severity of conduct and emotional problems were modelled as independent variables in two-part regression models in which the dependent variable was costs of GP services from data collection sweeps up to mid-adulthood. All analyses were adjusted for covariates (cognitive ability, mother's education, housing tenure, father's social class and childhood physical disability). RESULTS: Adolescent conduct and emotional problems, particularly when coexisting, were associated with relatively high GP costs in adulthood up to age 50. Associations were generally stronger in females than males. CONCLUSION: Associations between adolescent mental health problems and annual GP cost were evident decades later, to age 50, suggesting that there could be significant future savings to healthcare budgets if rates of adolescent conduct and emotional problems could be reduced. TRIAL REGISTRATION: Not applicable.

Association between carotid atherosclerosis and brain activation patterns during the Stroop task in older adults: An fNIRS investigation.

There is an increasing body of evidence suggesting that vascular disease could contribute to cognitive decline and overt dementia. Of particular interest is atherosclerosis, as it is not only associated with dementia, but could be a potential mechanism through which cardiovascular disease directly impacts brain health. In this work, we evaluated the differences in functional near infrared spectroscopy (fNIRS)-based measures of brain activation, task performance, and the change in central hemodynamics (mean arterial pressure (MAP) and heart rate (HR)) during a Stroop color-word task in individuals with atherosclerosis, defined as bilateral carotid plaques (n = 33) and healthy age-matched controls (n = 33). In the healthy control group, the left prefrontal cortex (LPFC) was the only region showing evidence of activation when comparing the incongruous with the nominal Stroop test. A smaller extent of brain activation was observed in the Plaque group compared with the healthy controls (1) globally, as measured by oxygenated hemoglobin (p = 0.036) and (2) in the LPFC (p = 0.02) and left sensorimotor cortices (LMC)(p = 0.008) as measured by deoxygenated hemoglobin. There were no significant differences in HR, MAP, or task performance (both in terms of the time required to complete the task and number of errors made) between Plaque and control groups. These results suggest that carotid atherosclerosis is associated with altered functional brain activation patterns despite no evidence of impaired performance of the Stroop task or central hemodynamic changes.

Psychological distress from early adulthood to early old age: evidence from the 1946, 1958 and 1970 British birth cohorts.

BACKGROUND: Existing evidence on profiles of psychological distress across adulthood uses cross-sectional or longitudinal studies with short observation periods. The objective of this research was to study the profile of psychological distress within the same individuals from early adulthood to early old age across three British birth cohorts. METHODS: We used data from three British birth cohorts: born in 1946 (n = 3093), 1958 (n = 13 250) and 1970 (n = 12 019). The profile of psychological distress - expressed both as probability of being a clinical case or a count of symptoms based on comparable items within and across cohorts - was modelled using the multilevel regression framework. RESULTS: In both 1958 and 1970 cohorts, there was an initial drop in the probability of being a case between ages 23-26 and 33-34. Subsequently, the predicted probability of being a case increased from 12.5% at age 36 to 19.5% at age 53 in the 1946 cohort; from 8.0% at age 33 to 13.7% at age 42 in the 1958 cohort and from 15.7% at age 34 to 19.7% at age 42 in the 1970 cohort. In the 1946 cohort, there was a drop in the probability of caseness between ages 60-64 and 69 (19.5% v. 15.2%). Consistent results were obtained with the continuous version of the outcome. CONCLUSIONS: Across three post-war British birth cohorts midlife appears to be a particularly vulnerable phase for experiencing psychological distress. Understanding the reasons for this will be important for the prevention and management of mental health problems.

The Power of Birth Cohorts to Study Risk Factors for Cognitive Impairment.

PURPOSE OF REVIEW: Birth cohorts are studies of people the same time; some of which have continuously followed participants across the life course. These are powerful designs for studying predictors of age-related outcomes, especially when information on predictors is collected before these outcomes are known. This article reviews recent findings from these cohorts for the outcomes of cognitive function, cognitive impairment, and risk of dementia, in relation to prior cognitive function, and social and biological predictors. RECENT FINDINGS: Cognitive function and impairment are predicted by a wide range of factors, including childhood cognition, education, occupational status and complexity, and biological factors, including genetic and epigenetic. The particular importance of high and rising blood pressure in midlife is highlighted, with some insight into brain mechanisms involved. Some limitations are noted, including sources of bias in the data. Despite these limitations, birth cohorts have provided valuable insights into factors across the life course associated with cognitive impairment.