Associations Between Longitudinal Trajectories of Cognitive and Social Activities and Brain Health in Old Age

Importance: Prior neuroimaging studies have found that late-life participation in cognitive (eg, reading) and social (eg, visiting friends and family) leisure activities are associated with magnetic resonance imaging (MRI) markers of the aging brain, but little is known about the neural and cognitive correlates of changes in leisure activities during the life span. / Objectives: To examine trajectories of cognitive and social activities from midlife to late life and evaluate whether these trajectories are associated with brain structure, functional connectivity, and cognition. / Design, Setting, and Participants: This prospective cohort included participants enrolled in the Whitehall II study and its MRI substudy based in the UK. Participants provided information on their leisure activities at 5 times during calendar years 1997 to 1999, 2002 to 2004, 2006, 2007 to 2009, and 2011 to 2013 and underwent MRI and cognitive battery testing from January 1, 2012, to December 31, 2016. Data analysis was performed from October 7, 2017, to July 15, 2019. / Main Outcome and Measures: Growth curve models and latent class growth analysis were used to identify longitudinal trajectories of cognitive and social activities. Multiple linear regression was used to evaluate associations between activity trajectories and gray matter, white matter microstructure, functional connectivity, and cognition. / Results: A total of 574 individuals (468 [81.5%] men; mean [SD] age, 69.9 [4.9] years; median Montreal Cognitive Assessment score, 28 [interquartile range, 26-28]) were included in the present analysis. During a mean (SD) of 15 (4.2) years, cognitive and social activity levels increased during midlife before reaching a plateau in late life. Both baseline (global cognition: unstandardized β [SE], 0.955 [0.285], uncorrected P = .001; executive function: β [SE], 1.831 [0.499], uncorrected P < .001; memory: β [SE], 1.394 [0.550], uncorrected P = .01; processing speed: β [SE], 1.514 [0.528], uncorrected P = .004) and change (global cognition: β [SE], -1.382 [0.492], uncorrected P = .005, executive function: β [SE], -2.219 [0.865], uncorrected P = .01; memory: β [SE], -2.355 [0.948], uncorrected P = .01) in cognitive activities were associated with multiple domains of cognition as well as global gray matter volume (β [SE], -0.910 [0.388], uncorrected P = .02). Baseline (β [SE], 1.695 [0.525], uncorrected P = .001) and change (β [SE], 2.542 [1.026], uncorrected P = .01) in social activities were associated only with executive function, in addition to voxelwise measures of functional connectivity that involved sensorimotor (quadratic change in social activities: number of voxels, 306; P = 0.01) and temporoparietal (linear change in social activities: number of voxels, 16; P = .02) networks. Otherwise, no voxelwise associations were found with gray matter, white matter, or resting-state functional connectivity. False discovery rate corrections for multiple comparisons suggested that the association between cognitive activity levels and executive function was robust (β [SE], 1.831 [0.499], false discovery rate P < .001). / Conclusions and Relevance: The findings suggest that a life course approach may delineate the association between leisure activities and cognitive and brain health and that interventions aimed at improving and maintaining cognitive engagement may be valuable for the cognitive health of community-dwelling older adults

Sub-threshold depressive symptoms and brain structure: A magnetic resonance imaging study within the Whitehall II cohort

BACKGROUND: Late-life sub-threshold depressive symptoms (i.e. depressive symptoms that do not meet the criteria for a diagnosis of major depressive disorder) are associated with impaired physical health and function, and increased risk of major depressive disorder. Magnetic resonance imaging (MRI) studies examining late-life major depressive disorder find structural brain changes in grey and white matter. However, the extent to which late-life sub-threshold depression is associated with similar hallmarks is not well established. METHODS: Participants with no history of major depressive disorder were selected from the Whitehall Imaging Sub-Study (n=358, mean age 69±5 years, 17% female). Depressive symptoms were measured using the Centre for Epidemiological Studies Depression Scale (CES-D) at three previous Whitehall II Study phases (2003-04, 2007-09 and 2012-13) and at the time of the MRI scan (2012-14). The relationships between current and cumulative depressive symptoms and MRI brain measures were explored using Voxel-Based Morphometry (VBM) for grey matter and Tract Based Spatial Statistics (TBSS) for white matter. RESULTS: Current sub-threshold depressive symptoms were associated with significant reductions in fractional anisotropy and increases in axial and radial diffusivity. There were no significant relationships between current depressive symptoms and grey matter measures, or cumulative depressive symptoms and MRI measures. LIMITATIONS: The prevalence (10%) of sub-threshold depressive symptoms means that analyses may be underpowered to detect subtle differences in brain structure. CONCLUSIONS: Current sub-threshold depressive symptoms are associated with changes in white matter microstructure, indicating that even mild depressive symptoms are associated with similar MRI hallmarks to those in major depressive disorder

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

Predicting cognitive resilience from midlife lifestyle and multi-modal MRI: A 30-year prospective cohort study

BACKGROUND: There is significant heterogeneity in the clinical expression of structural brain abnormalities, including Alzheimer's disease biomarkers. Some individuals preserve their memory despite the presence of risk factors or pathological brain changes, indicating resilience. We aimed to test whether resilient individuals could be distinguished from those who develop cognitive impairment, using sociodemographic variables and neuroimaging. METHODS: We included 550 older adults participating in the Whitehall II study with longitudinal data, cognitive test results, and multi-modal MRI. Hippocampal atrophy was defined as Scheltens Scores >0. Resilient individuals (n = 184) were defined by high cognitive performance despite hippocampal atrophy (HA). Non-resilient participants (n = 133) were defined by low cognitive performance (≥1.5 standard deviations (S.D.) below the group mean) in the presence of HA. Dynamic and static exposures were evaluated for their ability to predict later resilience status using multivariable logistic regression. In a brain-wide analysis we tested for group differences in the integrity of white matter (structural connectivity) and resting-state networks (functional connectivity). FINDINGS: Younger age (OR: 0.87, 95% CI: 0.83 to 0.92, p<0.001), higher premorbid FSIQ (OR: 1.06, 95% CI: 1.03 to 1.10, p<0.0001) and social class (OR 1 vs. 3: 4.99, 95% CI: 1.30 to 19.16, p = 0.02, OR 2 vs. 3: 8.43, 95% CI: 1.80 to 39.45, p = 0.007) were independently associated with resilience. Resilient individuals could be differentiated from non-resilient participants by higher fractional anisotropy (FA), and less association between anterior and posterior resting state networks. Higher FA had a significantly more positive effect on cognitive performance in participants with HA, compared to those without. CONCLUSIONS: Resilient individuals could be distinguished from those who developed impairments on the basis of sociodemographic characteristics, brain structural and functional connectivity, but not midlife lifestyles. There was a synergistic deleterious effect of hippocampal atrophy and poor white matter integrity on cognitive performance. Exploiting and supporting neural correlates of resilience could offer a fresh approach to postpone or avoid the appearance of clinical symptoms

Acceptability and feasibility of peer assisted supervision and support for intervention practitioners: a Q-methodology evaluation

Evidence-based interventions often include quality improvement methods to support fidelity and improve client outcomes. Clinical supervision is promoted as an effective way of developing practitioner confidence and competence in delivery; however, supervision is often inconsistent and embedded in hierarchical line management structures that may limit the opportunity for reflective learning. The Peer Assisted Supervision and Support (PASS) supervision model uses peer relationships to promote the self-regulatory capacity of practitioners to improve intervention delivery. The aim of the present study was to assess the acceptability and feasibility of PASS amongst parenting intervention practitioners. A Q-methodology approach was used to generate data and 30 practitioners volunteered to participate in the study. Data were analyzed and interpreted using standard Q-methodology procedures and by-person factor analysis yielded three factors. There was consensus that PASS was acceptable. Participants shared the view that PASS facilitated an environment of support where negative aspects of interpersonal relationships that might develop in supervision were not evident. Two factors represented the viewpoint that PASS was also a feasible model of supervision. However, the third factor was comprised of practitioners who reported that PASS could be time consuming and difficult to fit into existing work demands. There were differences across the three factors in the extent to which practitioners considered PASS impacted on their intervention delivery. The findings highlight the importance of organizational mechanisms that support practitioner engagement in supervision

Towards a typology for constrained climate model forecasts

In recent years several methodologies have been developed to combine and interpret ensembles of climate models with the aim of quantifying uncertainties in climate projections. Constrained climate model forecasts have been generated by combining various choices of metrics used to weight individual ensemble members, with diverse approaches to sampling the ensemble. The forecasts obtained are often significantly different, even when based on the same model output. Therefore, a climate model forecast classification system can serve two roles: to provide a way for forecast producers to self-classify their forecasts; and to provide information on the methodological assumptions underlying the forecast generation and its uncertainty when forecasts are used for impacts studies. In this review we propose a possible classification system based on choices of metrics and sampling strategies. We illustrate the impact of some of the possible choices in the uncertainty quantification of large scale projections of temperature and precipitation changes, and briefly discuss possible connections between climate forecast uncertainty quantification and decision making approaches in the climate change context

Timing of immune escape linked to success or failure of vaccination

Successful vaccination against HIV should limit viral replication sufficiently to prevent the emergence of viral immune escape mutations. Broadly directed immunity is likely to be required to limit opportunities for immune escape variants to flourish. We studied the emergence of an SIV Gag cytotoxic T cell immune escape variant in pigtail macaques expressing the Mane-A*10 MHC I allele using a quantitative RT-PCR to measure viral loads of escape and wild type variants. Animals receiving whole Gag expressing vaccines completely controlled an SIVmac251 challenge, had broader CTL responses and exhibited minimal CTL escape. In contrast, animals vaccinated with only a single CTL epitope and challenged with the same SIVmac251 stock had high levels of viral replication and rapid CTL escape. Unvaccinated na&iuml;ve animals exhibited a slower emergence of immune escape variants. Thus narrowly directed vaccination against a single epitope resulted in rapid immune escape and viral levels equivalent to that of na&iuml;ve unvaccinated animals. These results emphasize the importance of inducing broadly directed HIV-specific immunity that effectively quashes early viral replication and limits the generation of immune escape variants. This has important implications for the selection of HIV vaccines for expanded human trials.<br /

Active Site Mutations Change the Cleavage Specificity of Neprilysin

Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe563 and Ser546. Among the mutants studied in detail we observed changes in their activity towards leucine5-enkephalin, insulin B chain, and amyloid β1–40. For example, NEPF563I displayed an increase in preference towards cleaving leucine5-enkephalin relative to insulin B chain, while mutant NEPS546E was less discriminating than neprilysin. Mutants NEPF563L and NEPS546E exhibit different cleavage site preferences than neprilysin with insulin B chain and amyloid ß1–40 as substrates. These data indicate that it is possible to alter the cleavage site specificity of neprilysin opening the way for the development of substrate specific or substrate exclusive forms of the enzyme with enhanced therapeutic potential

APOE and immunity: Research highlights

INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development