Does functional system segregation mediate the effects of lifestyle on cognition in older adults?

Healthy aging is typically accompanied by cognitive decline. Previous work has shown that engaging in multiple, non-work activities during midlife can have a protective effect on cognition several decades later, rendering it less dependent on brain structural health; the definition of "cognitive reserve". Other work has shown that increasing age is associated with reduced segregation of large-scale brain functional networks. Here we tested the hypothesis that functional segregation (SyS) mediates this effect of middle-aged lifestyle on late-life cognition. We used fMRI data from three tasks in the CamCAN dataset, together with cognitive data on fluid intelligence, episodic memory, and retrospective lifestyle data from the Lifetime of Experiences Questionnaire (LEQ). In all three tasks, we showed that SyS related to fluid intelligence even after adjusting for the (nonlinear) age effects. However, we found no evidence that SyS in late-life mediated the relationship between non-specific (non-occupation) midlife activities and either measure of cognition in late-life. Thus, the brain correlates of cognitive reserve arising from mid-life activities remain to be discovered.

Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

Associations of depression and regional brain structure across the adult lifespan: Pooled analyses of six population-based and two clinical cohort studies in the European Lifebrain consortium.

OBJECTIVE: Major depressive disorder has been associated with lower prefrontal thickness and hippocampal volume, but it is unknown whether this association also holds for depressive symptoms in the general population. We investigated associations of depressive symptoms and depression status with brain structures across population-based and patient-control cohorts, and explored whether these associations are similar over the lifespan and across sexes. METHODS: We included 3,447 participants aged 18-89 years from six population-based and two clinical patient-control cohorts of the European Lifebrain consortium. Cross-sectional meta-analyses using individual person data were performed for associations of depressive symptoms and depression status with FreeSurfer-derived thickness of bilateral rostral anterior cingulate cortex (rACC) and medial orbitofrontal cortex (mOFC), and hippocampal and total grey matter volume (GMV), separately for population-based and clinical cohorts. RESULTS: Across patient-control cohorts, depressive symptoms and presence of mild-to-severe depression were associated with lower mOFC thickness (rsymptoms = -0.15/ rstatus = -0.22), rACC thickness (rsymptoms = -0.20/ rstatus = -0.25), hippocampal volume (rsymptoms = -0.13/ rstatus = 0.13) and total GMV (rsymptoms = -0.21/ rstatus = -0.25). Effect sizes were slightly larger for presence of moderate-to-severe depression. Associations were similar across age groups and sex. Across population-based cohorts, no associations between depression and brain structures were observed. CONCLUSIONS: Fitting with previous meta-analyses, depressive symptoms and depression status were associated with lower mOFC, rACC thickness, and hippocampal and total grey matter volume in clinical patient-control cohorts, although effect sizes were small. The absence of consistent associations in population-based cohorts with mostly mild depressive symptoms, suggests that significantly lower thickness and volume of the studied brain structures are only detectable in clinical populations with more severe depressive symptoms.

The role of the anterior temporal cortex in action: evidence from fMRI multivariate searchlight analysis during real object grasping.

Intelligent manipulation of handheld tools marks a major discontinuity between humans and our closest ancestors. Here we identified neural representations about how tools are typically manipulated within left anterior temporal cortex, by shifting a searchlight classifier through whole-brain real action fMRI data when participants grasped 3D-printed tools in ways considered typical for use (i.e., by their handle). These neural representations were automatically evocated as task performance did not require semantic processing. In fact, findings from a behavioural motion-capture experiment confirmed that actions with tools (relative to non-tool) incurred additional processing costs, as would be suspected if semantic areas are being automatically engaged. These results substantiate theories of semantic cognition that claim the anterior temporal cortex combines sensorimotor and semantic content for advanced behaviours like tool manipulation.

Ageing and the Ipsilateral M1 BOLD Response: A Connectivity Study.

Young people exhibit a negative BOLD response in ipsilateral primary motor cortex (M1) when making unilateral movements, such as button presses. This negative BOLD response becomes more positive as people age. In this study, we investigated why this occurs, in terms of the underlying effective connectivity and haemodynamics. We applied dynamic causal modeling (DCM) to task fMRI data from 635 participants aged 18-88 from the Cam-CAN dataset, who performed a cued button pressing task with their right hand. We found that connectivity from contralateral supplementary motor area (SMA) and dorsal premotor cortex (PMd) to ipsilateral M1 became more positive with age, explaining 44% of the variability across people in ipsilateral M1 responses. In contrast, connectivity from contralateral M1 to ipsilateral M1 was weaker and did not correlate with individual differences in rM1 BOLD. Neurovascular and haemodynamic parameters in the model were not able to explain the age-related shift to positive BOLD. Our results add to a body of evidence implicating neural, rather than vascular factors as the predominant cause of negative BOLD-while emphasising the importance of inter-hemispheric connectivity. This study provides a foundation for investigating the clinical and lifestyle factors that determine the sign and amplitude of the M1 BOLD response in ageing, which could serve as a proxy for neural and vascular health, via the underlying neurovascular mechanisms.

Does Hemispheric Asymmetry Reduction in Older Adults in Motor Cortex Reflect Compensation?

Older adults tend to display greater brain activation in the nondominant hemisphere during even basic sensorimotor responses. It is debated whether this hemispheric asymmetry reduction in older adults (HAROLD) reflects a compensatory mechanism. Across two independent fMRI experiments involving adult life span human samples (N = 586 and N = 81, approximately half female) who performed right-hand finger responses, we distinguished between these hypotheses using behavioral and multivariate Bayes (MVB) decoding approaches. Standard univariate analyses replicated a HAROLD pattern in motor cortex, but in and out of scanner behavioral results both demonstrated evidence against a compensatory relationship in that reaction time measures of task performance in older adults did not relate to ipsilateral motor activity. Likewise, MVB showed that this increased ipsilateral activity in older adults did not carry additional information, and if anything, combining ipsilateral with contralateral activity patterns reduced action decoding in older adults (at least in experiment 1). These results contradict the hypothesis that HAROLD is compensatory and instead suggest that the age-related ipsilateral hyperactivation is nonspecific, consistent with alternative hypotheses about age-related reductions in neural efficiency/differentiation or interhemispheric inhibition.SIGNIFICANCE STATEMENT A key goal in the cognitive neuroscience of aging is to provide a mechanistic explanation of how brain-behavior relationships change with age. One interpretation of the common finding that task-based hemispheric activity becomes more symmetrical in older adults is that this shift reflects a compensatory mechanism, with the nondominant hemisphere needing to help out with computations normally performed by the dominant hemisphere. Contrary to this view, our behavioral and brain data indicate that the additional activity in ipsilateral motor cortex in older adults is not reflective of better task performance nor better neural representations of finger actions.

Hand-Selective Visual Regions Represent How to Grasp 3D Tools: Brain Decoding during Real Actions.

Most neuroimaging experiments that investigate how tools and their actions are represented in the brain use visual paradigms where tools or hands are displayed as 2D images and no real movements are performed. These studies discovered selective visual responses in occipitotemporal and parietal cortices for viewing pictures of hands or tools, which are assumed to reflect action processing, but this has rarely been directly investigated. Here, we examined the responses of independently visually defined category-selective brain areas when participants grasped 3D tools (N = 20; 9 females). Using real-action fMRI and multivoxel pattern analysis, we found that grasp typicality representations (i.e., whether a tool is grasped appropriately for use) were decodable from hand-selective areas in occipitotemporal and parietal cortices, but not from tool-, object-, or body-selective areas, even if partially overlapping. Importantly, these effects were exclusive for actions with tools, but not for biomechanically matched actions with control nontools. In addition, grasp typicality decoding was significantly higher in hand than tool-selective parietal regions. Notably, grasp typicality representations were automatically evoked even when there was no requirement for tool use and participants were naive to object category (tool vs nontools). Finding a specificity for typical tool grasping in hand-selective, rather than tool-selective, regions challenges the long-standing assumption that activation for viewing tool images reflects sensorimotor processing linked to tool manipulation. Instead, our results show that typicality representations for tool grasping are automatically evoked in visual regions specialized for representing the human hand, the primary tool of the brain for interacting with the world.

Educational attainment does not influence brain aging.

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer's disease.

Aging and Alzheimer's disease (AD) are associated with progressive brain disorganization. Although structural asymmetry is an organizing feature of the cerebral cortex it is unknown whether continuous age- and AD-related cortical degradation alters cortical asymmetry. Here, in multiple longitudinal adult lifespan cohorts we show that higher-order cortical regions exhibiting pronounced asymmetry at age ~20 also show progressive asymmetry-loss across the adult lifespan. Hence, accelerated thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This organizational principle showed high consistency across cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Asymmetry-change was further accelerated in AD. Results suggest a system-wide dedifferentiation of the adaptive asymmetric organization of heteromodal cortex in aging and AD.

Effect of apolipoprotein E polymorphism on cognition and brain in the Cambridge Centre for Ageing and Neuroscience cohort.

Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the 'antagonistic pleiotropy' hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report - https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18-88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.