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Healthy aging has been associated with a decrease in functional network specialization. Importantly, variability of alterations of functional connectivity is especially high across older adults. Whole-brain functional network reorganization, though, and its impact on cognitive performance within particularly the older generation is still a matter of debate. We assessed resting state functional connectivity (RSFC) in 772 older adults (55–85 years, 421 males) using a graph-theoretical approach. Results show overall age-related increases of between- and decreases of within-network RSFC. With similar phenomena observed in young to middle-aged adults, i.e. that RSFC reorganizes towards more pronounced functional network integration, the current results amend such evidence for the old age. The results furthermore indicate that RSFC reorganization in older adults particularly pertain to early sensory networks (e.g. visual and sensorimotor network). Importantly, RSFC differences of these early sensory networks were found to be a relevant mediator in terms of the age-related cognitive performance differences. Further, we found systematic sex-related network differences with females showing patterns of more segregation (i.e. default mode and ventral attention network) and males showing a higher integrated network system (particularly for the sensorimotor network). These findings underpin the notion of sex-related connectivity differences, possibly facilitating sex-related behavioral functioning. ∙Across aging, older adults’ functional connectome reorganizes towards higher network integration.∙Age-related differences in older adults predominantly pertain to networks implicated in primary information processing.∙Primary processing networks were found to mediate age-related cognitive performance differences.∙Males and females showed different connectivity patterns, potentially reflecting sex-specific behavioral functioning.

Lifestyle may be one source of unexplained variance in the great interindividual variability of the brain in age-related structural differences. While physical and social activity may protect against structural decline, other lifestyle behaviors may be accelerating factors. We examined whether riskier lifestyle correlates with accelerated brain aging using the BrainAGE score in 622 older adults from the 1000BRAINS cohort. Lifestyle was measured using a combined lifestyle risk score, composed of risk (smoking, alcohol intake) and protective variables (social integration and physical activity). We estimated individual BrainAGE from T1-weighted MRI data indicating accelerated brain atrophy by higher values. Then, the effect of combined lifestyle risk and individual lifestyle variables was regressed against BrainAGE. One unit increase in combined lifestyle risk predicted 5.04 months of additional BrainAGE. This prediction was driven by smoking (0.6 additional months of BrainAGE per pack-year) and physical activity (0.55 less months in BrainAGE per metabolic equivalent). Stratification by sex revealed a stronger association between physical activity and BrainAGE in males than females. Overall, our observations may be helpful with regard to lifestyle-related tailored prevention measures that slow changes in brain structure in older adults.

In the normal aging process, the functional connectome restructures and shows a shift from more segregated to more integrated brain networks, which manifests itself in highly different cognitive performances in older adults. Underpinnings of this reorganization are not fully understood, but may be related to age‐related differences in structural connectivity, the underlying scaffold for information exchange between regions. The structure–function relationship might be a promising factor to understand the neurobiological sources of interindividual cognitive variability, but remain unclear in older adults. Here, we used diffusion weighted and resting‐state functional magnetic resonance imaging as well as cognitive performance data of 573 older subjects from the 1000BRAINS cohort (55–85 years, 287 males) and performed a partial least square regression on 400 regional functional and structural connectivity (FC and SC, respectively) estimates comprising seven resting‐state networks. Our aim was to identify FC and SC patterns that are, together with cognitive performance, characteristic of the older adults aging process. Results revealed three different aging profiles prevalent in older adults. FC was found to behave differently depending on the severity of age‐related SC deteriorations. A functionally highly interconnected system is associated with a structural connectome that shows only minor age‐related decreases. Because this connectivity profile was associated with the most severe age‐related cognitive decline, a more interconnected FC system in older adults points to a process of dedifferentiation. Thus, functional network integration appears to increase primarily when SC begins to decline, but this does not appear to mitigate the decline in cognitive performance. Aging is accompanied by a functional reorganization which manifests itself in cognitive performance differences, especially in older adults. Sources of functional reorganization are not fully understood but have been associated with structural connectivity differences. Based on a large cohort of older adults we show that functional connectivity behaves in relation to age‐related structural connectivity differences and further, that a functional dedifferentiated system, associated with minor structural connectivity decreases, is nonbeneficial in terms of cognitive performance maintenance.

•VAB mechanistically confirm the hypothesis that inter-hemispheric SC serves as a pivotal basis for homotopic FC.•Global neuromodulation increases with age and with SC deterioration, but it is negatively related to verbal memory and concept shifting.•Increased SC-FC tethering might suggest an amplification of loss of dynamical flexibility, especially in poor cognitive performers.•Global modulation increase seems not to happen for the high performing group, likely due to better brain maintenance.•SBI confirms the increase of SC neuromodulation with aging and retrieves working points with the same age-declining FC and FCD features. The mechanisms of cognitive decline and its variability during healthy aging are not fully understood, but have been associated with reorganization of white matter tracts and functional brain networks. Here, we built a brain network modeling framework to infer the causal link between structural connectivity and functional architecture and the consequent cognitive decline in aging. By applying in-silico interhemispheric degradation of structural connectivity, we reproduced the process of functional dedifferentiation during aging. Thereby, we found the global modulation of brain dynamics by structural connectivity to increase with age, which was steeper in older adults with poor cognitive performance. We validated our causal hypothesis via a deep-learning Bayesian approach. Our results might be the first mechanistic demonstration of dedifferentiation during aging leading to cognitive decline.

Lifestyle contributes to inter-individual variability in brain aging, but previous studies focused on the effects of single lifestyle variables. Here, we studied the combined and individual contributions of four lifestyle variables - alcohol consumption, smoking, physical activity, and social integration - to brain structure and functional connectivity in a population-based cohort of 549 older adults. A combined lifestyle risk score was associated with decreased gyrification in left premotor and right prefrontal cortex, and higher functional connectivity to sensorimotor and prefrontal cortex. While structural differences were driven by alcohol consumption, physical activity, and social integration, higher functional connectivity was driven by smoking. Results suggest that combining differentially contributing lifestyle variables may be more than the sum of its parts. Associations generally were neither altered by adjustment for genetic risk, nor by depressive symptomatology or education, underlining the relevance of daily habits for brain health. Lifestyle factors such as smoking and exercise contribute to the health of the brain during aging, but previous studies have focused on the effects of single lifestyle variables. Here, the authors examine the combined and individual effects of four lifestyle variables on brain structure and function.

Neuropsychological studies reported that shift workers show reduced cognitive performance and circadian dysfunctions which may impact structural and functional brain networks. Here we tested the hypothesis whether night shift work is associated with resting-state functional connectivity (RSFC), cortical thickness and gray matter volume in participants of the 1000BRAINS study for whom information on night shift work and imaging data were available. 13 PRESENT and 89 FORMER night shift workers as well as 430 control participants who had never worked in shift (NEVER) met these criteria and were included in our study. No associations between night shift work, three graph-theoretical measures of RSFC of 7 functional brain networks and brain morphology were found after multiple comparison correction. Preceding multiple comparison correction, our results hinted at an association between more years of shift work and higher segregation of the visual network in PRESENT shift workers and between shift work experience and lower gray matter volume of the left thalamus. Extensive neuropsychological investigations supplementing objective imaging methodology did not reveal an association between night shift work and cognition after multiple comparison correction. Our pilot study suggests that night shift work does not elicit general alterations in brain networks and affects the brain only to a limited extent. These results now need to be corroborated in studies with larger numbers of participants.

Bilingualism is associated with higher gray matter volume (GMV) as a form of brain reserve in brain regions such as the inferior frontal gyrus (IFG) and the inferior parietal lobule (IPL). A recent cross-sectional study reported the age-related GMV decline in the left IFG and IPL to be steeper for bilinguals than for monolinguals. The present study aimed at supporting this finding for the first time with longitudinal data. In the current study, 200 participants aged 19 to 79 years (87 monolinguals, 113 sequential bilinguals, mostly native German speakers with variable second language background) were included. Trajectories of GMV decline in the bilateral IFG and IPL were analyzed in mono- and bilinguals over two time points (mean time interval: 3.6 years). For four regions of interest (left/right IFG and left/right IPL), mixed Analyses of Covariance were conducted to assess (i) GMV changes over time, (ii) GMV differences for language groups (monolinguals/bilinguals), and (iii) the interaction between time point and language group. Corresponding analyses were conducted for the two factors of GMV, surface area (SA) and cortical thickness (CT). There was higher GMV in bilinguals compared to monolinguals in the IPL, but not IFG. While the left and right IFG and the right IPL displayed a similar GMV change in mono- and bilinguals, GMV decline within the left IPL was significantly steeper in bilinguals. There was greater SA in bilinguals in the bilateral IPL and a steeper CT decline in bilinguals within in the left IPL. The cross-sectional observations of a steeper GMV decline in bilinguals could be confirmed for the left IPL. Additionally, the higher GMV in bilinguals in the bilateral IPL may indicate that bilingualism contributes to brain reserve especially in posterior brain regions. SA appeared to contribute to bilinguals' higher GMV in the bilateral IPL, while CT seemed to account for the steeper structural decline in bilinguals in the left IPL. The present findings demonstrate the importance of time as an additional factor when assessing the neuroprotective effects of bilingualism on structural features of the human brain.

Aging is associated with brain atrophy, functional brain network reorganization and decline of cognitive performance, albeit characterized by high interindividual variability. Among environmental influencing factors accounting for this variability, nutrition and particularly vitamin supply is thought to play an important role. While evidence exists that supplementation of vitamins B6 and B1 might be beneficial for cognition and brain structure, at least in deficient states and neurodegenerative diseases, little is known about this relation during healthy aging and in relation to reorganization of functional brain networks. We thus assessed the relation between blood levels of vitamins B1 and B6 and cognitive performance, cortical folding, and functional resting-state connectivity in a large sample of older adults ( > 600; age: 55-85 years), drawn from the population-based 1000BRAINS study. In addition to blood sampling, subjects underwent structural and functional resting-state neuroimaging as well as extensive neuropsychological testing in the domains of executive functions, (working) memory, attention, and language. Brain regions showing changes in the local gyrification index as calculated using FreeSurfer in relation to vitamin levels were used for subsequent seed-based resting-state functional connectivity analysis. For B6, a positive correlation with local cortical folding was found throughout the brain, while only slight changes in functional connectivity were observed. Contrarily, for B1, a negative correlation with cortical folding as well as problem solving and visuo-spatial working memory performance was found, which was accompanied by pronounced increases of interhemispheric and decreases of intrahemispheric functional connectivity. While the effects for B6 expand previous knowledge on beneficial effects of B6 supplementation on brain structure, they also showed that additional effects on cognition might not be recognizable in healthy older subjects with normal B6 blood levels. The cortical atrophy and pronounced functional reorganization associated with B1, contrarily, was more in line with the theory of a disturbed B1 metabolism in older adults, leading to B1 utilization deficits, and thus, an effective B1 deficiency in the brain, despite normal to high-normal blood levels.

Cross-sectional studies indicate that normal aging is accompanied by decreases in brain structure. Longitudinal studies, however, are relatively rare and inconsistent regarding their outcomes. Particularly the heterogeneity of methods, sample characteristics and the high inter-individual variability in older adults prevent the deduction of general trends. Therefore, the current study aimed to compare longitudinal age-related changes in brain structure (measured through cortical thickness) in two large independent samples of healthy older adults ( n = 161 each); the Longitudinal Healthy Aging Brain (LHAB) database project at the University of Zurich, Switzerland, and 1000BRAINS at the Research Center Juelich, Germany. Annual percentage changes in the two samples revealed stable to slight decreases in cortical thickness over time. After correction for major covariates, i.e., baseline age, sex, education, and image quality, sample differences were only marginally present. Results suggest that general trends across time might be generalizable over independent samples, assuming the same methodology is used, and similar sample characteristics are present.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.