Cross-sectional and Longitudinal Age-related Disintegration in Functional Connectivity: Reference Ability Neural Network Cohort.

Some theories of aging have linked age-related cognitive decline to a reduction in distinctiveness of neural processing. Observed age-related correlation increases among disparate cognitive tasks have supported the dedifferentiation hypothesis. We previously showed cross-sectional evidence for age-related correlation decreases instead, supporting an alternative disintegration hypothesis. In the current study, we extended our previous research to a longitudinal sample. We tested 135 participants (20-80 years) at two time points-baseline and 5-year follow-up-on a battery of 12 in-scanner tests, each tapping one of four reference abilities. We performed between-tasks correlations within domain (convergent) and between domain (discriminant) at both the behavioral and neural level, calculating a single measure of construct validity (convergent - discriminant). Cross-sectionally, behavioral construct validity was significantly different from chance at each time point, but longitudinal change was not significant. Analysis by median age split revealed that older adults showed higher behavioral validity, driven by higher discriminant validity (lower between-tasks correlations). Participant-level neural validity decreased over time, with convergent validity consistently greater than discriminant validity; this finding was also observed at the cross-sectional level. In addition, a disproportionate decrease in neural validity with age remained significant after controlling for demographic factors. Factors predicting longitudinal changes in global cognition (mean performance across all 12 tasks) included age, change in neural validity, education, and National Adult Reading Test (premorbid intelligence). Change in neural validity partially mediated the effect of age on change in global cognition. Our findings support the theory of age-related disintegration, linking cognitive decline to changes in neural representations over time.

Childhood engagement in cognitively stimulating activities moderates relationships between brain structure and cognitive function in adulthood.

Greater engagement in cognitively stimulating activities (CSA) during adulthood has been shown to protect against neurocognitive decline, but no studies have investigated whether CSA during childhood protects against effects of brain changes on cognition later in life. The current study tested the moderating role of childhood CSA in the relationships between brain structure and cognitive performance during adulthood. At baseline (N=250) and 5-year follow-up (N=204) healthy adults aged 20-80 underwent MRI to assess four structural brain measures and completed neuropsychological tests to measure three cognitive domains. Participants were categorized into low and high childhood CSA based on self-report questionnaires. Results of multivariable linear regressions analyzing interactions between CSA, brain structure, and cognition showed that higher childhood CSA was associated with a weaker relationship between cortical thickness and memory at baseline, and attenuated the effects of change in cortical thickness and brain volume on decline in processing speed over time. These findings suggest higher CSA during childhood may mitigate the effects of brain structure changes on cognitive function later in life.

Brain reserve affects the expression of cognitive reserve networks.

Cognitive reserve (CR) explains differential susceptibility of cognitive performance to neuropathology. However, as brain pathologies progress, cognitive decline occurs even in individuals with initially high CR. The interplay between the structural brain health (= level of brain reserve) and CR-related brain networks therefore requires further research. Our sample included 142 individuals aged 60-70 years. National Adult Reading Test intelligence quotient (NART-IQ) was our CR proxy. On an in-scanner Letter Sternberg task, we used ordinal trend (OrT) analysis to extract a task-related brain activation pattern (OrT slope) for each participant that captures increased expression with task load (one, three, and six letters). We assessed whether OrT slope represents a neural mechanism underlying CR by associating it with task performance and NART-IQ. Additionally, we investigated how the following brain reserve measures affect the association between NART-IQ and OrT slope: mean cortical thickness, total gray matter volume, and brain volumes proximal to the areas contained in the OrT patterns. We found that higher OrT slope was associated with better task performance and higher NART-IQ. Further, the brain reserve measures were not directly associated with OrT slope, but they affected the relationship between NART-IQ and OrT slope: NART-IQ was associated with OrT slope only in individuals with high brain reserve. The degree of brain reserve has an impact on how (and perhaps whether) CR can be implemented in brain networks in older individuals.

In vivo tau is associated with change in memory and processing speed, but not reasoning, in cognitively unimpaired older adults.

The relationship between tau deposition and cognitive decline in cognitively healthy older adults is still unclear. The tau PET tracer 18F-MK-6240 has shown favorable imaging characteristics to identify early tau deposition in aging. We evaluated the relationship between in vivo tau levels (18F-MK-6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, a set of regions of interest (ROIs) was selected a priori based on previous literature: (1) total-ROI comprising selected areas, (2) medial temporal lobe-ROI, and (3) lateral temporal lobe-ROI and cingulate/parietal lobe-ROI. Higher tau burden in most ROIs was associated with a steeper decline in memory and speed. There were no associations between tau and reasoning change. The novelty of this finding is that tau burden may affect not only episodic memory, a well-established finding but also processing speed. Our finding reinforces the notion that early tau deposition in areas related to Alzheimer's disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample with low amyloid-ß pathology.

Personality traits and cognitive reserve-High openness benefits cognition in the presence of age-related brain changes.

Cognitive reserve explains differential susceptibility of cognitive performance to neuropathology. We investigated whether certain personality traits underlie cognitive reserve and are accordingly associated with better cognition and less cognitive decline in the presence of age-related brain changes. We included healthy adults aged 19-80 years for cross-sectional (N=399) and longitudinal (N=273, mean follow-up time=5 years, SD=0.7 years) analyses. Assessment of the BIG5 personality traits openness, conscientiousness, extraversion, agreeableness, and neuroticism was questionnaire-based. Each cognitive domain (perceptual speed, memory, fluid reasoning, vocabulary) was measured with up to six tasks. Cognitive domain-specific brain status variables were obtained by combining 77 structural brain measures into single scores using elastic net regularization. These brain status variables explained up to 43.1% of the variance in cognitive performance. We found that higher openness was associated with higher fluid reasoning and better vocabulary after controlling for brain status, age, and sex. Further, lower brain status was associated with a greater decline in perceptual speed only in individuals with low openness. We conclude that high openness benefits cognitive reserve.

Neurophysiological markers in community-dwelling older adults with mild cognitive impairment: an EEG study.

BACKGROUND: Neurodegeneration and structural changes in the brain due to amyloid deposition have been observed even in individuals with mild cognitive impairment (MCI). EEG measurement is considered an effective tool because it is noninvasive, has few restrictions on the measurement environment, and is simple and easy to use. In this study, we investigated the neurophysiological characteristics of community-dwelling older adults with MCI using EEG. METHODS: Demographic characteristics, cognitive function, physical function, resting-state MRI and electroencephalogram (rs-EEG), event-related potentials (ERPs) during Simon tasks, and task proportion of correct responses and reaction times (RTs) were obtained from 402 healthy controls (HC) and 47 MCI participants. We introduced exact low-resolution brain electromagnetic tomography-independent component analysis (eLORETA-ICA) to assess the rs-EEG network in community-dwelling older adults with MCI. RESULTS: A lower proportion of correct responses to the Simon task and slower RTs were observed in the MCI group (p < 0.01). Despite no difference in brain volume between the HC and MCI groups, significant decreases in dorsal attention network (DAN) activity (p < 0.05) and N2 amplitude of ERP (p < 0.001) were observed in the MCI group. Moreover, DAN activity demonstrated a correlation with education (Rs = 0.32, p = 0.027), global cognitive function (Rs = 0.32, p = 0.030), and processing speed (Rs = 0.37, p = 0.010) in the MCI group. The discrimination accuracy for MCI with the addition of the eLORETA-ICA network ranged from 0.7817 to 0.7929, and the area under the curve ranged from 0.8492 to 0.8495. CONCLUSIONS: The eLORETA-ICA approach of rs-EEG using noninvasive and relatively inexpensive EEG demonstrates specific changes in elders with MCI. It may provide a simple and valid assessment method with few restrictions on the measurement environment and may be useful for early detection of MCI in community-dwelling older adults.

Association of Cognitive Polygenic Index and Cognitive Performance with Age in Cognitively Healthy Adults.

Genome-wide association studies have discovered common genetic variants associated with cognitive performance. Polygenic scores that summarize these discoveries explain up to 10% of the variance in cognitive test performance in samples of adults. However, the role these genetics play in cognitive aging is not well understood. We analyzed data from 168 cognitively healthy participants aged 23-77 years old, with data on genetics, neuropsychological assessment, and brain-imaging measurements from two large ongoing studies, the Reference Abilities Neural Networks, and the Cognitive Reserve study. We tested whether a polygenic index previously related to cognition (Cog PGI) would moderate the relationship between age and measurements of the cognitive domains extracted from a neuropsychological evaluation: fluid reasoning, memory, vocabulary, and speed of processing. We further explored the relationship of Cog PGI and age on cognition using Johnson-Neyman intervals for two-way interactions. Sex, education, and brain measures of cortical thickness, total gray matter volume, and white matter hyperintensity were considered covariates. The analysis controlled for population structure-ancestry. There was a significant interaction effect of Cog PGI on the association between age and the domains of memory (Standardized coefficient = -0.158, p-value = 0.022), fluid reasoning (Standardized coefficient = -0.146, p-value = 0.020), and vocabulary (Standardized coefficient = -0.191, p-value = 0.001). Higher PGI strengthened the negative relationship between age and the domains of memory and fluid reasoning while PGI weakened the positive relationship between age and vocabulary. Based on the Johnson-Neyman intervals, Cog PGI was significantly associated with domains of memory, reasoning, and vocabulary for younger adults. There is a significant moderation effect of genetic predisposition for cognition for the association between age and cognitive performance. Genetics discovered in genome-wide association studies of cognitive performance show a stronger association in young and midlife older adults.

Simple topological task-based functional connectivity features predict longitudinal behavioral change of fluid reasoning in the RANN cohort.

Recent attention has been given to topological data analysis (TDA), and more specifically persistent homology (PH), to identify the underlying shape of brain network connectivity beyond simple edge pairings by computing connective components across different connectivity thresholds (see Sizemore et al., 2019). In the present study, we applied PH to task-based functional connectivity, computing 0-dimension Betti (B0) curves and calculating the area under these curves (AUC); AUC indicates how quickly a single connected component is formed across correlation filtration thresholds, with lower values interpreted as potentially analogous to lower whole-brain system segregation (e.g., Gracia-Tabuenca et al., 2020). One hundred sixty-three participants from the Reference Ability Neural Network (RANN) longitudinal lifespan cohort (age 20-80 years) were tested in-scanner at baseline and five-year follow-up on a battery of tests comprising four domains of cognition (i.e., Stern et al., 2014). We tested for 1.) age-related change in the AUC of the B0 curve over time, 2.) the predictive utility of AUC in accounting for longitudinal change in behavioral performance and 3.) compared system segregation to the PH approach. Results demonstrated longitudinal age-related decreases in AUC for Fluid Reasoning, with these decreases predicting longitudinal declines in cognition, even after controlling for demographic and brain integrity factors; moreover, change in AUC partially mediated the effect of age on change in cognitive performance. System segregation also significantly decreased with age in three of the four cognitive domains but did not predict change in cognition. These results argue for greater application of TDA to the study of aging.

Older adults compensate for switch, but not mixing costs, relative to younger adults on an intrinsically cued task switching experiment.

Introduction: Aging negatively impacts the ability to rapidly and successfully switch between two or more tasks that have different rules or objectives. However, previous work has shown that the context impacts the extent of this age-related impairment: while there is relative age-related invariance when participants must rapidly switch back and forth between two simple tasks (often called "switch costs"), age-related differences emerge when the contexts changes from one in which only one task must be performed to one in which multiple tasks must be performed, but a trial-level switch is not required (e.g., task repeat trials within dual task blocks, often called "mixing costs"). Here, we explored these two kinds of costs behaviorally, and also investigated the neural correlates of these effects. Methods: Seventy-one younger adults and 175 older adults completed a task-switching experiment while they underwent fMRI brain imaging. We investigated the impact of age on behavioral performance and neural activity considering two types of potential costs: switch costs (dual-task switch trials minus dual-task non-switch trials), and mixing costs (dual-task non-switch minus single-task trials). Results: We replicated previous behavioral findings, with greater age associated with mixing, but not switch costs. Neurally, we found age-related compensatory activations for switch costs in the dorsal lateral prefrontal cortex, pars opercularis, superior temporal gyrus, and the posterior and anterior cingulate, but age-related under recruitment for mixing costs in fronto-parietal areas including the supramarginal gyrus and pre and supplemental motor areas. Discussion: These results suggest an age-based dissociation between executive components that contribute to task switching.

Persistent homology-based functional connectivity and its association with cognitive ability: Life-span study.

Brain-segregation attributes in resting-state functional networks have been widely investigated to understand cognition and cognitive aging using various approaches [e.g., average connectivity within/between networks and brain system segregation (BSS)]. While these approaches have assumed that resting-state functional networks operate in a modular structure, a complementary perspective assumes that a core-periphery or rich club structure accounts for brain functions where the hubs are tightly interconnected to each other to allow for integrated processing. In this article, we apply a novel method, persistent homology (PH), to develop an alternative to standard functional connectivity by quantifying the pattern of information during the integrated processing. We also investigate whether PH-based functional connectivity explains cognitive performance and compare the amount of variability in explaining cognitive performance for three sets of independent variables: (1) PH-based functional connectivity, (2) graph theory-based measures, and (3) BSS. Resting-state functional connectivity data were extracted from 279 healthy participants, and cognitive ability scores were generated in four domains (fluid reasoning, episodic memory, vocabulary, and processing speed). The results first highlight the pattern of brain-information flow over whole brain regions (i.e., integrated processing) accounts for more variance of cognitive abilities than other methods. The results also show that fluid reasoning and vocabulary performance significantly decrease as the strength of the additional information flow on functional connectivity with the shortest path increases. While PH has been applied to functional connectivity analysis in recent studies, our results demonstrate potential utility of PH-based functional connectivity in understanding cognitive function.

Distinct and joint effects of low and high levels of Aß and tau deposition on cortical thickness.

Alzheimer's disease (AD) is defined by the presence of Amyloid-ß (Aß),tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aß deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aß andtau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aß, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aß and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed thatin participants with normal levels of global Aßdeposition, Aß uptakewassignificantly associated with increasedcortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aßandtau, theresonancebetween them, defined as their correlation throughout the cortex, wasassociated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aß deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aß and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aß/tau synergy inAD pathogenesis.

Effects of Brain Maintenance and Cognitive Reserve on Age-Related Decline in Three Cognitive Abilities.

OBJECTIVES: Age-related cognitive changes can be influenced by both brain maintenance (BM), which refers to the relative absence over time of changes in neural resources or neuropathologic changes, and cognitive reserve (CR), which encompasses brain processes that allow for better-than-expected behavioral performance given the degree of life-course-related brain changes. This study evaluated the effects of age, BM, and CR on longitudinal changes over 2 visits, 5 years apart, in 3 cognitive abilities that capture most of age-related variability. METHODS: Participants included 254 healthy adults aged 20-80 years at recruitment. Potential BM was estimated using whole-brain cortical thickness and white matter mean diffusivity at both visits. Education and intelligence quotient (IQ; estimated with American National Adult Reading Test) were tested as moderating factors for cognitive changes in the 3 cognitive abilities. RESULTS: Consistent with BM-after accounting for age, sex, and baseline performance-individual differences in the preservation of mean diffusivity and cortical thickness were independently associated with relative preservation in the 3 abilities. Consistent with CR-after accounting for age, sex, baseline performance, and structural brain changes-higher IQ, but not education, was associated with reduced 5-year decline in reasoning (ß = 0.387, p = .002), and education was associated with reduced decline in speed (ß = 0.237, p = .039). DISCUSSION: These results demonstrate that both CR and BM can moderate cognitive changes in healthy aging and that the 2 mechanisms can make differential contributions to preserved cognition.

Assessing Flexibility of Solution Strategy: Strategy Shifting as a Measure of Cognitive Reserve.

OBJECTIVES: This series of experiments explores whether flexibility in strategy shifting might function as an expression of cognitive reserve (CR). METHODS: A reasoning task was designed using matrix reasoning stimuli that each required 1 of 2 specific solution strategies: logicoanalytic and visuospatial. It was formatted as a task-switching paradigm, assessing the ability to switch between solution strategies as measured by switch costs. Study 1 was done on Amazon Mechanical Turk and included an assessment of CR proxies. Study 2 used participants who had been studied extensively with neuropsychological assessments and structural neuroimaging. RESULTS: Study 1 found that switch costs increased with aging. In addition, a relationship between switch costs and CR proxies was noted, suggesting a relationship between the flexibility of strategy shifting and CR. The results of Study 2 again indicated that age negatively affected strategy-shifting flexibility, but that individuals with higher CR as measured with standard proxies performed better. The flexibility measure accounted for additional variance in cognitive performance over that explained by cortical thickness, suggesting that it may contribute to CR. DISCUSSION: Overall, the results are consistent with the idea that flexibility in strategy shifting might be 1 cognitive process that underlies cognitive reserve.

Disruption of early visual processing in amyloid-positive healthy individuals and mild cognitive impairment.

BACKGROUND: Amyloid deposition is a primary predictor of Alzheimer's disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI). METHODS: vERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time-frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT). RESULTS: Neurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r = - .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%. DISCUSSION: vERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition.

Brain connectomics: time for a molecular imaging perspective?

In the past two decades brain connectomics has evolved into a major concept in neuroscience. However, the current perspective on brain connectivity and how it underpins brain function relies mainly on the hemodynamic signal of functional magnetic resonance imaging (MRI). Molecular imaging provides unique information inaccessible to MRI-based and electrophysiological techniques. Thus, positron emission tomography (PET) has been successfully applied to measure neural activity, neurotransmission, and proteinopathies in normal and pathological cognition. Here, we position molecular imaging within the brain connectivity framework from the perspective of timeliness, validity, reproducibility, and resolution. We encourage the neuroscientific community to take an integrative approach whereby MRI-based, electrophysiological techniques, and molecular imaging contribute to our understanding of the brain connectome.

Association of homocysteine-related subcortical brain atrophy with white matter lesion volume and cognition in healthy aging.

Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50-89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.

Neural similarity across task load relates to cognitive reserve and brain maintenance measures on the Letter Sternberg task: a longitudinal study.

The aging process is characterized by change across several measures that index cognitive status and brain integrity. In the present study, 54 cognitively-healthy younger and older adults, were analyzed, longitudinally, on a verbal working memory task to investigate the effect of brain maintenance (i.e., cortical thickness) and cognitive reserve (i.e., NART IQ as proxy) factors on a derived measure of neural efficiency. Participants were scanned using fMRI while presented with the Letter Sternberg task, a verbal working memory task consisting of encoding, maintenance and retrieval phases, where cognitive load is manipulated by varying the number of presented items (i.e., between one and six letters). Via correlation analysis, we looked at region-level and whole-brain relationships between load levels within each phase and then computed a global task measure, what we term phase specificity, to analyze how similar neural responses were across load levels within each phase compared to between each phase. We found that longitudinal change in phase specificity was positively related to longitudinal change in cortical thickness, at both the whole-brain and regional level. Additionally, baseline NART IQ was positively related to longitudinal change in phase specificity over time. Furthermore, we found a longitudinal effect of sex on change in phase specificity, such that females displayed higher phase specificity over time. Cross-sectional findings aligned with longitudinal findings, with the notable exception of behavioral performance being positively linked to phase specificity cross-sectionally at baseline. Taken together, our findings suggest that phase specificity positively relates to brain maintenance and reserve factors and should be better investigated as a measure of neural efficiency.

Effects of aging on cognitive and brain inter-network integration patterns underlying usual and dual-task gait performance.

Introduction: Aging affects the interplay between cognition and gait performance. Neuroimaging studies reported associations between gait performance and structural measures; however, functional connectivity (FC) analysis of imaging data can help to identify dynamic neural mechanisms underlying optimal performance. Here, we investigated the effects on divergent cognitive and inter-network FC patterns underlying gait performance during usual (UW) and dual-task (DT) walking. Methods: A total of 115 community-dwelling, healthy participants between 20 and 80 years were enrolled. All participants underwent comprehensive cognitive and gait assessments in two conditions and resting state functional MRI (fMRI) scans. Inter-network FC from motor-related to 6 primary cognitive networks were estimated. Step-wise regression models tested the relationships between gait parameters, inter-network FC, neuropsychological scores, and demographic variables. A threshold of p < 0.05 was adopted for all statistical analyses. Results: UW was largely associated with FC levels between motor and sustained attention networks. DT performance was associated with inter-network FC between motor and divided attention, and processing speed in the overall group. In young adults, UW was associated with inter-network FC between motor and sustained attention networks. On the other hand, DT performance was associated with cognitive performance, as well as inter-network connectivity between motor and divided attention networks (VAN and SAL). In contrast, the older age group (> 65 years) showed increased integration between motor, dorsal, and ventral attention, as well as default-mode networks, which was negatively associated with UW gait performance. Inverse associations between motor and sustained attention inter-network connectivity and DT performance were observed. Conclusion: While UW relies on inter-network FC between motor and sustained attention networks, DT performance relies on additional cognitive capacities, increased motor, and executive control network integration. FC analyses demonstrate that the decline in cognitive performance with aging leads to the reliance on additional neural resources to maintain routine walking tasks.

Physical activity moderates the association between white matter hyperintensity burden and cognitive change.

Objective: Greater physical activity (PA) could delay cognitive decline, yet the underlying mechanisms remain unclear. White matter hyperintensity (WMH) burden is one of the key brain pathologies that have been shown to predict faster cognitive decline at a late age. One possible pathway is that PA may help maintain cognition by mitigating the detrimental effects of brain pathologies, like WMH, on cognitive change. This study aims to examine whether PA moderates the association between WMH burden and cognitive change. Materials and methods: This population-based longitudinal study included 198 dementia-free adults aged 20-80 years. Leisure-time physical activity (LTPA) was assessed by a self-reported questionnaire. Occupational physical activity (OPA) was a factor score measuring the physical demands of each job. Total physical activity (TPA) was operationalized as the average of z-scores of LTPA and OPA. Outcome variables included 5-year changes in global cognition and in four reference abilities (fluid reasoning, processing speed, memory, and vocabulary). Multivariable linear regression models were used to estimate the moderation effect of PA on the association between white matter hyperintensities and cognitive change, adjusting for age, sex, education, and baseline cognition. Results: Over approximately 5 years, global cognition (p < 0.001), reasoning (p < 0.001), speed (p < 0.001), and memory (p < 0.05) scores declined, and vocabulary (p < 0.001) increased. Higher WMH burden was correlated with more decline in global cognition (Spearman's rho = -0.229, p = 0.001), reasoning (rho = -0.402, p < 0.001), and speed (rho = -0.319, p < 0.001), and less increase in vocabulary (rho = -0.316, p < 0.001). Greater TPA attenuated the association between WMH burden and changes in reasoning (ßTPA^*WMH = 0.029, 95% CI = 0.006-0.052, p = 0.013), speed (ßTPA^*WMH = 0.035, 95% CI = -0.004-0.065, p = 0.028), and vocabulary (ßTPA^*WMH = 0.034, 95% CI = 0.004-0.065, p = 0.029). OPA seemed to be the factor that exerted a stronger moderation on the relationship between WMH burden and cognitive change. Conclusion: Physical activity may help maintain reasoning, speed, and vocabulary abilities in face of WMH burden. The cognitive reserve potential of PA warrants further examination.

Mediterranean Diet and White Matter Hyperintensity Change over Time in Cognitively Intact Adults.

Current evidence on the impact of Mediterranean diet (MeDi) on white matter hyperintensity (WMH) trajectory is scarce. This study aims to examine whether greater adherence to MeDi is associated with less accumulation of WMH. This population-based longitudinal study included 183 cognitively intact adults aged 20−80 years. The MeDi score was obtained from a self-reported food frequency questionnaire; WMH was assessed by 3T MRI. Multivariable linear regression was used to estimate the effect of MeDi on WMH change. Covariates included socio-demographic factors and brain markers. Moderation effects by age, gender, and race/ethnicity were examined, followed by stratification analyses. Among all participants, WMH increased from baseline to follow-up (mean difference [follow-up-baseline] [standard deviation] = 0.31 [0.48], p < 0.001). MeDi adherence was negatively associated with the increase in WMH (ß = −0.014, 95% CI = −0.026−−0.001, p = 0.034), adjusting for all covariates. The association between MeDi and WMH change was moderated by age (young group = reference, p-interaction[middle-aged × MeDi] = 0.075, p-interaction[older × MeDi] = 0.037). The association between MeDi and WMH change was observed among the young group (ß = −0.035, 95% CI = −0.058−−0.013, p = 0.003), but not among other age groups. Moderation effects by gender and race/ethnicity did not reach significance. Greater adherence to MeDi was associated with a lesser increase in WMH over time. Following a healthy diet, especially at younger age, may help to maintain a healthy brain.