Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging

Cognitive Diversity in a Healthy Aging Cohort: Cross-Domain Cognition in the Cam-CAN Project.

Objective: Studies of "healthy" cognitive aging often focus on a limited set of measures that decline with age. The current study argues that defining and supporting healthy cognition requires understanding diverse cognitive performance across the lifespan. Method: Data from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) cohort was examined across a range of cognitive domains. Performance was related to lifestyle including education, social engagement, and enrichment activities. Results: Results indicate variable relationships between cognition and age (positive, negative, or no relationship). Principal components analysis indicated maintained cognitive diversity across the adult lifespan, and that cognition-lifestyle relationships differed by age and domain. Discussion: Our findings support a view of normal cognitive aging as a lifelong developmental process with diverse relationships between cognition, lifestyle, and age. This reinforces the need for large-scale studies of cognitive aging to include a wider range of both ages and cognitive tasks.The Cambridge Centre for Aging and Neuroscience (Cam-CAN) research was supported by the Biotechnology and Biological Sciences Research Council (grant number BB/H008217/1)

Neuroanatomical Correlates of Fluid Intelligence in Healthy Adults and Persons with Vascular Risk Factors

The main objective of this study was to examine the effects of regional brain changes on cognitive decline and the modifying influence of vascular risk (VR) factors. We present latent difference score analyses of associations among 5-year changes in 12 regional brain volumes and age-sensitive cognitive functions in 87 adults (32 with identifiable VR factors). We found reliable individual differences in volume change for 11 of the 12 brain regions but not in the cognitive measures that showed average longitudinal decline. Thus, associations between rates of change in fluid intelligence and brain volumes could not be assessed. We observed, however, that lower levels of fluid intelligence were associated with smaller prefrontal and hippocampal volumes. Lower fluid intelligence scores were also linked to greater longitudinal shrinkage of the entorhinal cortex (EC). After accounting for the effects of age, sex, and VR factors, the orbitofrontal cortex and the prefrontal white matter (PFw) volumes as well as the 5-year change in the EC volume predicted fluid intelligence level. VR was independently associated with smaller prefrontal volumes and lower fluid intelligence. Thus, prefrontal and medial-temporal systems may play different roles in age-related differences and changes in cognitive performanc

White Matter Tract Covariance Patterns Predict Age-Declining Cognitive Abilities

Previous studies investigating the relationship of white matter (WM) integrity to cognitive abilities and aging have either focused on a global measure or a few selected WM tracts. Ideally, contribution from all of the WM tracts should be evaluated at the same time. However, the high collinearity among WM tracts precludes systematic examination of WM tracts simultaneously without sacrificing statistical power due to stringent multiple-comparison corrections. Multivariate covariance techniques enable comprehensive simultaneous examination of all WM tracts without being penalized for high collinearity among observations. METHOD: In this study, Scaled Subprofile Modeling (SSM) was applied to the mean integrity of 18 major WM tracts to extract covariance patterns that optimally predicted four cognitive abilities (perceptual speed, episodic memory, fluid reasoning, and vocabulary) in 346 participants across ages 20 to 79years old. Using expression of the covariance patterns, age-independent effects of white matter integrity on cognition and the indirect effect of WM integrity on age-related differences in cognition were tested separately, but inferences from the indirect analyses were cautiously made given that cross-sectional data set was used in the analysis. RESULTS: A separate covariance pattern was identified that significantly predicted each cognitive ability after controlling for age except for vocabulary, but the age by WM covariance pattern interaction was not significant for any of the three abilities. Furthermore, each of the patterns mediated the effect of age on the respective cognitive ability. A distinct set of WM tracts was most influential in each of the three patterns. The WM covariance pattern accounting for fluid reasoning showed the most number of influential WM tracts whereas the episodic memory pattern showed the least number. CONCLUSION: Specific patterns of WM tracts make significant contributions to the age-related differences in perceptual speed, episodic memory, and fluid reasoning but not vocabulary. Other measures of brain health will need to be explored to reveal the major influences on the vocabulary ability

The unity and diversity of executive functions: A systematic review and re-analysis of latent variable studies.

Confirmatory factor analysis (CFA) has been frequently applied to executive function measurement since first used to identify a three-factor model of inhibition, updating, and shifting; however, subsequent CFAs have supported inconsistent models across the life span, ranging from unidimensional to nested-factor models (i.e., bifactor without inhibition). This systematic review summarized CFAs on performance-based tests of executive functions and reanalyzed summary data to identify best-fitting models. Eligible CFAs involved 46 samples (N = 9,756). The most frequently accepted models varied by age (i.e., preschool = one/two-factor; school-age = three-factor; adolescent/adult = three/nested-factor; older adult = two/three-factor), and most often included updating/working memory, inhibition, and shifting factors. A bootstrap reanalysis simulated 5,000 samples from 21 correlation matrices (11 child/adolescent; 10 adult) from studies including the three most common factors, fitting seven competing models. Model results were summarized as the mean percent accepted (i.e., average rate at which models converged and met fit thresholds: CFI ≥ .90/RMSEA ≤ .08) and mean percent selected (i.e., average rate at which a model showed superior fit to other models: ΔCFI ≥ .005/.010/ΔRMSEA ≤ -.010/-.015). No model consistently converged and met fit criteria in all samples. Among adult samples, the nested-factor was accepted (41-42%) and selected (8-30%) most often. Among child/adolescent samples, the unidimensional model was accepted (32-36%) and selected (21-53%) most often, with some support for two-factor models without a differentiated shifting factor. Results show some evidence for greater unidimensionality of executive function among child/adolescent samples and both unity and diversity among adult samples. However, low rates of model acceptance/selection suggest possible bias toward the publication of well-fitting but potentially nonreplicable models with underpowered samples. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

Age Differentiation within Gray Matter, White Matter, and between Memory and White Matter in an Adult Life Span Cohort.

It is well established that brain structures and cognitive functions change across the life span. A long-standing hypothesis called "age differentiation" additionally posits that the relations between cognitive functions also change with age. To date, however, evidence for age-related differentiation is mixed, and no study has examined differentiation of the relationship between brain and cognition. Here we use multigroup structural equation models (SEMs) and SEM trees to study differences within and between brain and cognition across the adult life span (18-88 years) in a large (N > 646, closely matched across sexes), population-derived sample of healthy human adults from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.org). After factor analyses of gray matter volume (from T1- and T2-weighted MRI) and white matter organization (fractional anisotropy from diffusion-weighted MRI), we found evidence for the differentiation of gray and white matter, such that the covariance between brain factors decreased with age. However, we found no evidence for age differentiation among fluid intelligence, language, and memory, suggesting a relatively stable covariance pattern among cognitive factors. Finally, we observed a specific pattern of age differentiation between brain and cognitive factors, such that a white matter factor, which loaded most strongly on the hippocampal cingulum, became less correlated with memory performance in later life. These patterns are compatible with the reorganization of cognitive functions in the face of neural decline, and/or with the emergence of specific subpopulations in old age.SIGNIFICANCE STATEMENT The theory of age differentiation posits age-related changes in the relationships among cognitive domains, either weakening (differentiation) or strengthening (dedifferentiation), but evidence for this hypothesis is mixed. Using age-varying covariance models in a large cross-sectional adult life span sample, we found age-related reductions in the covariance among both brain measures (neural differentiation), but no covariance change among cognitive factors of fluid intelligence, language, and memory. We also observed evidence of uncoupling (differentiation) between a white matter factor and cognitive factors in older age, most strongly for memory. Together, our findings support age-related differentiation as a complex, multifaceted pattern that differs for brain and cognition, and discuss several mechanisms that might explain the changing relationship between brain and cognition

Central adiposity and brain vulnerability in mid-life : evidence for early risk

This set of projects focused on visceral fat, measured using proximal and direct methods. Specifically, I was interested in the effects of visceral fat on brain structure and integrity in middle age. Study 1 looked at waist to hip ratio (WHR) as a proximal measure of visceral fat and used statistical mediation to directly examine a possible mechanism behind the relationship between visceral fat and cognitive decline. Reductions in executive function seen in middle-aged adults with high visceral fat were found to occur in the context of lowered serum brain derived neurotrophic factor (BDNF) a key neurotrophin involved in synaptic plasticity as well as neuronal regeneration. Study 2 utilized Dual Energy X Ray Absorptiometry (DXA) to directly estimate visceral fat mass and volume as well as thickness of the cortical mantle in middle age. High-resolution Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) images were used. High visceral fat was found to predict increased thickness in the posterior cingulate cortex independently of age and cardiovascular risk in a cognitively intact middle-aged sample. Study 3 examined changes in concentrations of crucial cerebral metabolites in the posterior cingulate cortex among individuals with high visceral fat. Results indicated that visceral fat predicted reduced concentrations of N Acetyl Asparate, a marker of neuronal viability and increased concentrations of myo-inositol, a glial marker that is implicated in a number of disease states including prodromal Alzheimer’s Disease and Multiple Sclerosis. Collectively, the 3 studies highlight important evidence for early brain vulnerability even in cognitively intact middle- aged adults with high levels of cognitive reserve. An important next step would be to examine modifiable mediators of these relationships, such as inflammation and BDNF so that targeted interventions may be developed.Psycholog