Common Brain Structural Alterations Associated with Cardiovascular Disease Risk Factors and Alzheimer’s Dementia: Future Directions and Implications

At rest, the brain's sensorimotor and higher cognitive systems engage in organized patterns of correlated activity forming resting-state networks. An important empirical question is how functional connectivity and structural connectivity within and between resting-state networks change with age. In this study we use network modeling techniques to identify significant changes in network organization across the human lifespan. The results of this study demonstrate that whole-brain functional and structural connectivity both exhibit reorganization with age. On average, functional connections within resting-state networks weaken in magnitude while connections between resting-state networks tend to increase. These changes can be localized to a small subset of functional connections that exhibit systematic changes across the lifespan. Collectively, changes in functional connectivity are also manifest at a system-wide level, as components of the control, default mode, saliency/ventral attention, dorsal attention, and visual networks become less functionally cohesive, as evidenced by decreased component modularity. Paralleling this functional reorganization is a decrease in the density and weight of anatomical white-matter connections. Hub regions are particularly affected by these changes, and the capacity of those regions to communicate with other regions exhibits a lifelong pattern of decline. Finally, the relationship between functional connectivity and structural connectivity also appears to change with age; functional connectivity along multi-step structural paths tends to be stronger in older subjects than in younger subjects. Overall, our analysis points to age-related changes in inter-regional communication unfolding within and between resting-state networks. Copyright © 2014 Elsevier Inc. All rights reserved.

Longitudinal clinical-pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) as important factors in the development of Alzheimer's disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical-pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.

Objective Mixed neuropathologies are the most common cause of dementia at the population level, but how different neuropathologies contribute to cognitive decline at the individual level remains unknown. We quantified the contribution of nine neuropathologies to cognitive loss at an individual level. Methods Participants (n=1,079) came from 2 longitudinal clinical-pathologic studies of aging. All completed 2+ cognitive evaluations (maximum = 22), died and underwent neuropathologic examinations to identify Alzheimer's disease (AD), other neurodegenerative diseases, and vascular pathologies. Linear mixed models examined associations of neuropathologies with cognitive decline and estimated the proportion of cognitive loss accounted for by each neuropathology at a person-specific level. Results Neuropathology was ubiquitous, with 94% of participants having 1+, 78% having 2+, 58% having 3+, and 35% having 4+. AD was most frequent (65%) but rarely occurred in isolation (9%). Remarkably, more than 230 different neuropathologic combinations were observed, each of which occurred in <6% of the cohort. The relative contributions of specific neuropathologies to cognitive loss varied widely across individuals. Although AD accounted for an average of about 50% of the observed cognitive loss, the proportion accounted for at the individual level ranged widely from 22% to 100%. Lewy bodies and hippocampal sclerosis also had potent effects, but again their impacts varied at the person-specific level. Interpretation There is much greater heterogeneity in the comorbidity and cognitive impact of age-related neuropathologies than currently appreciated, suggesting an urgent need for novel therapeutic approaches that embrace the complexity of disease to combat cognitive decline in old age.