Neurovascular mechanisms of cognitive aging: A multimodal neuroimaging investigation

Bowie, Daniel Christopher

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https://hdl.handle.net/2142/122025 Copy

Description

Title

Neurovascular mechanisms of cognitive aging: A multimodal neuroimaging investigation

Author(s)

Bowie, Daniel Christopher

Issue Date

2023-11-29

Director of Research (if dissertation) or Advisor (if thesis)

• Fabiani, Monica
• Gratton, Gabriele

Doctoral Committee Chair(s)

• Fabiani, Monica
• Gratton, Gabriele

Committee Member(s)

• Sutton, Brad
• Sadaghiani, Sepideh
• Gratton, Caterina

Department of Study

Psychology

Discipline

Psychology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• cognitive aging
• cerebrovascular health
• MCI
• sex differences
• functional connectivity
• pulse-DOT
• white matter lesions

Abstract

Cerebrovascular health gradually declines during normal, nonpathological aging due to the vascular phenomenon of arteriosclerosis, which manifests as stiffening, or a loss in elasticity, of the cerebral arteries. This stiffening contributes to the chronic cerebral hypoperfusion of oxygenated blood, which is proposed to, in part, contribute to the loss of cerebral white matter, manifesting as demyelination due to the loss of myelin-producing oligodendrocytes. Gradual degradation of the myelin sheath slows the rate at which action potentials are propagated and information s exchanged between neurons—this likely has consequences for the brain’s fundamental functional organization, which is segregated (or modular) in nature, with the brain’s primary functional units organized into many networks that putatively subserve various sensory and higher-order cognitive processes, such as vision and attentional control, for example. However, during biological aging, the integrity of the brain’s functional organization breaks down, as networks dedifferentiate, presumably reflecting a decrease in functional specialization of these networks. Importantly, network dedifferentiation may have consequences for cognition, which highlights the significance of understanding the neurobiological mechanisms preceding this neurophysiological outcome. Therefore, utilizing a multimodal neuroimaging approach and structural equation modeling techniques, I investigate the mechanisms by which age-related declines in cerebrovascular health contribute to cognitive decline, which may provide an early and accessible point of intervention. In Chapter 1, I provide an overview of a cascade model of neurocognitive aging that positions age-related declines in cerebrovascular health as potential causal precursors to declines in neuroanatomical, neurophysiological, and cognitive health. Then, brief reviews of research on the relationship between vascular health, cerebral white matter lesions, and functional network organization are provided. Chapter 2 attempts to establish the temporal ordering of some events putatively involved in cognitive aging, including the acceleration of cerebral arteriosclerosis and white matter degradation. We show, using diffuse optical imaging measures of the cerebral arterial pulse and an independent peripheral measure of arterial elasticity (pulse pressure), that declines in arterial health temporally precede the accelerated onset of white matter lesion development, which is consistent with the mechanistic ordering posited in the model. Additionally, using multiple-mediator path analysis, we demonstrate that age-related declines in cerebral arterial health are associated with increased white matter lesion burden that indirectly and deleteriously affects fluid cognition, but not crystallized cognition, further highlighting the critical role that vascular health may play in accelerating cognitive aging. In Chapter 3, we probe the contributions of white matter lesions and cortical atrophy to declines in functional network segregation, and we estimate inflection points corresponding to accelerated age-related declines in network segregation. Parallel mediation analyses suggest that age negatively impacts global and association segregation via the indirect effect of white matter lesion burden, but not via the indirect effect of cortical atrophy. Follow-up analyses also indicate that the cingulo-opercular network, one of six association networks, may be particularly vulnerable to age-related declines in cerebral white matter, which requires further exploration. Concerning the inflection point estimates, although not significant, only estimates of global segregation were consistent with prior literature, possibly indicating that segregation generally precipitously declines in one’s late fifties, if at all. Chapter 4 examines sex-related differences in the age-related progression of arteriosclerosis using various indices and attempts to establish the relationship between vascular health, white matter lesions, and network segregation using mediation analyses. Consistent with prior literature, results indicate that women are generally protected from steep declines in vascular health until approximately age 50, roughly corresponding to the onset of menopause—the subsequent drop in production of estrogens, which provide vasoprotective effects, it at least partly responsible for the concomitant acceleration in arteriosclerosis. Lastly, for all indices of vascular health, when controlling for sex, we observe a significant indirect on network segregation via white matter lesions on global and association segregation, once again suggesting that association networks may be especially vulnerable to negative vascular outcomes. To conclude, Chapter 5 summarizes and contextualizes the findings of this dissertation and suggests future improvements, such as the utilization of large, longitudinal datasets and alternative, complementary statistical methods for estimating inflection points. Nevertheless, the evidence provided clearly indicates that cerebrovascular health is integral to the rate at which brain structure and function declines with age, emphasizing the importance of maintaining its integrity via regular exercise and proper nutrition.

Graduation Semester

2023-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Daniel Bowie

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