Author ORCID Identifier

https://orcid.org/0000-0002-0155-9792

Date Available

12-1-2024

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Neuroscience

Advisor

Dr. Brian T. Gold

Abstract

Vascular contributions to cognitive impairment and dementia (VCID) represents the intersection between cerebrovascular disease and cognitive decline. Cerebral small vessel disease (cSVD) is an important risk factor that may precede the onset of VCID by years. cSVD is characterized by in-vivo neuroimaging biomarkers including enlarged perivascular spaces (ePVS). PVS are the site of interchange between interstitial fluid (ISF) and cerebrospinal fluid (CSF) which is believed to play a role in the removal of brain waste. Reduced clearance may lead to enlargement of the PVS and subsequent accumulation of toxic solutes characteristic of neurodegeneration. Given the presence of ePVS in brain regions that support cognition, quantitative ePVS counts could serve as an early biomarker of VCID in older adults. Based on the literature we hypothesized that ePVS burden would predict longitudinal cognitive decline and a longitudinal increase in cSVD burden. Furthermore, we predicted that cerebrovascular dysfunction disrupts CSF-ISF interchange leading to backup and subsequent enlargement of the perivascular space. Three experiments were carried out among a cohort of community dwelling older adults to test these hypotheses. For all experiments, participants were scanned on a 3T Siemens Prisma magnetic resonance imaging scanner. ePVS were manually counted in brain regions with the highest ePVS burden using T1 MPRAGE, T2 FLAIR, and Quantitative Susceptibility Mapping images. In Experiment 1 we tested whether baseline ePVS burden predicts longitudinal changes in standardized cognitive measures including the Montreal Cognitive Assessment (MoCA), the Clinical Dementia Rating (CDR®) Dementia Staging Instrument Sum of Boxes, and composite measures of executive function and episodic memory. Results from 83 community dwelling older adults showed that basal ganglia ePVS predicted worse performance over time on the CDR® Sum of Boxes, a measure of cognitive and functional status. In Experiment 2, we tested whether baseline ePVS burden predicts longitudinal changes in white matter hyperintensity volume (WMH), a commonly used proxy for cSVD burden. Results from 74 older adults showed that ePVS burden in the basal ganglia was significantly associated with baseline periventricular and whole brain WMH volume but was not predictive of longitudinal burden. Experiment 3 investigated cerebrovascular dysfunction as a mechanistic contributor to perivascular space enlargement among 50 older adults. Using blood oxygen-level dependent functional magnetic resonance imaging cerebrovascular reactivity (CVR), we found that cerebrovascular dysfunction at baseline significantly predicted an increase in longitudinal basal ganglia ePVS burden. Together, these findings suggest ePVS may be a clinically useful neuroimaging biomarker of cSVD and VCID. Furthermore, the evidence we provide for a potential mechanism of perivascular space enlargement may point towards potential avenues of therapeutic intervention.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.257

Funding Information

This study was supported by a Ruth L. Kirschstein National Research Service Award from the National Institute on Aging (1F30AG079506) in 2023, a predoctoral fellowship from the American Heart Association (903649) in 2022, and a predoctoral appointment to the Sanders Brown Center on Aging Translational Research in Alzheimer's and Related Dementias training grant (5T32AG057461-03) in 2021.

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