Investigating Enlarged Perivascular Spaces as a Neuroimaging Biomarker of Cerebral Small Vessel Disease

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ABSTRACT Cerebral small vessel disease (cSVD) is an important risk factor that may arise years before the onset of vascular contributions to cognitive impairment and dementia (VCID). cSVD is characterized by in-vivo neuroimaging biomarkers including enlarged perivascular spaces (ePVS). PVS are the site of interchange between interstitial fluid and cerebrospinal fluid 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 their presence in brain regions that support cognition, we hypothesize that quantitative, cross-sectional ePVS counts in cognitively normal older adults could serve as an early biomarker of VCID. Specifically, we anticipate ePVS will predict cognitive dysfunction and increased white matter lesion burden after three years. We will test this hypothesis in a cohort of 121 cognitively normal older adults ranging in age from 60-86 at baseline. Participants are scanned on a 3T Siemens Prisma magnetic resonance imaging scanner with a 64-channel head coil. ePVS are manually counted by an experienced rater blinded to participant demographics following consensus guidelines using T1 MPRAGE, T2 FLAIR, and Quantitative Susceptibility Mapping images. All ePVS are counted in a single, axial slice of four brain regions with high ePVS burden including the centrum semiovale (CS ePVS), basal ganglia (BG ePVS), hippocampus, and midbrain. Aim 1 will test the hypothesis that CS ePVS predict longitudinal changes in executive function, a specific cognitive domain affected in VCID. Our preliminary data using the same cohort include a negative relationship between CS ePVS and baseline Montreal Cognitive Assessment (MoCA) score, a standardized screening tool of global cognition. Aim 2 will test the hypothesis that baseline CS ePVS burden predicts increased deep white matter hyperintensity (WMH) volume in the centrum semiovale after three years. This expands on preliminary findings that CS ePVS are positively related to whole brain WMH volume, a marker of advanced cSVD. In Aim 3, regional cerebrovascular reactivity (CVR), a measure of microvascular dysfunction, will be analyzed using a novel BOLD- fMRI testing paradigm, as a potential mechanistic contributor of ePVS. The cross-sectional relationship between BG ePVS and basal ganglia CVR will be analyzed to capitalize on our preliminary data which show a negative relationship between BG ePVS and global CVR. We will further test an alternative hypothesis that the cerebrospinal fluid amyloid-beta 42/40 ratio, a biomarker of amyloid burden, is more closely associated with ePVS than CVR. These experiments will be carried out at the University of Kentucky Magnetic Resonance and Imaging Center and the Sanders-Brown Center on Aging, under the direction of an expert team of scientist and clinician mentors. This F30 predoctoral fellowship will provide the requisite experience, training, and knowledge to aid the trainee’s transition into the next step of his career as a scientist-neuroradiologist in the field of neuroscience of aging measuring similar endpoints using basic and translational neuroimaging techniques.