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Abstract
Cerebrovascular disease (CVD) is a leading cause of morbidity and mortality, with manifold clinical consequences including vascular dementia (VaD), the second most common dementia subtype. CVD also worsens the risk and expression of Alzheimer’s disease (AD). Diagnosing VaD requires determining whether a patient’s cognitive deficits can be explained by the current CVD burden. However, CVD is markedly pleomorphic and its full extent has been difficult to determine. Traditional markers of CVD such as white matter hyperintensities (WMH) are inconsistently associated with clinical outcomes. There is an unmet need to better quantify total CVD burden and relate it to cognition and dementia.
CVD indices have been published, which combine information from several neuroimaging markers, in the hope to better capture the variability seen on neuroimaging and lead to more robust associations with cognition.
In this thesis, the existing literature on neuroimaging and neuropathological indices of CVD was systematically reviewed. The contributions of two common but under-researched MRI CVD markers, cerebral microbleeds (CMB) and dilated perivascular spaces (PVS), were then assessed. The second chapter examines the association of CMB with both cross sectional and longitudinal impairment, finding associations with executive function and visuospatial function respectively. There was no existing reliable rating scale for quantification of PVS and the development of this is the theme of the third chapter. The fourth chapter examines the associations of dilated PVS with longitudinal cognitive impairment and incident dementia. I found that individuals with the most severe PVS had declines in Global Cognition and their presence triples the risk of developing dementia over 8 years.
The fifth chapter describes the development of an MRI-based composite CVD index and its validation in two independent cohorts. Peak skeletonised mean diffusivity, a DTI measure, and WMH volume contributed most to the variability seen in Global Cognition. The Index explained 9% of the proportion of the variance seen in the development sample and 5 and 13 % in the validation cohorts respectively. It performed better than the most widely used CVD index in all cohorts examined.
This work broadens the range of vascular pathologies used in the determination of the total CVD burden. The resulting composite index, while needing further refinement, represents a promising step-forward in the assessment of such burden in an individual, which could potentially help clinicians and researchers in determining the vascular contributions to dementia.
