Patterns of Pathological Progression in Parkinson's Disease Revealed Through Cytoarchitectonic Mapping of Brain MRI

The rapid upturn in global prevalence of Parkinson’s disease has led to increased interest in understanding the etiology, progression, and treatment of this neurodegenerative disease. Despite extensive study, a particular lack of understanding remains with respect to patterns of disease progression. The prevailing theory, first proposed by Braak, suggests that pathological misfolded α-synuclein protein spreads throughout the brain in an ascending manner beginning in deep brain structures and ending in the neocortex. Braak’s original study, conducted in post-mortem human tissue, is supported by in-vivo animal, ex-vivo human, and in-vitro studies with less supporting evidence emerging from in-vivo human studies. This dissertation, after reviewing the current state of the Parkinson’s progression literature, will evaluate Braak’s hypothesis by recreating elements of the original experiment in-vivo using human MRI. Here, we present a series of studies utilizing a technique for measuring regional grey matter integrity in-vivo through probabilistic cytoarchitectonic mapping of structural brain MRI processed with voxel-based morphometry. By measuring regional grey matter density with probabilistic brain masks created through histological analysis of post-mortem tissue, we expect the results of the forthcoming studies to represent a more faithful replication of Braak’s original work than has previously been attempted. The studies to follow will reveal that cytoarchitectonic mapping of grey matter density is a reliable and reproducible technique sensitive to changes in neurodegenerative disease which occur over very short intervals. We will further demonstrate that loss of grey matter density in Parkinson’s disease 1) follows an ascending pattern, 2) is negatively associated with duration of disease, and 3) is greater in subcortical than cortical brain regions over time when measured from diagnostic baseline. Additionally, we will propose clinical relevance for grey matter density of the basal forebrain in predicting psychosis and wider cognitive function. As a whole, this dissertation is an important piece of in-vivo support for organized, ascending pathological progression in Parkinson’s disease.