BRAIN NETWORKS AS TARGETS OF NEURODEGENERATION IN PD AND AD

Abstract

Our main objective is to uncover mechanisms of disease initiation and propagation in Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Human functional brain imaging has shown that the brain is organized in large-scale networks. These have been identified mainly from resting state functional MRI (rsfMRI) and diffusion tractography (DTI). Also, recent evidence suggests that neurodegenerative diseases may be the result of prion-like spreading of misfolded proteins. A misfolded protein is thought to spread via neuronal projections and then induce further misfolding and neurodegeneration in target regions. Transneuronal spread has been demonstrated in animal models for tau and beta-amyloid (implicated in AD) and alpha-synuclein (PD). Accordingly, MRI studies in AD and fronto-temporal dementia (FTD) show that the patterns of atrophy in different syndromes demonstrate overlap with intrinsic brain networks found in healthy individuals. AD appears to target the default mode network, a set of interconnected brain areas implicated in monitoring and memory retrieval. Conversely, variants of FTD target different networks; for example, the behavioral variant of FTD, which is characterized by impulsivity and disordered emotional regulation, targets a brain network implicated in reward and motivation. We used the Parkinson’s Progression Markers Initiative (PPMI), a large open-source database of imaging and clinical data in de novo PD patients. We performed deformation based morphometry and independent component analysis to identify areas showing atrophy in PD patients compared to control subjects. Striatum, basal forebrain, amygdala, hippocampus, insula and anterior cingulate cortex demonstrated atrophy in proportion to clinical disease severity, consistent with the scheme proposed by Braak from postmortem data. We also show that these regions form a connected intrinsic network. Moreover, we show that disease patterns follow brain connectomics, compatible with an epicenter in the substantia nigra. Finally we find that cognitive impairment at visit 2 is associated with progression of atrophy in the entorhinal cortex.