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The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson's disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson's disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15 745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson's disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson's disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson's disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson's disease, particularly the processes involving iron accumulation. [ABSTRACT FROM AUTHOR]

Visual hallucinations are common in Parkinson's disease and are associated with poorer prognosis. Imaging studies show white matter loss and functional connectivity changes with Parkinson's visual hallucinations, but the biological factors underlying selective vulnerability of affected parts of the brain network are unknown. Recent models for Parkinson's disease hallucinations suggest they arise due to a shift in the relative effects of different networks. Understanding how structural connectivity affects the interplay between networks will provide important mechanistic insights. To address this, we investigated the structural connectivity changes that accompany visual hallucinations in Parkinson's disease and the organizational and gene expression characteristics of the preferentially affected areas of the network. We performed diffusion-weighted imaging in 100 patients with Parkinson's disease (81 without hallucinations, 19 with visual hallucinations) and 34 healthy age-matched controls. We used network-based statistics to identify changes in structural connectivity in Parkinson's disease patients with hallucinations and performed an analysis of controllability, an emerging technique that allows quantification of the influence a brain region has across the rest of the network. Using these techniques, we identified a subnetwork of reduced connectivity in Parkinson's disease hallucinations. We then used the Allen Institute for Brain Sciences human transcriptome atlas to identify regional gene expression patterns associated with affected areas of the network. Within this network, Parkinson's disease patients with hallucinations showed reduced controllability (less influence over other brain regions), than Parkinson's disease patients without hallucinations and controls. This subnetwork appears to be critical for overall brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork. Gene expression analysis of gene modules related to the affected subnetwork revealed that down-weighted genes were most significantly enriched in genes related to mRNA and chromosome metabolic processes (with enrichment in oligodendrocytes) and upweighted genes to protein localization (with enrichment in neuronal cells). Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions. Expression of genes related to mRNA metabolism and membrane localization may be implicated, providing potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Keywords: neuroimaging; Parkinson's disease; regional gene expression EN neuroimaging Parkinson's disease regional gene expression 3740 3742 3 06/10/21 20210601 NES 210601 Differences in regional gene expression may partly explain the selective vulnerability of specific brain regions to neurodegeneration in Parkinson's disease (PD). Regional expression of synaptic transfer genes is correlated with regional grey matter atrophy in PD (Freeze et al., 2018), and synapse-related genes are more highly expressed in regions affected early in Braak staging (Keo et al., 2020). Although it is unclear whether this differential pattern of expression is also seen in PD brains, these findings highlight the potential importance of synaptic dysfunction and cholinergic transmission in PD. [Extracted from the article]