Objective: In this study, we used brain free water scores and regional gene expression profiles from the Allen Human Brain Atlas transcriptomic data to investigate possible genetic mechanisms underlying regional microstructural alterations in Parkinson’s disease.

Background: Free-water imaging has been suggested as an early diagnostic, differential diagnostic and progressive maker of Parkinson’s disease. However, the mechanisms underlying the increased free water values in Parkinson’s disease remain poorly understood.

Method: In the present study, we measured cortical and subcortical free water values in 128 patients with Parkinson’s disease and 45 healthy controls with diffusion-weighted MRI (Table 1). Partial least squares regression was performed to identify the gene expression patterns underlying free water changes in patients with Parkinson’s disease. Gene set enrichment analysis was used to assess the biological processes and cell types enriched in these gene expression patterns. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems associated with free water changes in Parkinson’s disease (Figure 1). All comparisons were tested against null models that preserved spatial autocorrelation between brain regions.

Results: Increased free water scores were detected in widespread cortical and subcortical regions in Parkinson’s disease (Figure 2). The gene expression weights existed a significantly positive relationship with the free water score (Figure 3). We found that genes involved in protein binding, synapse, axon, cell projection and neuron projection were strong contributors to the increased free water values in Parkinson’s disease (Figure 4). In addition, increased free water values were significantly expressed in GABAergic and glutamatergic neurons, and were associated with the GABA transmitter system.

Conclusion: Our findings offer mechanistic insights into regional microstructural alterations in Parkinson’s disease, particularly the processes involving protein binding, synapse and axon, and may provide potential therapeutic targets in Parkinson’s disease.

Figure 1. Methodology framework.

Figure 2. Regional free water difference.

Figure 3. Spatial distribution of gene expression.

Figure 4. Enrichment analysis for genes.

Table 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/increased-brain-free-water-is-associated-with-regional-gene-expression-in-parkinsons-disease/