Integrative analysis of spontaneous brain activity in Parkinson's disease: associations with gene expression, cell...

Parkinson's disease (PD) shows widespread alterations in intrinsic brain activity, yet the molecular and cellular bases of these disruptions remain unclear. Resting-state fMRI metrics-amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo)-offer complementary views of spontaneous neural activity but have rarely been examined within an integrated biological framework.

We studied 31 PD patients and 28 healthy controls using voxel-wise ALFF and ReHo analyses combined with cortical transcriptomic data from the Allen Human Brain Atlas, cell type-specific gene expression, and PET-derived neurotransmitter receptor density maps. Partial least squares regression identified gene expression patterns associated with PD-related imaging alterations. Enrichment analyses, cell type overlap, and spatial correlations with neurotransmitter receptor distributions were subsequently performed.

PD patients showed decreased ALFF in the left putamen, precentral gyrus, and middle frontal gyrus, and decreased ReHo in the left thalamus and cerebellum. ALFF alterations corresponded to negatively loaded PLS1 genes enriched for immune and neuroinflammatory pathways, predominantly expressed in microglia, astrocytes, oligodendrocytes, and endothelial cells. ReHo changes corresponded to positively loaded PLS2 genes enriched for receptor-mediated signaling and transcriptional regulation, mainly expressed by astrocytes. Both ALFF and ReHo patterns showed strong spatial coupling with 5HT2a receptor density, suggesting serotonergic involvement.

This multimodal analysis links PD-related ALFF and ReHo alterations to distinct yet converging transcriptomic, cellular, and neurochemical substrates. The findings suggest that PD-related functional alterations spatially align with glial-neurovascular transcriptional gradients and serotonergic receptor distribution, providing convergent but indirect evidence for their involvement in PD-related network reorganization.