Distinct cortical morphometric inverse divergence changes in Parkinson's disease correlate with transcriptional...

Growing evidence shows that parkinson's disease (PD) is a heterogeneous neurodegenerative disorder associated with region-specific changes in brain anatomy. However, the genetic mechanisms underlining these abnormalities are unclear. We aim to investigate PD neuroanatomical subtypes and uncover the specific brain-wide gene expression associated with morphometric abnormalities in each PD subtype. The morphometric inverse divergence (MIND) algorithm was used to quantify the morphological similarity based on multiple MRI features in 127 patients with PD and 101 healthy controls (HC). Then, heterogeneity through discriminant analysis (HYDRA) was employed to investigate the PD subtypes based on the MIND strength. Intergroup comparisons were conducted to assess MIND strength and clinical behavioral differences among PD subtypes and HC. Finally, we explored the associations between MIND network changes and gene expression in each PD subtype through partial least squares (PLS) regression, functional enrichment of PLS-weighted genes and transcriptional signature assessment of cell types. We identified two distinct subtypes of PD-related MIND changes, indicating that MIND decreased mainly in the frontal and cingulate cortices in subtype 1, and increased mainly in the occipital cortex and postcentral gyrus in subtype 2 (Bonferroni correction, p < 0.05). Both PD subtypes exhibited impaired cognitive function compared to HC, with subtype 2 showing lower Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and Hoehn and Yahr (H&Y) scores than subtype 1. Moreover, genetic commonalities analysis were identified 5 shared negative genes in the PD subtypes. Subtype 1 PLS1 genes were functionally enriched in biological processes related to synaptic function, neurodevelopment and degeneration. In addition, subtype 2 PLS1 genes showed additional involvement of metabolic pathways alongside synaptic function. Moreover, we identified MIND-related genes involved in inhibitory and excitatory neurons in subtype 1. In subtype 2, MIND-related genes were involved in astrocytes besides excitatory and inhibitory neurons. Our findings suggest two distinct neuroanatomical subtypes in PD, deepening the understanding of the heterogeneity of PD by bridging the gap between the transcriptome and neuroimaging.