Imaging Transcriptomic Signatures Associated with Brain Atrophy Across Clinical Subtypes of Parkinson’s Disease

Background: Parkinson’s disease (PD) motor subtypes, tremor-dominant (TD) and postural instability/gait difficulty (PIGD), exhibit divergent brain atrophy patterns, yet the transcriptomic basis of this subtype-associated vulnerability remains incompletely understood. We employed an integrative imaging transcriptomics approach to identify both different and shared transcriptomic signatures associated with regional gray matter volume in PD and its clinical subtypes (TD and PIGD). Methods: Ninety-nine PD patients (50 TD, 47 PIGD, 2 indeterminate) and 70 healthy controls (HCs) underwent 3T MRI, regional gray matter volume differences were assessed between PD subtypes and HCs. Partial least squares (PLS) regression linked atrophy patterns to Allen Human Brain Atlas gene expression across brain regions, followed by functional enrichment, pathology-related gene enrichment, cell-type enrichment, and neurotransmitter system mapping. Results: PIGD and TD showed partially overlapping atrophy patterns, with relatively greater cortical and subcortical involvement in PIGD and a narrower pattern in TD. PLS identified 78 shared and hundreds of subtype-associated genes. PIGD-associated genes were tentatively enriched in synaptic pathways and overlapped significantly with alpha-synuclein pathology-related genes, while TD-associated genes were enriched in chromatin regulation and proteostasis. Neurotransmitter mapping revealed broad neurotransmitter involvement in PIGD versus more restricted dominance in TD. Conclusions: PD subtypes exhibit both shared and subtype-associated transcriptomic signatures underlying regional atrophy vulnerability, with PIGD showing relatively more pronounced synaptic disruption and broader neurotransmitter involvement. These findings shed light on the molecular underpinnings that may contribute to the heterogeneity of disease distribution in PD clinical subtypes and may inform the development of targeted therapeutic strategies.