Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies

Area of Science:

• Neuroscience
• Genetics
• Sleep Medicine

Background:

• Isolated rapid eye movement sleep behaviour disorder (iRBD) is a precursor to synucleinopathies like Parkinson's disease and dementia with Lewy bodies.
• Patients with iRBD exhibit brain atrophy, but the underlying mechanisms are not well understood.
• Understanding these mechanisms is crucial for early diagnosis and intervention in neurodegenerative diseases.

Purpose of the Study:

• To investigate gene expression and connectivity patterns associated with cortical thickness and surface area changes in iRBD patients.
• To identify the specific biological processes, cell types, and brain networks involved in iRBD-related brain atrophy.
• To differentiate iRBD-related brain changes from those seen in Alzheimer's disease.

Main Methods:

• Utilized advanced imaging transcriptomics and spatial mapping on MRI data from 171 iRBD patients and 238 controls.
• Applied partial least squares regression, gene set enrichment analysis, and virtual histology to analyze gene expression patterns.
• Employed structural and functional connectivity analyses, alongside spatial mapping, to examine network constraints and specific brain systems.

Main Results:

• Cortical thinning in iRBD is primarily driven by genes related to mitochondrial function and macroautophagy.
• Brain atrophy patterns in iRBD are constrained by structural and functional brain connectomes, mapping to motor and planning networks.
• Cortical surface area changes are associated with inflammatory response genes and distinct spatial patterns, differing from Alzheimer's disease.

Conclusions:

• Brain atrophy in synucleinopathies like iRBD is influenced by specific genes (mitochondrial, autophagy, inflammatory) and constrained by distinct brain networks.
• The findings highlight unique molecular and network mechanisms underlying iRBD-related brain changes, differentiating them from Alzheimer's disease.
• This research provides insights into the early pathological processes in synucleinopathies, potentially aiding in early detection and therapeutic strategies.