Diffusion Magnetic Resonance Imaging of Cortical Microstructure Differs in Nonmanifest and Manifest Genetic Parkinson's Disease

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Abstract
Background: Previous investigations into neurodegenerative diseases demonstrated the utility of cortical diffusivity metrics in assessing microstructural changes. Objective: The objective of this study was to explore cortical diffusivity metrics in genetic Parkinson's disease (PD) with glucocerebrosidase 1 (GBA1) and Leucine‐rich repeat kinase 2 (LRRK2) mutations, encompassing both nonmanifest carriers (NMCs) and manifest PD, and healthy control subjects (HCs). Methods: T1‐structural and diffusion magnetic resonance imaging (MRI) scans were analyzed to calculate diffusion metrics related to cortical columnar structure (angle between the radial minicolumnar axis and the principal diffusion direction [AngleR], parallel diffusivity [ParlPD], perpendicular diffusivity of multiple components [PerpPD + ]) and cortical mean diffusivity for 143 participants (60 HCs, 19 NMC GBA1, 30 NMC LRRK2, 11 PD GBA1, and 23 PD LRRK2) from the Parkinson's Progression Markers Initiative (PPMI). The first available time point including both T1‐weighted and diffusion MRI acquisitions was used for each participant. Whole‐brain, regional, and functional hierarchy macroregional values were used to investigate group differences. Results are reported after multiple comparison correction. Results: Grouped together, results indicated significantly lower ParlPD values in manifest PD compared with the NMC group in whole‐brain analysis. Regional analyses showed a progressive reduction in cortical ParlPD across the genetic groups, primarily in mesocortex (Braak stage 4) for NMC cases, extending to neocortex (Braak stage 5) for manifest genetic PD. Subgroup analyses demonstrated a more pronounced pattern of cortical alterations in subjects with GBA1 mutations compared with patients with LRRK2 mutations. Conclusions: Cortical diffusivity metrics effectively capture cortical architectural changes across clinical stages of genetic PD, supporting their use as microstructural markers of neurodegeneration in PD. © 2026 International Parkinson and Movement Disorder Society.

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