Objective: To investigate brain glucose metabolic patterns and their relationship with clinical features in GBA1 mutation carriers with PD (GBA-PD), asymptomatic carriers (GBA-nonPD), and PD patients without GBA mutations (nonGBA-PD).

Background: Variants in GBA1 gene are among the most common genetic risk factors for Parkinson’s disease (PD). However, their effects on brain glucose metabolism and early clinical manifestations in asymptomatic carriers remain incompletely understood.

Method: Data on motor and non-motor symptoms, neuropsychological function, and [¹⁸F]FDG-PET were collected. PET images were preprocessed using SPM12, and individual hypometabolism maps were generated. Hypometabolic epicenters were identified in the PD cohort as the top 5% of hypometabolic regions (highest SPM t-scores). Cluster analysis was applied to these epicenters to identify metabolic subgroups, and clinical differences between clusters were assessed using linear regression models. Voxel-wise comparisons between GBA-PD and nonGBA-PD were performed to identify the GBA-related hypometabolic pattern. The resulting cluster was binarized into a region of interest (ROI), mean metabolic values were extracted for GBA-PD and GBA-nonPD participants, and transformed into Euclidean distances to identify GBA-nonPD individuals exhibiting PD-like metabolic patterns.

Results: Fifty-five participants were included (17 GBA-PD, 23 nonGBA-PD and 15 GBA-nonPD). Among PD subjects, two metabolic subgroups emerged: severe and mild hypometabolism. 65% of GBA-PD and 54% of nonGBA-PD individuals belonged to the severe cluster, which was associated with poorer executive function performances. Voxel-wise analyses revealed more extensive posterior cortical hypometabolism in GBA-PD compared with nonGBA-PD. Notably, 27% of asymptomatic GBA-nonPD carriers already exhibited a GBA-PD–like posterior hypometabolic pattern within the ROI, indicating early metabolic changes that precede clinical manifestation.

Conclusion: GBA-PD participants showed more severe posterior cortical hypometabolism, consistent with a more aggressive disease phenotype and increased dementia risk. Notably, a subset of asymptomatic GBA-nonPD carriers displayed a GBA-PD-like posterior hypometabolic pattern, potentially representing an early biomarker of phenoconversion risk.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/posterior-cortical-hypometabolism-in-gba1-variant-carriers-with-and-without-parkinsons-disease/