Objective: to investigate cerebral glucose metabolism via fluorodeoxyglucose positron emission tomography (FDG-PET) and its correlation to clinical features in Parkinson’s disease (PD) patients with GBA1 mutations (GBA-PD) and non-mutated (nonGBA-PD) PD.

Background: GBA1 mutations are the most common genetic risk factor for PD and are linked to a more aggressive disease course. However, their impact on cerebral metabolism and associated cognitive function remains unexplored

Method: 44 PD patients (15 GBA-PD, 29 nonGBA-PD) underwent comprehensive clinical and neuropsychological assessments. Brain hypometabolism was evaluated through FDG-PET, processed using a Statistical Parametric Mapping (SPM) pipeline. Group differences in hypometabolism were assessed via second-level SPM regression, while hierarchical clustering identified metabolic subtypes from regional hypometabolism values in individual SPM t-maps. Voxel-wise analyses identified shared hypometabolic patterns within clusters. Clinical and neuropsychological differences between groups, as well as between metabolic clusters, were assessed using the Mann-Whitney U-test

Results: The two PD cohorts had comparable age at evaluation, disease duration, and MoCA scores. GBA-PD patients exhibited an earlier disease onset and worse visuospatial (Rey–Osterrieth Complex Figure Test, copy task), visual-perceptual, and executive (Trail Making Test) functions compared to nonGBA-PD. Voxel-wise analysis revealed greater hypometabolism in the occipito-parietal cortex of GBA-PD. Unsupervised clustering identified two distinct metabolic subtypes: Cluster 1 (42% of the cohort, 63% GBA-PD) showed widespread occipito-parietal hypometabolism, whereas Cluster 2 (58% of the cohort, 81.8% nonGBA-PD) had more scattered hypometabolism affecting both cortical and subcortical regions. Cluster 1 showed poorer visuospatial, visual-perceptual, memory, and executive function performance compared to Cluster 2 and, within Cluster 1, occipital hypometabolism was significantly associated with a more severe cognitive profile.

Conclusion: FDG-PET findings suggest that posterior cortical hypometabolism is more common in GBA-PD and may serve as an early marker of PD dementia, preceding the clinical manifested cognitive dysfunctions. These results reinforce the role of GBA1 mutations in a more severe cognitive phenotype and highlight metabolic biomarkers as potential predictors of disease progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebral-glucose-metabolic-features-of-gba-parkinsons-disease-as-a-window-into-cognitive-impairment/