Clinical and Dopamine Transporter Imaging Trajectories in a Cohort of Parkinson's Disease Patients with GBA Mutations

Background: Glucosylceramidase (GBA) mutations are considered the most common genetic risk factors for developing Parkinson's disease (PD). Objectives: We aimed to assess, at different time points, the integrity of brain striatal and extra-striatal dopamine pathways and clinical phenotype of a group of PD subjects bearing heterozygous GBA mutations (GBA-PD), compared with a group of idiopathic PD patients (iPD) stratified by age at disease onset. A longitudinal approach was adopted to evaluate the progression over time for clinical and 123I-FP-CIT SPECT imaging features. Methods: We considered 46 GBA-PD patients and 339 iPD patients, subdivided into two groups according to age at PD onset (n = 58 < 50 years and n = 281 > 50 years). We measured differences in the occurrence/severity/progression of motor and non-motor features, 123I-FP-CIT standard uptake value ratios (SUVr) in striatal and extra-striatal regions, and global cognitive deterioration over time in a subset of 168 cases with available follow-up. Results: At baseline, the GBA-PD cohort showed more severe motor and cognitive deficits than the early-iPD cohort. The 123I-FP-CIT SUVr reduction in the striatal and the extra-striatal regions was more marked in the GBA-PD than the early- and late-iPD cohorts. Both GBA-PD and late-iPD patients had a significant annual deterioration in their global cognitive performance, while the early-iPD group showed global cognitive stability over time. At follow-up, the iPD cohorts became similar to the GBA-PD group in 123I-FP-CIT SUVr reduction. Conclusion: These new findings support the hypothesis of a biological role of GBA mutations in accelerating the early neurodegenerative processes in PD, leading to the malignant clinical phenotype. © 2021 International Parkinson and Movement Disorder Society.