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

Abstract

A BS TRACT: 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 123 I-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, 123 I-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 123 I-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 123 I-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.

Neuroimaging in Glucocerebrosidase‐Associated Parkinsonism: A Systematic Review

“…These imaging findings were in line with clinical observations demonstrating a more rapid trajectory of motor and cognitive impairment in GBA‐PD compared to iPD 18 . Also a study conducted on the Parkinson's Progression Markers Initiative (PPMI) cohort reported significant GM differences in GBA‐PD compared with iPD patients 17 . In particular, both GBA‐PD and late‐onset (LO)‐iPD showed greater structural volume reductions compared with the early‐onset (EO)‐iPD group.…”

“…The clinical follow‐up (up to 6 years) in this cohort showed greater worsening in motor, cognitive, and autonomic functions in GBA‐PD versus EO‐iPD and in LO‐iPD versus EO‐iPD but no differences between GBA‐iPD and LO‐iPD. LO‐iPD is associated with a more aggressive form of disease 51 : the findings of this study (see the Nigrostriatal Imaging section) support the hypothesis that GBA mutations participate to accelerate the neurodegenerative processes in PD 17 …”

“…More insights from longitudinal studies demonstrated that GBA‐PD show a more advanced disease at both structural MRI and 123‐FP‐CIT‐SPECT imaging, 17,18 which is reached by iPD after 5 and 2 years, respectively. Importantly, the trajectory of worsening of imaging features corresponded to a more aggressive clinical worsening, in both motor and nonmotor features.…”

“…LO-iPD is associated with a more aggressive form of disease 51 : the findings of this study (see the Nigrostriatal Imaging section) support the hypothesis that GBA mutations participate to accelerate the neurodegenerative processes in PD. 17 Conversely, in other studies, no differences in GM have been reported between GBA-PD, iPD, and controls 20 and between GBA-PD, PD with LRRK2 mutations (LRRK2-PD), and iPD, 19 although, in the latter study, lower GM volumes were reported in bilateral hippocampus, nucleus accumbens, caudate, thalamus, putamen and amygdala, and the right pallidum in patients with PD (eg, GBA-PD, LRRK2-PD, and iPD) compared to unaffected participants (eg, GBA-NMC, LRRK2-NMC, and controls).…”

Glucocerebrosidase mutations and Parkinson disease

“…Utilising fluorodopa PET and transcranial sonography, no significant difference in nigrostriatal imaging has been reported between iPD and GBA1 -PD patients (Kono et al 2007 ; Kraoua et al 2009 ; Goker-Alpan et al 2012 ; Barrett et al 2013 ; Lopez et al 2020 ). Longitudinal investigations using single-photon emission computerised tomography (SPECT) and structural MRI have revealed a more accelerated disease course in GBA1 -PD compared to iPD (Caminiti et al 2022 ; Leocadi et al 2022 ). Of note, iPD patients demonstrated similar patterns of cortical thinning to GBA1-PD 5 years post baseline MRI scans (Leocadi et al 2022 ).…”