Objective: To explore the regional cholinergic innervation and clinical characteristics of de novo Parkinson’s disease (PD) patients carrying GBA variants.

Background: The most common genetic risk factor for PD involve mutations of the GBA1-gene (GBA), encoding the lysosomal enzyme glucocerebrosidase (GCase). Patients with GBA mutations (GBA-PD) seem to have an earlier age of onset, and faster disease progression with more severe cognitive impairment and postural instability and gait problems. These symptoms suggest cholinergic denervation. Vesicular acetylcholine transporter (VAChT) PET imaging provides the opportunity to investigate regional cholinergic innervation and its relationship with clinical symptomology. In-depth characterization of GBA-PD is of great importance for the validity of GBA-PD as a distinct clinical PD subtype with potential personalized treatment approaches.

Method: 131 newly diagnosed, treatment-naïve PD patients, with a confirmed presynaptic dopaminergic deficit on the dopaminergic PET scan, were included as part of the Dutch Parkinson Cohort (DUPARC) study. Assessment included extensive neuropsychological assessment covering all cognitive domains, motor performance using the MDS-UPDRS III, and cholinergic PET imaging using the VAChT tracer [¹⁸F]fluoroethoxybenzovesamicol.  DNA was isolated from saliva samples.  Full GBA1-gene sequencing was performed to evaluate GBA variants.

Results: The incidence of the different GBA variants in our de novo PD cohort will be presented. Clinical characteristics of the GBA-PD compared to the non-GBA PD group will be shown, including the incidence of PD-related mild cognitive impairment (PD-MCI), cognitive profile and motor subtype. In addition, the difference in cholinergic innervation topography between both groups is demonstrated.

Conclusion: In conclusion, this study improves our understanding of the cholinergic innervation and cognitive function of de novo, treatment-naïve, GBA-PD patients. Phenotyping early GBA-PD patients offers useful prognostic and therapeutic information, in particular regarding the cognitive deterioration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cholinergic-innervation-and-cognitive-functioning-in-de-novo-parkinsons-patients-with-gba-variations/