Objective: To prevent cognitive decline in GBA-associated Parkinson’s Disease (PD).

Background: Dementia represents a key milestone in the course of PD with limited effective treatments so far. Importantly, people with PD carrying a GBA mutation (PD_GBA) have a more severe course of disease with rapid cognitive decline. In contrast to PD without GBA mutation, where Aß-pathology contributes to cognitive decline as represented by a high proportion CSF Abeta_{1_42} profiles, this is NOT the case in PD_GBA. Rather, PD_GBA present with a predominantly α-synuclein-driven CSF profile with decreased CSF levels of total α-synuclein and normal Abeta_1-42 and t-Tau/p-Tau values. These findings were confirmed in patients with dementia with Lewy bodies carrying GBA mutations (DLB_GBA) who represent a clinical and histopathological continuum to PD. More recently we have shown that CSF α-synuclein seeding activity is highest in PD_GBA and DLB_GBA compared to other genetic and non-genetic forms, indicating that pathologic conformations of this protein are found at a higher concentration. Accordingly, histopathological studies show wide-spread α-synuclein pathology in brains of this PD_GBA. Based on these results, we suggest that it is the heavy cerebral α-synuclein deposition that is causally linked to the accelerated progression with cognitive decline in PD_GBA.

Method: We will conduct a proof-of-concept multicenter, international, randomized, double-blind, placebo-controlled clinical trial to investigate the efficacy of the monoclonal anti-α-synuclein antibody Prasinezumab (F. Hoffmann-La Roche Ltd) to prevent cognitive decline in non-demented PD_GBA.

Results: We will present the details of the trial design on the poster. Inclusion criteria will include stratification by GBA mutation severity and will be set to include PD_GBA in the prodromal phase for the development of dementia.

Conclusion: This is the first proof-of-concept clinical trial in PD addressing cognitive decline with a modifying agent based on a clear biological stratification and applied in a clearly defined prodromal phase preceding dementia to overcome the big challenge in modifying treatments of being “too late”. Thereby, this study is an example of an academic/industry partnership for translational research combining knowledge from basic research models and biomarker studies to the clinical application in a clearly hypothesis-driven way.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/proof-of-concept-clinical-trial-prevent-cognitive-decline-in-gba-associated-parkinsons-disease/