Avenali, M;
Caminiti, SP;
Gegg, M;
Cerri, S;
Mitrotti, P;
Bandirali, L;
Toffoli, M;
... Blandini, F; + view all
(2025)
Combined Assessment of Blood Glucocerebrosidase Activity and Α-Synuclein Levels in Gba1 Mutation Carriers: a Novel Potential Biomarker.
Parkinsonism and Related Disorders
, 135
, Article 107854. 10.1016/j.parkreldis.2025.107854.
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Abstract
INTRODUCTION: Heterozygous variants in the GBA1 gene encoding the glucocerebrosidase enzyme (GCase) are the most frequent genetic risk factor for Parkinson's Disease (PD). Yet, only a minority of GBA1 carriers will eventually develop overt PD, and the mechanisms underlying such reduced penetrance are still largely unexplored. Decreased GCase and increased α-synuclein levels are individually considered promising prognostic blood biomarkers for GBA-PD. Here, we aim to assess the combined role of decreased GCase activity and increased α-synuclein levels as a potential biochemical signature of worse outcome in GBA1 population. METHODS: Ninety-eight subjects (30 GBA-nonPD, 29 GBA-PD and 39 healthy controls) underwent a detailed clinical assessment, as well as measurement of GCase activity and total α-synuclein levels in peripheral blood mononuclear cells (PBMCs). ROC curve analysis and a two-step clustering analysis were performed to classify subjects based on their combined GCase and α-synuclein biochemical profile. Clinical scores were analysed across clusters. RESULTS: ROC curve analysis based on α-synuclein/GCase activity ratio was able to discriminate GBA1 positive individuals from healthy controls. We identified two separate biochemical clusters – a benign (high GCase/mid-low α-synuclein) and a malignant (low GCase/high α-synuclein) cluster. All healthy controls belonged to the benign cluster, while 59% of GBA-PD and 47% of GBA-nonPD fell into the malignant cluster. GBA-nonPD within the malignant cluster had greater depressive symptoms, and GBA-PD showed worse cognitive performance. CONCLUSIONS: We report for the first time that the combined assessment of blood GCase activity and α-synuclein levels can define two distinctive biochemical clusters able to discriminate GBA-nonPD subjects with greater preclinical non-motor symptoms and GBA-PD patients with a worse cognitive profile. Longitudinal studies are needed to confirm the accuracy of this potential biomarker.
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