Objective: To investigate glucocerebrosidase (GCase) enzymatic activity and different forms of α-synuclein (aggregated -Asyn_a – and monomeric – Asyn_m) in peripheral blood mononuclear cells (PBMCs) in a large cohort of Parkinson’s disease (PD) patients with and without GBA1 mutations and GBA positive non-manifesting carriers.

Background: Previous measures of total or oligomeric Asyn in peripheral biofluids were hampered by great variability, yielding inconclusive results which limited their clinical application. Mutations in the GBA1 gene, encoding the enzyme GCase, are the major genetic risk factor for PD. Reduced GCase activity has been linked to increased Asyn_a, however these two biomarkers and their interplay have been poorly investigated in PBMCs.

Method: We collected motor and non-motor clinical data, as well as blood samples, from 225 participants, including 57 GBA-PD, 74 idiopathic PD (iPD), 77 healthy controls (HC), and 17 unaffected GBA1 carriers. GCase activity was measured using a fluorometric assay, whereas Asyn_m and Asyn_a were assessed by ELISA. We first evaluated sensitivity and specificity of each biomarker and then explored the potential associations between biochemical and clinical features.

Results: AUC analysis revealed that Asyn_a, Asyn_a/GCase, and Asyn_m/Asyn_a were able to differentiate the whole PD cohort from HC. Asyn_a/GCase ratio best predicted PD status in GBA-PD compared to iPD. Asyn_a, Asyn_a/GCase, and Asyn_m/Asyn_a were able to classify most PD patients (>80%) as high-risk, compared to HC median probability risk. Asyn_a/GCase ratio identified all GBA-nonPD individuals as high-risk. Asyn_a levels significantly correlated with UPSIT scores in PD patients. Asyn_a/GCase was significantly higher in GBA-PD patients with severe motor impairment than in those with mild symptoms, and in those with clinical REM Sleep Behaviour Disorders than in those without.

Conclusion: Asyn_a and Asyn_a/GCase are promising biomarkers for supporting diagnosis of PD. The biochemical stratification approach not only distinguished PD patients from HC but also identified differences in GBA-nonPD individuals, suggesting its potential to predict disease progression in asymptomatic carriers.

References: 1. Avenali M. et al., Profiling the Biochemical Signature of GBA‐Related Parkinson’s Disease in Peripheral Blood Mononuclear Cells, (2021), Mov. Disord., doi: 10.1002/mds.28496.
2. Tokuda T. et al., Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease, (2010), Neurology, doi: 10.1212/WNL.0b013e3181fd613b.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/blood-based-biomarkers-for-diagnosis-and-prediction-of-parkinsons-disease-in-gba1-individuals/