Study Rationale: Novel disease-modifying treatments for Parkinson’s disease (PD) are urgently needed as the prevalence of the disease is increasing and no cure is available. At this point, we have limited information about the abundance of chemical modifications in the alpha-synuclein present in such biomarkers are evaluating and stratifying patients for inclusion in clinical trials. Here, we use newly developed “AlphaLISA assays” to provide quantitative readouts of alpha-synuclein modifications in brain tissue extracts and biofluids from people with early and more advanced PD versus healthy controls.
Hypothesis: We hypothesize that we can detect chemical modifications of alpha-synuclein in biofluids and can use this information to discriminate between PD, Dementia with Lewy body (DLB), Multiple system atrophy (MSA) and healthy controls, which will allow us to define disease stages and alpha-synuclein molecular subtypes in early and more advanced stages of PD.
Study Design: We will use newly developed AlphaLISA assays to detect a variety of alpha-synuclein modifications, including truncation and phosphorylation, in postmortem brain samples, cerebrospinal fluid, blood samples from healthy controls and individuals with PD, DLB and MSA. We will then compare the diagnostic accuracy and clinical sensitivity across synucleinopathies and samples.
Impact on Diagnosis/Treatment of Parkinson’s disease: Next, we will further validate quantitative alpha-synuclein modification assays for different biological samples. In addition, we will evaluate clinical sensitivity, specificity and stage-appropriateness in PD, DLB, MSA patient samples. The results will inform which samples and assays are most sensitive for use for stratification of patients for upcoming clinical trials.
Next Steps for Development: Protocols for assay performance will be validated between different analysis sites (Roche and VUmc) and for implementation across other laboratories. Next, we can evaluate the tests in large longitudinal patient cohorts to fine-tune our understanding of alpha-synuclein modifications in the human body and their relation to clinical heterogeneity.