Study Rationale: Essentially nothing is known about the sequence of biological and physiological events that ultimately lead to the clinical manifestations of Parkinson’s disease (PD). The existence of asymptomatic carriers of gene mutations that eventually lead to PD offers the opportunity to examine this trajectory at its earliest possible stages. Carriers of mutations in SNCA, the gene encoding alpha-synuclein, have been studied in our Center; however, no one has yet undertaken a systematic longitudinal follow-up of biological and physiological manifestations in these individuals. Of particular relevance are biological changes related to alpha-synuclein itself.
Hypothesis: We hypothesize that longitudinal evaluation of individuals carrying an SNCA mutation will provide a trajectory of the evolution of biological and physiological events related to the disease process of PD at its earliest stages.
Study Design: We will identify new asymptomatic individuals who carry two SNCA mutations that are commonly found in Greece: the p.A53T and the p.A30G mutation. These subjects will be enrolled in PPMI and follow the relevant systematic longitudinal protocol, most importantly testing for alpha-synuclein biomarkers via methods such as the Seeding Amplification Assay (SAA). In parallel, we will perform additional tests, including studies to identify sleep impairment or subtle changes in the autonomic nervous system. We will also assess whether alpha-synuclein, in either its normal or aggregated forms, increases over time in neuronal extracellular vesicles derived from serum of these individuals.
Impact on Diagnosis/Treatment of Parkinson’s disease: By comparing the temporal sequence of PD-associated pathologies, we hope to be able to answer the question of when, how and where does PD start. Determining the earliest events in the disease process has implications for the early diagnosis and treatment of PD.
Next Steps for Development: If a biological or physiological marker is identified as the first in the series of events leading to PD, it could be applied to larger populations at risk of developing the disease.