Biomarkers and risk factors for prodromal Parkinson's disease and its progression

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PROJECT SUMMARY The highest priority recommended by NINDS for clinical Parkinson’s research is to define “the features and natural history of prodromal Parkinson disease (PPD), including the events that underlie phenoconversion to clinically manifest PD, and biomarkers or other determinants of prodromal subtypes with the goal of providing sufficient rationale to initiate proof-of-concept prevention trials....” We are in a privileged position to address this priority by leveraging 25 years of research on PD in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), large cohorts of women and men recruited in mid-adult life and followed prospectively for over 30 years. In 2012, we screened the active participants in these cohorts for probable REM sleep behavior disorder (pRBD) and constipation, and selected a sub-cohort enriched for these features for further investigation (the ProPD cohort). This sub-cohort included 20,455 individuals who have so far completed two olfactory tests and two comprehensive mailed surveys of non-motor and early motor features of PPD, and have been actively followed until 2018. We are now proposing to extend the longitudinal follow-up of this unique cohort and its source population to monitor the progression of prodromal features and phenoconversion to clinically manifest PD (“phenoconversion”, for brevity), thus providing important insights on the course of PPD and fill the gap between current knowledge and what we need to know for implementing prevention trials. Further, as part of the proposed project, we will examine the impact of covid-19 on PPD and its progression and collect new biological samples to evaluate the sebum volatilome and metabolome, novel promising and non-invasive biomarkers that could play an important role in the early identification of PPD. The Aims of the study include: i) to obtain an in-depth descriptive characterization of PPD and its heterogeneity; ii) to identify risk factors for PPD progression and phenoconversion; iii) to assess the impact of SARS-Cov2/covid-19 on features of prodromal PD and phenoconversion; and iv) to evaluate the relationship between the sebum volatilome and metabolome with prodromal features and manifest PD (sebum samples will be collected from individuals with high probability of PPD, manifest PD, and matched controls). A unique and virtually irreproducible strength of the proposed study are the data prospectively collected since mid-adult life (men were 40 to 65 at recruitment, women 30 to 55) on lifestyle and medical history, including risk factors for PD and several features associated with PPD. If funded, the proposed study stands to lead to groundbreaking discoveries and create an invaluable resource that will offer numerous opportunities for further in-depth investigations on PPD and its determinants. Most importantly, the information generated by the proposed investigation will be pivotal to assess the feasibility of prevention trials and inform their design.