Who to Enroll in Parkinson Disease Prevention Trials?

Abstract

Therapies that prevent the occurrence of Parkinson disease (PD) (primary prevention) or mitigate the progression of symptoms in those with early disease (secondary prevention) are a critical unmet need in disease management. Despite great promise, PD prevention trials have not yet demonstrated success. Initiation of treatment too late in the disease course and the heterogeneity of disease are obstacles that may have contributed to the failure. Genetically stratified groups offer many advantages to primary and secondary prevention trials. In addition to their ease of identification, they decrease disease heterogeneity on several levels. Particularly, they comprise a phenotypically and pathologically enriched group with defined clinical features, pathogenic mechanisms and associated proteins that may serve as specific trial endpoints, therapeutic targets and biomarkers for disease state, and pharmacodynamic and pharmacokinetic status. However, challenges arise from genetic variant heterogeneity, from reduced penetrance whereby many carriers will not develop PD, and in recruiting a population that will meet the desired outcome in the proposed study duration. In this review, we discussed the opportunities afforded by the enrollment of genetically stratified cohorts (i.e., leucine-rich repeat kinase 2 and glucocerebrosidase 1) into prevention trials with a primary focus on primary prevention trials. We also outlined challenges surrounding the enrollment of these cohorts and offered suggestions to leverage their many advantages.

Who is at Risk of Parkinson Disease? Refining the Preclinical Phase of GBA1 and LRRK2 Variant Carriers: a Clinical, Biochemical, and Imaging Approach

“…Similarly, for LRRK2 carriers, it has been suggested that non-LRRK2 genetic factors may influence PD penetrance [43]. Polygenic risk score (PRS), for instance, was associated with higher penetrance of PD in large cohorts of LRRK2-G2019S carriers [44,45], and the combination of MDS Research Criteria for Prodromal PD with PRS has been proposed for LRRK2-NMC to identify subjects at higher risk [3].…”

“…To increase our ability to detect high-risk individuals, clustering clinical and historical data with biochemical markers represents a reasonable option [3].…”

“…The negative impact that the global burden of PD will have on those individuals primarily affected (patients and caregivers), economics and societies, is substantial [2]. Research efforts should therefore focus on interventions designed to prevent disease occurrence in healthy individuals and slow down progression in the early stages of manifest disease [3].…”

Path to Parkinson Disease Prevention

“…Genetically defined at-risk populations, as summarized by Niotis et al, 8 provide illustrative examples. The penetrance of many PD pathogenic genetic variants is being estimated with increasing precision.…”

Planning for Prevention of Parkinson Disease

“…Genetically At-Risk Individuals Although many genetic variants have been associated with PD, the 2 that are best positioned for prevention trials are the pathogenic LRRK2 and GBA variants. 20 Prevention studies in genetically at-risk individuals are not unique to PD and are preceded by those in other neurodegenerative diseases, as above, along with other studies in medicine investigating BRCA1 and BRCA2 variants in breast and ovarian cancer, APC variants in familial adenomatous polyposis, and more recently, Phe508del allele carriers in cystic fibrosis. However, studying pathogenic variant carriers in PD does pose some distinct practical and ethical challenges.…”