Longitudinal Monitoring of Parkinson's Disease in Different Ethnic Cohorts: The DodoNA and LONG-PD Study

Abstract

Background: Different factors influence severity, progression, and outcomes in Parkinson's disease (PD). Lack of standardized clinical assessment limits comparison of outcomes and availability of well-characterized cohorts for collaborative studies. Methods: Structured clinical documentation support (SCDS) was developed within the DNA Predictions to Improve Neurological Health (DodoNA) project to standardize clinical assessment and identify molecular predictors of disease progression. The Longitudinal Clinical and Genetic Study of Parkinson's Disease (LONG-PD) was launched within the Genetic Epidemiology of Parkinson's disease (GEoPD) consortium using a Research Electronic Data Capture (REDCap) format mirroring the DodoNA SCDS. Demographics, education, exposures, age at onset (AAO), Unified Parkinson's Disease Rating Scale (UPDRS) parts I-VI or Movement Disorders Society (MDS)-UPDRS, Montreal Cognitive Assessment (MoCA)/Short Test of Mental Status (STMS)/Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Epworth Sleepiness Scale (ESS), dopaminergic therapy, family history, nursing home placement, death and blood samples were collected. DodoNA participants (396) with 6 years of follow-up and 346 LONG-PD participants with up to 3 years of follow-up were analyzed using group-based trajectory modeling (GBTM) focused on: AAO, education, family history, MMSE/MoCA/STMS, UPDRS II-II, UPDRS-III tremor and bradykinesia sub-scores, Hoehn and Yahr staging (H&Y) stage, disease subtype, dopaminergic therapy, and presence of autonomic symptoms. The analysis was performed with either cohort as the training/test set. Results: Patients are classified into slowly and rapidly progressing courses by AAO, MMSE score, H &Y stage, UPDRS-III tremor and bradykinesia sub-scores relatively early in the disease course. Late AAO and male sex assigned patients to the rapidly progressing group, whereas tremor to the slower progressing group. Classification is independent of which cohort serves as the training set. Frequencies of disease-causing variants in LRRK2 and GBA were 1.89 and 2.96%, respectively. Conclusions: Standardized clinical assessment provides accurate phenotypic characterization in pragmatic clinical settings. Trajectory analysis identified two different trajectories of disease progression and determinants of classification. Accurate phenotypic characterization is essential in interpreting genomic information that is generated within consortia, such as the GEoPD, formed to understand the genetic epidemiology of PD. Furthermore, the LONGPD study protocol has served as the prototype for collecting standardized phenotypic information at GEoPD sites. With genomic analysis, this will elucidate disease etiology and lead to targeted therapies that can improve disease outcomes.