Identifying Individuals in the Prodromal Phase of Parkinson's Disease: A Prospective Cohort Study.

OBJECTIVE

We prospectively evaluated how well combinations of signs and symptoms can identify individuals in the prodromal phase of Parkinson's disease (PD).

METHODS

The study comprised 6,108 men who underwent repeated assessments of key prodromal features and were prospectively followed for the development of PD. Two composite measures of prodromal PD were evaluated: (i) the co-occurrence of constipation, probable rapid eye movement (REM) sleep behavior disorder (pRBD), and hyposmia, and (ii) the probability of prodromal PD based on the Movement Disorders Society (MDS) research criteria. We also examined the progression and heterogeneity of the prodromal PD phase.

RESULTS

One hundred three individuals were newly diagnosed with PD over an average follow-up of 3.4 years. Men with constipation, pRBD, and hyposmia had a 23-fold higher risk of receiving a PD diagnosis in the subsequent 3 years, compared with men without these features (risk ratio [RR] = 23.35, 95% confidence interval [CI] = 10.62-51.33). The risk of PD was 21-fold higher in men with a probability of prodromal PD ≥ 0.8 compared with those with a probability < 0.2 (RR = 21.96, 95% CI = 11.17-43.17). Both the co-occurrence of the 3 non-motor features and an MDS-based probability ≥ 0.8 had comparable predictive values, and both were stronger predictors of PD than any of the features individually. We identified 2 prodromal PD subtypes where RBD and visual color impairment were key discriminators.

INTERPRETATION: Our study demonstrates that combinations of key signs and symptoms strongly predict future clinically manifest PD. These measures may be integrated into screening strategies to identify individuals who could be targeted for enrollment into PD prevention trials. ANN NEUROL 2025;97:720-729.