Relationship between frailty and disease progression in Parkinson's disease: a 3-year longitudinal study

Parkinson's disease (PD) shows substantial variability in presentation and progression. Frailty, a multidimensional construct reflecting biological aging, is a determinant of clinical outcomes in several neurodegenerative disorders. While cross-sectional studies suggest that frailty modulates the clinical phenotype of PD, affecting motor and non-motor symptoms, its longitudinal prognostic relevance remains unclear. In this 3-year, single-center cohort study, we investigated whether frailty, measured using a validated 50-item frailty index (FI), predicts clinical progression, motor complications, and mortality in a cohort of 109 PD patients. Clinical assessment included MDS-UPDRS parts III and IV, Non-Motor Symptoms Scale, Hoehn & Yahr stage, Montreal Cognitive Assessment, and levodopa equivalent daily dose (LEDD). Associations between baseline FI and follow-up outcomes were examined using simple and multiple linear regression models. Patients were stratified into three frailty groups at baseline to examine group-level differences in clinical progression and mortality, which were assessed using mixed-effects models and contingency analyses. Higher baseline FI independently predicted greater severity of treatment-related motor complications at follow-up (β = 8.3; p = 0.04) and greater worsening of these complications over time (β = 11.4; p = 0.017) and showed trends toward greater non-motor symptom burden and cognitive decline. No significant association was observed between baseline FI and motor progression. Patients classified as frail at baseline displayed greater clinical deterioration across multiple domains, higher LEDD requirements, and had increased mortality (χ² = 16.5, p < 0.001) compared to less frail counterparts. In conclusion, frailty predicts worse clinical trajectories and increased mortality in PD, supporting its utility as a prognostic biomarker. Incorporating frailty assessment into routine care may improve risk stratification and guide personalized therapeutic approaches in PD patients.