Objective: To estimate the specific hazard of motor and nonmotor milestones of Parkinson’s disease (PD) progression in the long term.

Background: Parkinson’s disease greatly varies in its clinical manifestations and evolution according to age and disease duration. However, the pace and specific interplay of these different timescales is currently poorly understood.

Methods: We conducted a retrospective cohort study of PD-outpatients visiting Lyon’s university hospital-based movement disorders center. Seven clinical milestones of PD progression were analyzed encompassing four domains: (1) motor (motor fluctuations, dyskinesias); (2) axial (postural instability and falls, freezing of gait); (3) neuropsychiatric (impulse control disorders, hallucinations) and (4) cognitive (dementia) complications. We estimated the outcome-specific hazard rate for each complication independently using parsimonious smooth parametric Poisson regression models with one-year constant risk periods for disease duration, age at diagnosis and current age.

Results: A total of 1232 PD-patients experienced 1527 disease-related complications in up to 12 years follow-up. Outcome-specific baseline hazard dramatically increased with disease duration for all complications. Hazard rates at 5-years were greatest for motor fluctuations and lowest for dementia in patients aged 65 at diagnosis, ranging from 124.8 [95% CI, 95.1-163.9] per 1.000 person-years in men and 166.7 [95% CI, 125.7-221.2] in women for motor fluctuations, to 8.1 [95% CI, 5.2-12.4] in men and 7.6 [95% CI, 4.6-12.9] in women for dementia. Non-(log)linear associations were found for age at diagnosis, predicting dramatic increase in hazard for axial complications after 70 years, and for motor fluctuations, dyskinesias and impulse control disorders before 60 years. Hallucinations (HR, 1.03 [95% CI, 1.01-1.04]) and dementia (HR, 1.1 [95% CI, 1.07-1.14]) were log-linearly predicted by age at diagnosis. Disease duration and age at diagnosis statistically interacted for postural instability and falls, suggesting age-related accelerated pathological processes linked to postural instability in PD.

Conclusions: Progression to motor and nonmotor milestones in PD is determined by disease duration and age at diagnosis in nonlinear patterns and their interaction. This strongly suggests disease duration- and age-specific thresholds in the multiple neurodegenerative processes accumulating in PD at different paces.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nonlinearities-in-outcome-specific-hazard-of-motor-and-nonmotor-long-term-complications-of-parkinsons-disease/