NeuralCipher Research overview
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Abstract A composite milestone was recently proposed as a measure of Parkinson’s disease (PD) progression, including 5-year clinical outcomes on various domains (Walking/balance, Motor complications, Cognition, Autonomic dysfunction, Functional dependence, Activities of daily living) derived from clinical scales. This study explored the composite milestone behaviour in a wider PD sample over up to 10 years via descriptives and the Kaplan-Meier estimator, potential baseline predictors of time to first and second consecutive milestone occurrence with shared frailty Cox regression models, its stability via counts and proportions, and its potential as a trial endpoint with sample size calculations (log-rank test, HR = 0.70 and 0.50, 80% power, α = 0.05). In the pooled Critical Path for Parkinson’s (CPP) consortium integrated dataset cohort (n = 3491, 4 observational and 7 interventional studies), the median time to composite milestone was 4.5 years. Overall, greater baseline age, disease severity (MDS-UPDRS parts I + II+III), decreased cognition (MoCA) and a non-tremor-dominant (non-TD) phenotype significantly predicted faster time to first milestone occurrence. Age, disease severity (MDS-UPDRS I + II+III), motor state (Hoehn &Yahr) and non-TD phenotypes also predicted faster time to two consecutive milestones. Additional individual study predictors included decreased olfaction (UPSIT score), depressive symptoms (GDS-15) and greater disease duration and disability (Schwab & England ADL score). Dopaminergic medication did not predict time to composite milestone. “Cognition” and “Walking and balance” were the most common and robust composite milestone domains. With first milestone occurrence as the endpoint, a total sample size of 624 would be required for a two-arm two-year trial in an advanced PD population. The composite milestone behaves in line with existing knowledge of PD natural history and allows for reasonable sample sizes in an advanced PD cohort. Further refinement of the composite milestone, with a view to simplifying it and including patient input, will increase its feasibility and acceptability as a trial endpoint.
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