Impact of Anticholinergic and Dopamine Receptor Blocking Drug Exposure on Parkinson Disease Trajectory and Outcomes

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Project Summary/Abstract Cognitive impairment and falls leading to hip fracture are leading causes of institutionalization and mortality in Parkinson disease (PD), a neurological disorder which predominantly affects the most rapidly growing segment of the U.S. population (older adults). Preventing falls or delaying the onset of dementia in PD would have a substantial public health impact. Drugs with anticholinergic (ACH) effects or dopamine receptor blocking (DRB) activity have been demonstrated to impair gait, cause cognitive dysfunction, hasten the progression of dementia and increase mortality. Parkinson disease patients are particularly vulnerable to adverse effects of ACH and DRB drugs due to PD-related disruption of central dopaminergic and cholinergic pathways. Furthermore, PD pharmacotherapy trials use gait and cognition as markers of disease progression without considering ACH or DRB burden. Yet, no clinical guidelines limiting the use of ACH or DRB drugs exist, representing a fundamental gap in knowledge this revised proposal will address. We plan to use Medicare prescription, clinical, and utilization data and rich clinical research data from a longitudinal cohort study of individuals with PD to identify the pharmacological determinants of preventable adverse health outcomes and unreliable clinical trial endpoints in PD. This study will 1) produce highly useful benchmark data on variation in prescribing in PD and 2) address a crucial clinical issue—comparative safety among therapeutic alternatives for medications with ACH and DRB potential in PD. We expect to fundamentally advance the field of clinical neurology by providing a strong evidence base for clinical guidelines and care quality indicators related to ACH and DRB burden in PD. Our results will also have a positive translational impact because defining the impact of ACH drugs on research measurements of disease trajectory and clinical outcomes will alter data collection and analysis strategies for future PD neuroprotective drug trials, improving the ability of such trials to identify effective drugs. We also directly address a priority recommendation from the 2014 NINDS Parkinson's Disease Research Agenda: `to determine factors that facilitate health services interventions'- by combining qualitative and quantitative data to produce new insights into potentially preventable outcomes in PD that directly translate into policy initiatives.