DESCRIPTION: Parkinson's disease (PD) is an incurable neurodegenerative disorder affecting approximately 1 million US adults and about 80,000 Veterans. PD causes significant morbidity due to motor and non-motor symptoms across its prolonged course with an annual economic burden of $14 billion in the US alone. Motor symptoms associated with loss of dopaminergic neurons in PD may be temporarily improved with dopamine replacing medicines, but disease-modifying therapies that delay or prevent neuronal loss are lacking and sorely needed. Exercise is promising as a disease-modifying therapy because it protects dopaminergic neurons in animal models of PD and has been associated with measures of neuroplasticity in PD patients. Unfortunately, more than half of dopaminergic neurons in the substantia nigra are lost before motor symptoms occur making it difficult to identify patients early enough to benefit from potentially disease-modifying therapies. Early "prodromal" PD can be identified using non-motor features including olfactory dysfunction and other biomarkers such as dopamine transporter (DaT) brain imaging abnormalities that are apparent years before motor symptoms. However, these strategies would be difficult and costly to implement on a population level without first identifying high-risk individuals for screening. Commonly prescribed dopamine blocking antipsychotic drugs cause debilitating PD-like motor dysfunction that is difficult to treat, and in some patients this findin may serve as a "stress test" for failing dopaminergic networks unmasking symptoms long before they would normally appear. Identifying prodromal PD among drug-induced parkinsonism patients offers a unique and unexplored opportunity for early intervention. In the proposed studies, we will employ a tiered screening strategy with inexpensive and non-invasive olfactory testing in drug-induced parkinsonism patients followed by DaT imaging in individuals with olfactory impairment to identify a cohort of patients with presumed prodromal PD. Subjects with presumed prodromal PD will then be randomized to a home-based exercise intervention ({5} times weekly aerobic walking confirmed by remote activity monitors) or no intervention. In this cohort, we will assess: 1) Short-term symptomatic effects of exercise on motor function in drug-induced parkinsonism using standard clinical measures (Unified Parkinson's Disease Rating Scale) and quantitative gait assessments after 8 weeks of intervention; 2) a potential disease-modifying effect after 52 weeks of exercise by comparing the rate of change in quantitative DaT imaging; and 3) the mechanisms and biochemical correlates of exercise-induced changes using a panel of serum biomarkers implicated in exercise and/or PD risk including brain-derived neurotrophic factor, uric acid, and apolipoproteinA1. Differences in the rate of change between groups will be assessed using independent samples t-tests and linear mixed-effects models adjusting for age and gender. Our preliminary data demonstrates a strong association between olfactory impairment and abnormal DaT imaging in drug- induced parkinsonism. Based on power calculations allowing for 20% dropout, we will screen approximately 250 drug-induced parkinsonism subjects using olfactory testing, with the expectation that approximately 88 will have abnormal DaT imaging and agree to participate in the intervention trial. Antipsychotic drugs are widely prescribed for a growing list of approved indications and off-label uses including bipolar disorder, depression and post-traumatic stress disorder. Studying drug-induced parkinsonism patients with prodromal PD will allow us to identify which individuals are at risk, characterize the natural history of progression and evaluate appropriate management strategies at the earliest stages of PD. Exercise as a putative disease-modifying therapy offers significant advantages including cost, ease of access and lack of toxicity compared with unproven pharmacologic interventions especially if offered early enough to have meaningful clinical impact.

PUBLIC HEALTH RELEVANCE Parkinson's disease (PD) is a common neurodegenerative disorder affecting approximately 80,000 veterans, representing a priority area for VA research. Current medicines for PD only improve symptoms, treatments that slow disease progression are needed, and earlier diagnosis of PD may be the key to their development. PD symptoms can be mimicked by medicines (most commonly antipsychotic drugs that block dopamine), and some of these patients actually have underlying "prodromal" PD that was "unmasked" years before it would have caused symptoms. This problem is increasing as these medicines are now used for common conditions including post-traumatic stress disorder and depression. We will identify prodromal PD in patients with drug- induced symptoms using brain scans. These patients will be enrolled in a randomized clinical trial of aerobic exercise which slows progression in animal models of PD and has other health benefits. We will measure the effect of exercise on symptoms, disease progression (using brain scans) and markers of PD risk (using blood tests). These studies will improve early PD diagnosis and potentially identify a way to slow progression of PD.