Effect of Exercise in Parkinsonism
Effect of Exercise in Parkinsonism
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. The investigators 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. The investigators 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.
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 finding 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, the investigators 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, the investigators 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. The investigators' 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, the investigators 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.
Inclusion Criteria:

 -  Veteran

 -  Subjects with parkinsonian signs:

 -  rest tremor

 -  rigidity

 -  bradykinesia

 -  Parkinsonian signs occurring after the institution of therapy with a medication having
 a known association with DIP, examples include:

 -  haloperidol

 -  chlorpromazine

 -  fluphenazine

 -  perphenazine

 -  risperidone

 -  thioridazine

 -  thiothixene

 -  lithium

 -  valproic acid

 -  ziprasidone

 -  olanzapine

 -  aripiprazole

 -  Potential subjects with DIP will be pre-screened using a brief (12 item) scratch and
 sniff smell test with hyposmic subjects invited to learn more about the study.

 -  clinical diagnosis of H/Y <=2 PD

 Exclusion Criteria:

 -  Subjects with a known diagnosis of atypical parkinsonian syndrome, i.e.:

 -  dementia with Lewy bodies

 -  progressive supranuclear palsy

 -  corticobasal degeneration

 -  multiple system atrophy)

 -  or other neurodegenerative condition

 -  Subjects with a history of:

 -  sinus trauma or surgery

 -  encephalitis

 -  current nasal congestion or other known reason for olfactory impairment

 -  Subjects with a contraindication to DaTI (sensitivity or allergy to iodine, treatment
 with a drug with a significant effect on DaTscan that cannot be temporarily weaned)

 -  Subjects with known unstable cardiac, pulmonary, orthopedic or other conditions that
 would preclude safe participation in exercise training

 -  Subjects currently engaging in exercise more than 45 minutes per day, 3 days per week