Effect of Exercise in Parkinsonism

Effect of Exercise on Recovery in Drug-Induced Parkinsonism and Parkinson Disease

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.

Study Overview

• Status: Completed
• Conditions: Parkinson's Disease; Drug-induced Parkinsonism
• Intervention / Treatment: Behavioral: Exercise

Detailed 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 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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Exercise; aerobic walking	Behavioral: Exercise; Aerobic walking
No Intervention: No exercise; normal activity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Dopamine Transporter Imaging	change in semi-quantitative Ioflupane-I123 uptake comparing exercise to no intervention.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Overall Motor Function	change in UPRS motor exam at 8 weeks. Minimum 0, Maximum 108. Higher scores indicate more severe disease.	8 weeks

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: University of Pennsylvania
• Investigators: Principal Investigator: James F Morley, MD, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2016
• Primary Completion (Actual): January 31, 2022
• Study Completion (Actual): January 31, 2022

Study Registration Dates

• First Submitted: November 4, 2015
• First Submitted That Met QC Criteria: November 4, 2015
• First Posted (Estimated): November 6, 2015

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 9, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: exercise; Parkinson Disease
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Parkinsonian Disorders; Parkinson Disease, Secondary
• Other Study ID Numbers: N2012-W

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No