This study will evaluate the safety and feasibility of a home-based, virtually-supervised, combined high intensity endurance and resistance training program in people with Parkinson's disease. It will also evaluate the effects of exercise on cognition and underlying exercise-related biological markers (biomarkers).

Cognitive impairment begins early in Parkinson's disease (PD) and progresses to dementia in a majority of patients, impairing quality of life and contributing to growing health-related costs. Physical exercise has potent anti-aging effects and improves many outcomes in PD including cognition. Identifying biomarkers that respond to exercise, and how they associate with cognition and underlying disease pathology, may elucidate key mechanisms for countering cognitive decline. This is a randomized-controlled trial that evaluates safety and feasibility of a home-based exercise intervention in people with PD and measure its effects on cognition and circulating biomarkers of aging and stress. Thirty-two participants with PD will be randomized to receive a home-based, trainer-supervised endurance and resistance training program (exercise group) or no exercise (wait list control group) for 26 weeks. Cognitive assessments and patient reported outcomes will be obtained at baseline and at end of 26 weeks. Biomarkers in periphery (blood, saliva) and brain [cerebrospinal fluid (CSF)] will also be measured before and after the 26-week exercise intervention.

Inclusion Criteria:

1. Diagnosis of idiopathic Parkinson's disease (PD) based on MDS criteria, with bradykinesia plus one of the other cardinal signs of PD (resting tremor, rigidity), without any other known or suspected cause of parkinsonism.
2. Modified Hoehn and Yahr stage less than 4
3. Age 40-80 years at time of screening
4. If being treated with PD symptomatic medications (i.e.g., rasagiline, carbidopa/levodopa, dopamine agonists, amantadine, anti-cholinergics), stable doses for greater than or equal to 2 months prior to baseline. If not being treated with PD symptomatic medication at time of screening, deemed unlikely to require symptomatic medication for next 6 months.

Exclusion Criteria:

1. A diagnosis of atypical parkinsonism, drug-induced parkinsonism, essential tremor, primary dystonia or other diagnoses that explain symptoms other than PD.

2. A diagnosis of a significant neurological disease other than PD that would interfere with ability to perform study procedures or assessments.

3. Significant cognitive impairment defined as Montreal Cognitive Assessment (MoCA)<23 or any impairment that would, in the opinion of the investigator, interfere with ability to follow exercise directions.

4. Beck Depression Inventory II (BDI) score > 16, indicating depression that precludes ability to exercise.

5. Use of neuroleptics/dopamine receptor blockers for more than 30 days in the year prior to baseline visit, or any use within 30 days of baseline visit.

6. Recent use of psychotropic medications (e.g., recent use of psychotropic medications (i.e., anxiolytics, hypnotics, benzodiazepines, antidepressants) where dosage has not been stable for more than 30 days prior to screening.

7. Presence of known cardiovascular, metabolic, or renal disease or individuals with major signs or symptoms suggestive of cardiovascular, metabolic, or renal disease without medical clearance to participate in the exercise program.

8. Presence of any of the following laboratory abnormalities on screening labs:

   1. Abnormal liver function (AST or ALT more than 2 times the upper limit of normal)
   2. Abnormal renal function (creatinine clearance calculated by the Cockcroft-Gault equation <50mL/min or estimated glomerular filtration rate using the MDRD4 equation or the CKD-EPI equation <45mL/min/1.73m2)
   3. Complete Blood Count out of range on screening labs and physician's judgment that abnormal value is clinically significant.

9. Uncontrolled hypertension (resting blood pressure >150/90 mmHg).

10. Orthostatic hypotension and standing systolic BP below 100. Orthostatic hypotension is a reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing.

11. Already participating in 120 minutes or more of moderate intensity exercise per week.

12. Serious illness (requiring systemic treatment and/or hospitalization) within the last 4 weeks.

13. History of any other medical problem or injury that may interfere with ability to exercise.

14. Condition that precludes the safe performance of routine lumbar puncture, including:

    1. INR > 1.4 or other coagulopathy
    2. Platelet cell count of < 50,000/μL
    3. Infection at the desired lumbar puncture site
    4. Taking anti-coagulant medication within 90 days of baseline (Note: low dose aspirin is permitted)
    5. Suspected non-communicating hydrocephalus or intracranial mass
    6. Prohibitive lumbar spinal disease

15. Enrollment in another investigational study that includes an intervention; participation in non-interventional studies may be permitted

16. Receipt of any non-PD investigational product or device or participation in a non-PD drug research study within a period of 30 days (or 5 half-lives of the drug, whichever is longer) before baseline.

17. History of frequent falls (i.e. falling multiple times per week) or considered high fall risk based on investigator assessment

18. Lack of access to computer/tablet and WiFi or any other technical challenges that in the opinion of the investigator would prevent participation in the virtually supervised exercise training program.