NAD Supplementation in Parkinson's Disease

This is a single-site, randomized, placebo-controlled clinical trial evaluating oral nicotinamide riboside (NR), a form of vitamin B3, in adults over 55 years of age with Parkinson's disease. NR is commercially available as a dietary supplement, however, its use in this study for Parkinson's disease is considered investigational because it is not approved by the U.S. Food and Drug Administration as a treatment for Parkinson's disease.

The purpose of this study is to explore whether daily NR supplementation over 12 weeks may improve measures related to brain health, memory, motor function, physical performance, and vascular function in participants with Parkinson's disease. Participants will be randomly assigned to receive either NR or placebo. Neither the participants nor the investigators will choose the assigned group.

Study participation includes 3 in-person visits: screening, baseline, and follow-up. Study procedures include collection of medical and health information, questionnaires, blood draw, memory and cognitive testing, non-invasive measurements of brain activity and blood vessel function, walking and balance assessments, grip strength testing, and use of a study watch to assess activity and sleep patterns.

The study procedures will be conducted at the Translational Geroscience Laboratory at the University of Oklahoma Health Sciences Center.

• Nicotinamide Riboside (NR) (Dietary supplement): Participants will be randomized to receive either oral nicotinamide riboside at a total daily dose of 1 g or an identically appearing placebo for 12 weeks.
• Oral placebo capsules (Dietary supplement): 1 g identically appearing placebo capsule

Primary outcomes

• Change in task-evoked neurovascular coupling response measured by functional near-infrared spectroscopy [Baseline to 12 weeks]: Neurovascular coupling will be assessed using functional near-infrared spectroscopy during study tasks. The primary reported value will be the change in task-evoked oxygenated hemoglobin response (change in oxygenated hemoglobin concentration in micromolar) from baseline to the 12-week follow-up visit. Changes will be compared between participants assigned to nicotinamide riboside and participants assigned to placebo.

Secondary outcomes

• Change in NIH Toolbox Cognitive Battery score [Baseline to 12 weeks]: Cognitive performance will be assessed using the NIH Toolbox Cognitive Battery, a computer-based set of tests designed to measure cognitive domains such as memory, attention, executive function, and processing speed. The reported outcome will be the change in NIH Toolbox Cognitive Battery score from baseline to the 12-week follow-up visit. Changes will be compared between participants assigned to nicotinamide riboside and participants assigned to placebo.
• Change in timed walking test completion [Baseline to 12 weeks]: Walking performance will be assessed using a timed walking test. The reported outcome will be the change in time (seconds) required to complete the walking test from baseline to the 12-week follow-up visit.
• Change in gait speed during single and dual-task walking [Baseline to 12 weeks]: Gait speed will be measured using a pressure-sensing walkway during normal walking and while participants walk and perform a cognitive task, such as serial subtraction. The reported outcome will be the change in gait speed (meter/second) from baseline to the 12-week follow-up visit.
• Change in handgrip strength [Baseline to 12 weeks]: Handgrip strength will be measured using a hand-grip dynamometer. Three trials will be performed for each hand, and the reported value (kilograms-force) will be the average grip strength. The reported outcome will be the change in average handgrip strength from baseline to the 12-week follow-up visit.
• Change in static balance performance [Baseline to 12 weeks]: Static balance will be assessed while participants stand with eyes open and eyes closed on both a firm surface and a foam surface. The reported outcome will be the change in the selected balance parameter (seconds, sway area and center-of-pressure displacement) from baseline to the 12-week follow-up visit.

Other outcomes

• Change from baseline in NAD⁺ concentrations and circulating NAD-related metabolites [Baseline to 12 weeks]: NAD⁺ concentrations and circulating NAD-related metabolites will be measured from blood samples collected at baseline and after 12 weeks of treatment. Changes from baseline to the 12-week follow-up visit will be compared between participants assigned to nicotinamide riboside and participants assigned to placebo.
• Change in Montreal Cognitive Assessment score [Baseline to 12 weeks]: Global cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA), a brief screening tool used to evaluate memory and thinking problems. The reported outcome will be the change in total MoCA score (MoCA total score, range 0-30 points) from baseline to the 12-week follow-up visit and changes will be compared between participants assigned to nicotinamide riboside and participants assigned to placebo.
• Change in Parkinson's motor rating scale score [Baseline to 12 weeks]: Motor function will be assessed using a standard Parkinson's disease motor rating scale. The reported outcome will be the change in total motor score from baseline to the 12-week follow-up visit. Changes will be compared between participants assigned to nicotinamide riboside and participants assigned to placebo. Unit of Measure: Points on a scale
• Change in body composition [Baseline to 12 weeks]: Body fat percentage will be measured using a body composition scale. The reported outcome (percent) will be the change in body fat percentage from baseline to the 12-week follow-up visit.
• Change in skeletal muscle mass [Baseline to 12 weeks]: Skeletal muscle mass will be measured using a body composition scale. The reported outcome (kilograms) will be the change in skeletal muscle mass from baseline to the 12-week follow-up visit.
• Change in sleep quality questionnaire score [Baseline to 12 weeks]: Sleep quality will be assessed using a standardized sleep quality questionnaire. The reported outcome will be the change in total sleep quality score from baseline to the 12-week follow-up visit. Changes will be compared between participants assigned to nicotinamide riboside and participants assigned to placebo. Unit of Measure: Points on a scale
• Change in fatigue questionnaire score [Baseline to 12 weeks]: Fatigue will be assessed using a standardized fatigue questionnaire. The reported outcome will be the change in total fatigue score from baseline to the 12-week follow-up visit. Unit of Measure: Points on a scale
• Change in food security questionnaire score [Baseline to 12 weeks]: Food security will be assessed using a standardized food security questionnaire with a 30-day lookback period. The reported outcome will be the change in food security score from baseline to the 12-week follow-up visit. Unit of Measure: Points on a scale
• Change in pain score [Baseline to 12 weeks]: Pain will be assessed using a standardized pain scale or questionnaire. The reported outcome will be the change in pain score from baseline to the 12-week follow-up visit. Unit of Measure: Points on a scale
• Change in daily step count measured by wrist-worn activity monitor watch [Baseline to 12 weeks]: Physical activity will be assessed using a wrist-worn activity monitor. The reported outcome will be the change in average daily step count from baseline to the 12-week follow-up period. Unit of Measure: Steps per day
• Change in total sleep time measured by wrist-worn activity monitor watch [Baseline to 12 weeks]: Sleep duration will be assessed using a wrist-worn activity monitor. The reported outcome will be the change in average total sleep time from baseline to the 12-week follow-up period. Unit of Measure: Minutes per night

Sex: All, ages: 55 Years to 85 Years

Inclusion Criteria:

* Clinical diagnosis of Parkinson's disease according to Movement Disorder Society clinical diagnostic criteria (59), Hoehn and Yahr stages I-III at enrollment (ON medication state when applicable) (60).
* Age ≥55 years at enrollment.
* Adequate hearing and visual acuity to participate in the examinations
* Ability to provide written informed consent in English.
* Ability to complete study procedures, including seated tasks and walking tasks (with or without an assistive device, if needed for safety).
* Stable antiparkinsonian medication regimen for ≥4 weeks prior to baseline (or drug-naive).

Exclusion Criteria:

* Not able to communicate or follow instructions due to aphasia or severe cognitive impairment.
* Active CNS disease including multiple sclerosis, uncontrolled seizures, active cancer.
* Cerebrovascular accident other than TIA within 60 days prior to Visit 0.
* Major psychiatric disease, including major depression not currently controlled on medications, alcohol or drug abuse.
* Abnormal kidney function (creatinine >2mg/dL or EGFR <30mL/min) by most recent labs within 6 months prior to Visit 0.
* Elevated liver enzymes (AST and/or ALT above x2 upper limit of normal) by most recent labs within 6 months prior to Visit 0.
* Treatment with other NAD enhancers (Nicotinamide riboside or nicotinamide mononucleotide) within 4 weeks prior to randomization.
* Any other medical condition and/or unstable or severe medical illness which, in the opinion of investigator, would render the patient inappropriate or too unstable to complete the study protocol.

• Andriy Yabluchanskiy, MD, PhD, Principal investigator, University of Oklahoma Health Campus