Effects of Nicotinamide Riboside on Bioenergetics and Oxidative Stress in Mild Cognitive Impairment/Alzheimer's Dementia

Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Dementia

The primary aim of this study is to investigate the effects of exogenously administered nicotinamide riboside (NR) on brain energy metabolism, oxidative stress, and cognitive function in individuals with mild cognitive impairment (MCI) and mild Alzheimer's dementia (AD).

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment; Mild Alzheimer Disease
• Intervention / Treatment: Drug: Nicotinamide riboside

Detailed Description

Mitochondrial function is mediated, in part, by nicotinamide adenine dinucleotide (NAD). Unfortunately, decreases in NAD+ levels are associated with normal aging, and also with numerous diseases such as AD. Accumulating evidence suggests that NR can enhance mitochondrial function and help slow or reverse these age-related abnormalities. Numerous preclinical and clinical studies have been performed using NR and related compounds to boost NAD+ level in human subjects with various diseases or animal models. However, no studies to date have investigated in vivo metabolic and bioenergetic changes (target engagement) associated with NR supplementation. In this project, we aim to investigate the neurobiological mechanisms and clinical effects of NR in patients with MCI and mild AD using in vivo novel neuroimaging techniques.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Fei Du, PhD; Phone Number: 6178552710; Email: fdu@mclean.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Belmont, Massachusetts, United States, 02478
      • Recruiting
      • McLean Hospital
      • Contact: Fei Du, PhD; Phone Number: 617-855-2710; Email: fdu@mclean.harvard.edu
      • Contact: Brent Forester, MD, MSc; Phone Number: (617) 855-3622; Email: bforester@partners.org
      • Principal Investigator: Fei Du, PhD
      • Principal Investigator: Brent Forester, MD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ability of the participant and/or his/her legally authorized representative to understand the purpose and risks of the study, to provide signed and dated informed consent, and to authorize the use of confidential health information.
• Ability to speak and read fluently in English
• 55-89 years old (inclusive)
• Normal or corrected to normal hearing and vision

• Meet clinical diagnostic criteria for MCI or Mild AD, according to the following criteria:

  1. CDR Global Score of 0.5 (MCI) or 1.0 (mild AD)
  2. 2018 NIA-AA guidelines for MCI/mild AD
• Study partner available for the duration of trial participation
• At least one copy of the APOE ε4 allele or AD+ including Amyloid positive PET scan, Tau positive PET Scan (MK6240 et al.), or CSF AD biomarkers [i.e., amyloid-beta beta (Aβ42) total (T)-tau, and phosphorylated (P)-tau]
• An aggregate risk score > 4 according to the risk analysis method developed by Sabbagh et al. (2017)
• For individuals who are taking niacin (or a vitamin supplement with niacin) of >200mg, the completion of a two-week wash-out period

Exclusion Criteria:

• Current serious or unstable medical or neurological condition that could affect cognitive functioning, as determined by study clinician
• Clinically unstable mood or anxiety disorder within 6 months prior to screening, as determined by study clinician
• Lifetime history of psychotic disorder (i.e. Schizophrenia, Schizoaffective Disorder), as determined by study clinician
• Diagnosis of a mitochondrial disorder
• Any MRI safety contraindications
• History of drug hypersensitivity or intolerance to NR
• Transient ischemic attack or stroke within 1 year prior to screening
• History of alcohol or substance abuse within prior year, as determined by study clinician and urine toxicology screen
• History of head injury rated as moderate or worse, per DSM-5 criteria
• History of seizure within prior 10 years
• Current use of medication with known adverse effects on cognition (benzodiazepines, barbiturates, opiate analgesics, first generation antipsychotic medication, centrally acting anticholinergics, sedating antihistamines, tricyclic anti-depressants)
• Change in dose of any psychiatric medications within 4 weeks of screening visit
• Prior use of L-DOPA, any anti-Parkinsonian medication, or prior treatment with anti-amyloid immunotherapy
• Current use of putative mitochondrial enhancers and antioxidants (e.g carnitine, creatine Co-Q10, N-acetyl cysteine [NAC], pramipexole)
• Initiation of treatment or change in dosing of acetylcholinesterase inhibitors (AChEIs) and memantine within 4 weeks of baseline visit
• Prior use of prescription narcotics 4 weeks before baseline visit
• Female subjects who are pregnant or breastfeeding
• The use of current use of niacin (or a vitamin supplement with niacin) >200mg within the last two weeks prior to study visit.
• Current or lifetime history of cancer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mild Cognitive Impairment and Alzheimer's Dementia; Participants will take 4 pills every day, each containing 250 mg NR (NIAGEN® by Chromadex; www.chromadex.com), via the oral route, for 12 weeks.	Drug: Nicotinamide riboside; Participants will take 4 pills every day, each containing 250 mg NR (NIAGEN® by Chromadex; www.chromadex.com), via the oral route, for 12 weeks.; Other Names: Chromadex NIAGEN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in brain NAD+	Changes in brain NAD+ levels	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Changes in brain redox state	Changes in brain NAD+/NADH ratio	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in mitochondrial function	Changes in brain CK/ATPase activity	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Changes in antioxidant glutathione (GSH) levels	Changes in brain GSH levels	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in cognitive status	Changes in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores. The RBANS provides a total score from 40-160, with a higher score indicating a better outcome.	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Changes in functional status	Changes in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores. The ADCS-ADL provides a total score from 0-78, with a higher score indicating lower severity and a better outcome.	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Changes in mood	Changes in Patient Health Questionnaire (PHQ-9) scores. The PHQ-9 provides a total score from 0-27, with a higher score indicating more symptoms of depression.	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Changes in behavioral or psychiatric symptoms resulting from memory problem	Changes in The Neuropsychiatric Inventory Questionnaire (NPI-Q) responses. The NPI-Q is scored in 12 domains which assess the severity and distress of specific mood, behavioral, or psychiatric symptoms resulting from memory problems. Higher scores indicate greater severity or caregiver distress associated with each of the behavioral and psychiatric symptoms.	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Changes in spirituality and religious beliefs	Changes in responses to series of brief psychometrically valid and reliable measures of spirituality/religion administered in order to evaluate spiritual/religious predictors of adjustment to AD as indexed by emotional, behavioral, neurocognitive, and neural assessments.	Baseline and 12 weeks, pre- and post- 1000 mg NR daily

Collaborators and Investigators

• Sponsor: Mclean Hospital
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Fei Du, PhD, McLean Hospital; Principal Investigator: Brent Forester, MD, MSc, McLean Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2022
• Primary Completion (Anticipated): April 30, 2025
• Study Completion (Anticipated): April 30, 2025

Study Registration Dates

• First Submitted: May 29, 2020
• First Submitted That Met QC Criteria: June 11, 2020
• First Posted (Actual): June 12, 2020

Study Record Updates

• Last Update Posted (Actual): April 4, 2023
• Last Update Submitted That Met QC Criteria: April 3, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Mild Cognitive Impairment; Bioenergetics; Mild Alzheimer's Dementia
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Cognition Disorders; Dementia; Alzheimer Disease; Cognitive Dysfunction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 2020P001652; 1R01AG066670 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The proposed research will include data and biosamples from 50 subjects who will receive open-label treatment with nicotinamide riboside (NR) throughout the duration of the 12-week study. At the time of publication of the primary results or within 9 months of database lock, whichever comes first, we will create deidentified datasets, which could be available for research purposes to qualified individuals within the scientific community.
• IPD Sharing Time Frame: At the time of publication of the primary results or within 9 months of database lock, whichever comes first, we will create deidentified datasets, which could be available for research purposes to qualified individuals within the scientific community.
• IPD Sharing Access Criteria: Data are available to users only under a data-sharing agreement. All users will provide to PIs a proposal of hypotheses, variables needed to test these hypotheses, and plans for dissemination of findings. All users will indicate in a signed document: (1) a commitment to using the data only for research purposes and not to identify any participant, clinician, or plan; (2) a plan for securing the data using appropriate technology/data use protocols; (3) an agreement to either destroy or return the data once analyses are completed or by a specific negotiated date; (4) appropriate IRB approval; (5) a commitment that the information provided to users will not be used for commercial purposes, will not be redistributed to third parties, or shared with any others not on the research team; (6) adequate funding/resources to analyze the data and publish results. All findings generated will be described via peer-reviewed articles in scientific journals made available via PubMed Central.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

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