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

Mild Cognitive Impairment Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04430517
• Other study ID #: 2020P001652
• Secondary ID: 1R01AG066670
• Status: Recruiting
• Phase: Early Phase 1
• Start date: March 2, 2022
• Est. completion date: April 30, 2025

Study information

• Verified date: April 2023
• Source: Mclean Hospital
• Contact: Fei Du, PhD
• Phone: 6178552710
• Email: fdu[@]mclean.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: April 30, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years to 89 Years

Eligibility

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 e4 allele or AD+ including Amyloid positive PET scan, Tau positive PET Scan (MK6240 et al.), or CSF AD biomarkers [i.e., amyloid-beta beta (Aß42) 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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction
• Dementia
• Mild Cognitive Impairment

Intervention

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.

Locations

Country	Name	City	State
United States	McLean Hospital	Belmont	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Mclean Hospital	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	Changes in brain NAD+	Changes in brain NAD+ levels	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Primary	Changes in brain redox state	Changes in brain NAD+/NADH ratio	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Secondary	Changes in mitochondrial function	Changes in brain CK/ATPase activity	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Secondary	Changes in antioxidant glutathione (GSH) levels	Changes in brain GSH levels	Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily