Clinical trial NCT04430517: Effects of Nicotinamide Riboside on Bioenergetics and Oxidative Stress in Mild Cognitive Impairment/Alzheimer's Dementia
Official title: Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Dementia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Mild Cognitive Impairment
Mild Alzheimer Disease
Keywords: Mild Cognitive Impairment
Bioenergetics
Mild Alzheimer's Dementia
Lead sponsor: Mclean Hospital
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2020-06-12
Enrollment: 50
Sex: ALL
Minimum age (years): 55
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Changes in brain NAD+
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
measure: Changes in brain redox state
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Secondary outcomes:
measure: Changes in mitochondrial function
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
measure: Changes in antioxidant glutathione (GSH) levels
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
Other outcomes:
measure: Changes in cognitive status
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
measure: Changes in functional status
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
measure: Changes in mood
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
measure: Changes in behavioral or psychiatric symptoms resulting from memory problem
timeFrame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
measure: Changes in spirituality and religious beliefs
timeFrame: Baseline and 12 weeks, pre- and post- 1000 mg NR daily
Locations:
city: Belmont
country: United States
facility: McLean Hospital
state: Massachusetts
Study officials:
affiliation: Mclean Hospital
name: Fei Du, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mclean Hospital
name: Brent Forester, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: