Clinical trial NCT04740580: Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease
Official title: Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Alzheimer Disease
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: The Methodist Hospital Research Institute
First posted: 2021-02-05
Enrollment: 52
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Placebo-controlled trial
Primary purpose: OTHER

Brief summary: Alzheimer's disease (AD) is associated with significant, progressive cognitive decline. Key defects in mitochondrial fuel metabolism insulin resistance, inflammation and decreased brain glucose uptake are linked to AD. This trial will investigate the effects of supplementing glycine and N-acetylcysteine vs. alanine as placebo on these defects in AD, and examine the effects on cognition.

Detailed description: Glutathione (GSH) deficiency, oxidative stress, mitochondrial dysfunction, insulin resistance and inflammation are linked to Alzheimer's disease (AD). In prior studies, investigators have shown that GSH deficiency contributes to mitochondrial impairment and oxidative stress, and that GSH deficiency can be corrected by supplementing its precursors glycine and cysteine (provided as N-acetylcysteine, NAC), with the combination termed GlyNAC.

This randomized clinical trial will evaluate the effect of GlyNAC vs. alanine placebo supplementation provided for 24-weeks to patients with AD, and measure changes in cognition, GSH concentrations, oxidative stress, brain glucose uptake, brain inflammation and insulin resistance.

Participants who are positive for a beta-amyloid PET scan and meeting cognitive screening criteria will be recruited, and enrolled only after meeting eligibility criteria. Before beginning study supplementation they will undergo imaging studies (MRI, FDG-PET and TSPO-PET scans), and only the FDG- and TSPO-PET scans will be repeated after completing 24-weeks of nutrient supplementation. Cognitive measurements, metabolic and mitochondrial measurements (as described below) will be done before supplementation, and after 12-weeks and 24-weeks of completing supplementation.

Eligibility criteria: Inclusion Criteria:

* Age 55-85 years;
* Gradual and progressive memory loss for more than 1 year, with a Montreal Cognitive Assessment score of 10-20;
* Amyloid positivity on PET scan;
* Availability of a study partner.

Exclusion Criteria:

* hospitalization in past 3 months;
* use of insulin medications;
* untreated thyroid disease;
* creatinine levels \>1.5 mg/dL;
* hemoglobin concentration \<11.0 g/dL;
* known liver disease, or AST/ALT level \>2x ULN;
* history of stroke, brain tumor, active heart failure or active cancer (removable basal cell cancers will not be an exclusion criteria);
* untreated depression or other severe psychiatric disorders;
* pregnancy or nursing (unlikely in this population)

Primary outcomes:
measure: Cognition
timeFrame: Day 0 of supplementation, and 12-weeks and 24-weeks after starting supplementation
measure: Brain glucose uptake
timeFrame: Done before supplementation and 24-weeks after starting supplementation
measure: Brain inflammation
timeFrame: Done before supplementation and 24-weeks after starting supplementation
Secondary outcomes:
measure: Activities of daily living
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Mitochondrial fuel oxidation
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Red-blood cell glutathione, glycine, cysteine and glutamic aid
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Oxidative stress
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Damage due to oxidative stress
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Inflammatory cytokines
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Endothelial dysfunction
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Plasma concentration of Brain-derived neurotropic factor (BDNF)
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
measure: Mitochondrial energetics
timeFrame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Other outcomes:
Locations:
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Rajagopal V Sekhar, M.D.
role: PRINCIPAL_INVESTIGATOR
References: