Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease
- Conditions
- Alzheimer Disease
- Interventions
- Dietary Supplement: AlanineDietary Supplement: GlycineDietary Supplement: N-acetylcysteine
- Registration Number
- NCT04740580
- Lead Sponsor
- Baylor College of Medicine
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 52
- 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.
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Alanine Alanine Alanine is an amino-acid (protein), and not a precursor of glutathione synthesis Glycine plus N-acetylcysteine N-acetylcysteine Glycine and cysteine are amino-acid (protein) precursors of glutathione. Cysteine is provided as N-acetylcysteine Glycine plus N-acetylcysteine Glycine Glycine and cysteine are amino-acid (protein) precursors of glutathione. Cysteine is provided as N-acetylcysteine
- Primary Outcome Measures
Name Time Method Cognition Day 0 of supplementation, and 12-weeks and 24-weeks after starting supplementation Measured using ADAS-Cog testing
Brain inflammation Done before supplementation and 24-weeks after starting supplementation Done using brain TSPO-PET scan
Brain glucose uptake Done before supplementation and 24-weeks after starting supplementation Measured using brain FDG-PET scan
- Secondary Outcome Measures
Name Time Method Plasma concentration of Brain-derived neurotropic factor (BDNF) Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured using an ELISA kit
Activities of daily living Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured using the ADCS-ADL scale
Mitochondrial fuel oxidation Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured using indirect calorimetry in the fasted and post-glucose fed state
Inflammatory cytokines Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured as plasma concentrations of IL6, TNFa
Endothelial dysfunction Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured as plasma concentrations of sICAM1, sVCAM1, E-selectin
Oxidative stress Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured as plasma concentrations of TBARS and malondialdehyde
Damage due to oxidative stress Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured as plasma concentration of isoprostanes
Mitochondrial energetics Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured using the Oroboros high-resolution respirometer
Red-blood cell glutathione, glycine, cysteine and glutamic aid Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation Measured using UPLC
Trial Locations
- Locations (1)
Baylor College of Medicine
🇺🇸Houston, Texas, United States