Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Early Phase 1 |
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 will be recruited, and enrolled only after meeting eligibility criteria. Before beginning study supplementation they will undergo imaging studies (MRI, Tau-PET, 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Glycine plus N-acetylcysteine Glycine and cysteine are amino-acid (protein) precursors of glutathione. Cysteine is provided as N-acetylcysteine |
Dietary Supplement: Glycine
The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC)
Dietary Supplement: N-acetylcysteine
The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC)
|
| Placebo Comparator: Alanine Alanine is an amino-acid (protein), and not a precursor of glutathione synthesis |
Dietary Supplement: Alanine
The placebo arm will supplement Alanine
|
Outcome Measures
Primary Outcome Measures
- Cognition [Day 0 of supplementation, and 12-weeks and 24-weeks after starting supplementation]
Measured using ADAS-Cog testing
- Brain glucose uptake [Done before supplementation and 24-weeks after starting supplementation]
Measured using brain FDG-PET scan
- Brain inflammation [Done before supplementation and 24-weeks after starting supplementation]
Done using brain TSPO-PET scan
Secondary Outcome Measures
- 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
- Red-blood cell glutathione, glycine, cysteine and glutamic aid [Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation]
Measured using UPLC
- 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
- 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
- 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
- Mitochondrial energetics [Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation]
Measured using the Oroboros high-resolution respirometer
Eligibility Criteria
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;
-
Tau positivity on PET scan;
-
Availability of a study partner.
Exclusion Criteria:
-
hospitalization in past 3 months;
-
known diabetes or use of anti-diabetic 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)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Baylor College of Medicine | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Baylor College of Medicine
- The Methodist Hospital Research Institute
Investigators
- Principal Investigator: Rajagopal V Sekhar, M.D., Baylor College of Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H48186