Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

Alzheimer Disease Clinical Trial

Official title:

Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04740580
• Other study ID #: H48186
• Status: Recruiting
• Phase: Early Phase 1
• Start date: February 15, 2022
• Est. completion date: December 31, 2026

Study information

• Verified date: March 2024
• Source: Baylor College of Medicine
• Contact: Rajagopal V Sekhar, M.D.
• Phone: 7137983908
• Email: rsekhar[@]bcm.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 52
• Est. completion date: December 31, 2026
• Est. primary completion date: April 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years to 85 Years

Eligibility

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)

Related Conditions & MeSH terms

• Alzheimer Disease
• Inflammation

Intervention

Dietary Supplement:
• Glycine
The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC)
• N-acetylcysteine
The active arm will supplement a combination of glycine and N-acetylcysteine (GlyNAC)
• Alanine
The placebo arm will supplement Alanine

Locations

Country	Name	City	State
United States	Baylor College of Medicine	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Baylor College of Medicine	The Methodist Hospital Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cognition	Measured using ADAS-Cog testing	Day 0 of supplementation, and 12-weeks and 24-weeks after starting supplementation
Primary	Brain glucose uptake	Measured using brain FDG-PET scan	Done before supplementation and 24-weeks after starting supplementation
Primary	Brain inflammation	Done using brain TSPO-PET scan	Done before supplementation and 24-weeks after starting supplementation
Secondary	Activities of daily living	Measured using the ADCS-ADL scale	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Mitochondrial fuel oxidation	Measured using indirect calorimetry in the fasted and post-glucose fed state	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Red-blood cell glutathione, glycine, cysteine and glutamic aid	Measured using UPLC	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Oxidative stress	Measured as plasma concentrations of TBARS and malondialdehyde	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Damage due to oxidative stress	Measured as plasma concentration of isoprostanes	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Inflammatory cytokines	Measured as plasma concentrations of IL6, TNFa	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Endothelial dysfunction	Measured as plasma concentrations of sICAM1, sVCAM1, E-selectin	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Plasma concentration of Brain-derived neurotropic factor (BDNF)	Measured using an ELISA kit	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation
Secondary	Mitochondrial energetics	Measured using the Oroboros high-resolution respirometer	Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation