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Glutathione and Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT04740580
Recruitment Status : Not yet recruiting
First Posted : February 5, 2021
Last Update Posted : May 10, 2021
Sponsor:
Collaborator:
Nantz National Alzheimer's Center, Methodist Hospital, Houston, TX
Information provided by (Responsible Party):
Rajagopal V Sekhar, 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.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Dietary Supplement: Glycine Dietary Supplement: N-acetylcysteine Dietary Supplement: Alanine 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Placebo-controlled trial
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Other
Official Title: Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease
Estimated Study Start Date : July 1, 2021
Estimated Primary Completion Date : May 31, 2025
Estimated Study Completion Date : May 31, 2025


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




Primary Outcome Measures :
  1. Cognition [ Time Frame: Day 0 of supplementation, and 12-weeks and 24-weeks after starting supplementation ]
    Measured using ADAS-Cog testing

  2. Brain glucose uptake [ Time Frame: Done before supplementation and 24-weeks after starting supplementation ]
    Measured using brain FDG-PET scan

  3. Brain inflammation [ Time Frame: Done before supplementation and 24-weeks after starting supplementation ]
    Done using brain TSPO-PET scan


Secondary Outcome Measures :
  1. Activities of daily living [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured using the ADCS-ADL scale

  2. Mitochondrial fuel oxidation [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured using indirect calorimetry in the fasted and post-glucose fed state

  3. Red-blood cell glutathione, glycine, cysteine and glutamic aid [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured using UPLC

  4. Oxidative stress [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured as plasma concentrations of TBARS and malondialdehyde

  5. Damage due to oxidative stress [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured as plasma concentration of isoprostanes

  6. Inflammatory cytokines [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured as plasma concentrations of IL6, TNFa

  7. Endothelial dysfunction [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured as plasma concentrations of sICAM1, sVCAM1, E-selectin

  8. Plasma concentration of Brain-derived neurotropic factor (BDNF) [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured using an ELISA kit

  9. Mitochondrial energetics [ Time Frame: Day 0 of supplementation, 12-weeks and 24-weeks after starting supplementation ]
    Measured using the Oroboros high-resolution respirometer



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Ages Eligible for Study:   55 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04740580


Contacts
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Contact: Rajagopal V Sekhar, M.D. 7137983908 rsekhar@bcm.edu

Locations
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United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Contact: Rajagopal V Sekhar, MD    713-798-3908    rsekhar@bcm.edu   
Sponsors and Collaborators
Baylor College of Medicine
Nantz National Alzheimer's Center, Methodist Hospital, Houston, TX
Investigators
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Principal Investigator: Rajagopal V Sekhar, M.D. Baylor College of Medicine
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Responsible Party: Rajagopal V Sekhar, Associate Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT04740580    
Other Study ID Numbers: H48186
First Posted: February 5, 2021    Key Record Dates
Last Update Posted: May 10, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Acetylcysteine
N-monoacetylcystine
Glycine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes
Glycine Agents
Neurotransmitter Agents