Glutathione in Mild Cognitive Impairment

Study Overview
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Brief Summary
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Elderly humans have an increased risk of dementia which begins as mild defects in memory called mild cognitive impairment. Glutathione (GSH), a key endogenous antioxidant has been linked to cognition. This exploratory study will investigate mechanisms linked to GSH for cognitive impairment (and improvement) by studying humans with mild cognitive impairment who will be evaluated 12-weeks after receiving either N-acetylcysteine and glycine (GSH precursors), or receiving alanine, and a further 12-weeks after stopping these supplements.

Detailed Description
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Subjects with MCI will be recruited by written informed consent using forms approved by the Baylor IRB. Subjects will stop nonvitamin supplements for 4wks before screening labs (blood count, HbA1c, glucose, lipid profile, liver profile, blood urea nitrogen, Creatinine, thyroid stimulating hormone, free T4), and for the entire 24wks duration of the study. 60 fasted subjects will have the following measures before and after 12wks of supplementation with cysteine (as N-acetylcysteine) plus glycine vs alanine: (1) Cognitive function using ADCS-PACC (Alzheimer's Disease Co-operative Study-Preclinical Alzheimer's Cognitive Composite which includes Free and Cued Selective Reminding Test, Immediate and Delayed paragraph recall score, Digit-Symbol Substitution Test, Mini mental state examination; (2) Red-cell concentrations of GSH, cysteine, glycine, glutamic acid; plasma malondialdehyde, F2/F3-isoprostanes, sICAM, sVCAM, E-selectin; endothelial function; (3) Mitochondrial glucose oxidation by calorimetry. Measures will be repeated for washout effects 12-wks after stopping supplements.

Official Title
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Glutathione in Mild Cognitive Impairment

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Dietary Supplement: Glycine
* Dietary Supplement: N-acetylcysteine (NAC)
* Dietary Supplement: Alanine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria at study entry: (1) Diagnosis of Mild Cognitive Impairment Exclusion Criteria at study entry: (1) hospitalization within past 3 months; (2) known diabetes; (3) creatinine greater than or equal to 1.5 mg/dL; (4) hemoglobin concentration less than 11 g/dL; (5) known liver disease, or AST/ALT greater than or equal to 2x ULN; (6) history of stroke, brain tumor, or active heart failure; (7) history of psychiatric disorders; (8) untreated depression.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MCI-active<br>30 Subjects with MCI will receive N-acetylcysteine and glycine for 12-weeks. ll subjects will be studied at baseline prior to supplementation, after completing 12-weeks of supplementation, and 12-weeks after stopping supplementation (i.e. at 24-weeks). Supplements are only provided for first 12-weeks. | Dietary Supplement: Glycine<br>* Dietary Supplement: glycine will be supplemented in the active arm for 12-weeks<br>Dietary Supplement: N-acetylcysteine (NAC)<br>* Dietary Supplement: NAC will be supplemented in the active arm for 12-weeks<br>|
| Placebo Comparator: MCI-placebo<br>30 subjects will received alanine for 12-weeks. All subjects will be studied at baseline prior to supplementation, after completing 12-weeks of supplementation, and 12-weeks after stopping supplementation (i.e. at 24-weeks). Supplements are only provided for first 12-weeks | Dietary Supplement: Alanine<br>* Dietary Supplement: Alanine will be supplemented in the placebo arm for 12-weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition | Measured using ADCS-PACC | Change between 0-weeks and 12-weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of Glutathione, cysteine, glycine, glutamic acid | Measured in red cells | Change between 0-weeks and 12-weeks | 
| Concentrations of malondialdehyde, F2,F3 isoprostanes | Measured in plasma | Change between 0-weeks and 12-weeks | 
| Endothelial function markers sICAM, sVCAM, E-selectin | Measured in plasma | Change between 0-weeks and 12-weeks | 
| Endothelial function | Measured using the EndoPAT system | Change between 0-weeks and 12-weeks | 
| Mitochondrial fuel oxidation in fasted and fed states | Measured using calorimetry | Change between 0-weeks and 12-weeks |