Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease

Study Overview
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Brief Summary
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A double-blind, placebo-controlled study that aims to investigate the effect of 2-week and 12-week administration of USP methylene blue (MB) on cerebral blood flow, functional connectivity, memory and attention cognitive abilities using fMRI and behavioral measures in healthy aging, mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) subjects.

Detailed Description
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Healthy aging and aging human subjects with mild cognitive impairment and mild Alzheimer's disease from the TARCC cohort and South Texas will be studied using a double-blind, placebo-controlled design. After informed consent and familiarity with the tasks and the MRI environment, the subject will enter an MRI scanner and perform the following 6 tasks. fMRI and behavioral data will be collected simultaneously while inside the scanner. Delayed match-to-sample task: The subject views a pattern for a few seconds and then is prompted to recall the memorized pattern using a response system (approx. 10 mins). Face-name task: The subject is shown blocks of stimuli where a novel or familiar face is paired with a name. In a later run, the subjects are asked whether the correct name is matched with the correct face. (approx. 10 mins). Psychomotor vigilance task: The subject receives a visual cue that alerts them to press a button as fast as possible. (approx. 10 mins). Cerebral Blood Flow and Resting State fMRI: Subject scanned with eyes closed and told to not think about a particular topic, each lasting about 10 minutes. fMRI data acquisition: fMRI and neuropsychological battery measurements will be made before the intervention. These measurements will then be repeated after 2 weeks and 12 weeks. fMRI will image changes in regional brain activity associated with these tasks. The MRI pulse sequences include diffusion tensor imaging, standard and non-invasive anatomical and quantitative MRI for coregistration and blood-oxygen-level dependent (BOLD) fMRI. CO2 challenge: Cerebral blood flow measurements will be obtained while the subject rests in the scanner after administration of medical-grade 5% CO2 in air for 3-5 minutes. This will be repeated on weeks 2 and 12. Data analysis: Standard fMRI analysis will be analyzed using established fMRI software. Statistical parametric analysis will be performed to generate activation maps. fMRI data will be corrected for multiple comparisons using a false discovery rate (q < 0.05) and threshold for cluster values to conservatively control for type I error. Behavioral data will be analyzed with paired t-test and ANOVA calculations used for group comparison with p < 0.05 (with Bonferroni correction) considered statistically significant. Expected results: The investigators predict that, compared to placebo, MB will: i) improve working memory retention in a delayed match-to-sample task by memory performance and enhanced fMRI responses in the prefrontal cortex and parietal lobes, ii) improve episodic memory as determined by fMRI activation in the hippocampus, medial temporal lobes and prefrontal cortex iii) reduce reaction time in a psychomotor vigilance test and enhance fMRI responses within a cortical sustained attention network iv) improve CBF and v) improve fMRI connectivity in default mode and visuospatial and memory networks/subnetworks. The fMRI and behavioral performance effects on memory will be greater in the MCI and mild AD groups than in the healthy aging group. The effects will be greater in the MCI and AD groups than in the control groups. Power analysis: Sample sizes were calculated using an fMRI power tool based on pilot data from the current study for a power of 80%, alpha = 0.05, False Discovery Rate < 0.05, to detect statistical difference between MB and placebo23. The investigators estimate they will need 20-25 subjects per arm of group (complete studies) and thus will recruit 200-240 subjects to account for potential failed studies.

Official Title
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Cognitive and Functional Connectivity Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease

Conditions
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Mild Cognitive Impairment, MCI, Aging, Alzheimer's Disease, AD

Intervention / Treatment
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* Drug: Methylene Blue
* Drug: FD&C Blue # 2
* Drug: Phenazopyridine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for all subjects: 45-89 years old All genders All minorities English, Spanish, or multilingual speakers Postmenopausal or surgically sterile females only. Inclusion for MCI group only: participants will meet the criteria for amnestic and non-amnestic MCI such as those currently used by Texas Alzheimer's Research and Care Consortium (TARCC) consensus diagnosis Inclusion for AD group only: Alzheimer's Early-stage, sporadic-type Exclusion Criteria: Pregnancy or breastfeeding Contraindication for MRI (Claustrophobia and magnetic metal implants) Glucose-6-phosphate deficiency, methemoglobinemia Allergy to MB Color-blindness Craniotomy, craniectomy or endovascular neurosurgery A current diagnosis of stroke, transient ischemic attack (TIA), any primary neurodegenerative disorder, or any other causes of neuropsychologic disturbances or secondary dementia (MCI or AD does not exclude subject) A serious intercurrent illness likely to cause death within the next 5 years, such as terminal cancer Alcohol and/or drug abuse Any detection of an unknown disease process (eg. new tumor) on the study's neuroimaging at the discretion of the investigators A systolic blood pressure ≥180 mmHg and/or a diastolic blood pressure ≥105 mmHg Severe difficulty or an inability to perform any one of the 6 Katz Activities of Daily Living Patients who are unlikely to comply with trial visit schedule or with trial medication, On any psychiatric serotonergic antidepressant medication or psychotropic medication within the last 5 weeks Diagnosis of epilepsy, traumatic brain injury with loss of consciousness, psychosis, panic attacks, Chronic kidney disease, cirrhosis, liver or renal transplants Known hypersensitivity to thiazide diuretics and phenothiazines Any other condition, which in the opinion of the investigator, would put the participant at risk and warrant exclusion from the study

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Aging MB<br>Methylene Blue (USP grade, 282mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: Methylene Blue<br> <br> * Other names: Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|
| Placebo Comparator: Healthy Aging Placebo<br>Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: FD&C Blue # 2<br> <br> * Other names: Placebo;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|
| Experimental: Mild Cognitive Impairment (MCI) MB<br>Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: Methylene Blue<br> <br> * Other names: Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|
| Placebo Comparator: Mild Cognitive Impairment (MCI) Placebo<br>Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: FD&C Blue # 2<br> <br> * Other names: Placebo;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|
| Experimental: Mild Alzheimer's Disease (AD) MB<br>Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: Methylene Blue<br> <br> * Other names: Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|
| Placebo Comparator: Mild Alzheimer's Disease (AD) Placebo<br>Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: FD&C Blue # 2<br> <br> * Other names: Placebo;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|
| Experimental: Healthy Middle Age MB<br>Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: Methylene Blue<br> <br> * Other names: Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|
| Placebo Comparator: Healthy Middle Age Placebo<br>Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) | Drug: FD&C Blue # 2<br> <br> * Other names: Placebo;Drug: Phenazopyridine hydrochloride<br> <br> * Other names: Azo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Working memory task | fMRI measurement of task blocked activation | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 
| Working memory task response | Working memory task behavioral measures (ie. correct number of responses) | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 
| Episodic memory task | fMRI measurement of task blocked activation | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 
| Episodic memory task response | Face-Name Task behavioral measures (ie. correct recalls) | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 
| Sustained attention task | fMRI measurement of task blocked activation | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 
| Sustained attention task reaction time | Psychomotor vigilance task (PVT) behavioral measures (ie. reaction time) | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 
| Neuropsychological battery composite score | TARCC designed neurocognitive tests | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral blood flow measures | Resting measurements will be used to assess response and CBF using fMRI | baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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methylene blue, fMRI