Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease
- Conditions
- Alzheimer's DiseaseMild Cognitive ImpairmentMCIAgingAD
- Interventions
- Registration Number
- NCT02380573
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 117
Not provided
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Healthy Aging Placebo Phenazopyridine hydrochloride Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Alzheimer's Disease (AD) Placebo Phenazopyridine hydrochloride Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Healthy Middle Age MB Phenazopyridine hydrochloride Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Healthy Middle Age Placebo Phenazopyridine hydrochloride Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Healthy Aging MB Phenazopyridine hydrochloride Methylene Blue (USP grade, 282mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Healthy Aging Placebo FD&C Blue # 2 Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Cognitive Impairment (MCI) MB Phenazopyridine hydrochloride Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Cognitive Impairment (MCI) Placebo FD&C Blue # 2 Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Cognitive Impairment (MCI) Placebo Phenazopyridine hydrochloride Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Alzheimer's Disease (AD) MB Phenazopyridine hydrochloride Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Alzheimer's Disease (AD) Placebo FD&C Blue # 2 Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Healthy Middle Age Placebo FD&C Blue # 2 Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Healthy Aging MB Methylene Blue Methylene Blue (USP grade, 282mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Cognitive Impairment (MCI) MB Methylene Blue Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Mild Alzheimer's Disease (AD) MB Methylene Blue Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks) Healthy Middle Age MB Methylene Blue Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
- Primary Outcome Measures
Name Time Method fMRI Measurement baseline, 2 weeks and 12 weeks fMRI measurement of task blocked activation during Wechsler Memory Scale III
Wechsler Memory Scale, Third Edition baseline, 2 weeks ± 3 days, 12 weeks ± 3 days Working memory task behavioral measures (ie. correct number of responses) Score is 0-104, with higher scores being better.
fMRI During FNAME baseline, 2 weeks ± 3 days,12 weeks ± 3 days Functional Magnetic Resonance Imaging (fMRI) measurement of task blocked activation.
Measure reflects blood flow counts, and is not a scale with a high or low score.FNAME baseline, 2 weeks ± 3 days,12 weeks ± 3 days Face-Name Task behavioral measures (ie. correct recalls). The FNAME is a cross-modal associative memory test which includes 16 face-name pairs and 16 face-occupation pairs, with a total of 32 pairs to remember. Scores range from 0-32, higher scores are better
fMRI During Psychomotor Vigilance Task baseline,2 weeks ± 3 days,12 weeks ± 3 days fMRI measurement of task blocked activation
Psychomotor Vigilance Task baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days Psychomotor vigilance task (PVT) behavioral measures (ie. reaction time). The primary outcome measures of PVT performance, lapses, are defined as reaction times exceeding 500 msec or failure to react. The PVT lapses are believed to represent perceptual, processing, or executive failures in the central nervous system (CNS) Lower scores are better, as they indicate quicker reaction times.
Wechsler Memory Scale III, Logical Memory Subset baseline, then 12 weeks ± 3 days The patient is read two stories, out loud, by the test administrator. After each story is read, the patient is then asked to tell the story back to the administrator, as well as possible. Scores range from 0-75, with higher scores indicating better outcome.
Mini-Mental State Exam (MMSE) baseline, 2 weeks ± 3 days,12 weeks ± 3 days Short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings. The MMSE contains 11 questions with scores ranging from 1-5 depending on how many responses are required for each question. One point is assigned for each correct answer. The total score can range from 0-30 with a higher score indicating better cognitive skills.
CLOX: An Executive Clock Drawing Test baseline, 2 weeks ± 3 days, 12 weeks ± 3 days The subject draws a clock that says 1:45. Performance is rated according to the CLOX directions, and scored as "CLOX1" with scores ranging from 0-15 with a lower score indicating greater impairment. CLOX1 reflects performance in a novel and ambiguous situation. The CLOX's second step is a simple copying task. The examiner allows the patient to observe him or her drawing a clock in the circle provided on the scoring sheet. The examiner sets the hands again to "1:45", places the 12, 6, 3, and 9 first, and makes the hands into arrows. The patient is allowed to copy the examiner's clock. This clock is scored as "CLOX2" with scores ranging from 0-15 with a lower score indicating greater impairment. Participants can earn up to 15 points for each test, this is summed to give a possible score out of 30 with a higher score indicating less cognitive impairment. Scores reported are from inter-rater reliability
- Secondary Outcome Measures
Name Time Method Cerebral Blood Flow Measures baseline, 2 weeks ± 3 days, 12 weeks ± 3 days Resting measurements will be used to assess response and CBF using fMRI. Scores are baseline, percent change between baseline and 2 weeks, baseline and 12 weeks
Trial Locations
- Locations (1)
Research Imaging Institute, The University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States