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

Aging Clinical Trial

— MB2  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02380573
• Other study ID #: HSC20150410H
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 2015
• Est. completion date: July 2023

Study information

• Verified date: August 2022
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 117
• Est. completion date: July 2023
• Est. primary completion date: April 21, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 45 Years to 89 Years

Eligibility

Inclusion Criteria for all subjects:

1. 45-89 years old

2. All genders

3. All minorities

4. English, Spanish, or multilingual speakers

5. Postmenopausal or surgically sterile females only.

6. 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

7. Inclusion for AD group only: Alzheimer's Early-stage, sporadic-type

Exclusion Criteria:

1. Pregnancy or breastfeeding

2. Contraindication for MRI (Claustrophobia and magnetic metal implants)

3. Glucose-6-phosphate deficiency, methemoglobinemia

4. Allergy to MB

5. Color-blindness

6. Craniotomy, craniectomy or endovascular neurosurgery

7. 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)

8. A serious intercurrent illness likely to cause death within the next 5 years, such as terminal cancer

9. Alcohol and/or drug abuse

10. Any detection of an unknown disease process (eg. new tumor) on the study's neuroimaging at the discretion of the investigators

11. A systolic blood pressure =180 mmHg and/or a diastolic blood pressure =105 mmHg

12. Severe difficulty or an inability to perform any one of the 6 Katz Activities of Daily Living

13. Patients who are unlikely to comply with trial visit schedule or with trial medication,

14. On any psychiatric serotonergic antidepressant medication or psychotropic medication within the last 5 weeks

15. Diagnosis of epilepsy, traumatic brain injury with loss of consciousness, psychosis, panic attacks,

16. Chronic kidney disease, cirrhosis, liver or renal transplants

17. Known hypersensitivity to thiazide diuretics and phenothiazines

18. Any other condition, which in the opinion of the investigator, would put the participant at risk and warrant exclusion from the study

Related Conditions & MeSH terms

• AD
• Aging
• Alzheimer Disease
• Alzheimer's Disease
• Cognitive Dysfunction
• MCI
• Mild Cognitive Impairment

Intervention

Drug:
• Methylene Blue

• FD&C Blue # 2

• Phenazopyridine hydrochloride

Locations

Country	Name	City	State
United States	Research Imaging Institute, The University of Texas Health Science Center at San Antonio	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	Texas Alzheimer's Research and Care Consortium (TARCC)

Country where clinical trial is conducted

United States, 

References & Publications (15)

Bruchey AK, Gonzalez-Lima F. Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue. Am J Pharmacol Toxicol. 2008 Jan 1;3(1):72-79. — View Citation

Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem. 2004 Sep-Oct;11(5):633-40. — View Citation

Huang S, Du F, Shih YY, Shen Q, Gonzalez-Lima F, Duong TQ. Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia. Neuroimage. 2013 May 15;72:237-42. doi: 10.1016/j.neuroimage.2013.01.027. Epub 2013 Jan 26. — View Citation

Lin AL, Poteet E, Du F, Gourav RC, Liu R, Wen Y, Bresnen A, Huang S, Fox PT, Yang SH, Duong TQ. Methylene blue as a cerebral metabolic and hemodynamic enhancer. PLoS One. 2012;7(10):e46585. doi: 10.1371/journal.pone.0046585. Epub 2012 Oct 9. — View Citation

Long JA, Watts LT, Chemello J, Huang S, Shen Q, Duong TQ. Multiparametric and longitudinal MRI characterization of mild traumatic brain injury in rats. J Neurotrauma. 2015 Apr 15;32(8):598-607. doi: 10.1089/neu.2014.3563. Epub 2015 Jan 22. — View Citation

Mackworth JF. Vigilance, arousal, and habituation. Psychol Rev. 1968 Jul;75(4):308-22. Review. — View Citation

Naylor GJ, Martin B, Hopwood SE, Watson Y. A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry. 1986 Aug;21(10):915-20. — View Citation

Peter C, Hongwan D, Küpfer A, Lauterburg BH. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol. 2000 Jun;56(3):247-50. — View Citation

Rodriguez P, Jiang Z, Huang S, Shen Q, Duong TQ. Methylene blue treatment delays progression of perfusion-diffusion mismatch to infarct in permanent ischemic stroke. Brain Res. 2014 Nov 7;1588:144-9. doi: 10.1016/j.brainres.2014.09.007. Epub 2014 Sep 8. — View Citation

Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45. doi: 10.1016/j.pneurobio.2011.10.007. Epub 2011 Nov 3. Review. — View Citation

Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P. Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study. Hum Brain Mapp. 2005 Dec;26(4):231-9. — View Citation

Shen Q, Du F, Huang S, Rodriguez P, Watts LT, Duong TQ. Neuroprotective efficacy of methylene blue in ischemic stroke: an MRI study. PLoS One. 2013 Nov 21;8(11):e79833. doi: 10.1371/journal.pone.0079833. eCollection 2013. — View Citation

Talley Watts L, Long JA, Chemello J, Van Koughnet S, Fernandez A, Huang S, Shen Q, Duong TQ. Methylene blue is neuroprotective against mild traumatic brain injury. J Neurotrauma. 2014 Jun 1;31(11):1063-71. doi: 10.1089/neu.2013.3193. Epub 2014 Apr 8. — View Citation

Telch MJ, Bruchey AK, Rosenfield D, Cobb AR, Smits J, Pahl S, Gonzalez-Lima F. Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. Am J Psychiatry. 2014 Oct;171(10):1091-8. doi: 10.1176/appi.ajp.2014.13101407. — View Citation

Wang L, Li H, Liang Y, Zhang J, Li X, Shu N, Wang YY, Zhang Z. Amnestic mild cognitive impairment: topological reorganization of the default-mode network. Radiology. 2013 Aug;268(2):501-14. doi: 10.1148/radiol.13121573. Epub 2013 Mar 12. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Functional Connectivity measures	fMRI measurements will be obtained while the subject rests in the scanner	baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Other	CO2 challenge	Cerebral blood flow measurements will be acquired during a brief (3-5 minutes) inhalation of medical-grade 5% CO2 in air.	baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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

External Links

•   Research Imaging Institute
•   Texas Alzheimer's Research and Care Consortium