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Measuring Fluid Flow in the Brain Using Alcohol and MRI in Healthy Participants

Studies

Study First Submitted Date 2020-10-23
Study First Posted Date 2020-10-29
Last Update Posted Date 2023-05-10
Start Month Year January 2024
Primary Completion Month Year January 2025
Verification Month Year May 2023
Verification Date 2023-05-31
Last Update Posted Date 2023-05-10

Detailed Descriptions

Sequence: 20842034
Description Study hypothesis: Intracranial interstitial fluid (ISF) flow is crucial for adequate clearance of extracellular waste products from the brain parenchyma. Recent demonstrations have shown that its deficiency leads to their accumulation in neurodegenerative disorders. The hypothesis of this project is MRS and/or MTI can be used to give a quantitative measure of intracranial interstitial fluid flow. Goals: The primary goal is to provide a quantitative measure of ISF flow rate through the brain parenchyma. This will be performed by making multiple measurements of the characteristic ethanol peak at different time points with MRS or ethanol-related decreases in water saturation signal in MTI, following its ingestion. This will allow the transit of ethanol, which is equal to the transit of ISF, to be obtained and reported using common transport parameters such as time-to-peak (TTP) and mean transit time (MTT). Secondary objectives include determining a range of values that may be considered normal ranges for ISF flow rates in healthy individuals. This will be helpful in future experiments when such values will be compared with rates measuring for individuals with various different types of intracranial pathology. INVESTIGATION STUDY DESIGN: This pilot project will be experimental with the aim of determining the best quantitative criteria from ethanol MRS or MTI labeling of intracranial ISF flow data to give a reliable clearance metric. To achieve this, the initial proof of concept study will involve 10 healthy male volunteers between the ages of 20-75 undergoing the ethanol-MRS or MTI protocol. This work will be quantitative in nature, since discrete MR signals will be measured and analyzed. Data Collection Study participants will be required to have fasted a minimum of 6 hours prior to initiating the experiment and refrained from alcohol ingestion for 12 hours. A quick screen will be performed by a research team member of the participant’s medications, alcohol consumption, and any neurological conditions prior to moving forward with the examination to verify all volunteers meet all inclusion criteria for the study. Data will be acquired using either magnetic resonance spectroscopy (MRS), magnetic resonance spectroscopic imaging (MRSI), or magnetization transfer imaging (MTI). A relatively short acquisition (5-7 minutes) will be repeated to acquire a time course for ethanol transit through the brain. Each study participant will undergo pre-ethanol ingestion MR acquisition. The volunteer will then be given an ethanol-containing beverage. The ethanol content will be approximately 0.5 g/kg, mixed in 355 mL of a non-caffeinated, sugar-free carbonated drink as done previously in other human ethanol MRS experiments (7). The drink must be consumed within 5 minutes and may be provided through clear plastic tubing so the subject does not have to be removed from the scanner. Blood alcohol concentration (BAC) levels for this work are not expected to exceed 0.05%, considered a low level, at the end of the experiment. After consuming the ethanol-containing beverage, scout images will be acquired again to re-localize the voxels for each subsequent spectral image if study participants need to be placed back in the MR scanner (ie. did not ingest ethanol through tubing). MRS, MRSI, or MTI will be performed at ~5-7 minutes/spectrum or image, repeating the process continuously for 60-90 minutes. During the scanning, the patient may be asked to breathe through the ClearMateTM, a specially designed, MR-compatible non-rebreathing circuit that provides oxygen and carbon dioxide that quickly decreases a person’s blood alcohol level. After the final acquisition, the patient will be taken to a supervised area where he/she will remain until blood ethanol levels are registered below 0.05% via a standard breathalyzer test. Once the participant has met this requirement and state that they feel safe to leave the premises, they will be free to go within the recommendations of the study and their participation considered to be complete. Breath sampling will be performed at 30-minute intervals if it is still high. Finally, since the most accurate way to assess the blood alcohol kinetics is by making comparisons of arterial and venous blood levels, peripheral arterial lines will be inserted (by a Sunnybrook staff anesthesiologist) in a few select study participants. Periodic arterial blood samples from these individuals will be measured for the blood alcohol content and compared with the values for blood samples drawn concurrently from the peripheral intravenous line.

Facilities

Sequence: 201200893
Name Sunnybrook Research Institute
City Toronto
State Ontario
Zip M4N 3M5
Country Canada

Facility Contacts

Sequence: 28268554 Sequence: 28268555
Facility Id 201200893 Facility Id 201200893
Contact Type primary Contact Type backup
Name Wilfred W Lam, DPhil Name Bharathy Lingamoorthy
Email lamw@sri.utoronto.ca Email bharathy.lingamoorthy@sunnybrook.ca
Phone 416-480-6100 Phone 416-480-4293
Phone Extension 63390

Facility Investigators

Sequence: 18431175
Facility Id 201200893
Role Sub-Investigator
Name Jesse M Klostranec, MD

Conditions

Sequence: 52479744
Name Diagnostic Technics, Neurological
Downcase Name diagnostic technics, neurological

Id Information

Sequence: 40379472
Id Source org_study_id
Id Value 023-2020

Countries

Sequence: 42815159
Name Canada
Removed False

Design Groups

Sequence: 55935799 Sequence: 55935800 Sequence: 55935801 Sequence: 55935802 Sequence: 55935803 Sequence: 55935804 Sequence: 55935805 Sequence: 55935806 Sequence: 55935807
Group Type Active Comparator Group Type Active Comparator Group Type Active Comparator Group Type Active Comparator Group Type Active Comparator Group Type Active Comparator Group Type Active Comparator Group Type Active Comparator Group Type Active Comparator
Title Single-voxel MRS Title Multi-voxel MRSI Title Magnetization Transfer Imaging Title Single-voxel MRS + ClearMate(TM) Title Multi-voxel MRSI + ClearMate(TM) Title Magnetization Transfer Imaging + ClearMate(TM) Title Single-voxel MRS + CM + Blood Sampling Title Multi-voxel MRSI + CM + Blood Sampling Title Magnetization Transfer Imaging + CM + Blood Sampling
Description MRS Description MRSI Description MTI Description MRS+CM Description MRSI+CM Description MTI+CM Description MRS+CM+B Description MRSI+CM+B Description MTI+CM+B

Interventions

Sequence: 52789470 Sequence: 52789465 Sequence: 52789466 Sequence: 52789467 Sequence: 52789468 Sequence: 52789469
Intervention Type Diagnostic Test Intervention Type Diagnostic Test Intervention Type Diagnostic Test Intervention Type Diagnostic Test Intervention Type Other Intervention Type Device
Name Blood sampling Name Single-voxel MRS Name Multi-voxel MRSI Name Magnetization Transfer Imaging Name Alcohol ingestion Name ClearMate
Description Participants will have a peripheral arterial and peripheral venous line inserted and periodic arterial and venous blood samples will be measured for blood alcohol content. Description Diagnostic test is a single voxel MRS scan Description Diagnostic test is a multi-voxel MRS imaging scan Description Diagnostic test is a set of magnetic transfer weighted images Description Participants will ingest an ethanol-containing beverage of approximately 0.5g/kg of ethanol mixed in 355 mL of a non-caffeinated, sugar-free carbonated drink which must be consumed in 5 minutes Description Participants will breathe through the ClearMate, an MR-compatible non-rebreathing circuit which provides oxygen and carbon dioxide that quickly decreases a person’s blood alcohol level.

Design Outcomes

Sequence: 178536739 Sequence: 178536740
Outcome Type primary Outcome Type secondary
Measure Intracranial Interstitial Fluid Flow Rate Measure Blood alcohol levels
Time Frame Within 1 week of actual measurement Time Frame Within 1 week of blood samples
Description The calculated flow rate of intracranial interstitial fluid and its standard deviation Description Level of alcohol in venous and arterial blood during the examination

Sponsors

Sequence: 48605980 Sequence: 48605981
Agency Class OTHER Agency Class OTHER
Lead Or Collaborator lead Lead Or Collaborator collaborator
Name Sunnybrook Health Sciences Centre Name University Health Network, Toronto

Overall Officials

Sequence: 29447065 Sequence: 29447066
Role Principal Investigator Role Principal Investigator
Name Greg J Stanisz, PhD Name David Mikulis, MD
Affiliation Sunnybrook Research Institute Affiliation Krembil Research Institute

Design Group Interventions

Sequence: 68571744 Sequence: 68571745 Sequence: 68571746 Sequence: 68571747 Sequence: 68571748 Sequence: 68571749 Sequence: 68571750 Sequence: 68571751 Sequence: 68571752 Sequence: 68571753 Sequence: 68571754 Sequence: 68571755 Sequence: 68571756 Sequence: 68571757 Sequence: 68571758 Sequence: 68571759 Sequence: 68571760 Sequence: 68571761 Sequence: 68571762 Sequence: 68571763 Sequence: 68571764 Sequence: 68571765 Sequence: 68571766 Sequence: 68571767 Sequence: 68571768 Sequence: 68571769 Sequence: 68571770
Design Group Id 55935799 Design Group Id 55935805 Design Group Id 55935802 Design Group Id 55935800 Design Group Id 55935806 Design Group Id 55935803 Design Group Id 55935801 Design Group Id 55935807 Design Group Id 55935804 Design Group Id 55935801 Design Group Id 55935807 Design Group Id 55935804 Design Group Id 55935800 Design Group Id 55935806 Design Group Id 55935803 Design Group Id 55935799 Design Group Id 55935805 Design Group Id 55935802 Design Group Id 55935807 Design Group Id 55935804 Design Group Id 55935806 Design Group Id 55935803 Design Group Id 55935805 Design Group Id 55935802 Design Group Id 55935807 Design Group Id 55935806 Design Group Id 55935805
Intervention Id 52789465 Intervention Id 52789465 Intervention Id 52789465 Intervention Id 52789466 Intervention Id 52789466 Intervention Id 52789466 Intervention Id 52789467 Intervention Id 52789467 Intervention Id 52789467 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789468 Intervention Id 52789469 Intervention Id 52789469 Intervention Id 52789469 Intervention Id 52789469 Intervention Id 52789469 Intervention Id 52789469 Intervention Id 52789470 Intervention Id 52789470 Intervention Id 52789470

Eligibilities

Sequence: 30942332
Gender Male
Minimum Age 20 Years
Maximum Age 75 Years
Healthy Volunteers Accepts Healthy Volunteers
Criteria Inclusion Criteria: Ability to consent, effectively communicate with the investigator, and comply with study protocols Low consumer of ethanol (less than 6 drinks per week where a drink is 1 oz of distilled spirits, 6 oz wine, 12 oz beer) Exclusion Criteria: Contraindications to MRI History of alcohol or substance abuse History of liver pathology Currently taking medication such as metronidazole which could induce a disulfiram reaction with ethanol
Adult True
Child False
Older Adult True

Calculated Values

Sequence: 254282927
Number Of Facilities 1
Registered In Calendar Year 2020
Were Results Reported False
Has Us Facility False
Has Single Facility True
Minimum Age Num 20
Maximum Age Num 75
Minimum Age Unit Years
Maximum Age Unit Years
Number Of Primary Outcomes To Measure 1
Number Of Secondary Outcomes To Measure 1

Designs

Sequence: 30687942
Allocation Non-Randomized
Intervention Model Sequential Assignment
Observational Model
Primary Purpose Diagnostic
Time Perspective
Masking None (Open Label)
Intervention Model Description The study will begin with the simplest imaging measurements, and only proceed to longer or more complicated measurements if necessary. Re-breathing apparatus will be used only once the imaging measurement has been decided upon, and blood sampling will be used only on a few subjects to confirm the results. Thus, while there are 9 arms to this trial, it is possible that as few as 3 arms will actually be used.

Responsible Parties

Sequence: 29054679
Responsible Party Type Sponsor