Intracranial interstitial fluid (ISF) flow is crucial for adequate clearance of extracellular waste products from the brain parenchyma. Recent demonstrations have shown that a deficiency in flow leads to the accumulation of such waste products in neurodegenerative disorders. Unfortunately, no clinical investigation that gives a quantitative measure of ISF flow exists. Such a test could prove very useful in the clinical setting for multiple neurologic disorders by providing a measure of potential diagnostic importance, as well as yielding a means to monitor response to treatment.

The investigators hypothesize that such an investigation can be developed using magnetic resonance spectroscopy to give a quantitative measure of ISF flow, using spectroscopy of ethanol as a dynamic marker of interstitial fluid. Beneficially, the approach is non-invasive. This pilot project aims to develop this technique with proof of concept in healthy volunteers (males in the age range of 20-75).

This pilot project aims to develop the technique, demonstrating its ability to detect ISF flow and potential differences in rates among healthy volunteers. Success at this stage will give rise to this technique being extended to studies involving individuals with various forms of intracranial pathology for comparison with values seen in healthy individuals, with the ultimate goal of it providing a measure of diagnostic significance in multiple clinical scenarios.

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 (i.e., 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 ClearMate (CM), 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.

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