Dynamic Magnetic Resonance Imaging of Human Subarachnoid Space Using Intrathecal Gadolinium Contrast

Study Description:

In this study, we will gather safety data on and establish the technical feasibility of bypassing the blood-brain-barrier (BBB) with intrathecal (IT) gadolinium-based contrast agent (GBCA) tracer injection (0.25 ml gadobutrol at a concentration of 1.0 mmol/ml) to dynamically image the subarachnoid space (SAS) in human healthy volunteers. We will also obtain preliminary data on whether this approach will enable us to reliably visualize physiological meningeal lymphatic drainage pathways within the parasagittal dura (PSD) and connections to cerebrospinal fluid (CSF) compartments using serial contrast-enhanced magnetic resonance imaging (CE-MRI) with minimal confounding signal from tracer blood egress. In exploratory analysis, we will quantify temporal clearance kinetics and investigate distribution patterns of GBCA enhancement in the PSD, CSF spaces, and brain parenchyma in up to 12 healthy volunteers using repeated in vivo CE-MRI over 10 days. Safety/tolerability of the IT GBCA administration will be assessed descriptively over the entire 12-week study period.

Objectives:

Primary objective: To track safety/tolerability of IT GBCA administration in healthy human volunteers.

Secondary objective: To establish technical feasibility of dynamic subarachnoid-space imaging using IT GBCA administration in healthy human volunteers.

Exploratory objectives: To explore patterns of dynamic meningeal lymphatic clearance pathway interconnections in vivo under physiological conditions in human healthy volunteers, and to obtain preliminary data regarding the effect of aging on CSF dynamics and CSF-to-blood tracer clearance.

Endpoints:

Primary endpoint: Occurrence of intervention-emergent adverse events at the participant level assessed descriptively over the 12-week study period.

Secondary outcome measure: MRI detection status (yes/no) of contrast in the cerebral SAS at 24 hours.

Exploratory outcome measures: Changes in contrast-to-noise ratio (CNR) and clearance kinetics of SAS to brain parenchyma over 48h.

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet all the following criteria:

• Healthy volunteer.
• Age >= 18 years.

To explore age-related effects on tracer dynamics and clearance, 3 cohorts of participants will be recruited: 1) 18-30 years, 2) 30-55 years, and 3) >55 years; with 2 males and 2 females in each age group.

• Able to give written and oral informed consent.
• Prior evaluation under NIH protocol 89N0045.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• History of chronic neurological illness, or significant concurrent medical illness.
• Contraindication to 3- or 7-tesla MRI
• Hypersensitivity reactions to contrast agents.
• History of severe allergic reactions.
• Pregnancy or breastfeeding.
• Renal dysfunction or other serious comorbidities.
• Platelet count <100,000/microliter, INR > 1.5 or prolonged PT or aPTT at baseline.
• Any of the following imaging findings: Mass effect, midline shift, herniation (tonsillar, uncal, subfalcine), or Chiari malformation.
• History of seizures or seizure disorder.
• Anti-coagulation therapy.
• Unwilling to allow coded samples to be processed offsite.
• Unwilling to have coded samples and/or data saved or used in other studies.