FIGURE 8:

Intrathecal enhanced MRI (gMRI): Normalized, percentage T1 signal increase in the brain extravascular compartment at 3, 24, and 48 hours after administration of the MRI contrast agent gadobutrol (0.5 mmol, molecular $\text{size}\hspace{0.17em}\text{=}\hspace{0.17em}\text{0}.6\hspace{0.17em}\text{kD}$) in CSF at the lumbar level. Tracer enrichment in the subarachnoid and ventricular compartment is subtracted from the images. The methodology can demonstrate the potential for reaching the extra-BBB compartment in brain tissue with therapeutic drugs intrathecally, and be used to assess brain clearance rate of molecules larger than water. Tracer studies in humans have indicated that clearance from CSF is a limiting step for brain clearance. CSF tracer enrichment in brain tissue is highly dependent on tracer reaching each region of the brain surface, which can vary substantially. In this patient, who was under work-up of a pineal cyst, brain-wide enhancement in the cerebral cortex and subcortical WM occurred, but not in deep WM, which is typical. It therefore seems likely that ISF of deep cerebral WM derives from other sources than CSF, and that CSF-ISF exchange has no major role in brain molecular clearance from deep structures. Of note is also the very limited CSF tracer enhancement in the basal ganglia, which differs significantly from rodent studies, and in spite of vivid tracer enhancement in visually enlarged PVS (not shown). (Image: Vegard Vinje, PhD, Simula Research Laboratory, Oslo, Norway)