Brain-wide glymphatic enhancement and clearance in humans assessed with MRI
Geir Ringstad, … , Kent-Andre Mardal, Per K. Eide
Geir Ringstad, … , Kent-Andre Mardal, Per K. Eide
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e121537. https://doi.org/10.1172/jci.insight.121537.
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Clinical Medicine Neuroscience

Brain-wide glymphatic enhancement and clearance in humans assessed with MRI

Abstract

To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.

Authors

Geir Ringstad, Lars M. Valnes, Anders M. Dale, Are H. Pripp, Svein-Are S. Vatnehol, Kyrre E. Emblem, Kent-Andre Mardal, Per K. Eide

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Figure 4

CSF tracer enrichment over time in one iNPH subject.

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CSF tracer enrichment over time in one iNPH subject. The brain-wide enri...
The brain-wide enrichment of CSF tracer over time is shown in one iNPH individual. The percentage change in signal unit ratio is indicated by the color scale. The centripetal pattern of enrichment is comparable with that in REF individuals. In iNPH, there is also enrichment of periventricular white matter due to ventricular reflux of CSF tracer substance (ventricular CSF space is subtracted). While clearance of tracer was delayed in iNPH, enrichment occurred with at least the same rate as in REF. This may be attributed to enlarged perivascular spaces in iNPH, where neurodegeneration and vascular disease typically are important associated features. Regions with the initial, and most, tracer enrichment are nearby the course of large artery trunks at the brain surface (as further outlined in the legend to Figure 1), indicating the important role of CSF pulsations for brain tracer enrichment. These regions (entorhinal, hippocampus, insula, cingulum, etc.) also correspond to areas that traditionally are included in the limbic system (“limbic enhancement”) and also are areas typically susceptible to consecutive tau propagation in Alzheimer’s disease. This should be noted, as reduced clearance of CSF tracer through the glymphatic system has been proposed as instrumental in the pathogenesis of neurodegenerative disease.