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JCI Insight. 2018 Jul 12;3(13). pii: 121537. doi: 10.1172/jci.insight.121537. [Epub ahead of print]

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

Author information

1
Division of Radiology and Nuclear Medicine, Department of Radiology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
2
Institute of Clinical Medicine, Faculty of Medicine, and.
3
Department of Mathematics, University of Oslo, Oslo, Norway.
4
Department of Neurosciences.
5
Department of Radiology, and.
6
Multimodal Imaging Laboratory, UCSD, La Jolla, California, USA.
7
Oslo Centre of Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway.
8
The Intervention Centre, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
9
Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway.
10
Center for Biomedical Computing, Simula Research Laboratory, Lysaker, Norway.
11
Department of Neurosurgery, Oslo University Hospital - Rikshospitalet, Oslo, Norway.

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.

KEYWORDS:

Alzheimer’s disease; Dementia; Neurodegeneration; Neuroscience

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