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.

Measuring Glymphatic Flow in Man Using Quantitative Contrast-Enhanced MRI

“…A few studies used MR imaging qualitatively to investigate glymphatic flow in rodents 8 and humans. [9][10][11][12] Our report improves on those studies by quantifying contrast concentration. We are only aware of a single study that has used similar quantification in rats at 9.4T.…”

“…Qualitative MR imaging using percentage signal enhancement on T1-weighted images has been reported in animal models 8 and humans. [9][10][11][12] However, the percentage signal change on a T1weighted image with contrast concentration depends on the intrinsic T1 of each tissue, the corresponding change in T2 * , and the imaging parameters selected. To be able to apply pharmacokinetic models requires consistent determination of contrast concentrations across tissue types and concentrations.…”

Uncertainty quantification of parenchymal tracer distribution using random diffusion and convective velocity fields

“…The MRI-studies [64,63] only provide quantitative values of tracer enhancement signal intensity, and not tracer concentrations. As the relation between signal intensity and concentration is nonlinear [20], we have not made a direct comparison between these two quantities.…”

“…First, we consider the simplifying but common assumption that the effective diffusion coefficient is spatially homogeneous: D * (ω) ∈ R. We account for the uncertainty in its value by modelling it as a random variable: [63] and where D * γ (ω) has a Gamma distribution with shape k = 3 and scale θ = 0.75 × D * Gad /k. The choice of shape and scaling parameters ensures that (i) the diffusion coefficient is positive, (ii) its expected value matches reported values of parenchymal gadobutrol diffusivity [63], and (iii) its variability allows for values up to 2-3 times larger or smaller than the average with low probability. The last modelling choice reflects diffusivity values in the range 1-10 × 10 −10 m/s 2 in agreement with previous reports [51].…”

Intracranial pressure elevation alters CSF clearance pathways

“…paravenous spaces surrounded by pial sleeves [71]. Although compelling evidence for such a route is lacking, a direct contact between paravenous spaces and lymphatic vessels has been hypothesized by some investigators [56]. It should also be noted that a direct route to cervical lymphatics was also envisioned in the paper first proposing the term "glymphatic pathway" [30].…”