Cerebrospinal fluid tracer efflux to parasagittal dura in humans

Abstract

The mechanisms behind molecular transport from cerebrospinal fluid to dural lymphatic vessels remain unknown. This study utilized magnetic resonance imaging along with cerebrospinal fluid tracer to visualize clearance pathways to human dural lymphatics in vivo. In 18 subjects with suspicion of various types of cerebrospinal fluid disorders, 3D T2-Fluid Attenuated Inversion Recovery, T1-black-blood, and T1 gradient echo acquisitions were obtained prior to intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as a cerebrospinal fluid tracer. Propagation of tracer was followed with T1 sequences at 3, 6, 24 and 48 h after the injection. The tracer escaped from cerebrospinal fluid into parasagittal dura along the superior sagittal sinus at areas nearby entry of cortical cerebral veins. The findings demonstrate that trans-arachnoid molecular passage does occur and suggest that parasagittal dura may serve as a bridging link between human brain and dural lymphatic vessels.

Fig. 1. 3D representation of parasagittal dura as defined from T2-FLAIR.

The brain is shown in oblique coronal view (a) and viewed from above (b). Parasagittal dura (dark yellow) as defined from T2-FLAIR and co-registered with rough segmentation of the brain (gray) and tracer enhancement in CSF (light blue) from T1 GRE at 48 h after intrathecal administration. The CSF tracer propagated toward the upper brain convexities and parasagittal dura at late time points (at 24 h and particularly at 48 h). A video-animation presenting the full longitudinal extension of parasagittal dura is presented in Supplementary Movie 2. Images: Tomas Sakinis, MD.

Fig. 2. Cerebrospinal fluid (CSF) tracer efflux to parasagittal dura in humans.

a Sagittal and coronal T2-FLAIR MR images, respectively, show the typical longitudinal and lateral extension of parasagittal dura (PSD) with high signal (arrows) in one study patient. b Section of coronal T2-FLAIR demonstrates the lateral extension of PSD (arrows). Similar sections (from T1-BB) reveal change in signal intensity of PSD from before (Pre) CSF tracer injection (c), and after 3 h (d), 6 h (e), 24 h (f) and 48 h (g). In h, the PSD is illustrated in yellow  color (for more details, see Supplementary Fig. 1; illustration: Øystein Horgmo, University of Oslo). The percentage change in normalized T1-BB signal units in CSF (blue line) and PSD (red line) for the entire cohort of 18 individuals is presented in i. The signal change was highly significant in both locations (linear mixed model analysis; *P < 0.05, **P < 0.01, ***P < 0.001) and was largest within the CSF. Also note that signal change peaked at 24 h in both CSF and PSD, and signal increase in these structures was highly associated (R = 0.92, P < 0.001). Error bars refer to 95% confidence intervals (CI).

Fig. 3. Visualization of the parasagittal dura and an arachnoid granulation.

The T1-BB images are shown for one individual (no. 8) prior to intrathecal gadobutrol injection (a), and after 3 h (b), 6 h (c) 24 h (d) and 48 h (e). The enrichment of CSF tracer is quantified as change in signal units (SU) within the parasagittal dura, CSF space and within one arachnoid granulation. The regions of interest are marked by an open circle. At 48 h (e), enhancement of the arachnoid granulation could no longer be detected. In f is illustrated the parasagittal dura (PSD, indicated with yellow color) and an arachnoid granulation (AG; illustration: Øystein Horgmo, University of Oslo). In g, the percentage change in normalized T1-BB signal units in CSF (blue line), PSD (red line) and arachnoid granulation (black line) in this individual is presented.

Fig. 4. Correlations between CSF tracer enhancement in parasagittal dura and nearby CSF space.

There was a highly significant positive correlation between CSF tracer enhancement within parasagittal dura and nearby CSF spaces at 3 h (a), 6 h (b), 24 h (c) and 48 h (d). Each plot presents the fit line and the Pearson correlation coefficient (R) with P-value.

Fig. 5. Evidence for CSF efflux along cranial nerves.

Posterior (a, b) and anterior (c, d) mid-coronal T1-BB from a patient (no. 10) under work-up for symptoms possibly related to an arachnoid cyst (asterisks in a and b, respectively) at the upper convexity of the right cerebral hemisphere. As compared to 3 h after intrathecal gadobutrol (a), the cyst enhanced homogenously at scans after 24 h (b). Enrichment of parasagittal dura (thick arrows) increased from 3 (a, c) to 24 h (b, d), respectively. CSF tracer within brain perivascular spaces is well illustrated with T1-BB MRI (exemplified as pointed out by arrowheads; d). In addition is shown CSF tracer enhancement below the skull base outlets of the jugular foramen (crosses) and hypoglossal canal (thin arrows) (a, b). In the same patient, there was no sign of tracer enhancement along the mandibular nerve below level of the oval foramen (asterisks) at any time point (c, d).

Fig. 6. Cartoon illustrating reported microstructural elements within the parasagittal dura based on refs. ^,.

a The parasagittal dura (PSD, colored yellow) contain a network of intradural channels (C, colored light blue), coalescing into lateral lacunae medially (not shown), being in close relation with a dense carpet of intradural arachnoid granulations (AG, orange color). PSD is most prominent at level where the cortical veins (V, dark blue) enter the superior sagittal sinus (SSS, dark blue). Lymphatic vessels (L, green) reside at the SSS wall. The microstructural elements within PSD are of sub-millimeter thickness and therefore not expected to be visualized on MRI with 1 mm resolution. D dura, GM gray matter, SAS subarachnoid space, WM white matter. Illustrations: Øystein Horgmo, University of Oslo.