A subset of arachnoid granulations in humans drain to the venous circulation via intradural lymphatic vascular channels

Abstract

OBJECTIVE The discovery of dural lymphatics has spurred interest in the mechanisms of drainage of interstitial fluid from the CNS, the anatomical components involved in clearance of macromolecules from the brain, mechanisms of entry and exit of immune components, and how these pathways may be involved in neurodegenerative diseases and cancer metastasis. In this study the authors describe connections between a subset of arachnoid granulations (AGs) and the venous circulation via intradural vascular channels (IVCs), which stain positively with established lymphatic markers. The authors postulate that the AGs may serve as a component of the human brain’s lymphatic system. METHODS AGs and IVCs were examined by high-resolution dissection under stereoscope bilaterally in 8 fresh and formalin-fixed human cadaveric heads. The superior sagittal sinus (SSS) and adjacent dura mater were immunostained with antibodies against Lyve-1 (lymphatic marker), podoplanin (lymphatic marker), CD45 (panhematopoietic marker), and DAPI (nuclear marker). RESULTS AGs can be classified as intradural or interdural, depending on their location and site of drainage. Interdural AGs are distinct from the dura, adhere to arachnoid membranes, and occasionally open directly in the inferolateral wall or floor of the SSS, although some cross the infradural folds of the dura’s inner layer to meet with intradural AGs and IVCs. Intradural AGs are located within the leaflets of the dura. The total number of openings from the AGs, lateral lacunae, and cortical veins into the SSS was 45 ± 5.62 per head. On average each cadaveric head contained 6 ± 1.30 intradural AGs. Some intradural AGs do not directly open into the SSS and use IVCs to connect to the venous circulation. Using immunostaining methods, the authors demonstrate that these tubular channels stain positively with vascular and lymphatic markers (Lyve-1, podoplanin). CONCLUSIONS AGs consist of two subtypes with differing modes of drainage into the SSS. A subset of AGs located intradurally use tubular channels, which stain positively with vascular and lymphatic markers to connect to the venous lacunae and ultimately to the SSS. The present study suggests that AGs may function as a component of brain lymphatics. This finding has important clinical implications for cancer metastasis to and from the CNS and may shed light on mechanisms of altered clearance of macromolecules in the setting of neurodegenerative diseases.

Molecular trans-dural efflux to skull bone marrow in humans with CSF disorders

“… 22 Another group demonstrated that a subset of arachnoid granulations in humans may drain CSF via lymphatic vessels to the venous circulation. 23 Furthermore, the adjacent dural sinus stroma was found to function as an immune hub allowing for CNS immune surveillance by trafficking T cells, 7 underlining the crucial role of this region for cross-talk between CNS-derived antigens and the peripheral immune system. However, the current findings of tracer enhancement in bone marrow at the skull vertex even remote to intradiploic dural extensions, indicate other physical connections between CSF and the bone marrow space in humans may also exist.…”

Cortical spreading depression and meningeal nociception

“…1 ). These zones, potentially a part of the arachnoid granulation anatomical structure ( Yagmurlu et al, 2021 ), have been suggested to serve as drainage entry points for CSF in the subarachnoid space into the dural lymphatic system ( Louveau et al, 2018 ). Importantly, these peri-sinus dural areas are located near a dense population of chemosensitive dural nociceptors ( Strassman et al, 2004 ).…”

The glymphatic system and subarachnoid hemorrhage: disruption and recovery

“…AG are protrusions of the arachnoid mater into the dural venous sinus that facilitate CSF reabsorption via vesicular transport [ 6 ]. Subsets of AG have also been implicated in lymphatic outflow of CSF via dural intravascular channels [ 7 ]. While these findings imply an important role for AG mediated CSF turn-over, studies also have found that patients with AG agenesis have seemingly normal CSF flow, suggesting bulk flow may occur through perivascular routes via the glymphatic system (GS) [ 8 ].…”

“…The endfeet of astroglial cells densely express AQP4 water channels which assist the flow of CSF into the brain parenchyma [ 16 ]. Within the brain interstitium, the CSF is dispersed by a net fluid movement directed towards the venous perivascular and perineuronal spaces [ 7 ]. Ultimately, CSF exits along the meningeal lymphatic vessels and AG [ 9 , 12 , 19 ].…”