Magnetic resonance imaging of cerebrospinal fluid outflow after low-rate lateral ventricle infusion in mice

Abstract

The anatomical routes for the clearance of cerebrospinal fluid (CSF) remain incompletely understood. However, recent evidence has given strong support for routes leading to lymphatic vessels. A current debate centers upon the routes through which CSF can access lymphatics, with evidence emerging for either direct routes to meningeal lymphatics or along cranial nerves to reach lymphatics outside the skull. Here, a method was established to infuse contrast agent into the ventricles using indwelling cannulae during imaging of mice at 2 and 12 months of age by magnetic resonance imaging. As expected, a significant decline in overall CSF turnover was found with aging. Quantifications demonstrated that the bulk of the contrast agent flowed from the ventricles to the subarachnoid space in the basal cisterns. Comparatively little contrast agent signal was found at the dorsal aspect of the skull. The imaging dynamics from the two cohorts revealed that the contrast agent cleared from the cranium through the cribriform plate to the nasopharyngeal lymphatics. On decalcified sections, we confirmed that fluorescentlylabeled ovalbumin drains through the cribriform plate and can be found within lymphatics surrounding the nasopharynx. In conclusion, routes leading to nasopharyngeal lymphatics appear to be a major efflux pathway for cranial CSF.

3D-imaging reveals conserved cerebrospinal fluid drainage via meningeal lymphatic vasculature in mice and humans

“…Cavernous lymphatics may thus drain peri-venous efflux from their tributary cerebral veins (superficial and deep middle cerebral veins, and hypophyseal vein), and possibly from orbital veins (superior and inferior ophthalmic), into collecting scLNs and dcLNs. The nasopharynx provided a support to the most anterior lymphatic drainage from the cavernous sinus, in agreement with the recent observation that the nasopharyngeal route has a main role in the extracranial drainage of CSF outflow (Decker et al, 2021).…”

“…The cavernous sinus collects blood from the superficial and deep middle cerebral veins and the ophtalmic and facial regions (Haines, 2018). CSF drainage from this anterior region has been identified (Antila et al, 2017;Ma et al, 2017;Decker et al, 2021), but the lymphatic circuitry involved remained unknown because the anterior and middle fossae of the skull base are difficult to assess by classical immunohistological techniques. In humans, the dural lymphatic architecture remains largely undefined (Absinta et al, 2017;Ding et al, 2021), despite the potential interest of dural lymphatic imaging for the prognosis of neurological diseases.…”

Conserved meningeal lymphatic drainage circuits in mice and humans

“…4, A, E–G, and I–K ). The nasopharyngeal lymphatics were recently shown to mediate extracranial drainage of CSF outflow ( Decker et al, 2021 ).…”

“…The CAV collects blood from the superficial and deep middle cerebral veins and the ophthalmic and facial regions ( Haines, 2018 ). CSF drainage from this anterior region has been identified ( Antila et al, 2017 ; Ma et al, 2017 ; Decker et al, 2021 ), but the lymphatic circuitry involved remained unknown because the anterior and middle fossae of the skull base are difficult to assess by classic immunohistological techniques. In humans, noninvasive imaging of dural lymphatic is of interest for the diagnosis and prognosis of neurological diseases ( Absinta et al, 2017 ; Ding et al, 2021 ), and different MRI protocols to detect MLVs have been reported ( Absinta et al, 2017 ; Ringstad and Eide, 2020 ; Wu et al, 2020 ; Ding et al, 2021 ; Albayram et al, 2022 ).…”

Innate Lymphoid Cells in the Central Nervous System

“…The sinuses in the dura mater are the neuro-immunological interface where CNS-derived antigens accumulate and the local antigen presenting cells (APCs) prime patrolling T cells ( 7 ). Dural lymphatic vessels lining the sinuses collect CSF from the subarachnoid space and interstitial fluid (ISF) from the brain and drain via connections through the nasal-cribriform plate into the nasopharynx lymphatic vasculature ( 8 ) towards the mandibular and deep cervical lymph nodes (dcLN) ( 9 , 10 ). Therefore, the meninges is a critical neuro-immunological interface where immune cells are situated to sense threatening factors such as pathogens and antigens ( 7 ).…”