The peri-olfactory pathway: an "e-scent-ial" route for cerebrospinal fluid clearance?

Abstract

The circulation of cerebrospinal fluid (CSF) plays a key role in maintaining the homeostasis of the central nervous system (CNS). Production of CSF occurs primarily at the choroid plexuses within the ventricles of the brain. The fluid and its solutes then flow within the subarachnoid spaces of the cranial and spinal compartments, where a tightly controlled exchange with the interstitial fluid of the CNS parenchyma occurs. Remarkably, the mechanisms of clearance for this important fluid are still incompletely understood. An intense debate about the main routes of CSF outflow that originated in the late 19th century has continued to the present day with some favouring a direct efflux through arachnoid villi to the dural venous sinuses or others proposing routes to lymphatic vessels located in proximity to exiting cranial nerves or within the dura mater layer of the meninges surrounding the CNS.1Proulx S.T. Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics.Cell Mol Life Sci. 2021; 78: 2429-2457Google Scholar Indeed, dozens of physiological studies in rodents and larger mammals have provided strong evidence for a lymphatic, rather than venous, outflow of CSF.1Proulx S.T. Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics.Cell Mol Life Sci. 2021; 78: 2429-2457Google Scholar,2Ma Q. Ineichen B.V. Detmar M. Proulx S.T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice.Nat Commun. 2017; 8: 1434Google Scholar Much of this research has indicated the existence of an egress pathway to lymphatics along olfactory nerve bundles through the cribriform plate of the ethmoid bone. On the other hand, in vivo studies in humans have been much more challenging to carry out as these experiments typically require the introduction of an exogenous tracer, usually into the intrathecal space of the spine by lumbar puncture. In pioneering studies from Norway, Ringstad and Eide have performed a series of MRI investigations involving intrathecal administration of a gadolinium contrast agent that is often used in patients with suspected disturbances of CSF flow. In these studies, a significant signal enhancement from the contrast agent was found within the dura mater near the parasagittal sinus, near the basal skull foramina and within draining cervical lymph nodes.3Ringstad G. Eide P.K. Cerebrospinal fluid tracer efflux to parasagittal dura in humans.Nat Commun. 2020; 11: 354Google Scholar,4Eide P.K. Vatnehol S.A.S. Emblem K.E. Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes.Sci Rep. 2018; 8: 7194Google Scholar However, these authors could not detect a significant enhancement of contrast agent within the nasal turbinates in their cohort of patients,5Melin E. Eide P.K. Ringstad G. In vivo assessment of cerebrospinal fluid efflux to nasal mucosa in humans.Sci Rep. 2020; 10: 14974Google Scholar in opposition to an earlier clinical report using PET imaging.6de Leon M.J. Li Y. Okamura N. et al.Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET.J Nucl Med. 2017; 58: 1471-1476Google Scholar In the December 2022 issue of eBiomedicine, Zhou et al. have recruited an impressive cohort of 92 patients, with a majority suffering from peripheral neuropathies that would likely have limited effect on CSF circulation.7Zhou Y. Ran W. Luo Z. et al.Impaired peri-olfactory cerebrospinal fluid clearance is associated with ageing, cognitive decline and dyssomnia.eBioMedicine. 2022; 86: 104381Google Scholar The patients were injected with gadodiamide contrast agent and were given MRI scans before injection and at 4.5, 15 and 39 h after injection. In an unbiased approach, the authors assessed three potential CSF outflow pathways simultaneously: to the parasagittal dura, through the cribriform plate to the nasal turbinates and along the perineural space of the optic nerve, as well as accumulation of the contrast agent at the draining deep cervical lymph nodes. Significant contrast enhancement was found at each of these evaluated areas providing clinical evidence for multiple active sites of CSF outflow to the lymphatic system. Taking advantage of the large range of subjects, the authors performed correlation analysis between measurements of efflux and patient age and assessments of quality of sleep and cognitive decline (which were both determined by telephone survey). Interestingly, significant negative correlations were found between increasing age and clearance function at the peri-olfactory nerve and parasagittal dura regions. The authors also determined that impairments in sleep quality and cognitive function were most closely associated with a reduced clearance of contrast agent to the nasal turbinate regions, indicating that the peri-olfactory nerve pathway may be of particular importance. One limitation of the study is that the resolution of the MRI technique does not allow direct visualization of contrast agent drainage within lymphatic vessels at the three assessed regions, thus the authors are correct to describe these routes as “putative” clearance pathways at this point. In addition, small molecular weight contrast agents are not ideal for the assessment of CSF clearance as significant diffusion into the CNS parenchyma or extracranial interstitial tissue may occur. However, clinically-approved macromolecular contrast agents are lacking at this time. Finally, other potential efflux routes from the basal skull or spine8Jacob L. de Brito Neto J. Lenck S. et al.Conserved meningeal lymphatic drainage circuits in mice and humans.J Exp Med. 2022; 219e20220035Google Scholar,9Ma Q. Decker Y. Müller A. Ineichen B.V. Proulx S.T. Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels.J Exp Med. 2019; 216: 2492-2502Google Scholar would need to be evaluated. This may require the development of whole-body scanning techniques, ideally with multiple timepoints in the hours immediately following injection. These intriguing findings have provided more evidence for a concept of a decline in CSF turnover during physiological ageing,2Ma Q. Ineichen B.V. Detmar M. Proulx S.T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice.Nat Commun. 2017; 8: 1434Google Scholar,10Decker Y. Kramer J. Xin L. et al.Magnetic resonance imaging of cerebrospinal fluid outflow after low-rate lateral ventricle infusion in mice.JCI Insight. 2022; 7e150881Google Scholar which may play a role in the accumulation of toxic metabolites such as amyloid beta. More research would be necessary to determine at which stage a functional decline may occur in patients suffering from cognitive decline or if the frequent loss of olfactory function seen in early-stage Alzheimer's disease may be related to a reduction of CSF clearance along olfactory nerves. S.T.P. is the sole author. The author has no conflicts of interest to disclose.