CSF circulation and dispersion yield rapid clearance from intracranial compartments

In this paper, we used a computational model to estimate the clearance of a tracer driven by the circulation of cerebrospinal fluid (CSF) produced in the choroid plexus (CP) located within the lateral ventricles. CSF was assumed to exit the subarachnoid space (SAS) via different outflow routes such as the parasagittal dura, cribriform plate, and/or meningeal lymphatics. We also modelled a reverse case where fluid was produced within the spinal canal and absorbed in the choroid plexus in line with observations on certain iNPH patients. No directional interstitial fluid flow was assumed within the brain parenchyma. Tracers were injected into the foramen magnum. The models demonstrate that convection in the subarachnoid space yields rapid clearance from both the SAS and the brain interstitial fluid and can speed up intracranial clearance from years, as would be the case for purely diffusive transport, to days.publishedVersio

Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders

Clearance of neurotoxic brain proteins via cerebrospinal fluid (CSF) to blood has recently emerged to be crucial, and plasma biomarkers of neurodegeneration were newly introduced to predict neurological disease. This study examines in 106 individuals with neurological disorders associations between plasma biomarkers [40 and 42 amino acid-long amyloid-β (Aβ40 and Aβ42), total-tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)] and magnetic resonance imaging measures of CSF-mediated clearance from brain via extra-vascular pathways (proxy of glymphatic function) and CSF-to-blood clearance variables from pharmacokinetic modeling (proxy of meningeal lymphatic egress). We also examine how biomarkers vary during daytime and associate with subjective sleep quality. Plasma concentrations of neurodegeneration markers associate with indices of glymphatic and meningeal lymphatic functions in individual- and disease-specific manners, vary during daytime, but are unaffected by sleep quality. The results suggest that plasma concentrations of neurodegeneration biomarkers associate with measures of glymphatic and meningeal lymphatic function

Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 "ISMRM Imaging Neurofluids Study group" Workshop in Rome

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1. Technical Efficacy: Stage 3

Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 “<scp>ISMRM</scp> Imaging Neurofluids Study group” Workshop in Rome

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three‐day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery.Evidence level: 1Technical Efficacy: Stage

Imaging cerebrospinal fluid dynamics in idiopathic normal pressure hydrocephalus

In this thesis, magnetic resonance imaging (MRI) is used to explore short- and long term characteristics of cerebrospinal fluid (CSF) flow in patients with idiopathic normal pressure hydrocephalus (iNPH). Typical symptoms like gait disorder, urinary incontinence and dementia may be improved with surgical shunting, and responders to treatment can be identified by monitoring of intracranial pressure (ICP) pulsatility, but with a small risk of complications. In search for non-invasive diagnostic alternatives, radiological markers of CSF flow pulsatility (i.e. the aqueductal stroke volume and the peak-to-peak pulse pressure gradient at the craniocervical junction) derived from phase-contrast MRI (PC-MRI) were compared with over-night ICP monitoring. In this, no signs of association with ICP parameters or clinical symptoms could be demonstrated. PC-MRI did, however, reveal net CSF flow into the ventricular compartment in patients with pathological ICP pulsatility. This finding was supported by observations made in a study of CSF tracer (MRI contrast agent) propagation through the intracranial subarachnoid and brain compartments over a 24 hours` time span. Furthermore, the CSF tracer distributed at the brain surface along major artery trunks, but with delay in iNPH compared to references, and tracer clearance rate was also reduced in iNPH. At 24-hour scans, the tracer enriched brain tissue, indicating communication between the subarachnoid spaces and extra-vascular brain compartment. A paravascular pathway for brain clearance of cellular waste products, which was recently identified in rodent studies and denoted the “glymphatic” system, may thus also be present in humans. Glymphatic impairment in iNPH may possibly be instrumental in iNPH dementia

Functional analysis of the human perivascular subarachnoid space

Abstract The human subarachnoid space harbors the cerebrospinal fluid, which flows within a landscape of blood vessels and trabeculae. Functional implications of subarachnoid space anatomy remain far less understood. This study of 75 patients utilizes a cerebrospinal fluid tracer (gadobutrol) and consecutive magnetic resonance imaging to investigate features of early (i.e. within 2-3 h after injection) tracer propagation within the subarachnoid space. There is a time-dependent perivascular pattern of enrichment antegrade along the major cerebral artery trunks; the anterior-, middle-, and posterior cerebral arteries. The correlation between time of first enrichment around arteries and early enrichment in nearby cerebral cortex is significant. These observations suggest the existence of a compartmentalized subarachnoid space, where perivascular ensheathment of arteries facilitates antegrade tracer passage towards brain tissue. Periarterial transport is impaired in subjects with reduced intracranial pressure-volume reserve capacity and in idiopathic normal pressure hydrocephalus patients who also show increased perivascular space size

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

Abstract Dural sinuses were recently identified as a hub for peripheral immune surveillance of brain-derived antigens cleared through cerebrospinal fluid. However, animal studies have also indicated that substances and cells may enter the intracranial compartment directly from bone marrow. We utilized magnetic resonance imaging and a cerebrospinal fluid tracer to investigate in vivo whether intracranial molecules can move via dura to skull bone marrow in patients with suspicion of cerebrospinal fluid disorders. Tracer enrichment in cerebrospinal fluid, dural regions and within skull bone marrow was assessed up to 48 hours after intrathecal administration of gadobutrol (0.5 ml, 1 mmol/ml) in 53 patients. In subjects diagnosed with disease, tracer enrichment within diploe of skull bone marrow was demonstrated nearby the parasagittal dura, nearby extensions of parasagittal dura into diploe, and in diploe of skull bone remote from the dura extensions. This crossing of meningeal and skull barriers suggests that bone marrow may contribute in brain immune surveillance also in humans

Cerebrospinal fluid egress to human parasagittal dura and the impact of sleep deprivation

Emerging evidence suggests that the glymphatic system and meningeal lymphatic vessels are instrumental for clearance of toxic metabolites from the brain. Animal and human studies suggest that glymphatic circulation is up-regulated during sleep. Meningeal lymphatic clearance may be more efficient in the wake state, as shown in rodents. We have previously shown clearance of cerebrospinal fluid directly from the subarachnoid space to the parasagittal dura, which harbors meningeal lymphatic vessels. Hence, assessing molecular clearance from parasagittal dura provides an opportunity to decipher the role of sleep/sleep deprivation in human lymphatic clearance function. In this study, we applied magnetic resonance imaging to explore whether sleep deprivation modifies molecular clearance from human parasagittal dura, utilizing an intrathecal magnetic resonance imaging contrast agent as tracer. We hypothesized that tracer enhancement in parasagittal dura would differ after sleep deprivation. One group of individuals (n = 7) underwent one night’s total sleep deprivation while a control group (n = 9) was allowed unrestricted sleep. There were no sleep restrictions after the 24-hour time point. After one night of sleep deprivation (at 24 h), we found neither evidence for altered tracer enrichment in the parasagittal dura, nor after a day of unrestricted sleep (at 48 h). The hypothesis of altered molecular egress to parasagittal dura after sleep deprivation was not supported by our data. Further studies are required to determine the role of sleep for molecular clearance from cerebrospinal fluid to meningeal lymphatic vessels in humans