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

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

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

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

In vivo assessment of cerebrospinal fluid efflux to nasal mucosa in humans

Abstract Extra-vascular molecular clearance routes from the brain and cerebrospinal fluid (CSF) remain insufficiently characterized in humans. Animal studies consistently suggest that the cribriform plate and nasal lymphatic vessels are crucial for molecular clearance from CSF. In this study, we aimed to examine human in vivo transport of a CSF tracer from CSF to nasal mucosa. We hypothesised a CSF tracer would enrich in nasal mucosa provided that nasal lymphatic drainage has a significant role in CSF molecular clearance. Consecutive magnetic resonance imaging during 48 h after intrathecal administration of a tracer (gadobutrol) was performed in 24 patients. Despite a strong enrichment of CSF tracer in CSF spaces nearby the cribriform plate, there was no significant enrichment of CSF tracer in nasal mucosa, as measured in superior, medial and inferior turbinates, or in the nasal septum. Therefore, this in vivo study questions the importance of CSF drainage to the human nasal mucosa and emphasizes the need of further human studies

Magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in idiopathic normal pressure hydrocephalus

Abstract Disturbed clearance of toxic metabolites from the brain via cerebrospinal fluid is emerging as an important mechanism behind dementia and neurodegeneration. To this end, magnetic resonance imaging work-up of dementia diseases is largely focused on anatomical derangements of the brain. This study explores magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in patients with the dementia subtype idiopathic normal pressure hydrocephalus and a cohort of reference subjects. All study participants underwent multi-phase magnetic resonance imaging up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as cerebrospinal fluid tracer. Imaging biomarkers of cerebrospinal fluid tracer dynamics (i.e. ventricular reflux grades 0–4 and clearance) were compared with anatomical magnetic resonance imaging biomarkers of cerebrospinal fluid space anatomy (Evans’ index, callosal angle and disproportional enlargement of subarachnoid spaces hydrocephalus) and neurodegeneration (Schelten’s medial temporal atrophy scores, Fazeka’s scores and entorhinal cortex thickness). The imaging scores were also related to a pulsatile intracranial pressure score indicative of intracranial compliance. In shunt-responsive idiopathic normal pressure hydrocephalus, the imaging biomarkers demonstrated significantly altered cerebrospinal fluid tracer dynamics (ventricular reflux grades 3–4 and reduced clearance of tracer), deranged cerebrospinal fluid space anatomy and pronounced neurodegeneration. The altered MRI biomarkers were accompanied by pressure indices of impaired intracranial compliance. In conclusion, we present novel magnetic resonance imaging biomarkers characterizing idiopathic normal pressure hydrocephalus pathophysiology, namely measures of cerebrospinal fluid molecular redistribution and clearance, which add information to traditional imaging scores of cerebrospinal fluid space anatomy and neurodegeneration

Glymphatic MRI in idiopathic normal pressure hydrocephalus

The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer’s disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging