Cerebrospinal Fluid Circulation Research Articles

Enlarged perivascular spaces and their association with motor, cognition, MRI markers and cerebrovascular risk factors in male fragile X premutation carriers

FMR1 premutation carriers (55–200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1–10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology.

Reduced cerebrospinal fluid motion in patients with Parkinson’s disease revealed by magnetic resonance imaging with low b-value diffusion weighted imaging

BackgroundParkinson’s disease is characterized by dopamine-responsive symptoms as well as aggregation of α-synuclein protofibrils. New diagnostic methods assess α-synuclein aggregation characteristics from cerebrospinal fluid (CSF) and recent pathophysiologic mechanisms suggest that CSF circulation disruptions may precipitate α-synuclein retention. Here, diffusion-weighted MRI with low-to-intermediate diffusion-weightings was applied to test the hypothesis that CSF motion is reduced in Parkinson’s disease relative to healthy participants.MethodsMulti-shell diffusion weighted MRI (spatial resolution = 1.8 × 1.8 × 4.0 mm) with low-to-intermediate diffusion weightings (b-values = 0, 50, 100, 200, 300, 700, and 1000 s/mm2) was applied over the approximate kinetic range of suprasellar cistern fluid motion at 3 Tesla in Parkinson’s disease (n = 27; age = 66 ± 6.7 years) and non-Parkinson’s control (n = 32; age = 68 ± 8.9 years) participants. Wilcoxon rank-sum tests were applied to test the primary hypothesis that the noise floor-corrected decay rate of CSF signal as a function of b-value, which reflects increasing fluid motion, is reduced within the suprasellar cistern of persons with versus without Parkinson’s disease and inversely relates to choroid plexus activity assessed from perfusion-weighted MRI (significance-criteria: p < 0.05).ResultsConsistent with the primary hypothesis, CSF decay rates were higher in healthy (D = 0.00673 ± 0.00213 mm2/s) relative to Parkinson’s disease (D = 0.00517 ± 0.00110 mm2/s) participants. This finding was preserved after controlling for age and sex and was observed in the posterior region of the suprasellar cistern (p < 0.001). An inverse correlation between choroid plexus perfusion and decay rate in the voxels within the suprasellar cistern (Spearman’s-r=-0.312; p = 0.019) was observed.ConclusionsMulti-shell diffusion MRI was applied to identify reduced CSF motion at the level of the suprasellar cistern in adults with versus without Parkinson’s disease; the strengths and limitations of this methodology are discussed in the context of the growing literature on CSF flow.

Diffusion magnetic resonance imaging of cerebrospinal fluid dynamics: Current techniques and future advancements.

Cerebrospinal fluid (CSF) plays a critical role in metabolic waste clearance from the brain, requiring its circulation throughout various brain pathways, including the ventricular system, subarachnoid spaces, para-arterial spaces, interstitial spaces, and para-venous spaces. The complexity of CSF circulation has posed a challenge in obtaining noninvasive measurements of CSF dynamics. The assessment of CSF dynamics throughout its various circulatory pathways is possible using diffusion magnetic resonance imaging (MRI) with optimized sensitivity to incoherent water movement across the brain. This review presents an overview of both established and emerging diffusion MRI techniques designed to measure CSF dynamics and their potential clinical applications. The discussion offers insights into the optimization of diffusion MRI acquisition parameters to enhance the sensitivity and specificity of diffusion metrics on underlying CSF dynamics. Lastly, we emphasize the importance of cautious interpretations of diffusion-based imaging, especially when differentiating between tissue- and fluid-related changes or elucidating structural versus functional alterations.

Is there a spinal tap responder in progressive supranuclear palsy? The first prospective study.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease, and sometimes shows idiopathic normal pressure hydrocephalus (iNPH)-like presentations. We aimed to evaluate spinal tap responsiveness in patients with PSP, including the effect of sham spinal tap. Eleven patients with PSP, ten with probable/definite iNPH, and eight control patients were prospectively enrolled. All participants underwent sham spinal tap and spinal tap procedures. Gait was evaluated using wearable inertial sensors. We defined "tap responders" as individuals with a 10% or more improvement from baseline in any of the gait parameters (timed up-and-go test total time, stride length, and velocity during straight walking under single-task and cognitive dual-task conditions). We compared the ratio of responders in patients with PSP to patients with iNPH and controls. The ratio of tap responders and the ratio of sham tap responders in patients with PSP were significantly higher than those in control patients, and not different from those in patients with iNPH. PSP patients with iNPH-like MRI features tended to respond to the spinal tap compared to those without such imaging features. Notably, one patient with PSP, who responded to the spinal tap beyond the effect of sham spinal tap, was treated by the shunt operation. This is the first prospective study to demonstrate tap and shunt responsiveness in patients with PSP while highlighting the placebo effects of the spinal tap in patients with PSP or iNPH. Our findings suggest that some PSP patients have impaired cerebrospinal fluid circulation, contributing to a distinct component of the clinical spectrum.

872 Natural History of Conservatively Managed Patients With Chiari Malformation Type I and Syringomyelia

INTRODUCTION: Chiari malformation type 1 (CM1) describes caudal ectopia of the cerebellar tonsils. Though often asymptomatic earlier in life and found incidentally on imaging, CM1 can disturb cerebrospinal fluid (CSF) flow and generate an array of symptoms. Surgical treatment for CM1 centers around procedures to increase the posterior fossa volume and improve CSF circulation. Many surgeons elect to operate on CM1 patients in the setting of a syrinx, making it difficult to understand the natural history of these patients. METHODS: Retrospective study of 37 CM1 patients with syrinx who were managed conservatively at our institution. All patients had initial and follow-up clinic visits with a neurologist or neurosurgeon. Of the 37 patients, 27 had initial and follow-up MRI images at least six months apart. Student t-tests were used to compare radiological parameters. RESULTS: A total of three patients saw complete resolution of their syrinxes. Regarding clinical symptomatology, 19 out of 32 patients who were initially symptomatic saw clinical improvement by follow up, while 13 remained stable, and five declined. Of the five patients that declined, three had worsening neurological conditions not attributed to the syrinx or CM1 while the remaining two patients were the only patients that declined surgery despite recommendation. A total of 16 patients saw decreases in both syrinx size and tonsillar descent. There were no statistically significant differences between tonsillar descent, syrinx size, and number of vertebral bodies spanned by syrinx between the initial and latest follow up. The presence of tonsillar pegging was predictive of decrease in syrinx size. Tonsillar descent and syrinx size were not predictive of clinical outcomes. CONCLUSIONS: Although the surgical treatment of the CM1 patient successfully resolves the syrinx, the natural history of the syrinx can be benign.

The Role of Phase-Contrast MRI in Diagnosing Cerebrospinal Fluid Flow Abnormalities.

Background Cerebrospinal fluid (CSF) dynamics play a crucial role in maintaining the homeostasis of the central nervous system (CNS). Any disruption in CSF flow can lead to various congenital and acquired conditions, impacting neurological function and overall health. This study aims to analyze the significance of phase-contrast MRI in evaluating abnormalities in CSF flow and its diagnostic utility in various CSF-related disorders. Phase contrast MRIhas emerged as a valuable tool for evaluating CSF dynamics non-invasively by examining CSF flow characteristics such as pulsatile flow patterns, hyperdynamic or hypodynamic flow, and disruptions in CSF circulation. Alterations in CSF pulsatility and stroke volume can indicate changes in intracranial compliance, vascular resistance, or CSF production and absorption rates. The findings of this study will advance our understanding of CSF physiology and its relevance in neurological pathologies, potentially leading to improved patient outcomes and management approaches. Materials and methods The study involved 36 patients and was conducted as an observational, prospective study over 18 months (October 2020 to March 2022) at the Department of Radiology, Saveetha Medical College and Hospital, Chennai. We utilized a 1.5 T Philips Multiva MRI scanner by Philips Healthcare in Amsterdam, Netherlands.The study included patients with suspected CSF flow abnormalities and abnormal MRI findings (normal pressure hydrocephalus (NPH), age-related brain atrophy, aqueduct stenosis (AS), Chiari malformation type 1, syringomyelia, or arachnoid cyst), alongside control exhibiting normal neurological symptoms and MRI results. Exclusions involved individuals with febrile seizures, neurological diseases, cerebrovascular accidents, anti-convulsive medication use, cardiac arrhythmia, or MRI contraindications. Post-processing involved analyzing stroke volume (SV), peak systolic velocity (PSV), end diastolic velocity (EDV), and mean flux. Statistical analysis was conducted using the StatisticalPackage for the Social Sciences (IBMSPSSStatisticsforWindows,IBMCorp., Version 24.0, Armonk,NY), employing the χ2-test for categorical variables and nonparametric tests like Mann-Whitney U and Kruskal-Wallis H-tests for quantitative variables. A p-value < 0.05 was considered significant. Results The 36 patients, aged 1 to 80 years, were referred by the neurology department and categorized into four subgroups based on clinical history and conventional MRI findings: NPH, AS, age-related brain atrophy, and a normal control group. MRI CSF flowmetry evaluation focused on PSV, PDV, and SV. We found peak diastolic velocity (PDV), PSV, and average blood velocity (ABV) to be significantly higher in NPH compared to the control group (PSV, EDV, and SV: 9.96 +/- 1.73, 4.72 +/- 0.62, and 63 +/- 12.88 for NPH versus 4.8 +/- 0.39, 3.21 +/- 0.55, and 20.72 +/- 5.7 for control, respectively; p = 0.000). Conversely, patients with age-related brain atrophy and AS exhibited lower values (1.6 +/- 0.44, 1.13 +/- 0.09, and 6.33 +/- 2.08 for AS, and 2.07 +/- 0.09, 1.62 +/- 0.33, and 6.8 +/- 2.16 for age-related brain atrophy versus control; p = 0.002). Conclusion MRI CSF flowmetry emerges as a rapid, accurate, and non-invasive diagnostic tool for various neurological disorders associated with abnormal CSF flow. Additionally, this technique may aid in selecting appropriate treatment strategies.

Adhesive arachnoiditis, subarachnoid hemorrhage, and intradural extramedullary thoracic cavernoma: illustrative case.

Spinal arachnoiditis can result from various factors, including spinal subarachnoid hemorrhage (sSAH). In this paper, the authors describe a case of intradural extramedullary cavernoma with an initial presentation of subarachnoid hemorrhage leading to multilevel spinal arachnoiditis to discuss the pathophysiology and optimal treatment strategy. Spinal intradural extramedullary cavernoma manifesting with sSAH is a rare clinical presentation; therefore, there is no clear strategy for the management of sSAH. Spinal arachnoiditis is a result of chronic inflammation of the pia arachnoid layer due to hematomyelia. No effective treatment that interrupts this inflammatory cascade and would also prevent the development of spinal arachnoiditis has been described to date. Lumbar drainage could aid in sSAH management, relieve spinal cord compression, and restore the normal spinal cerebrospinal fluid circulation gradient. It could help to clear the blood degradation products rapidly and prevent early inflammatory arachnoiditis development. Mini-invasive intrathecal endoscopic adhesiolysis appears to be a reasonable approach for reducing the risk of aggravating spinal arachnoiditis with a mechanical-surgical stimulus. Whether a conservative approach should be applied in these patients with mild myelopathy symptoms is still debatable.

Validating the accuracy of real-time phase-contrast MRI and quantifying the effects of free breathing on cerebrospinal fluid dynamics

BackgroundUnderstanding of the cerebrospinal fluid (CSF) circulation is essential for physiological studies and clinical diagnosis. Real-time phase contrast sequences (RT-PC) can quantify beat-to-beat CSF flow signals. However, the detailed effects of free-breathing on CSF parameters are not fully understood. This study aims to validate RT-PC’s accuracy by comparing it with the conventional phase-contrast sequence (CINE-PC) and quantify the effect of free-breathing on CSF parameters at the intracranial and extracranial levels using a time-domain multiparametric analysis method.MethodsThirty-six healthy participants underwent MRI in a 3T scanner for CSF oscillations quantification at the cervical spine (C2-C3) and Sylvian aqueduct, using CINE-PC and RT-PC. CINE-PC uses 32 velocity maps to represent dynamic CSF flow over an average cardiac cycle, while RT-PC continuously quantifies CSF flow over 45-seconds. Free-breathing signals were recorded from 25 participants. RT-PC signal was segmented into independent cardiac cycle flow curves (Qt) and reconstructed into an averaged Qt. To assess RT-PC’s accuracy, parameters such as segmented area, flow amplitude, and stroke volume (SV) of the reconstructed Qt from RT-PC were compared with those derived from the averaged Qt generated by CINE-PC. The breathing signal was used to categorize the Qt into expiratory or inspiratory phases, enabling the reconstruction of two Qt for inspiration and expiration. The breathing effects on various CSF parameters can be quantified by comparing these two reconstructed Qt.ResultsRT-PC overestimated CSF area (82.7% at aqueduct, 11.5% at C2-C3) compared to CINE-PC. Stroke volumes for CINE-PC were 615 mm³ (aqueduct) and 43 mm³ (spinal), and 581 mm³ (aqueduct) and 46 mm³ (spinal) for RT-PC. During thoracic pressure increase, spinal CSF net flow, flow amplitude, SV, and cardiac period increased by 6.3%, 6.8%, 14%, and 6%, respectively. Breathing effects on net flow showed a significant phase difference compared to the other parameters. Aqueduct-CSF flows were more affected by breathing than spinal-CSF.ConclusionsRT-PC accurately quantifies CSF oscillations in real-time and eliminates the need for cardiac synchronization, enabling the quantification of the cardiac and breathing components of CSF flow. This study quantifies the impact of free-breathing on CSF parameters, offering valuable physiological references for understanding the effects of breathing on CSF dynamics.

Subdural hygromas After Decompressive Craniotomies

Subdural hygromas occur after various brain interventions, are often asymptomatic but sometimes may require surgical treatment. They can develop in the immediate postoperative period, but they are more common a few weeks or even months after surgery. Subdural hygromas are particularly common after decompressive craniotomy in patients with traumatic brain injury or massive stroke. The pathogenesis is explained by the fact that a large bone defect causes a pressure difference in the skull, and a concomitant displacement of the ventricular system disrupts the normal cerebrospinal fluid circulation, contributing to the redistribution of cerebrospinal fluid flow into the subdural space.We review data from contemporary studies on subdural hygromas after decompressive craniotomy, their risk factors, and management strategies. We also present our case of recurrent subdural hygroma in a patient operated on for a ruptured aneurysm of the middle cerebral artery.

Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct.

Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.

Magnetic resonance imaging-based classification of the myodural bridge complex and its influencing factors

Cerebrospinal fluid (CSF) circulation is considered the third circulation of the human body. Recently, some scholars have proposed the myodural bridge (MDB) as a novel power source for CSF flow. Moreover, the suboccipital muscles can exert a driving force on the CSF via the MDB. This hypothesis is directly supported by head rotation and nodding movements, which can affect CSF circulation. The MDB has been validated as a normal structure in humans and mammals. In addition, the fusion of MDB fibers of different origins that act in concert with each other forms the MDB complex (MDBC). The MDBC may be associated with several CSF disorder-related neurological disorders in clinical practice. Therefore, the morphology of the MDBC and its influencing factors must be determined. In this study, T2-weighted imaging sagittal images of the cervical region were analyzed retrospectively in 1085 patients, and magnetic resonance imaging (MRI) typing of the MDBC was performed according to the imaging features of the MDBC in the posterior atlanto-occipital interspace (PAOiS) and posterior atlanto-axial interspace (PAAiS). The effects of age and age-related degenerative changes in the cervical spine on MRI staging of the MDBC were also determined. The results revealed four MRI types of the MDBC: type A (no MDBC hyposignal shadow connected to the dura mater in either the PAOiS or PAAiS), type B (MDBC hyposignal shadow connected to the dura mater in the PAOiS only), type C (MDBC hyposignal shadow connected to the dura mater in the PAAiS only), and type D (MDBC hyposignal shadow connected to the dura mater in both the PAOiS and PAAiS). The influencing factors for the MDBC typing were age (group), degree of intervertebral space stenosis, dorsal osteophytosis, and degenerative changes in the cervical spine (P < 0.05). With increasing age (10-year interval), the incidence of type B MDBC markedly decreased, whereas that of type A MDBC increased considerably. With the deepening of the degree of intervertebral space stenosis, the incidence of type C MDBC increased significantly, whereas that of type A MDBC decreased. In the presence of dorsal osteophytosis, the incidence of type C and D MDBCs significantly decreased, whereas that of type A increased. In the presence of protrusion of the intervertebral disc, the incidence of type B, C, and D MDBCs increased markedly, whereas that of type A MDBC decreased considerably, with cervical degenerative changes combined with spinal canal stenosis. Moreover, the incidence of both type C and D MDBCs increased, whereas that of type A MDBC decreased. Based on the MRI signal characteristics of the dural side of the MDBC, four types of the MDBC were identified. MDBC typing varies dynamically according to population distribution, depending on age and cervical degeneration (degree of intervertebral space stenosis, vertebral dorsal osteophytosis formation, simple protrusion of intervertebral disc, and cervical degeneration changes combined with spinal canal stenosis, except for the degree of protrusion of the intervertebral disc and the degree of spinal canal stenosis); however, it is not influenced by sex.

Multi-scale structures of the mammalian radial spoke and divergence of axonemal complexes in ependymal cilia

Radial spokes (RS) transmit mechanochemical signals between the central pair (CP) and axonemal dynein arms to coordinate ciliary motility. Atomic-resolution structures of metazoan RS and structures of axonemal complexes in ependymal cilia, whose rhythmic beating drives the circulation of cerebrospinal fluid, however, remain obscure. Here, we present near-atomic resolution cryo-EM structures of mouse RS head-neck complex in both monomer and dimer forms and reveal the intrinsic flexibility of the dimer. We also map the genetic mutations related to primary ciliary dyskinesia and asthenospermia on the head-neck complex. Moreover, we present the cryo-ET and sub-tomogram averaging map of mouse ependymal cilia and build the models for RS1-3, IDAs, and N-DRC. Contrary to the conserved RS structure, our cryo-ET map reveals the lack of IDA-b/c/e and the absence of Tektin filaments within the A-tubule of doublet microtubules in ependymal cilia compared with mammalian respiratory cilia and sperm flagella, further exemplifying the structural diversity of mammalian motile cilia. Our findings shed light on the stepwise mammalian RS assembly mechanism, the coordinated rigid and elastic RS-CP interaction modes beneficial for the regulation of asymmetric ciliary beating, and also facilitate understanding on the etiology of ciliary dyskinesia-related ciliopathies and on the ependymal cilia in the development of hydrocephalus.

Single-molecule imaging of aquaporin-4 array dynamics in astrocytes.

Aquaporin-4 (AQP4) facilitates water transport across astrocytic membranes in the brain, forming highly structured nanometric arrays. AQP4 has a central role in regulating cerebrospinal fluid (CSF) circulation and facilitating the clearance of solutes from the extracellular space of the brain. Adrenergic signaling has been shown to modulate the volume of the extracellular space of the brain via AQP4 localized at the end-feet of astrocytes, but the mechanisms by which AQP4 regulates CSF inflow and outflow in the brain remain elusive. Using advanced imaging techniques, including super-resolution microscopy and single-molecule tracking, we investigated the hypothesis that β-adrenergic receptor activation induces cellular changes that regulate AQP4 array size and mobility, thus influencing water transport in the brain. We report that the β-adrenergic agonist, isoproterenol hydrochloride, decreases AQP4 array size and enhances its membrane mobility, while hyperosmotic conditions induce the formation of larger, less mobile arrays. These findings reveal that AQP4 arrays are dynamic structures, responsive to adrenergic signals and osmotic changes, highlighting a novel regulatory mechanism of water transport in the brain. Our results provide insights into the molecular control of CSF circulation and extracellular brain space volume, laying the groundwork for understanding the relationship between astrocyte water transport, sleep physiology, and neurodegeneration.

Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage.

Rationale: Hydrocephalus is a substantial complication after intracerebral hemorrhage (ICH) or intraventricular hemorrhage (IVH) that leads to impaired cerebrospinal fluid (CSF) circulation. Recently, brain meningeal lymphatic vessels (mLVs) were shown to serve as critical drainage pathways for CSF. Our previous studies indicated that the degradation of neutrophil extracellular traps (NETs) after ICH/IVH alleviates hydrocephalus. However, the mechanisms by which NET degradation exerts beneficial effects in hydrocephalus remain unclear. Methods: A mouse model of hydrocephalus following IVH was established by infusing autologous blood into both wildtype and Cx3cr1-/- mice. By studying the features and processes of the model, we investigated the contribution of mLVs and NETs to the development and progression of hydrocephalus following secondary IVH. Results: This study observed the widespread presence of neutrophils, fibrin and NETs in mLVs following IVH, and the degradation of NETs alleviated hydrocephalus and brain injury. Importantly, the degradation of NETs improved CSF drainage by enhancing the recovery of lymphatic endothelial cells (LECs). Furthermore, our study showed that NETs activated the membrane protein CX3CR1 on LECs after IVH. In contrast, the repair of mLVs was promoted and the effects of hydrocephalus were ameliorated after CX3CR1 knockdown and in Cx3cr1-/- mice. Conclusion: Our findings indicated that mLVs participate in the development of brain injury and secondary hydrocephalus after IVH and that NETs contribute to acute LEC injury and lymphatic thrombosis. CX3CR1 is a key molecule in NET-induced LEC damage and meningeal lymphatic thrombosis, which leads to mLV dysfunction and exacerbates hydrocephalus and brain injury. NETs may be a critical target for preventing the obstruction of meningeal lymphatic drainage after IVH.

Contribution of Direct Cerebral Vascular Transport in Brain Substance Clearance.

The accumulation of harmful substances has long been recognized as a likely cause of many neurodegenerative diseases. The two classic brain clearance pathways are cerebrospinal fluid (CSF) and vascular circulation systems. Since the discovery of the glymphatic system, research on the CSF pathway has gained momentum, and impaired CSF clearance has been implicated in virtually all neurodegenerative animal models. However, the contribution of the direct participation of vascular transport across the blood-brain barrier in clearing substances is often ignored in glymphatic papers. Supportive evidence for the direct involvement of parenchymal vasculature in substance clearance is accumulated. First, multiple mechanisms have been proposed for the vascular drainage of exogenous and endogenous substances across the blood-brain barriers. Second, the "traditional" role of arachnoid villi and granulations as the main site for CSF draining into the vasculature system has been questioned. Third, MRI studies using different CSF tracers indicate that parenchymal vasculature directly participates in tracer efflux, consistent with immunohistochemical findings. Here we will review evidence in the literature that supports the direct participation of the parenchymal vascular system in substance clearance, in addition to the CSF clearance pathways.

The Physiological Occlusion of the Central Canal May Be a Prerequisite for Syringomyelia Formation.

Syringomyelia is a common central nervous system disease characterized by the dilation of the central canal (CC). Regarding the pathogenesis of syringomyelia, cerebrospinal fluid (CSF) circulation obstruction in the subarachnoid space (SAS) of the spinal cord has been widely accepted. However, clinical and animal studies on obstructing the CSF in SAS failed to form syringomyelia, challenging the theory of SAS obstruction. The precise pathogenesis remains unknown. We utilized an extradural compression rat model to investigate the pathogenesis underlying syringomyelia. Magnetic resonance imaging enabled detection of syringomyelia formation. To assess CSF flow within the SAS, Evans blue was infused into the cisterna magna. Histological analysis allowed morphological examination of the CC. Furthermore, CSF flow through the CC was traced using Ovalbumin Alexa-Flour 647 conjugate (OAF-647). Scanning electron microscopy (SEM) enabled visualization of ependymal cilia. The findings showed that the dura mater below the compression segment exhibited lighter coloration relative to the region above the compression, indicative of partial obstruction within the SAS. However, the degree of SAS occlusion did not significantly differ between syringomyelia (SM-Y group) and those without (SM-N group). Intriguingly, hematoxylin and eosin staining and CSF tracing revealed occlusion of the CC accompanied by reduced CSF flow in the SM-Y group compared to SM-N and control groups. SEM images uncovered impairment of ependymal cilia inside the syringomyelia. CC occlusion may represent a physiological prerequisite for syringomyelia formation, while SAS obstruction serves to initiate disease onset. The impairment of ependymal cilia appears to facilitate progression of syringomyelia.

Convergent differentiation of multiciliated cells

Multiciliated cells (MCCs) are epithelial cells that control body fluid flow and contribute to the clearance of pathogenic microbes and other particles from the airways, egg transport in oviducts, and circulation of cerebrospinal fluid in the central nervous system. Although MCCs have shared functions to control fluid flow via coordinated motility of multiple ciliary structures, they are found in multiple mammalian tissues originating from distinct germ layers and differentiate via distinct developmental pathways. To understand the similarities and differences of MCCs in multiple tissues, we investigated single-cell transcriptome data of nasal epithelial cells, bronchial tubes, fallopian tubes, and ependymal cells in the subventricular zone from humans and mice by cross-species data integration. Expression of cilia-associated genes was indistinguishable between these MCCs, although cell populations had unique properties by the species and tissue, demonstrating that they share the same final differentiation status for ciliary functions. We further analyzed the final differentiation step of MCCs from their distinctive progenitors and confirmed their convergent gene set expression for ciliogenesis at the final step. These results may provide new insight into understanding ciliogenesis during the developmental process.

SCO-spondin knockout mice exhibit small brain ventricles and mild spine deformation

Reissner’s fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.

Differentiated diagnostic and surgical algorithm for isolated and combined Chiari malformation Type I

Introduction: Arnold-Chiari malformation (ACM) type I is a craniovertebral junction pathology with ectopy of the cerebellar tonsils through the great occipital foramen with compression of the brain stem and upper cervical spinal cord. Until now, there have been more than 20 types of surgical interventions for the Arnold-Chiari malformation type. Objective: The main purpose of this research is the decompression of craniovertebral stem structures and occipital foramen, and the search for effective methods to repair cerebrospinal fluid (CSF) circulation. Methods: The complex examination and surgical treatment at the Neurosurgery Department No. 1 of the National Hospital of the Ministry of Health of the Kyrgyz Republic (Bishkek, Kyrgyzstan) passed 201 patients (aged 16-74) with symptomatic ACM I from 2008 to 2020.

The Role of Cerebrospinal Fluid Flow in the Subarachnoid Space in Beta‐Amyloid Clearance

AbstractBackgroundRecent studies identified the lymphatic drainage system in the brain. Here, cerebrospinal fluid (CSF) carries waste from brain tissue. However, it is still not well understood how CSF flow in the brain affects waste removal. In this study, we hypothesize that CSF flow patterns in the subarachnoid space will be correlated with beta‐amyloid deposition in the brain.MethodThirteen participants (7 Cognitively Normal and 2 Mild Cognitive Impairment, Age = 68±7.7 yrs. M/F = 5/4) who had prior amyloid PET imaging were recruited for CSF flow MRI from the Wake Forest Alzheimer’s Disease Research Center. The CSF flow patterns during the cardiac cycle were measured using the phase‐contrast MRI at the cerebral aqueduct, pontine cistern and cerebellomedullary cistern (Fig. 1). Images were acquired for 40 cardiac cycles with a pulse oximeter and CSF flow profiles were estimated using the retrospective cardiac gating method. PET Amyloid burden in the whole gray matter (GM) was measured as the standardized update value ratio (SUVR, cerebellar gray matter as a reference region) from the prior PET imaging and corresponding MRI.ResultCSF flow amplitude normalized by the brain tissue volume demonstrated moderate to strong correlations with beta‐Amyloid SUVR in GM (Fig. 2); Pearson’s correlation coefficient (rho) was ‐0.59 (p = 0.036) and ‐0.84 (p = 0.004) at pontine cistern and cerebellomedullary cistern, respectively. The lateral ventricle volume normalized by brain volume was also moderately correlated with GM SUVR (rho = 0.495).ConclusionAt an early stage of AD, the CSF circulation in the subarachnoid space could be correlated with beta‐Amyloid deposition. Therefore, CSF flow in the subarachnoid space could be a useful imaging marker to predict the clearance of beta‐amyloid in the brain.