Parasagittal Dural Space and Cerebrospinal Fluid (CSF) Changes Across the Lifespan in Healthy Adults: Implications for Glymphatic Flow

Abstract Background: Recent studies have suggested the importance of a glymphatic clearance pathway for brain parenchymal metabolic waste products. One fundamental but relatively under-explored component of this pathway is the anatomic region surrounding the superior sagittal sinus, which has been hypothesized to encompass lymphatic vessels. This so-called parasagittal dural (PSD) space likely plays a physiologically significant role at the distal intracranial component of the human glymphatic circuit, yet owing to the relative novelty of this discovery, fundamental gaps persist in our knowledge of how this space changes with normal aging and intracranial bulk fluid transport. Methods: We tested the hypotheses that volumetric magnetic resonance imaging (MRI) measures of the PSD space (i) are directly related to cerebrospinal fluid (CSF) flow at the cerebral aqueduct, and (ii) increase with age. Healthy participants (n=62; age range = 20-83 years) provided informed, written consent and multi-modal 3 Tesla MRI was performed including phase contrast assessment of the CSF flow through the aqueduct of Sylvius, T1-weighted and T2-weighted MRI for tissue volume and PSD assessment. Standard anatomical and cognitive testing were applied to confirm inclusion criteria. PSD volume was extracted using a recently validated neural networks algorithm. Non-parametric regression models were applied to evaluate how PSD volume related to tissue volume and age cross-sectionally, and separately how PSD volume related to CSF flux (significance criteria: two-sided p<0.05). Results: A significant enlargement of PSD volume in relation to normal aging (p<0.001, Spearman’s- =0.6), CSF volume (p<0.001, Spearman’s- =0.6) and bulk CSF flux through the aqueduct of Sylvius (anterograde and retrograde, p<0.001) were observed. The elevation in PSD volume was not significantly related to changes in tissue volume (p=0.11 and p=0.24 for gray and white matter, respectively). Findings are consistent with PSD volume increasing with age and bulk CSF flux.Conclusions: The findings of this study are two folds, first they highlight the feasibility of quantifying PSD volume non-invasively in vivo in humans using machine learning and non-contrast MRI. Second, that PSD volume increases with age, and relates to bulk CSF volume and flux. Values reported should provide useful normative ranges for how PSD volume adjusts with age, which will serve as a necessary pre-requisite for comparisons to persons with neurodegenerative disorders.

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Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection

10.1101/2020.11.09.374512 ◽

2020 ◽

Author(s):

Aditya Raghunandan ◽

Antonio Ladrón-de-Guevara ◽

Jeffrey Tithof ◽

Humberto Mestre ◽

Maiken Nedergaard ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Particle Tracking ◽

Bulk Flow ◽

Driving Mechanism ◽

Csf Flow ◽

Waste Products ◽

Cisterna Magna ◽

Tracer Particles ◽

Syringe Injection

AbstractCerebrospinal fluid (CSF) flowing through periarterial spaces is integral to the brain’s mechanism for clearing metabolic waste products. Experiments that track tracer particles injected into the cisterna magna of mouse brains have shown evidence of pulsatile CSF flow in pial periarterial spaces, with a bulk flow in the same direction as blood flow. However, the driving mechanism remains elusive. Several studies have suggested that the bulk flow might be an artifact, driven by the injection itself. Here, we address this hypothesis with new in vivo experiments where tracer particles are injected into the cisterna magna using a dual-syringe system, with simultaneous injection and withdrawal of equal amounts of fluid. This method produces no net increase in CSF volume and no significant increase in intracranial pressure. Yet, particle-tracking reveals flows in the pial periarterial spaces that are completely consistent with the flows observed in earlier experiments with single-syringe injection.

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Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep

Science ◽

10.1126/science.aax5440 ◽

2019 ◽

Vol 366 (6465) ◽

pp. 628-631 ◽

Cited By ~ 104

Author(s):

Nina E. Fultz ◽

Giorgio Bonmassar ◽

Kawin Setsompop ◽

Robert A. Stickgold ◽

Bruce R. Rosen ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Brain Function ◽

Slow Waves ◽

Neural Dynamics ◽

Rapid Eye Movement Sleep ◽

Csf Flow ◽

Csf Dynamics ◽

Macroscopic Scale ◽

Waste Products ◽

The Brain

Sleep is essential for both cognition and maintenance of healthy brain function. Slow waves in neural activity contribute to memory consolidation, whereas cerebrospinal fluid (CSF) clears metabolic waste products from the brain. Whether these two processes are related is not known. We used accelerated neuroimaging to measure physiological and neural dynamics in the human brain. We discovered a coherent pattern of oscillating electrophysiological, hemodynamic, and CSF dynamics that appears during non–rapid eye movement sleep. Neural slow waves are followed by hemodynamic oscillations, which in turn are coupled to CSF flow. These results demonstrate that the sleeping brain exhibits waves of CSF flow on a macroscopic scale, and these CSF dynamics are interlinked with neural and hemodynamic rhythms.

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Investigation of cerebrospinal fluid flow in the cerebral aqueduct using high-resolution phase contrast measurements at 7T MRI

Acta Radiologica ◽

10.1177/0284185117740762 ◽

2017 ◽

Vol 59 (8) ◽

pp. 988-996 ◽

Cited By ~ 6

Author(s):

Karin Markenroth Bloch ◽

Johannes Töger ◽

Freddy Ståhlberg

Keyword(s):

Cerebrospinal Fluid ◽

High Resolution ◽

Spatial Resolution ◽

Maximum Velocity ◽

Cerebral Aqueduct ◽

Mean Flow ◽

Csf Flow ◽

Flow Measurements ◽

Non Invasive ◽

Wide Range

Background The cerebral aqueduct is a central conduit for cerebrospinal fluid (CSF), and non-invasive quantification of CSF flow in the aqueduct may be an important tool for diagnosis and follow-up of treatment. Magnetic resonance (MR) methods at clinical field strengths are limited by low spatial resolution. Purpose To investigate the feasibility of high-resolution through-plane MR flow measurements (2D-PC) in the cerebral aqueduct at high field strength (7T). Material and Methods 2D-PC measurements in the aqueduct were performed in nine healthy individuals at 7T. Measurement accuracy was determined using a phantom. Aqueduct area, mean velocity, maximum velocity, minimum velocity, net flow, and mean flow were determined using in-plane resolutions 0.8 × 0.8, 0.5 × 0.5, 0.3 × 0.3, and 0.2 × 0.2 mm2. Feasibility criteria were defined based on scan time and spatial and temporal resolution. Results Phantom validation of 2D-PC MR showed good accuracy. In vivo, stroke volume was −8.2 ± 4.4, −4.7 ± 2.8, −6.0 ± 3.8, and −3.7 ± 2.1 µL for 0.8 × 0.8, 0.5 × 0.5, 0.3 × 0.3, and 0.2 × 0.2 mm2, respectively. The scan with 0.3 × 0.3 mm2 resolution fulfilled the feasibility criteria for a wide range of heart rates and aqueduct diameters. Conclusion 7T MR enables non-invasive quantification of CSF flow and velocity in the cerebral aqueduct with high spatial resolution.

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Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00251-6 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Per Kristian Eide ◽

Lars Magnus Valnes ◽

Erika Kristina Lindstrøm ◽

Kent-Andre Mardal ◽

Geir Ringstad

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Phase Contrast ◽

Flow Volume ◽

Nervous System Diseases ◽

Central Nervous System Diseases ◽

Csf Flow ◽

Phase Contrast Mri

Abstract Background Several central nervous system diseases are associated with disturbed cerebrospinal fluid (CSF) flow patterns and have typically been characterized in vivo by phase-contrast magnetic resonance imaging (MRI). This technique is, however, limited by its applicability in space and time. Phase-contrast MRI has yet to be compared directly with CSF tracer enhanced imaging, which can be considered gold standard for assessing long-term CSF flow dynamics within the intracranial compartment. Methods Here, we studied patients with various CSF disorders and compared MRI biomarkers of CSF space anatomy and phase-contrast MRI at level of the aqueduct and cranio-cervical junction with dynamic intrathecal contrast-enhanced MRI using the contrast agent gadobutrol as CSF tracer. Tracer enrichment of cerebral ventricles was graded 0–4 by visual assessment. An intracranial pressure (ICP) score was used as surrogate marker of intracranial compliance. Results The study included 94 patients and disclosed marked variation of CSF flow measures across disease categories. The grade of supra-aqueductal reflux of tracer varied, with strong reflux (grades 3–4) in half of patients. Ventricular tracer reflux correlated with stroke volume and aqueductal CSF pressure gradient. CSF flow in the cerebral aqueduct was retrograde (from 4th to 3rd ventricle) in one third of patients, with estimated CSF net flow volume about 1.0 L/24 h. In the cranio-cervical junction, net flow was cranially directed in 78% patients, with estimated CSF net flow volume about 4.7 L/24 h. Conclusions The present observations provide in vivo quantitative evidence for substantial variation in direction and magnitude of CSF flow, with re-direction of aqueductal flow in communicating hydrocephalus, and significant extra-cranial CSF production. The grading of ventricular reflux of tracer shows promise as a clinical useful method to assess CSF flow pattern disturbances in patients. Graphic abstract

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Cerebrospinal fluid dynamics in the human cranial subarachnoid space: an overlooked mediator of cerebral disease. I. Computational model

Journal of The Royal Society Interface ◽

10.1098/rsif.2010.0033 ◽

2010 ◽

Vol 7 (49) ◽

pp. 1195-1204 ◽

Cited By ~ 56

Author(s):

Sumeet Gupta ◽

Michaela Soellinger ◽

Deborah M. Grzybowski ◽

Peter Boesiger ◽

John Biddiscombe ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Subarachnoid Space ◽

Computational Analysis ◽

Three Dimensional ◽

Transport Processes ◽

Resonance Imaging ◽

Csf Flow ◽

Cerebral Disease ◽

Toxic Metabolites

Abnormal cerebrospinal fluid (CSF) flow is suspected to be a contributor to the pathogenesis of neurodegenerative diseases such as Alzheimer's through the accumulation of toxic metabolites, and to the malfunction of intracranial pressure regulation, possibly through disruption of neuroendocrine communication. For the understanding of transport processes involved in either, knowledge of in vivo CSF dynamics is important. We present a three-dimensional, transient, subject-specific computational analysis of CSF flow in the human cranial subarachnoid space (SAS) based on in vivo magnetic resonance imaging. We observed large variations in the spatial distribution of flow velocities with a temporal peak of 5 cm s −1 in the anterior SAS and less than 4 mm s −1 in the superior part. This could reflect dissimilar flushing requirements of brain areas that may show differences in susceptibility to pathological CSF flow. Our methods can be used to compare the transport of metabolites and neuroendocrine substances in healthy and diseased brains.

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Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection

eLife ◽

10.7554/elife.65958 ◽

2021 ◽

Vol 10 ◽

Author(s):

Aditya Raghunandan ◽

Antonio Ladron-de-Guevara ◽

Jeffrey Tithof ◽

Humberto Mestre ◽

Ting Du ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Bulk Flow ◽

Driving Mechanism ◽

Perivascular Spaces ◽

Pial Arteries ◽

Waste Products ◽

In Vivo Experiments ◽

Tracer Particles ◽

Syringe Injection

Cerebrospinal fluid (CSF) flowing through periarterial spaces is integral to the brain’s mechanism for clearing metabolic waste products. Experiments that track tracer particles injected into the cisterna magna (CM) of mouse brains have shown evidence of pulsatile CSF flow in perivascular spaces surrounding pial arteries, with a bulk flow in the same direction as blood flow. However, the driving mechanism remains elusive. Several studies have suggested that the bulk flow might be an artifact, driven by the injection itself. Here, we address this hypothesis with new in vivo experiments where tracer particles are injected into the CM using a dual-syringe system, with simultaneous injection and withdrawal of equal amounts of fluid. This method produces no net increase in CSF volume and no significant increase in intracranial pressure. Yet, particle-tracking reveals flows that are consistent in all respects with the flows observed in earlier experiments with single-syringe injection.

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COMPUTATIONAL INVESTIGATION ON CSF FLOW ANALYSIS IN THE THIRD VENTRICLE AND AQUEDUCT OF SYLVIUS

IIUM Engineering Journal ◽

10.31436/iiumej.v12i3.158 ◽

2011 ◽

Vol 12 (3) ◽

Cited By ~ 4

Author(s):

Edi Azali Hadzri ◽

Kahar Osman ◽

Mohamed Rafiq Abdul Kadir ◽

Azian Abdul Aziz

Keyword(s):

Fluid Dynamics ◽

Computational Fluid Dynamics ◽

Cerebrospinal Fluid ◽

Flow Rate ◽

Third Ventricle ◽

Region Of Interest ◽

Csf Flow ◽

The Third ◽

Aqueduct Of Sylvius ◽

Computational Fluid Dynamics Cfd

In this study, a three dimensional (3D) model of the third ventricle and aqueduct of Sylvius derived from MRI scans was constructed by using Computational Fluid Dynamics (CFD) modeling. Cerebrospinal fluid(CSF) can be modeled as a Newtonian Fluid and its flow through the region of interest (ROI) was visualized using Engineering Fluid Dynamics (EFD).The constructed ROI was regarded as rigid walled and only steady state flow was able to be defined due to the limitations of current software. Different flow rate was simulated at the Foramen of Monro and a small stenosis was modeled at the middle of the aqueduct of Sylvius at a fixed location. This was made corresponding to normal patients with variation of CSF flow rate physiologically and abnormal patients with tumor causing obstruction to or within the aqueduct of Sylvius, respectively. Due to the small dimensions of the ROI geometry, gravity and complex external gravity that acted upon it was considered to be neglected. The results show as the flow rate increase, the pressure drop of CSF in the ROI proportionally increased. For normal CSF flow rate, the presence of stenosis in the aqueduct demonstrates a significant increased pressure drop.ABSTRAK-Dalam kajian ini, model tiga dimensi (3D) untuk ventrikel ketiga dan akueduk Sylvius, yang terhasil daripada pengimejan resonans magnetik telah dikonstruksi menggunakan Permodelan Perkomputeran Dinamik Bendalir (Computational Fluid Dynamics (CFD)). Cecair serebrospinal (Cerebrospinal fluid (CSF)) dimodelkan sebagai bendalir Newtonan dan alirannya melalui kawasan kepentingan (region of interest (ROI)) digambarkan menggunakan Dinamik Bendalir Kejuruteraan (Engineering Fluid Dynamics (EFD)). Kawasan kepentingan yang dikonstruksi dianggap sebagai dinding tegar dan hanya aliran keadaan tunak yang dapat ditakrifkan berdasarkan pengehadan perisian komputer terkini. Kadar aliran yang berbeza disimulasikan di foramen monro dan laluan stenosis yang kecil dimodelkan di tengah-tengah akueduk Sylvius di satu lokasi yang telah ditetapkan. Kaedah ini dijalankan terhadap pesakit normal dengan variasi pada kadar aliran CSF, serta pesakit abnormal yang mempunyai tumor, penyebab sekatan terhadap atau melinkungi akueduk Sylvius. Disebabkan oleh ukuran geometri ROI kecil, tarikan graviti dan graviti luar kompleks yang bertindak ke atasnya diabaikan. Keputusan menunjukkan bahawa apabila kadar aliran meningkat, susutan tekanan CSF di dalam ROI meningkat dengan berkadar. Untuk kadar aliran CSF yang normal, kehadiran stenosis di dalam akueduk membuktikan pertambahan susutan tekanan yang ketara.

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Na-K activated adenosine triphosphatase formation of cerebrospinal fluid in the cat

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1964.206.5.1165 ◽

1964 ◽

Vol 206 (5) ◽

pp. 1165-1172 ◽

Cited By ~ 111

Author(s):

Thomas S. Vates ◽

Sjoerd L. Bonting ◽

W. Walter Oppelt

Keyword(s):

Cerebrospinal Fluid ◽

Choroid Plexus ◽

Formation Rate ◽

Cerebral Aqueduct ◽

Csf Flow ◽

Atpase System ◽

Na Ions ◽

Atpase Inhibition ◽

Csf Formation Rate

Digitalis-sensitive Na-K activated ATPase (Na-K ATPase), implicated in active cation transport, was shown to occur in cat choroid plexus. Cerebrospinal fluid (CSF) formation rate, measured by collection from cat cerebral aqueduct was inhibited 18% by intravenous desacetyl lanatoside C (0.2 mg/kg). Ouabain, placed intraventricularly, caused inhibition of flow, ranging from 100% by 10–5 mole to 0% by 5 x 10–10 mole. After 10–6 mole ouabain, Na-K ATPase activity in lateral ventricle choroid plexus was inhibited 69% without change in digitalis-insensitive, Mg activated ATPase and carbonic anhydrase activities. Ventriculocisternal perfusion with varying concentrations of ouabain, scillaren A, and hexahydroscillaren A gave CSF flow inhibition (inulin dilution technique) correlating quantitatively with in vitro Na-K ATPase inhibition. Other compounds studied were erythrophleine, cassaine, and l-norepinephrine. It is concluded that the choroid plexus Na-K ATPase system has a primary function in the formation of CSF in the cat, presumably through the active secretion of Na ions into the ventricle.

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Dynamic magnetic resonance imaging of the cerebrospinal fluid flow within the cerebral aqueduct by different FISIP 2D sequences

Vojnosanitetski pregled ◽

10.2298/vsp1005357l ◽

2010 ◽

Vol 67 (5) ◽

pp. 357-363

Author(s):

Milos Lucic ◽

Katarina Koprivsek ◽

Viktor Till ◽

Zoran Vesic

Keyword(s):

Magnetic Resonance Imaging ◽

Cerebrospinal Fluid ◽

Fluid Flow ◽

Magnetic Resonance ◽

Cine Mri ◽

Cerebral Aqueduct ◽

Resonance Imaging ◽

Csf Flow ◽

Cerebrospinal Fluid Flow ◽

Technical Parameters

Background/Aim. A vast majority of current radiogical techniques, such as computerized tomography (CT) and magnetic resonance imaging (MRI) have great potential of visualization and delineation of cerebrospinal fluid spaces morphology within cerebral aqueduct. The aim of this study was to determine the possibilities of two differently acquired FISP (Fast Imaging with Steady State Precession) 2D MR sequences in the estimation of the pulsatile cerebrospinal fluid (CSF) flow intensity through the normal cerebral aqueduct. Methods. Sixty eight volunteers underwent brain MRI on 1.5T MR imager with additionally performed ECG retrospectively gated FISP 2D sequences (first one, as the part of the standard software package, with following technical parameters: TR 40, TE 12, FA 17, Matrix: 192 ? 256, Acq 1, and the second one, experimentally developed by our investigation team: TR 30, TE 12, FA 70, Matrix: 192 ? 256, Acq 1) respectively at two fixed slice positions - midsagittal and perpendicular to cerebral aqueduct, displayed and evaluated by multiplegated images in a closed-loop cinematographic (CINE) format. Results. Normal brain morphology with preserved patency of the cerebral aqueduct in all of 68 healthy volunteers was demonstrated on MRI examination. Cerebrospinal fluid flow within the cerebral aqueduct was distinguishable on both CINE MRI studies in midsagittal plane, but the estimation of intraaqueductal CSF flow in perpendicular plane was possible on CINE MRI studies acquired with experimentally improved FISP 2D (TR 30, FA 70) sequence only. Conclusion. Due to the changes of technical parameters CINE MRI study acquired with FISP 2D (TR 30, FA 70) in perpendicular plane demonstrated significantly higher capability in the estimation of the CSF pulsation intensity within the cerebral aqueduct. .

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Evaluation of cerebrospinal fluid flow dynamic changes in patients with idiopathic intracranial hypertension using phase contrast cine MR imaging

The Egyptian Journal of Neurology Psychiatry and Neurosurgery ◽

10.1186/s41983-020-00227-7 ◽

2020 ◽

Vol 56 (1) ◽

Author(s):

Tamer Belal ◽

Abd-Elhalim Al Tantawy ◽

Fatema Mohamed Sherif ◽

Alshaimaa Ramadan

Keyword(s):

Cerebrospinal Fluid ◽

Medical Treatment ◽

Intracranial Hypertension ◽

Idiopathic Intracranial Hypertension ◽

Phase Contrast ◽

Cine Mri ◽

Mean Flow ◽

Csf Flow ◽

Flow Dynamic ◽

Dynamic Changes

Abstract Background Idiopathic intracranial hypertension (IIH) mainly affects overweight women in the middle age period. The pathophysiology of IIH stays unclear, but suggested mechanisms include excess CSF production, reduced CSF absorption, increased brain water content, and increased cerebral venous pressure Objectives To assess the cerebrospinal fluid (CSF) flow dynamic changes in aqueduct of Sylvius in patients of idiopathic intracranial hypertension (IIH) with new MRI technique: phase contrast cine MRI (PCC-MRI). Methods Thirty patients diagnosed with idiopathic intracranial hypertension were divided into 3 groups according to treatment options (no treatment, medical treatment, and medical treatment with repeated lumbar tapping). CSF flow data were evaluated by phase contrast cine MRI. Results PCC-MRI parameters were significantly higher in group who was on medical treatment (group II) than other groups. The sensitivity of PCC MRI parameters ranged from 56.7 (stroke volume (SV) and mean flow (MF)) to 83.3% (peak systolic velocity (PSV)). A statistically significant difference was found for the mean flow value (p 0.039) between the control group and IIH patients. Conclusion The most specific CSF flowmetry parameter detected to help diagnosis of IIH is mean flow especially among early discovered patients. PCC MRI can be used as non-invasive technique for diagnosis of IIH and treatment follow-up.

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