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      Cerebrospinal fluid volumetric net flow rate and direction in idiopathic normal pressure hydrocephalus

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          Abstract

          The aim of the present study was to examine cerebrospinal fluid (CSF) volumetric net flow rate and direction at the cranio-cervical junction (CCJ) and cerebral aqueduct in individuals with idiopathic normal pressure hydrocephalus (iNPH) using cardiac-gated phase-contrast magnetic resonance imaging (PC-MRI). An in-depth, pixel-by-pixel analysis of regions of interest from the CCJ and cerebral aqueduct, respectively, was done in 26 iNPH individuals, and in 4 healthy subjects for validation purposes. Results from patients were compared with over-night measurements of static and pulsatile intracranial pressure (ICP). In iNPH, CSF net flow at CCJ was cranially directed in 17/22 as well as in 4/4 healthy subjects. Estimated daily CSF volumetric net flow rate at CCJ was 6.9 ± 9.9 L/24 h in iNPH patients and 4.5 ± 5.0 L/24 h in healthy individuals. Within the cerebral aqueduct, the CSF net flow was antegrade in 7/21 iNPH patients and in 4/4 healthy subjects, while it was retrograde (i.e. towards ventricles) in 14/21 iNPH patients. Estimated daily CSF volumetric net flow rate in cerebral aqueduct was 1.1 ± 2.2 L/24 h in iNPH while 295 ± 53 mL/24 h in healthy individuals. Magnitude of cranially directed CSF net flow in cerebral aqueduct was highest in iNPH individuals with signs of impaired intracranial compliance. The study results indicate CSF flow volumes and direction that are profoundly different from previously assumed. We hypothesize that spinal CSF formation may serve to buffer increased demand for CSF flow through the glymphatic system during sleep and during deep inspiration to compensate for venous outflow.

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          Highlights

          • CSF flow was examined in the cranio-cervical junction and the cerebral aqueduct.

          • Phase-contrast MRI and in-depth pixel-pixel analysis of ROIs was performed.

          • There is redistribution of CSF flow in patients with iNPH.

          • The CSF flow volume and direction are different from previously assumed.

          • The observations indicate a role of spinal CSF formation.

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          Most cited references44

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          A new look at cerebrospinal fluid circulation

          According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation.
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            The Effect of Body Posture on Brain Glymphatic Transport.

            The glymphatic pathway expedites clearance of waste, including soluble amyloid β (Aβ) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aβ, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aβ clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans.
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              Inspiration is the major regulator of human CSF flow.

              The mechanisms behind CSF flow in humans are still not fully known. CSF circulates from its primary production sites at the choroid plexus through the brain ventricles to reach the outer surface of the brain in the subarachnoid spaces from where it drains into venous bloodstream and cervical lymphatics. According to a recent concept of brain fluid transport, established in rodents, CSF from the brain surface also enters the brain tissue along para-arterial routes and exits through paravenous spaces again into subarachnoid compartments. This unidirectional flow is mainly driven by arterial pulsation. To investigate how CSF flow is regulated in humans, we applied a novel real-time magnetic resonance imaging technique at high spatial (0.75 mm) and temporal (50 ms) resolution in healthy human subjects. We observed significant CSF flow exclusively with inspiration. In particular, during forced breathing, high CSF flow was elicited during every inspiration, whereas breath holding suppressed it. Only a minor flow component could be ascribed to cardiac pulsation. The present results unambiguously identify inspiration as the most important driving force for CSF flow in humans. Inspiratory thoracic pressure reduction is expected to directly modulate the hydrostatic pressure conditions for the low-resistance paravenous, venous, and lymphatic clearance routes of CSF. Furthermore, the experimental approach opens new clinical opportunities to study the pathophysiology of various forms of hydrocephalus and to design therapeutic strategies in relation to CSF flow alterations.
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                Author and article information

                Contributors
                Journal
                Neuroimage Clin
                Neuroimage Clin
                NeuroImage : Clinical
                Elsevier
                2213-1582
                14 September 2018
                2018
                14 September 2018
                : 20
                : 731-741
                Affiliations
                [a ]Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Oslo, Norway
                [b ]Division of Radiology and Nuclear Medicine, Department of Radiology, Oslo University Hospital - Rikshospitalet, Oslo, Norway
                [c ]Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
                [d ]Department of Numerical Analysis and Scientific Computing, Simula Research Laboratory, Oslo, Norway
                [e ]Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
                Author notes
                [* ]Corresponding author at: Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway. p.k.eide@ 123456medisin.uio.no peide@ 123456ous-hf.no
                [1]

                These authors contributed equally to this work.

                Article
                S2213-1582(18)30281-X
                10.1016/j.nicl.2018.09.006
                6154456
                30238917
                682f0159-9581-4928-8faa-c8d9b76cc54f
                © 2018 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 9 August 2018
                : 6 September 2018
                : 11 September 2018
                Categories
                Regular Article

                cerebrospinal fluid,phase-contrast mri,cranio-cervical junction,cerebral aqueduct,intracranial pressure,aqp4, aquaporin 4,ccj, cranio-cervical junction,csf, cerebrospinal fluid,fov, field of view,icp, intracranial pressure,inph, idiopathic normal pressure hydrocephalus,mwa, mean wave amplitude,pc-mri, phase-contrast magnetic resonance imaging,roi, region of interest,snr, signal-to-noise-ratio,tr, repetition time,te, echo time

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