Veins and Lymphatics 2019; volume 8:8470

Neurofluids: A holistic ing of the fluid dynamics, rather than focus- approach to their physiology, ing on a single compartment when analyzing Correspondence: Nivedita Agarwal, Hospital neurological diseases. This approach may S. Maria del Carmine, Corso Verona 4, 38068 interactive dynamics and contribute to advance our comprehension of Rovereto (TN), Italy. clinical implications for some common neurological disorders, Tel.: +39.0464.404066 E-mail: [email protected] neurological diseases paving the way to newer treatment options. Key words: Monro-Kellie; phase-contrast magnetic resonance imaging; neurofluids; Nivedita Agarwal,1,2 3 4 chronic cerebrospinal venous insufficiency; Christian Contarino, Eleuterio F. Toro Introduction glymphatic system; meningeal lymphatics: 1Section of Radiology, Hospital Santa IPAD. Maria del Carmine, Rovereto (TN), Neurological disorders constitute a Contributions: NA, designed the paper to link Italy; 2Center for Mind/Brain Sciences major public health challenge and are asso- ciated with life-long disability.1 Much mechanical aspects of neurofluid interaction CIMeC, University of Trento, Italy; progress has been made in understanding and neurological diseases as well as wrote the 3Computational Life Inc., Delaware, manuscript; CC, contributed to the revision of the etiopathogenesis of many of these, how- USA; 4Laboratory of Applied the paper and designed figures; EFT, con- ever, there are still several gaps in our tributed to the design of fluid mechanics Mathematics, University of Trento, Italy knowledge of many others, some of which framework of paper and holistic view of neu- are still considered idiopathic (a disease of rofluids as well as the writing of parts of the unknown etiology). paper. Abstract The Monro-Kellie hypothesis formulat- ed by the Scottish anatomist Alexander Conflict of interest: the authors declare no conflict of interest. There is increasing interest in under- Monro (secundus) and his former student standing the physiology of the extracellular George Kellie in 1783 remains a cardinal Received for publication: 7 August 20019. fluid compartments in the central nervous principle in understanding the physiology Revision received: 31 August 2019. 2 only system and their dynamic interaction. Such of the central nervous system (CNS). This Accepted for publication: 31 August 2019. interest has been in part prompted by a vig- hypothesis, as originally stated, maintains orous resurgence of the role of the venous that: i) brain contents are enclosed in a non- This work is licensed under a Creative system, the recent discoveries of the expandable bony skull; ii) the volume of Commons Attribution 4.0 License (by-nc 4.0). meningeal lymphatics, the brain waste skull contents is constant at all times;use iii) the ©Copyright: the Author(s), 2019 removal mechanisms and their potential brain parenchyma (BP) is largely incom- Licensee PAGEPress, Italy link to neurological diseases, such as idio- pressible; and iv) venous outflow must Veins and Lymphatics 2019; 8:8470 pathic intracranial hypertension, Ménière’s match the arterial blood inflow within the doi:10.4081/vl.2019.8470 disease, migraine, small vessel disease, and cardiac cycle.3 However, over the years, most neurodegenerative diseases. parts of the Monro-Kellie doctrine have The rigid cranial cavity houses several been challenged largely because it ignored space-competing material compartments: the presence of cerebrospinal fluid (CSF). logical diseases that may derive from specif- the brain parenchyma (BP) and four extra- We now know that in addition to venous ic alterations have been schematically illus- cellular fluids, namely arterial, venous, outflow, caudal displacement of CSF con- trated in Figure 1. This will form the basis of cerebrospinal fluid (CSF) and interstitial tributes to counterbalance arterial blood our understanding of the proposed brain fluid (ISF). During cardiac pulsations, the input within the rigid bony skull during waste clearance mechanisms and how a harmonious, temporal and spatial dynamic each cardiac cycle and these movements holistic approach could help provide answers interaction of all these fluid compartments occur in a precise temporal order.4 These to still unsolved questions. and the BP assures a constant intracranial newer concepts help us better understand volume at all times, consistent with the the dynamic interconnection between the Monro-Kellie hypothesis. TheNon-commercial dynamic various compartments and how anomalies interaction involves high-pressure input of in one can affect the dynamics of others.5 Cerebral arterial system arterial blood during systole and efflux of The cranium houses several space-compet- CSF into the spinal subarachnoid space ing material compartments: BP and four Paired internal carotid and vertebral (SSAS) followed by venous blood exiting extracellular fluids, namely arterial, venous, arteries assure a steady blood supply to the directly into the vertebral and internal jugu- interstitial fluid (ISF) and CSF. In light of cerebral hemispheres that anastomose at the lar veins towards the heart and intraventric- recent renewed interest in fluids such as level of the circle of Willis (Figure 2A). The ular CSF displacing caudally towards the ISF, the discovery of the meningeal lym- cardiac input to the brain is approximately SSAS. Arterial pulsatile energy is transmit- phatics6 and proposed mechanisms for brain 15-20% of the total cardiac output. For a ted to the BP that contributes to the smooth waste clearance mechanisms,7-9 it has healthy adult weighing 70 kgs, the cardiac movement of fluids in and out of the brain. become necessary not only to revisit the output is estimated at approximately 5 Perturbing any of these fluid compartments original Monro-Kellie doctrine but also to L/min and brain arterial input is about 750 will alter the entire brain dynamics, poten- comprehend the intricate interplay of the mL/min to 1000 mL/min. Each of these tially increase intracranial pressure, affect different CNS compartments. arteries will divide progressively into small- perfusion and hamper clearance capacity of We will do this by reviewing the relevant er branches (pial or leptomeningeal arteries) metabolic waste. anatomy and physiology of the BP and single as they reach the cortical surface in the cere- This review of all major extracellular CNS extracellular fluid compartments (we bral subarachnoid space (CSAS).10 fluid compartments within the brain, advo- will call them neurofluids). Key elements of The cortical surface is lined by glia lim- cates a holistic approach to our understand- such interactions and major possible neuro- itans, a structure that is made up of astrocyt-

[Veins and Lymphatics 2019; 8:8470] [page 49] Review ic end-feet and tight junctions. The pia Equation 3, shows how a change in ves- where ICP is intracranial pressure, JVP is mater overlies the glia limitans and fuses sel radius will determine a flow change jugular venous pressure and MAP is mean with the basement membrane (BM) of the exponentially to the power of four making it arterial pressure. The normal range of MAP pial arteries forming the outer wall of a fun- a powerful mechanism to instantly regulate is 70-100 mmHg. Brain capillaries are lined nel-shaped CSF-filled space.11 Cortical pia Q, or cerebral blood flow (CBF). with a single layer of continuous non-fenes- mater is also reflected over these lep- CPP is defined as: trated endothelial cells that are held togeth- tomeningeal arteries.12,13 The adventitial er with tight junctions and constitute the layer of leptomeningeal arteries is sur- CPP=MAP-max{ICP,JVP} (4) blood-brain barrier (BBB).21 Several specif- rounded by perivascular spaces (PVS), or compartments which are fluid-filled but also contain connective tissue and cells (Figure 1).12,14 PVS are an important exchange route for CSF and ISF for sub- stances including CSF-infused tracers to reach brain parenchyma alongside vessels.15 The arteriolar walls are lined with lay- ers of smooth muscle cells (SMCs) that form the tunica media and have contractile properties that ensure a constant cere- brovascular tone.16 These are innervated by the autonomous nervous system or extrinsic innervation. Sympathetic innervation will cause vasoconstriction in response to an increase in arterial pressure, and reduce blood flow, whereas parasympathetic inner- vation will cause vasodilation of arterioles only in a situation of low arterial pressure and increase blood flow.17 Capillaries are inner- vated by nerves arising within the brain. These are subcortical nuclei in the brain- use stem such as nucleus coeruleus, raphe nuclei and other nuclei in the basal fore- brain.18 This intrinsic innervation is more pronounced at the astrocyte-neuronal junc- tion.17 The contractile activities of SMCs and pericytes in the arterioles and capillar- Figure 1. Schematic drawing on a coronal section of the brain illustrating the interaction ies are major actors that modulate lumen between neurofluid compartments and brain parenchyma and possible neurological dis- diameter thereby determining the entity of eases due to their derangement: 1) Arterial system: branches of carotid arteries (CA) and cerebrovascular resistance (CVR) to flow vertebral arteries (not shown) reach the CSAS, the walls of which contain sympathetic and assures constant cerebral perfusion innervation for smooth muscle cells (ext.nerves) 2) CSF pathway: a) CSF is produced via choroid plexi (CP) in the ventricles and flows caudally through the foramina of Luschka pressure (CPP) through a unique process 19,20 and Magendie towards the cerebral subarachnoid space(CSAS), b) CSF flows caudally known as cerebral autoregulation (CA). and reaches the CSAS via foramen of Lushka and Magendie (LML) and towards the According to Poiseuille’s law, flow Q spinal (SSAS), c) CSF also moves through the ventricular ependymal wall towards the through a vascular segment of length L is brain parenchyma (BP), d) CSF drains into the dural venous sinus through arachnoid directly determined by the pressure drop DP granulations (Ag); e) CSF from the CSAS enters arterial perivascular space (APS) and into the BP through aquaporin 4 (AQP-4) water channels; d) CSF flows through the ventric- and inversely to the resistance to flowNon-commercial R: ular ependymal wall toward the brain parenchyma (BP) and extracellular space (ECS) where it intermingles with interstitial fluid (ISF); 3) Glymphatic theory: CSF from arterial perivascular space (APS) enters the BP via AQP-4 and mixes with ISF. Bulk flow and/or diffusion processes move ISF/CSF from the BP towards the venous perivascular space (1) (VPS), transporting metabolic waste out towards the CSAS and into the dural venous sinus. 4) Intramural periarterial drainage (IPAD): ISF flows is in the opposite direction to arterial flow along the basement membranes (BM) of arteries (zoomed box) and leaves the intracranial cavity along the walls of the CA into the deep cervical lymph nodes. where R is Extrinsic and intrinsic innervations lines the arterial and capillary wall respectively and determine cerebrovascular tone and contribute to cerebral autoregulation. 5) Venous sys- tem: bridging veins (BV) lie on the cortical surface in the CSAS and drain into the supe- (2) rior sagittal sinus (here shown as dural venous sinus). Venous blood flows out the intracranial cavity via internal jugular veins (IJV) and vertebral veins (not shown). 6) Meningeal lymphatics: lymphatic channels line dural venous sinus and provide an important pathway for CSF drainage towards the deep cervical lymph nodes. These can also be drained via perineural sheaths around cranial nerves and through the cribriform η is the blood viscosity and r is the vessel plate to reach deep cervical lymph nodes. 7) Brain parenchyma (BP) is made up of 80- radius. Thus, Q becomes: 85% of cells and intracellular fluid, the rest is made up of extracellular space (ECS) and contains ISF. A potential list of diseases, already published in the literature, that might affect one or more compartments are listed in the various boxes. CADASIL=cerebral auto- somal dominant arterial with subcortical infarcts and leucoencephalopathy, CAA=cere- (3) bral amyloid angiopathy, PEFA=protein elimination failure angiopathy.

[page 50] [Veins and Lymphatics 2019; 8:8470] Review ic molecules form the unique tight junction, production and absorption occurs within the such as occludins, claudins and junctional entire BP and that its formation in the Cerebral venous system adhesion molecules.22 BBB selectively choroid plexi and absorption in the dural restricts paracellular transport of solutes venous sinuses may be of less importance.35 Three different venous drainage net- and cells across brain capillaries and limits According to these authors, CSF is pro- works exist in the brain. An outer, superfi- dangerous fluctuations in local concentra- duced and absorbed at the capillary level cial segment of veins that drain the scalp, tions of ions, proteins, glucose, neuromodu- through Starling forces acting between plas- muscle and tendons and an intermediate ma and the extracellular fluid in the extra- segment that serves the skull tables and the lators, and neurotransmitters and to prevent 42 entry of pathogens and toxins inside the cellular space (ECS).35,36 There is also evi- dura mater (diploic veins). The third set of brain.23 dence for transependymal CSF flow into the veins are intra-parenchymal veins that may brain parenchymal ECS where it may inter- be further subdivided into superficial and mingle with ISF.27,37,38 deep veins (Figure 2B,C). Several anatomi- Intraventricular CSF flow is bidirec- cal variations are possible and veins can tional, primarily driven by cardiac activity vary in number, size, symmetry and their Cerebrospinal fluid 43 (expansion of choroidal arteries in the drainage patterns. The different venous There are multiple controversies and plexi), although it is also affected by breath- networks can communicate with each other lack of conclusive data in the literature ing.39 During systole, CSF from the ventric- according to physiological needs or patho- regarding CSF dynamics.24 The historical ular system flows caudally towards the logical conditions (Figure 3C). Intracranial understanding is that CSF is produced with- SSAS (also known as, net negative flow) veins and sinuses are valveless allowing in the choroid plexi in the lateral, third and and flows cranially during diastole (also flow to reverse in the case of downstream 44 the fourth ventricles and flows through the known as, net positive flow) with minimum venous obstruction. Bridging veins (BV) foramen of Magendie and Luschka into net displacement in the cranial direction. however, drain into dural sinuses at the CSAS and caudally towards the SSAS CSF dynamics can be quantified using vali- level of arachnoid granulation through a (Figure 1,2F). It is produced at a rate of 0.3- dated and more reliable cine phase-contrast cuff-like segment lined with circularly 45 0.4 mL/min25. Total CSF volume is approx- flow magnetic resonance imaging (PC- arranged SMC (Figure 2E). This segment imately 189±29 mL in adults and varies MRI) techniques.40,41 remainsonly closed until transmural pressure with age and gender.26 CSF subserves nutri- tional, immunologic, metabolic and clear- ance functions in addition to protecting the ABC brain and spine from external injury.27 use Choroidal capillaries are characterized by multiple fenestrations and are bounded by a single layer of choroidal epithelium. The CSF facing surface, or the apical sur- face of the epithelial cells, is lined with tight junctions and contain microvilli forming the blood-CSF barrier.28 Multiple ion channels and water ion channel aquaporin 1 (AQP-1) on the apical and the basolateral surfaces operate to create a favorable osmotic gradi- ent through secretion of Na+, facilitating water movement through AQP-1 channels across the CP epithelium into the ventricles.29 CSF is absorbed into the dural venous sinuses through subarachnoid gran- ulations or villi that contain Non-commercial fine water channels in their core12 (Figure 2E). Thus, CSF also enters PVS and flows in a cen- tripetal direction towards the BP via aqua- porin 4 water channels (AQP-4) (glymphat- ic theory)7,30,31 (Figure 1). CSF also exits through the cribriform plate towards nasal DE F lymphatics and the cranial cavity via major Figure 2. Normal anatomy. A) 3D time-of-flight (TOF) magnetic resonance angiography foramina of the skull base alongside cranial image illustrating the main intracranial arteries and the circle of Willis (COW). nerves, arteries, and veins towards the deep ICA=internal carotid artery, MCA=middle cerebral artery, ACA=anterior cerebral artery, cervical lymph nodes8,31-33 (Figure 1). In PCA= posterior cerebral artery, VA=vertebral artery; B) contrast enhanced magnetic res- addition, true meningeal lymphatics along onance venography (CE-MRV) illustrating the main superficial dural venous sinuses. SSS=superior sagittal sinus, TS=transverse sinus, SS=sigmoid sinus; C) CE-MRV showing the meninges surrounding the dural venous bridging veins (BV) or cortical veins; D) CE-MRV of the intracranial veins of the neck. sinuses also drain CSF towards the deep DCV=deep cervical veins, VP=vertebral plexi, IJV=internal jugular vein, AJV=anterior cervical lymph nodes as observed in both jugular vein; E) T2 weighted coronal MRI illustrates the subarachnoid space and its prin- animal6,33 and human studies34 (Figure 1). ciple contents. AG=arachnoid granulation, CSAS=cerebral subarachnoid space, WM=white matter, GM=gray matter, PA=pial artery; F) T1 weighted sagittal image. An alternative view of CSF dynamics, LV=lateral ventricle, 3V=third ventricle, AoS=aqueduct of Sylvius, 4V=fourth ventrice, also known as the Bulat-Klarica-Orešković SSAS=spinal subarachnoid space. hypothesis, strongly advocates that CSF

[Veins and Lymphatics 2019; 8:8470] [page 51] Review builds up such that BVs expand and venous ly affect Starling forces at the capillary bed necessary for optimal neuronal signaling, blood flows into the dural sinuses.46 BVs and perturb reabsorption of fluids and favor synaptic plasticity, sustain local and are sensitive to transmural pressure. solutes5,35,52,53 (Figure 3D-F). remote transmission of neurotransmitters Increase in ICP can cause a collapse of such (volume transmission), promote enzymatic veins, whereas an increase in venous sinus Interstitial fluid degradation of plaques and to support brain pressure will cause engorgement of BV. In The brain ECS accounts for about 15- repair mechanisms including clearance of both cases venous outflow will be severely 20% of the total brain volume.54 In an aver- metabolic waste.54,56 impacted (Figure 3). age 1400 mL of brain weight, 210-280 mL The water component of ISF is likely Intracranial venous vessels are in direct is made up of ECS. The geometry of ECS is derived through several different pathways. continuity with extracranial neck vessels characterized by tortuous spaces surround- First, it is a by-product of glucose oxidation and the intra- and extra-spinal venous sys- ing neural and glial cells. ECS contains ISF whereby glucose is converted to CO2 and −1 tems, also termed as the craniospinal and is made up of ECM, which is attached H2O at a rate of approximately 28 nl g −1 57 venous system (CSVS).47 The CSVS is an to cell membranes. The most important con- min . Second, Starling forces at the capil- extensive network of intricately communi- stituents of ECM are glycosaminoglycans, lary level cause water to filtrate from the 57 cating veins connected to the azygos, hemi- proteoglycans (e.g. hyaluronic acid), and blood plasma into the ECS. Third, part of azygos veins and both superior and the infe- glycoproteins (e.g. laminins, collagen, CSF that enters the BP via AQP-4 lined rior vena cava.47 Internal jugular veins (IJV) fibronectin) creating a negatively charged astrocytic end-feet, intermingles with ISF in 30 are considered the major recipients of environment to maintain a well-hydrated the BP. intracranial venous blood from the sigmoid ambient for cellular communication and The drainage of ISF has been the topic sinuses in around 72% of healthy individu- transport of substances.55 The cellular com- of intense research during the last few als (jugular drainers) (Figure 2D).48 position of the brain differs from region to decades starting from seminal works by 58 Veins carry oxygen-depleted blood region creating important changes to diffu- Helen Cserr. Two alternative pathways towards the heart. They also represent the sion properties which would either facilitate (one may not exclude the other) have 54 primary route for the removal of metabolic or further impede ISF movement. A dam- recently been proposed. The glymphatic waste products from tissues. The role of aged ECS will hinder flow of ISF thereby theoryonly proposes the movement of CSF from venous vessels in maintaining ICP is under- disrupting the electrochemical environment the CSAS towards the arterial perivascular scored by the fact that these high capaci- space (APS), which enters BP via AQP-4 tance vessels contain 70% of the entire intracranial blood volume such that both AB C passive and active control of venous SMCs use can cause important intracranial blood vol- ume shifts, significantly affecting ICP.49 Veins are easily collapsible and the cross- sectional area (CSA) of veins can be influ- enced by multiple internal and external fac- tors. Internal factors include upstream and downstream pressure, flow rates and gravi- tational forces whereas the predominant external factor is the surrounding ICP. There is also an active neurogenic control of venous vessels via monoaminergic inner- vation.50 DEF Recalling Equation (1), venous flow:

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where Pv is venous pressure, CVP is pres- sure within the right atrium (central venous pressure) and R represents resistance to flow (largely determined by venous CSA). In the veins, R is relatively low as they read- ily expand to allow venous blood to flow unhindered towards the heart. Both extracranial (e.g. IJV) and intracranial stric- Figure 3. Venous pathology. Top row: 26yr old M with headaches and visual acuity loss tures (e.g. dural venous sinus) will increase with chronic venous thrombosis A) CE-MRV shows multiple stenosis of the SSS, irregular the denominator R in equation 6, severely lumen of the BV which are puffed at the junction with the SSS; B) phase contrast coronal MRV shows multiple anastomosis of the intra and extracranial veins; C) digital subtrac- affecting Q unless compensatory mecha- tion angiography in the venous phase confirms massive anastomosis between the intra nisms, such as recruitment of additional col- and extracranial veins due to thrombosed dural venous sinuses. Middle row: a 34yr old F lateral venous outflow pathways become with a diagnosis of IIH D) bilateral papilledema in IIH, E) increased lumen of SSS and active (Figure 3A-C).51 Impaired venous all BV due to transverse sinus (TS) stenosis before stent placement in the TS, and F) reduction in the lumen (and thus volume) of the SSS and BV after stenting of the TS. outflow will result in engorgement of Bottom row: 25yr old F with a diagnosis of intracranial hypotension. upstream cortical veins, reduce CPP, direct-

[page 52] [Veins and Lymphatics 2019; 8:8470] Review water channels lined astrocytes. The CSF hand, is made up of heavily myelinated tional to the square of the distance (t∝x2) mixes with ISF and this fluid exits the space tracts creating a highly anisotropic environ- which means that diffusion is hopelessly around veins, or venular perivascular space ment that restricts the movement of water slow for long distances but fast for very (VPS) (Figure 1).7 This paravascular move- molecules in the direction of least resist- short distances. The thickness of brain cap- ment of fluids and solutes is probably facil- ance. The mechanical and visco-elastic illary walls is of the order of 1 mm and itated by arterial pulsations and respiration properties (brain compliance) of the BP therefore in this situation, diffusion is suffi- and represent the principal drivers of bulk vary and depend on cellular morphology, ciently fast. flow, although recent evidence demon- capillary distribution, the compactness of Transport across the vessel wall is a strates diffusion within the ECS to be more white matter axons, their orientation and two-way process; in addition to the delivery likely.59-61 An alternative model suggests ECM composition.70 These properties are of oxygen and nutrients from lumen to tis- that CSF enters BP through BM within the different both at a macroscale (WM is sue, there is absorption into the bloodstream walls of penetrating arteries whereas neuro- stiffer than GM) and at a microscale (corti- across the capillary/venule wall. Many dis- toxic waste such as amyloid b and t is cal GM is stiffer than hippocampal GM; eases are likely in part due to disturbance of removed via ISF drainage along the BM, WM in the corpus callosum is stiffer than the two types of transport: i) fast, long- assisted by contractile activity of the SMC WM in the corona radiata).70 Brain compli- range advective transport dominated by (aka vasomotion) in an opposite direction to ance is a measure that expresses the brain pressure gradients; and ii) slow, short- arterial flow towards the deep cervical pressure-volume relationship. In a well- range, diffusion dominated transport. The lymph nodes, also known as the intramural compliant BP, changes in volume will not integrity of the intricate morpho-functional periarterial drainage (IPAD)9,62,63 (Figure 1). affect pressure until it reaches a certain aspects of neurofluids and BP are major Computational modeling of IPAD suggests threshold, whereby even small volume determinants for the smooth delivery of that such movement of ISF is faster than changes would result in very large ICP vital substances for neuronal functioning 71 diffusion through BP.64 changes. Such characteristics are constant- and for effective transport of metabolic ly changing with water content in the brain, waste. Altered fluid dynamics will result in during both neurodevelopment in early altered pressure, altered flow, altered wall stages of life and neurodegeneration in later shearonly stresses, altered perfusion, altered Brain parenchyma stages of life and will affect brain compli- absorption, altered clearance of metabolic ance.72 In an early MRI-based study, Greitz waste, edema, accumulation and deposition With over 100 billion neurons, the brain et al. observed brain tissue pulsatile move- of materials in the vessel wall and the BP. is one of the most metabolically active, ment caused by systolic arterial expansion, Neurofluid dynamics are thus closely cou- high-energy demanding organ in the human noting that re-modelling of theuse brain pled to waste clearance mechanisms (Figure 65 body. Oxygen and glucose are primary enables its piston-like action that aids CSF 1). A major clinical implication of such substrates for the production of high energy venting to SSAS and compression of ventri- combined transport systems is their role in adenosine triphosphate molecules (ATP) cles, thus promoting intra-ventricular flow. clearance of metabolic waste and neurotox- + + that assure the functioning of Na -K They identify cranio-spinal dynamics, as ic substances such as amyloid b and t and ATPase pumps, necessary to maintain the the interplay resulting from the spatial their potential biophysical link of neuroflu- integrity of cell membranes and also to gen- requirements of BP and neurofluids. Brain id dynamics to neurological diseases, such erate action potentials that form the basis of compliance can be influenced by age-relat- as Alzheimer’s disease (AD), Parkinson’s all neuronal activity. This activity continues ed changes, pathological processes and also disease (PD), idiopathic intracranial hyper- relentlessly at all times including sleep.66 by simple manual external compression of tension (IIH), Ménière’s disease (MD), Since glucose is not stored in the brain, a IJVs, no doubt BP dynamics must be part of multiple sclerosis (MS), migraine and other steady supply of primary substrates is nec- any study concerned with cranio-spinal neurodegenerative diseases.74 There are essary for normal brain function and war- dynamics in a holistic setting, as advocated however many questions to be answered 73 rants an adequate CPP and CBF at all times. here. with regards to brain waste clearance sys- Interruption of CBF for just 10 seconds can tems. For example, the forces responsible cause neuronal dysfunction and if not for the transport of CSF into the BP, exit restored promptly, irreversible Non-commercialdamage can route through the VPS and the character of occur in a matter of a few minutes.67 Craniospinal inter-compartment such transport, advective or diffusive BP consists of gray matter (GM) and fluid dynamics and waste clear- remain controversial and yet to be identi- white matter (WM) (Figure 2E). There is an ance fied. outer layer of cortical GM and an inner Perhaps even more challenging, is the mass of WM. Within the depths of WM, Main tasks of the brain fluid-mediated interaction of these fluid transport systems there are additional nuclei of cells, also transport systems are: i) to supply oxygen with the venous system, especially in patho- known as subcortical gray matter nuclei and and nutrients to sustain high-energy physiological conditions. This point, to the are largely represented by basal ganglia, demands of the brain; and ii) to collect and authors’ knowledge, has not yet been thalami, and hippocampi. GM is a more remove metabolic waste efficiently, avoid- addressed. Here we anticipate some points hydrophilic environment that contains a ing an accumulation of neurotoxic materials that might be of interest to consider in cran- larger quantity of fluid, is less tightly in the brain’s delicate structures. The first iospinal venous pathological conditions. packed with cells and has a higher capillary task involves the arterial system providing First, recall that venous system: i) is a sink density reflective of its elevated energy fast advective transport of solutes in the to CSF via arachnoid-villi drainage into the needs.68 MRI based measurements have blood, which is then partly delivered at the superior sagittal sinus; ii) collects ISF and quantified a total CBV (arterial and venous) level of the microvasculature involving var- solutes that is reabsorbed across vessel in the GM to be about 5.5 mL and in the ious forms of transport across the vessel walls of capillary and venules; and iii) WM to be approximately 1.5 mL of every wall. As indicated by the Einstein space- CSF/ISF flows into the deep cervical lymph 100 mL of brain weight.69 WM, on the other time relation for diffusion, time is propor- nodes which empties lymph into the subcla-

[Veins and Lymphatics 2019; 8:8470] [page 53] Review vian veins between the internal and the sis78-80 SVD is also characterized by dilated tion.74 Higher number of venous collaterals external jugular vein junctions.75 This pow- PVS, considered a biomarker of reduced is present in MS patients with CCSVI as a erful role of the venous system cannot be drainage of ISF and solutes and correlate physiological compensatory response to undermined and must be incorporated in the directly with increased risk of vascular reduced venous output.84 global picture of waste drain mechanisms. dementia.79 Gliosis increases tortuosity of There is a direct interdependency A thorough quantitative investigation of the ECS and reduces brain compliance.54 between cerebral venous flow and CSF APS and VPS in BP is needed and seems to Failure of elimination of proteins and ISF dynamics such that intra and/or extracranial be lacking at present. From the point of along arterial walls via IPAD can occur in a strictures will directly affect CSF flow view of the clearance capacity of the lym- variety of genetic diseases such as cerebral parameters within the ventricular system in phatic system, the size of the VPS and its autosomal dominant arteriopathy and sub- normal and pathological conditions.4 In variability under pathological conditions cortical inflammatory leukoencephalopa- healthy subjects MR elastography and PC- seems most important. Transmural pressure thy, cerebral amyloid angiopathy and neu- MRI techniques have demonstrated that 81 across venular walls is the difference rodegenerative diseases (e.g. AD). compression of IJVs in the neck directly between pressure outside the venular wall Arteriole walls become fragile and prone to increases CSF pulsatility in the AoS, (external pressure) and the pressure from hemorrhage, there is increased amyloid- decreases CBF and, increases brain tissue 85-87 inside the venules (internal pressure).76 In beta deposition within the BP and arterial stiffness. The most striking evidence of this regard, it is reasonable to suggest that in walls, that lead to a cascade of events and such interdependency was communicated conditions of cerebral venous hypertension, finally neuronal degeneration, a mechanism by Hans Queckenstedt more than 100 years venous engorgement from the inside and common to protein elimination failure arte- ago (1916), modern confirmations of which 82 increased ICP from the outside would con- riopathies and dementia. are contained in the work of Alperin et al., trive to reduce the size of the VPS. Such who in the context of IIH discovered the changes will occur in cases of increased Venous pathology presence of both intracranial and extracra- pressure in the intra or extracranial venous The role of veins in neurological dis- nial venous strictures that impeded normal vessels.76,77 An obvious consequence of this eases was brought to the forefront by venous drainage thereby increasing would the hampering of fluid and solute Zamboni, ten years ago where he found a intracranialonly venous volume and overall transport proposed by Iliff et al.7 significantly increased number of patients altered intracranial dynamics, with raised with multiple sclerosis with inefficient ICP as one consequence.88,89 Extracranial extracranial venous drainage, also termed IJV compression was recently proposed as a chronic cerebrospinal venous insufficiency direct cause of dilated ventricles and 83 use Clinical implications (CCSVI). Various degree of CCSVI can increased ICP in a patient in a possibly new cause retrograde reflux of venous blood, syndrome which the authors call the JEDI The most complex morphological and increased intracranial venous pressure and syndrome (jugular entrapment, dilated ven- functional structure of the brain in which local venous hypertension, increase CSF tricles, intracranial hypertension).90 the microvasculature is embedded is the pulsatility in the AoS, reduce clearance of Intracranial venous strictures can also affect neurovascular unit (NVU), made up of neu- ISF, promote iron deposition, inflammation, cerebral venous outflow. An example of rons, astrocytes, and the vascular structures. breakdown of BBB and myelin disintegra- such strictures is the idiopathic intracranial The coupling of astrocytes and neurons in the delivery of glucose and oxygen and their combustion into ATP, the molecular processes underlying the constant and prompt turnover of neurotransmitters, the processes underlying synaptic activity, vol- ume transmission of neurotransmitters, ions and proteins, the maintenance of a healthy ECM, ISF flow, instant dynamic removal of waste products are just some of theNon-commercial func- tions of the NVU. Damage to the NVU at any level will cause irreversible damage to processes leading to the normal functioning of the neurons.

Arterial pathology Arterial hypertension and arterioloscle- rosis will weaken the walls, increase shear stress, alter the cerebral autoregulatory mechanisms, increase arterial pulsatility, affect Windkessel mechanism and conse- Figure 4. Impact of extracranial venous outflow strictures. Computational results from a 52 validated global, closed-loop mathematical model show that the entire fluid dynamics of quently reduce CBF and CPP. Chronic the craniospinal system is altered, including raised ICP and increased intracranial venous hypoperfusion will damage NVU, cause pressure. The figure shows computed cardiac-cycle averaged pressures for two anomalous rarefaction of WM, accelerate demyelina- cases A and B, compared to the healthy control (HC). The left frame shows pressures for tion, damage ECM, disintegrate the BBB, superior petrosal sinus (SPS), inferior petrosal sinus (IPS), transverse sinus (TS), superior SMC, and pericytes, resulting in lacunar sagittal sinus (SSS) and inferior sagittal sinus (ISS). The right frame shows pressures in brain parenchyma (ICP), vein of the cochlear aqueduct (VCAQ) and labyrinthine vein infarcts all of which are characteristic of (LABV). Reproduced from Toro et al., 2018.104 small vessel disease (SVD) and leukoaraio-

[page 54] [Veins and Lymphatics 2019; 8:8470] Review hypertension (IIH) characterized by a high extracranial venous outflow strictures and tion. Neurology 2001;56:1746-8. prevalence of dural venous sinus stenosis has demonstrated increased cerebral venous 4. Beggs CB. Cerebral venous outflow (in particular, transverse sinus).91,92 Studies pressure, increased ICP and disturbed over- and cerebrospinal fluid dynamics. consistently report increased CSF pulsatili- all cranio-spinal dynamics77,103 (Figure 4). Veins and Lymphatics 2014;3:1-8. ty in the AoS and reduced CBF, both param- These theoretical results have confirmed 5. Wilson MH. Monro-Kellie 2.0: The eters that can be improved after high vol- partial previous experimental results and dynamic vascular and venous patho- ume CSF removal during a lumbar puncture from now on they should be regarded as fact physiological components of intracra- or venous stenting but not medical treat- and no longer a matter of opinion or suppo- nial pressure. J Cereb Blood Flow ment alone.53 This knowledge is leading the sition. Metab 2016;36:1338-50. path towards newer and efficacious treat- 6. Louveau A, Smirnov I, Keyes TJ, et al. ments such as venous angioplasty and stent- Structural and functional features of ing.93 central nervous system lymphatic ves- Conclusions sels. Nature 2015;523:337-41. Alterations of CSF and ISF dynamics 7. Iliff JJ, Wang M, Liao Y, et al. A par- Clinicians and researchers tend to focus In CSF circulation disorders such as avascular pathway facilitates CSF flow on single isolated fluid systems, overshad- normal pressure hydrocephalus (NPH), PC- through the brain parenchyma and the owing the broader picture of neurofluid MRI have repeatedly shown increased CSF clearance of interstitial solutes, includ- dynamics within the brain. New observa- pulsatility in the AoS, reduced vascular ing amyloid β. Sci Transl Med tions and developments in neuroscience compliance and decreased arterial perfusion 2012;4:147ra111-147ra111. 94 force us to revise our old dogmas and chal- within the BP. Increased brain stiffness, 8. Benveniste H, Lee H, Volkow ND. The lenge us to adopt new concepts. By interro- gliosis, and demyelination of the periven- Glymphatic Pathway: Waste Removal gating different physiologic mechanisms tricular white matter are reflective of a more from the CNS via Cerebrospinal Fluid that may have been jeopardised in a disease global alteration that affects transependy- Transport. Neurosci 2016;23:454-65. at any one time, understanding the dynamic mal flow, macromolecule transependymal 9. Carare RO, Bernardes-Silva M, nature of the entire system and its individu- transport and overall neurofluid interactions Newman TA, et al. Solutes, but not al compartments, is likely the only way to only including CSF and ISF.10,95,96 The role of cells, drain from the brain parenchyma find answers to the several neurological dis- ISF flow has not yet gained sufficient atten- along basement membranes of capillar- eases that still remain without a specific eti- tion in the medical world, mostly because it ies and arteries: significance for cere- ology and treatment (including several idio- is hard to visualize and image the ECS and bral amyloid angiopathy and neuroim- pathic and atypical variants of diseases). its contents. ECS is a dynamic space greatly use munology. Neuropathol Appl The venous system in the brain has not yet affected by the physiologic activity of the Neurobiol 2008;34:131-44. been carefully studied in a clinical setting astrocytes and neurons but also by physio- 10. Linninger AA, Tangen K, Hsu C-Y, and requires urgent attention. Veins are the logic states such as sleep.97 Stagnant ISF, Frim D. Cerebrospinal Fluid sink of the entire fluid content in the brain impaired drainage of solutes, dilation of Mechanics and Its Coupling to and it would be irrational to not compre- PVS are known to cause atrophy of the sur- Cerebrovascular Dynamics. Annu Rev hend the extent of their involvement in neu- rounding axons leading to a vicious cycle of Fluid Mech 2016;48:219-57. rological diseases and to revisit treatment neurodegeneration.79,98 11. Zhang ET, Inman CBE, Weller RO. options. Potential consequences still to be Interrelationships of the pia mater and established include decreased cerebral per- the perivascular (Virchow-Robin) Meningeal lymphatics pathology fusion and disturbed CNS clearance system spaces in the human cerebrum. J Anat The recent discovery of meningeal lym- as a result of venous strictures. phatics and its drainage pathway within the 1990;170:111-23. outer meningeal layers surrounding the 12. Weller RO. Microscopic morphology dural venous sinus has been revolutionary and histology of the human meninges. Morphologie 2005;89:22-34. and since then a number of neurological References diseases have been shown to have altered 13. Marín-Padilla M. The human brain lymphatic drainage.6 In essence,Non-commercial solute 1. Feigin VL, Abajobir AA, H K, et al. intracerebral microvascular system: clearance through the CSF is achieved via Global, regional, and national burden development and structure. Front drainage into meningeal lymphatics that of neurological disorders during 1990- Neuroanat 2012;6:38. eCollection reach deep cervical lymph nodes. Damage 2015: a systematic analysis for the 2012. to these pathways, including experimental Global Burden of Disease Study 2015. 14. Abbott NJ, Pizzo ME, Preston JE, et al. ligation of deep cervical lymph nodes can Lancet Neurol 2017;16:877-97. The role of brain barriers in fluid cause neurodegeneration in particular AD, 2. Kellie G. An account of the appear- movement in the CNS: is there a aggravate PD and worsen stroke outcome.99- ances observed in the dissection of two “glymphatic” system? Acta 101 of three individuals presumed to have Neuropathol 2018;135:1-21. In quantitative science we either mea- perished in the storm of the 3d, and 15. Pizzo ME, Wolak DJ, Kumar NN, et al. sure or we compute. Real-life measure- whose bodies were discovered in the Intrathecal antibody distribution in the ments are difficult and even impossible vicinity of Leith on the morning of the rat brain: surface diffusion, perivascu- since they tend to involve invasive method- 4th, November 1821: with some reflec- lar transport and osmotic enhancement ology. Müller and Toro developed a com- tions on the pathology of the brain. of delivery. J Physiol 2017;596:445- prehensive mathematical model for all Royal College of Surgeons of England; 75. major full-body fluids, with special atten- 1824. Available from: 16. Hill RA, Tong L, Yuan P, et al. tion paid to craniospinal fluids and the https://archive.org/details/b22384315 Regional Blood Flow in the Normal venous system in particular.102 This model 3. Mokri B. The Monro-Kellie hypothe- and Ischemic Brain Is Controlled by has been used to study the effect of sis: applications in CSF volume deple- Arteriolar Smooth Muscle Cell

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