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. 2008 May 14;5:10.
doi: 10.1186/1743-8454-5-10.

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

Conrad E Johanson  1 , John A Duncan 3rd, Petra M Klinge, Thomas Brinker, Edward G Stopa, Gerald D Silverberg
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Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

Conrad E Johanson et al. Cerebrospinal Fluid Res. .
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Abstract

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces.

Outline: 1 Overview2 CSF formation2.1 Transcription factors2.2 Ion transporters2.3 Enzymes that modulate transport2.4 Aquaporins or water channels2.5 Receptors for neuropeptides3 CSF pressure3.1 Servomechanism regulatory hypothesis3.2 Ontogeny of CSF pressure generation3.3 Congenital hydrocephalus and periventricular regions3.4 Brain response to elevated CSF pressure3.5 Advances in measuring CSF waveforms4 CSF flow4.1 CSF flow and brain metabolism4.2 Flow effects on fetal germinal matrix4.3 Decreasing CSF flow in aging CNS4.4 Refinement of non-invasive flow measurements5 CSF volume5.1 Hemodynamic factors5.2 Hydrodynamic factors5.3 Neuroendocrine factors6 CSF turnover rate6.1 Adverse effect of ventriculomegaly6.2 Attenuated CSF sink action7 CSF composition7.1 Kidney-like action of CP-CSF system7.2 Altered CSF biochemistry in aging and disease7.3 Importance of clearance transport7.4 Therapeutic manipulation of composition8 CSF recycling in relation to ISF dynamics8.1 CSF exchange with brain interstitium8.2 Components of ISF movement in brain8.3 Compromised ISF/CSF dynamics and amyloid retention9 CSF reabsorption9.1 Arachnoidal outflow resistance9.2 Arachnoid villi vs. olfactory drainage routes9.3 Fluid reabsorption along spinal nerves9.4 Reabsorption across capillary aquaporin channels10 Developing translationally effective models for restoring CSF balance11 Conclusion.

Figures

Figure 1
Morphology of blood-brain-CSF interfaces: (A) Schema of main CNS compartments and interfaces. The blood-brain and blood-CSF barriers are true barriers with tight junctions between endothelial and epithelial cells, respectively. The brain-CSF interface, because of gap junctions between ependymal (or pia-glial) cells, is more permeable than brain or spinal cord capillaries and choroid plexus. (B) Blood-CSF barrier. CP is comprised of one cell layer of circumferentially arranged epithelial cells. Plexus capillaries, unlike counterparts in brain, are permeable to macromolecules. (C) Blood-brain barrier: Endothelial cells are linked by tight junctions, conferring low paracellular permeability. Endothelial cell pinocytotic vesicle paucity reflects minimal transcytosis. (D) Brain-CSF interface: Ependymal lining in lateral ventricles permits relatively free diffusion of solutes between brain ISF and large-cavity CSF. Motile cilia at ependymal cell apex move CSF downstream to SAS. Reprinted with permission from Advanced Drug Delivery Reviews [17].
Figure 2
Figure 2
Large-cavity CSF compartments and bulk flow. Extracellular fluid enables volume transmission (convection) of fluid from ventricles to SAS [7, 27]. CSF formed by lateral, 3rd and 4th ventricle CPs flows from the lateral to 3rd ventricle via the cerebral aqueduct and 4th ventricle to SAS in cisterna magna. Then CSF is transmitted by bulk flow through cisternal foramina (Magendie and Luschka) into basal cisterns. CSF is also convected from ventricles through velae channels to the quadrigeminal and ambient cisterns [167]. Thereafter fluid is convected to the SAS of the spinal cord and brain convexities. As CSF flows through the ventriculo-subarachnoid system, there are diffusional and bulk flow exchanges between CSF and brain [16, 24, 168, 169, 289], depending upon region-specific gradients for concentration and hydrostatic pressure that promote widespread distribution of CSF-borne materials [255]. Normally CSF is readily distributed from the ventricles to arachnoidal drainage sites. In hydrocephalus, flow pathways can be disrupted at multiple points.
Figure 3
Ultrastructure of choroid epithelium. CP from a lateral ventricle of an untreated adult Sprague-Dawley rat was fixed for electron microscopy with OsO4. There is a profusion of apical membrane (CSF-facing) microvilli (Mv) and many intracellular mitochondria (M). J refers to the tight junction welding two cells at their apical poles. C = centriole. G and ER, Golgi apparatus and endoplasmic reticulum. Nucleus (Nu) is oval and has a nucleolus. Arrowheads point to basal lamina at the plasma face of the epithelial cell; the basal lamina separates the choroid cell above from the interstitial fluid below. Basal labyrinth (BL) is the intertwining of basolateral membranes of adjacent cells. Choroidal morphology resembles proximal tubule, consistent with both cell types rapidly turning over fluid. Scale bar = 2 μm.
Figure 4
Mechanisms of CSF formation: Net ion transport and electrochemical gradients A. CSF secretion by CP is by net transport of Na+, K+, Cl-, HCO3- and water, from plasma to ventricles. Reabsorptive ion fluxes CSF to blood occur simultaneously with active secretion but overall, there is net movement of ions and water into ventricles. CSF osmolality resembles plasma. B. Na+ moves down a concentration gradient via secondary active transport (e.g., Na+-H+ exchange) in the basolateral membrane (Fig. 5) [38, 43]. K+, Cl- and HCO3- diffuse down their electrochemical gradients [38] via ion channels in apical membrane [50] (Fig. 5). Arrow for Na+ symbolizes a steep inward concentration and electrochemical gradient [38]. For K+, Cl- and HCO3-, the respective arrows depict outwardly-directed electrochemical gradients promoting ion diffusion via channels into CSF [50]. Choroidal cell concentrations (mM) for Na+, K+, Cl- and HCO3-, respectively, are about 48, 145, 65, and 9.5 for rat [38]. The potential difference across the CPe membranes is 45–50 mV, CSF being about 5 mV positive to plasma at pH 7.4.
Figure 5
Ion transporters and channels in mammalian choroidal epithelium. Typical CPe is schematized to localize transporters and channels that transfer ions and water [290]. CSF secretion results from coordinated transport of ions and water from basolateral membrane to cytoplasm, then sequentially across apical membrane into ventricles. On the plasma-facing membrane is parallel Na+-H+ and Cl--HCO3- exchange [38] bringing Na+ and Cl- into cells in exchange for H+ and HCO3-, respectively. Also basolaterally located is Na+-HCO3- cotransport (NBCn1) [41] and Na-dependent Cl--HCO3- exchange [42] that modulate pH and perhaps CSF formation. Apical Na+ pumping [49, 110] maintains a low cell Na+ that sets up a favorable basolateral gradient to drive Na+ uptake. Na+ is extruded into CSF mainly via the Na+ pump [110] and, under some conditions, the Na+-K+-2Cl- cotransporter [46]. K+-Cl- cotransport helps maintain cell volume [50]. Apical channels facilitate K+, Cl- and HCO3- diffusion into CSF [68]. Aquaporin 1 channels on CSF-facing membrane [77] mediate water flux into ventricles. Polarized distribution of carbonic anhydrase (c.a.) and Na+-K+-ATPase [51], and aquaporins, enable net ion and water translocation to CSF.
Figure 6
Frequency analysis of CSFP in patients with AD vs. AD-NPH syndrome. AD subjects by NINDS-ADRDA (Alzheimer's Disease and Related Disorders Association) criteria (n = 222) were initially screened to exclude NPH. 181 of these 222 patients had CSF pressure measurements (supine position). Seven subjects (4%) had a CSFP 220 mmH2O or greater, i.e., higher than the mean CSFP of 103 mmH2O for the AD-only group. The 7 subjects with elevated pressure had NPH as well as AD, i.e., the NPH-AD syndrome. The larger CSFP peak corresponds to the AD-only group; the smaller peak (higher pressures) pertains to AD-NPH hybrids. Reproduced from Silverberg et al [91].
Figure 7
Augmented intracranial pressure wave amplitude in shunt responders: The difference between shunt non-responders and shunt responders (i.e., improved CSF dynamics and brain function) 6–9 months after surgery with regard to preoperative mean ICP (P = 0.19) and mean ICP wave amplitude (P = 0.002; based on 1-way ANOVA of 6-sec time window data). Mean wave amplitude was 5 mm Hg in positive responders. Reproduced with permission from P. Eide [157].
Figure 8
Decreased expression of LRP-1 transporters in cortical vessels of rats with chronic hydrocephalus. A. Immunostaining (bold arrows) of lipoprotein receptor-related protein-1 (LRP-1) in endothelial membranes of sectioned capillaries and arterioles in cerebral cortex of Sprague-Dawley rats (1-year control) B. Attenuated LRP-1 staining (negative vessels surrounded by asterisks) after 6 wk of hydrocephalus induced by kaolin injection into cisterna magna. Findings suggest reduced Aβ removal from cortex to blood in chronic hydrocephalus. Bar = 50 μm. Images reproduced with permission from NeuroReport [219].
Figure 9
Fibrosis in senescent rat choroid plexus. Aging takes a toll on choroid plexus, functionally and structurally. This electron micrograph depicts massive collagen deposits in CP interstitium, i.e., between the vascular core and outer epithelial (E) ring. Fibrotic (F) bands in a 36-mo-old Brown-Norway/Fischer rat are 40–50 times thicker than corresponding collagenous layers in young adults. Excessive fibrosis likely impedes nutrient flow from plasma to ventricles and reabsorption of Aβ peptide fragments from CSF. Fibrosis in aging and AD also occurs in the arachnoid [240]. Consequently, fibrosis interferes with CSF dynamics via multiple effects. Appreciation is extended to P. McMillan for electron microscopy. Scale bar = 2 μm.
Figure 10
CSF reabsorption routes in the adult rat as revealed by recovered 125-labeled human serum albumin (HSA) in lymph nodes: Anesthetized male adult Wistar rats (n = 8) were killed 6 hr after 125I-HSA injection into lateral ventricle. HSA uptakes were averaged for bilateral and multiple nodes. Symbols indicate differences (P < 0.05) in test node activity relative to spleen (*) or popliteal (#) lymph nodes. Head and lymph node activities greater than spleen indicate tracer passage from CSF directly to submaxillary or cervical nodes. Lumbar node activity was above the spleen and popliteal nodes (not expected for direct CSF drainage). Reproduced with permission from M. Johnston and the American Journal of Physiology [268].
Figure 11
Immunostaining of cytoskeletal and junctional proteins in cultured human arachnoid granulation epithelial cells. A. Expression of intermediate filament protein vimentin (Cy3 conjugated anti-vimentin antibody). B. Expression of cytokeratin (FITC conjugate to broad spectrum anti-cytokeratin antibody). C. Expression of connexin43 (FITC conjugate); punctate distribution at borders (red arrows) points to gap junctions in cell culture. D. ZO-1 (tight junction) staining (FITC conjugate) at cell-cell borders (white arrow) demarcates overlapping filapodia (short linear structures in parallel). E. Expression of desmoplakin (with Alexa Fluor 555 conjugated secondary antibody) reveals desmosomes along adjacent cell borders (white arrows). F. Expression of E-cadherin, an epithelial-specific cell adhesion molecule, at periphery of cells (white arrows) in a pattern similar to that of connexin43 and ZO-1. All images have same scale (bar = 50 μm). Reproduced with permission of Holman et al [277].
Figure 12
Concerted transport at blood-brain and blood-CSF barriers: Cerebral capillaries and choroid plexuses transport different materials [16, 17, 27, 34]. Although there is transport overlap, the BBB largely supplies brain with glucose, amino acids, free fatty acids (FFA) and peptides, whereas BCSFB furnishes the CSF-brain nexus with vitamins, growth factors and proteins such as transthyretin. CNS fluid balance results from regulated water transport across AQP4 at BBB and AQP1 in BCSFB. The reabsorptive transporters LRP-1 and P-glycoprotein (Pgp) are expressed differentially in BBB [225, 229] and BCSFB [291]. Both interfaces have to be analyzed to characterize phenomena such as Aβ deposition in interstitium. To understand brain fluid composition and barrier interaction pathophysiologically, it is advantageous to analyze BBB and BCSFB concurrently.
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