|
  ReviewMultiplicity of cerebrospinal fluid functions: New challenges in health and diseaseConrad E Johanson1 1Department of Clinical Neurosciences, Warren Alpert Medical School at Brown University, Providence, RI 02903, USA 2International Neuroscience Institute Hannover, Rudolph-Pichlmayr-Str. 4, 30625 Hannover, Germany
Cerebrospinal Fluid Research 2008, 5:10doi:10.1186/1743-8454-5-10 The electronic version of this article is the complete one and can be found online at: http://www.cerebrospinalfluidresearch.com/content/5/1/10
©
2008 Johanson et al; licensee BioMed Central Ltd. AbstractThis 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. Outline1 Overview 2 CSF formation 2.1 Transcription factors 2.2 Ion transporters 2.3 Enzymes that modulate transport 2.4 Aquaporins or water channels 2.5 Receptors for neuropeptides 3 CSF pressure 3.1 Servomechanism regulatory hypothesis 3.2 Ontogeny of CSF pressure generation 3.3 Congenital hydrocephalus and periventricular regions 3.4 Brain response to elevated CSF pressure 3.5 Advances in measuring CSF waveforms 4 CSF flow 4.1 CSF flow and brain metabolism 4.2 Flow effects on fetal germinal matrix 4.3 Decreasing CSF flow in aging CNS 4.4 Refinement of non-invasive flow measurements 5 CSF volume 5.1 Hemodynamic factors 5.2 Hydrodynamic factors 5.3 Neuroendocrine factors 6 CSF turnover rate 6.1 Adverse effect of ventriculomegaly 6.2 Attenuated CSF sink action 7 CSF composition 7.1 Kidney-like action of CP-CSF system 7.2 Altered CSF biochemistry in aging and disease 7.3 Importance of clearance transport 7.4 Therapeutic manipulation of composition 8 CSF recycling in relation to ISF dynamics 8.1 CSF exchange with brain interstitium 8.2 Components of ISF movement in brain 8.3 Compromised ISF/CSF dynamics and amyloid retention 9 CSF reabsorption 9.1 Arachnoidal outflow resistance 9.2 Arachnoid villi vs. olfactory drainage routes 9.3 Fluid reabsorption along spinal nerves 9.4 Reabsorption across capillary aquaporin channels 10 Developing translationally effective models for restoring CSF balance 11 Conclusion 1 OverviewFree-flowing cerebrospinal fluid (CSF) finely-regulated in composition is vital to brain health [1,2]. Aging- or disease-induced alterations in CSF circulation adversely impact neuronal performance [2,3]. Throughout life the choroid plexus (CP)-CSF dynamics are damaged by tumors, infections, trauma, ischemia or hydrocephalus [4-8]. Severely disrupted CSF flow disturbs cognitive and motor functions [9]. CNS viability is taxed if key choroidal-CSF parameters are distorted. For health and disease it is essential to delineate interactions of CP and brain with the intervening CSF (Fig. 1).
Improved biotechnology and models can now precisely evaluate the role of the CP-CSF in modulating brain development, metabolism and aging [10-12]. Alternative transplant [13-15] and pharmacological strategies [16-18] utilizing the CP may be helpful in rescuing the debilitated CSF system. Such therapy to rectify CSF parameters would ultimately benefit neuronal network functions. This review sets forth new approaches to stabilize the CSF in disease or curb its deterioration in late-life stages [19]. CSF assessment should collectively consider physical, biochemical and physiological parameters (Table 1). In addition, the large-cavity CSF system is multi-compartmental (Fig. 2). Ventricles, cisterns and subarachnoid space (SAS) are serially linked. Upstream CSF transport phenomena exert effects downstream. Ventricular CSF is functionally interactive with the ependymal wall [1] as well as the more deeply-lying brain capillary surfaces [16,17]. Diffusion and bulk flow promote solute and water distribution both into and out of brain, depending upon prevailing regional gradients for concentration and hydrostatic pressure in various compartments (Fig. 1). It is thus pertinent to analyze CNS fluid spaces- how they are disrupted by ventricular dysfunction and might be modified by CSF-borne therapeutic agents. This should promote translational steps for managing CSF in neurodegenerative diseases and other disorders. Table 1. Physico-chemical properties and physiological parameters of the CSF system
2 CSF formationSeveral CNS regions form CSF or a CSF-like fluid. Although CP tissues generate about two thirds of the total production, extrachoroidal sources make up the balance [20]. The capillary-astrocyte complex in the blood-brain barrier (BBB) has been implicated as an active producer of brain interstitial fluid (ISF) [21], but normally at a rate substantially slower (1/100 when normalized for barrier surface area) than the blood-cerebrospinal fluid barrier BCSFB [22]. The working hypothesis that the BBB is a fluid generator, although attractive, needs substantiation. Another likely source of CSF, according to Pollay and Curl, is the ependyma lining the ventricles [23]. The arachnoid membrane with its relatively large surface area, although secreting peptides and proteins [24], probably does not actively form CSF. Because CP rapidly produces most of fluid within the CNS and has been extensively documented for CSF-forming capabilities [1], the discussion below focuses on choroidal epithelium. Originating in the ventricular interior of the brain, nascent CSF is continuously produced by the CPs in the lateral, 3rd and 4th ventricles. Because CNS metabolism is profoundly affected by CSF transport, it is imperative to delineate the physiological and molecular processes in CP that effect CSF secretion. CSF formation occurs in two stages: passive filtration of fluid across choroidal capillary endothelium [25], followed by a regulated active secretion across a single-layered epithelium (Fig. 3). Scores of investigations have characterized solute movement from blood to CSF by diffusion, facilitated transport and active transport. Such studies elucidate the nature and uniqueness of fluid transfer across the BCSFB.
Fluid is generated at a high capacity by the choroid plexus epithelial (CPe) cells [1]. The CPe secretory engine is fueled by a brisk arteriolar input of organic substrates and water to the extensive capillary plexus [1]. A blood flow of about 4 ml/min/g CP is converted to a CSF formation in mammals of approximately 0.4 ml/min/g. The smallest mammalian species in which formation rate has been quantified is the mouse which produces CSF at 3.3 × 10-4 ml/min [26]. If one extrapolates animal data to humans on the basis of CSF produced per volume of brain tissue, human CSF production should be about 0.8 ml/min. Measurements to date, however, show that human CSF production is roughly one-half that rate [3]. CSF formation begins as plasma is filtered across permeable choroidal capillaries [25]. Net filtration is proportional to the hydrostatic pressure gradient between blood and choroid interstitial fluid (ISF). Normally, in accord with Starling's law of filtration, fluid flows freely from plasma into ISF at the basolateral surface of the epithelial cells. Reduced blood flow to the plexus, via rate-limited tissue perfusion, curtails plasma filtration into the interstitium. Consequently in acute hydrocephalus the substantially elevated ventricular CSF pressure, when retrogradely transmitted to choroidal ISF, reduces plasma exudation into ISF. This decreases CSF formation. However with normal choroidal perfusion and CSF hydrodynamics, a continual stream of plasma ultrafiltrate (ions and water) is presented for fluid manufacture to transporters at the basolateral side of the epithelium. Transchoroidal secretion of water, ions and macromolecules drives the volume transmission of CSF (Fig. 2) down the ventriculo-cisternal axis [27]. Actively formed CSF stems from coordinated secretion of solutes across the thin epithelial interface (Fig. 3) between the inner choroidal plasma and outer ventricular fluid. The CP epithelium is polarized both structurally (Fig. 3) and functionally (Figs. 4 and 5). Pharmacological modeling of CSF dynamics is necessarily built on foundational knowledge of plexus blood flow as well as epithelial metabolism and transport (Fig. 5).
CSF formation involves an intricate array of transporters and channels in CPe. Salient elements of this complex process deserve highlighting. Accordingly, Fig. 4 schematically illustrates how choroid epithelial polarity (sidedness) relates to transcellular movement of solutes across the BCSFB. Although bidirectional transport of ions occurs at both poles of choroid epithelial cells, CSF formation is essentially the net transport of Na+, Cl-, K+, HCO3- and water from plasma to CP to CSF (Fig. 4A). Ions and water are taken up by facilitating mechanisms at the basolateral membrane, convected through cytoplasm, and then released or actively secreted into the ventricles on the apical side. Vectorially, favorable electrochemical gradients (energetically downhill) exist for Na+ movement inward at the plasma side and for K+, Cl- and HCO3- diffusion outward at the CSF side (Fig. 4B). Facilitated water flux via aquaporin (AQP) channels osmotically balances the collective ion transport and furnishes the medium for CSF circulation. CSF generation is a cardinal feature of brain fluid homeostasis [1]. To finely control the CSF formation rate is a challenge in treating diseases related to brain fluid disorders. Historically, emphasis has been placed on discovering new agents to relieve elevated CSF pressure (CSFP), i.e., intracranial pressure (ICP), in pediatric hydrocephalus patients. Projections point to the additional compelling need for increasing CSF turnover rate in geriatric patients, since many are taking diuretics and digitalis preparations that reduce CSF formation. This implicates a wider spectrum of CSF pharmacology. To individualize therapy for normal-pressure and high-pressure hydrocephalus, there should be a drug repertoire for up- and down-regulating CSF formation rates. Pharmacological targeting to modify CSF production by the CP will advance as cellular mechanisms are elucidated. To date, acetazolamide and furosemide are among only a few agents that have had clinical usefulness in controlling CSF formation and ICP, but side effects limit their usage [28,29]. Clearly, new agents are needed to restore CSF dynamics altered by disease and injury. Theoretically, nuclear, cytoplasmic and plasma membrane constituents are potential sites for drug actions to accelerate or reduce CSF production. Transcription factors in the nucleus, enzymes in the cytoplasm, and transporters/channels and receptors at the limiting plasma membrane are all potential drug targets. Five approaches to modify CSF formation rate, i.e., cutting-edge as well as established, are recapitulated in Table 2 and elaborated below: Table 2. Strategies for pharmacologically manipulating the rate of CSF formation by the epithelial cells of choroid plexus 2.1 Transcription factorsTraditionally CSF formation has been experimentally altered by interfering with membrane ion transporters or by reducing delivery of substrate. Nevertheless, metabolically upstream molecular manipulations for modulating CSF secretion deserve consideration. A novel approach is to target transcription factors as putative regulators of cellular enzymes in CSF formation. Mice lacking the transcription factors p73, foxJ1 and E2F5 develop non-obstructive hydrocephalus [30,31], possibly from CSF over secretion. Epithelial ultrastructure analysis and electron translucence in micrographs are consistent with accelerated fluid formation by CP [32]. It is intriguing that E2F5 in CPe is down-regulated as the cells mature (i.e. as they convert from pseudostratified to single cuboidal epithelium) in their ability to produce CSF [30]. Such ontogenetic findings on transcription factors in mice and human CP [30,31] prompt a new tack to augment CSF formation by manipulating E2F5 expression. Releasing the natural inhibitory brake on the manufacture of CSF would be a unique way to increase fluid transfer across CP. There is an experimental precedent for this theoretical approach. Resection of the sympathetic nerve from the superior cervical ganglion attenuates the inhibitory autonomic tone on CP. This increases CSF production [32]. Enhancing CSF formation and the associated sink action [33] on brain interstitial solutes may find application to aging, normal pressure hydrocephalus (NPH), and Alzheimer's disease (AD) patients who retain extracellular metabolites from sluggish fluid turnover [19]. 2.2 Ion transportersMost attempts to regulate CSF formation rate have been directed at altering ion movement via transporters in the basolateral (plasma-facing) and apical (CSF-facing) membranes of the CPe [1]. Because the CP is a kidney-type organ [34], with epithelial mechanisms [35] similar to those in the renal tubule that transfer a large volume of ions and water, many diuretic agents have been tested for ability to inhibit CSF formation [1,27]. Gaining insight on the many ion transporters and channels in CPe is key to attaining fine control of CSF production, upward as well as downward regulation. At the basolateral membrane, the uptake of Na+ and Cl- is the primary step in CSF formation (Fig. 5). Inward transport of fixed ions, Na+ and Cl-, is facilitated by carriers functionally dependent upon basolateral transmembrane gradients for Na+, Cl-, H+ and HCO3-. The basolateral Na+-H+ exchanger (NHE1) transfers Na into the choroid cell. This process is inhibited by the diuretic agent amiloride [36-38], which decreases CSF formation [36,38]. This action is analogous to the polyuria caused by inhibiting the proximal and distal tubule Na+-H+ exchanger (NHE3) that normally supports substantial fluid transfer in kidney [39]. The Cl--HCO3- exchanger translocates interstitial Cl- into the cytoplasm. Moreover the basolateral Na+-dependent Cl--HCO3- exchanger and the Na+-HCO3- cotransporter in CPe [40-42] may also be potential targets for controlling fluid movement. Na+ coupling to HCO3- transport is likely integral to nascent CSF generation [43,44]. Systemic metabolic alkalosis, in comparison to metabolic acidosis, promotes Na+ influx into CPe and subsequently into ventricular CSF [38]. Therefore basolateral HCO3- transport [40,42] by one or more mechanisms (Fig. 5) might be manipulated to modify HCO3- flux or alter choroid cell pH to modulate fluid formation. At the apical membrane Na+-K+-ATPase, the Na pump, is a workhorse that actively secretes Na into the ventricles (Fig. 5) thereby driving CSF formation. The Na pump critically keeps cell Na low [38] to set up a driving force (favorable gradient) for basolateral inward Na movement via the Na-cotransporters. Therefore, pharmacological disruption of the apical Na pump, by distorting transmembrane ion gradients, secondarily disables transport activity at the opposite basolateral face. The apically located Na+-K+-2Cl- cotransporter (NKCC1) is significant in regard to bidirectional transport capability. The ability of the cotransporter to transfer ions in both the secretory and reabsorptive modes [45] reflects a versatile transporter for regulating cell ion homeostasis and CSF dynamics. Interference with NKCC1 activity by bumetanide [46] or furosemide reduces CSF formation rate [47]. In both congenital [48] and aging [18] disorders, altered expression of NKCC1 in CPe is associated with diminished CSF formation rate. Drugs used in the aging population, e.g., the loop-diuretic furosemide and the cardiac glycosides (that inhibit the choroidal Na+ pump [49]), reduce CSF formation rate and may therefore exacerbate the deleterious effects of advanced age on the brain. Research is needed to address how apical membrane transporters, as well as ion channels for K+, Cl- and HCO3- [50], can be manipulated to increase or decrease CSF formation rate, depending upon specific clinical needs. 2.3 Enzymes that modulate transportIn experimental settings, Na+-K+-ATPase and carbonic anhydrase (c.a.) are the two enzymes in the CPe that have been the most extensively analyzed in inhibitory studies of CSF formation. Na+-K+-ATPase, or the Na+ pump, is atypically (amongst epithelia) located on the luminal or CSF face of the CPe. Therefore ouabain inhibits the Na+ pump (which is integral to CSF formation) when placed intraventricularly, but not intravenously. In addition to interfering with CSF production, the Na+-K+-ATPase inhibition also alters CPe volume, potential difference and ion homeostasis [51]; therefore, ouabain and other cardiac glycosides have limited value in regulating human CSF formation. On the other hand, the inhibition of c.a. by acetazolamide is not as harsh on CPe function, and so can be used therapeutically to reduce CSF generation. Because a variety of c.a. isoforms is expressed in CP, there are potentially multiple targets at the blood-CSF interface for regulating fluid dynamics. Ubiquitous enzymes in the c.a. group integrate cellular acid-base phenomena with CSF formation [52]. One of the earliest, but still clinically useful, means for decreasing CSF formation is to reduce the intracellular generation of labile ions (e.g., protons and bicarbonate) that feed fluid transporters at the plasma- and CSF-facing poles of the CPe. Cytosolic c.a. II catalyzes cellular hydration of CO2 to yield H+ and HCO3-. Acetazolamide, a sulfonamide drug, slows down this reaction [44]. Consequently this elevates choroidal cell pH, thus reducing H+ availability to basolateral Na+-H+ exchange [43,53,54]. Membrane-bound isoforms of c.a. (e.g., c.a. VIII) are likely proximate to basolateral HCO3- transporters (e.g., anion exchanger 2 or AE2) to which they supply HCO3- for exchange with interstitial Cl- [55]. It is worthwhile seeking non-sulfonamide agents to selectively inhibit specific c.a. isoforms, II, VIII and XII [56-58]. Identifying a drug for a specific line of attack [59] may help to reduce systemic side effects that attend chronic acetazolamide administration. Disruption of cellular acid-base balance by diminishing c.a. activity with acetazolamide provides deductive insights on the function of transporters and aquaporins. CPe pHi increases by 0.3 – 0.4 pH units after acute exposure (1 hr) to acetazolamide [43,53]. Chronic administration of acetazolamide markedly alters CP function and structure [60], including the apical microvilli which contain the AQP1 channels. In the kidney, and in the testis (another barrier tissue), acetazolamide down-regulates AQP1 expression [61-64], possibly by way of pHi change. With regard to fluid transfer in the kidney, the crucial importance of Na+-H+ antiport exchange (via NHE3) and pHi stability for maintaining intact AQP2 and NKCC2 systems is revealed in NHE3-knockout analyses [39]. In the physiologically analogous CPe, the coordination of multiple transporter systems (NHE1 and NKCC1) with AQP1 channel function evidently allows CPe ion and volume homeostasis to occur simultaneously with CSF secretion [38]. 2.4 Aquaporins or water channelsYet another potential avenue for regulating CSF formation exploits the expression plasticity of aquaporins (AQP) in CP [65,66]. Aquaporin channels, which facilitate water diffusion across the blood-CSF interface [67-69], appear in the developing CPe [70,71] and are retained throughout life. AQP1, initially designated as CHIP28 [72], is heavily expressed at the ventricular-facing membrane of CPe [73,74] but not in blood-brain barrier (BBB) endothelium. Thus by regulatory phosphorylation or ubiquitination of AQP1 [75], it may be possible to selectively modulate water movement from blood into the cerebral ventricles [76]. In AQP-1 null mice, there is a substantial reduction in CSF forming-capacity of the CP; and consequently, an associated lowering of the CSFP [77,78]. Such knock-out studies imply that the number of AQP1 channels in CPe apical membrane importantly determines CSF manufacturing ability. Of significance to CSF dynamics, nature performs an experiment in which there is AQP1 deficiency in late life [57]. Thus, aged (20-mo) Sprague-Dawley rats have substantially less AQP1 expression in CPe than do young adult counterparts [57]. Accordingly, senescent rats are less able to form CSF [79]. Human CPe expresses AQP1 [80]. This raises the possibility of therapeutically upregulating or restoring AQP1 expression in aged humans when the CSF turnover rate is compromised by AD and NPH [3,19]. Conversely in congenital hydrocephalus it may be feasible to down-regulate AQP1 expression or channel activity in CPe, thereby lowering CSFP by suppressing CSF formation rate [77,78]. Atrial natriuretic peptide (ANP), a CSF-modulator, has been implicated as a regulator of AQP1 channel function [69]. 2.5 Receptors for neuropeptidesNeuropeptides in CSF stimulate peptidergic receptors in CP to alter metabolism of 2nd messengers and the associated ion transport coupled to fluid formation [81]. Choroidal arginine vasopressin (AVP) is functionally interactive with various fluid-regulating peptides (Table 3). AVP release from CP, for autocrine inhibitory regulation, is promoted by angiotensin (Ang II) and basic fibroblast growth factor (FGF2). Upon stimulation, choroidal receptors for ANP and AVP both induce dark epithelial cells [82,83]in vitro as well as in vivo. Dark CPe cells have a neuroendocrine role to down -regulate CSF production. Stimulation of V1 vasopressinergic receptors induces dark cells [83], reduces Cl- efflux from CPe [83], and decreases CSF formation [84]. Moreover, ANP transcripts for three natriuretic receptors [85] that generate cyclic guanylyl monophosphate (cGMP) [86] are expressed in both intact and cultured CP. In some physiological settings ANP curtails CSF formation by CP [87]. This inhibition may be mediated by CPe dark cells [82] that are more frequent in hydrocephalus. Table 3. Neuropeptides/receptors that regulate CSF formation Also supporting this fluid homeostasis model are the observations of substantial plasticity of choroidal receptors for water-regulating neuropeptides when CSF dynamics are imbalanced. There is up-regulated or down-regulated density of CP receptors for ANP in hydrocephalus [88], depending upon the pathophysiology (kaolin-induced as well as congenital). CSF neuroendocrine regulation is also reflected by changes in ANP receptor density secondary to altered CSF hydrodynamics or fluid shifts in space flight [89]. Moreover there are more choroidal binding sites for AVP in AD [90], a disorder that can present with ventriculomegaly [3] and increased CSF pressure [91]. Peptide analogs of ANP and AVP [17] may prove beneficial for therapeutically modulating CSF parameters through action at CP neuropeptide receptors. 3 CSF pressureCSFP or ICP rises rapidly when there is a significant imbalance between CSF formation and drainage. Augmented ICP reduces cerebral blood flow (CBF) and oxygenation and, at the molecular level, may alter protein expression in neurons and glia. Therefore, because of potentially devastating effects of elevated ICP on brain functions, it is clinically important to assess factors that regulate CSF pressure and devise more effective ways to monitor and manage distorted ICP. 3.1 Servomechanism regulatory hypothesisICP is a complex function of hydrodynamic and hemodynamic parameters. In combination they produce, in adult humans, a CSFP of 100–200 mm H2O measured in the lateral recumbent position by lumbar puncture. This pressure is directly proportional to the CSF production rate and outflow resistance, which typically is 70 mm H2O/ml/min and greater in the 8th decade than in young adults [92]. On the hydrodynamics side, feedback down regulation of CSF formation can lower CSFP. Homeostatic adjustments to decrease fluid output by CP are critical because sustained CSFP elevation compromises the vascular supply to the CNS [93]. Accordingly, elucidation of neuroendocrine fluid regulation is essential for developing agents to manage CSFP. A key observation for constructing a CSFP regulatory model is that the CSF concentration of most neuropeptides, including ANP, depends upon a central (CNS) source rather than a peripheral (plasma) source [94]. Moreover, intraventricularly-administered ANP reduces CSFP elevated by ischemia [95] or congenital hydrocephalus [96]. Such findings prompt the pursuit of various elements comprising a central homeostatic system to regulate CSFP. Growing evidence supports a ventricular servomechanism to stabilize CSFP. One hypothesis posits pressure-sensitive regulatory elements in the CSF-periventricular nexus that respond by synthesizing/releasing peptides that target the CP [97]. A prime neuropeptide candidate for acutely regulating CSFP is ANP. Collective experimental and clinical evidence demonstrates that: i) the CSF titer of ANP increases proportionally to CSFP elevation [98], ii) the CSF level of ANP is elevated in high-pressure hydrocephalus [99,100], iii) the ANP receptors in CP undergo a Vmax adjustment to compensate for the CSFP increase in hydrocephalus [88,101], and iv) the CPe is bioreactive to ANP [82] and modulates CSF formation [102] by a cGMP-dependent mechanism [86,103]. The putative regulation of CP-CSF by ANP and AVP occurs in acute high-pressure hydrocephalus but evidently not in chronic NPH [104]. Interestingly the CP of immature rats (with a relatively low CSFP and incompletely-developed CSF secretion [33]) is less sensitive than the adult epithelium to modulation by ANP and AVP [83]. This is probably due to infant vs. adult differences in neuropeptide receptor density and coupling to CPe metabolism. 3.2 Ontogeny of CSF pressure generationIncreasing CSFP during development in rodents is temporally associated with the early phases of fluid formation by CP. CSF pressure in pentobarbitone-anesthetized exteriorized fetal rats (18–21 days p.c.) is about 20 mm H2O, rising to 34 mm H20 at 10 days postnatal and later [105]. The 1 – 3-week postnatal interval in the rat is a watershed period in the maturation of CP-CSF secretion [33,106]. Thus the increasing vascularity and arterial perfusion of the plexus in early postnatal life [107-109] foster the progressively increasing enzymatic and transport capabilities of the CPe [110,111]. Enhanced blood flow and metabolic rate combine to accelerate Na+ and Cl- transport into ventricles [112]. Such incremental fluid production by CP [113] elevates CSFP to a level found in adults [105]. Arterial pulsations in CP along with increasing fluid turnover set up a pressure head for moving CSF down the neuraxis [114] and developmentally opening up subarachnoid sites for reabsorption. This increased hemodynamic-hydrodynamic generation of CSF secretion and pressure pulse fosters a spurt in brain growth [106-113]. Maintaining appropriate CSFP in the developing CNS critically depends upon aqueductal patency and smooth CSF flow. Just as intraocular pressure importantly molds the shape of the developing eye, the typically-moderate rise in CSFP in perinatal stages of life [105] contributes to morphing the expanding CNS. 3.3 Congenital hydrocephalus and periventricular regionsUntoward effects on brain development, however, result from inordinately elevated CSFP secondary to blockage of the Sylvian aqueduct. Augmented CSFP has been observed in aqueduct-impaired hydrocephalic (H-Tx) rats, increasing 2-fold between 10 and 21 days after birth [115]. In other H-Tx studies, CSFP increased from about 20 mm H20 at 10 days after birth to as high as 90 mm H20 by 3 weeks [116,117]. Elevated pressure reflects blocked flow out of the lateral ventricle. The consequent CSF stasis in hydrocephalus interferes with cerebral and ventricular system development [118,119]. Transgenic mice lacking ependymal-specific expression of hydin [120], which facilitates ciliary functions, have gross distortions in the anatomical relationship between the ventricles and adjacent brain. Certain hydrocephalic malformations stem from metabolic, transport and ciliary deficiencies in the developing CP [121]. Systematic investigations should explore how faulty cilia development in the choroido-ependymal lining affects CSF formation, composition, volume and ultimately the CSFP. CSFP impacts periventricular protein expression and secretion into the ventricles. An optimally-growing CNS depends on delicately-balanced biophysical and biochemical phenomena in CSF [6]. In congenital hydrocephalus, however, there is not only increased pressure but also altered CSF composition [118,119,121]. Nerve growth factor concentration is elevated in CSF of children with congenital hydrocephalus [122], but cytokine levels are evidently stable (implying intact BBB function) [123]. Whereas some alterations in CSF constituents are due to interrupted CSF flow [119,121], other changes in composition are related to byproducts of pressure-induced oxidative damage to cells near the ventricles [124]. Other modifications of CSF chemistry in hydrocephalus, possibly homeostatic, may be due to pressure-induced up-regulation of proteins secreted by CPe, ependyma and periventricular tissue. One example is choroidal growth factor synthesis in response to augmented CSFP that follows ischemia [7] or trauma. CPe and ependyma are a plentiful source of growth factors [125,126] to repair tissue injured by elevated CSFP and its secondary effects [8]. The interaction between the pressures of the CSF and vascular systems, especially in the onset of hydrocephalus, awaits systematic investigation. Fascinatingly, the elevated arterial pressure in spontaneously hypertensive rats is linked to ventriculomegaly via effects on secretion by the subcommissural organ (SCO) in the aqueductal wall [127]. The SCO and its associated Reissner's fiber (RF) secrete into CSF glycoproteins essential for establishing normal CSF flow down the neuraxis for distal reabsorption. Therefore, a disrupted SCO-RF complex results in less efficient CSF flow and consequent hydrocephalus [128,129]. Compromised function of the SCO [130] as well as CP [121] leads to ventriculomegaly and imbalanced CSF dynamics. These observations point to the significance of the circumventricular organs in secreting factors to optimize developing CSF flow, volume and pressure. 3.4 Brain response to elevated CSF pressureIn addition to the pressure effects on the periventricular zone, there are several ways that CSFP impacts the brain globally. Responses to elevated CSFP can be broadly categorized by: i) how neural structure and metabolism are affected by modified CSF dynamics; and ii) how homeostatic transport interfaces that protect the parenchyma respond to neuropeptide up-regulation in CSF hypertension. For the first consideration, there are marked oxidative changes [131-133] in hydrocephalus that are reflected in the way that injured neurons metabolize neurotransmitters [134] and myelin [135]. Although beyond the scope of this review, the topic of deleterious anaerobic neuronal metabolism in hydrocephalus has been treated previously [136-138]. Concerning the second consideration, i.e., homeostatic mechanisms, the regulatory increases in ANP and AVP concentrations in CSF from elevated CSFP [98-100,104] evidently foster vascular perfusion of several regions. Even though up-regulated ANP may decrease CSF formation in ischemia and hydrocephalus, it does support CPe viability by increasing choroidal blood flow [139]. CSF-administered ANP and AVP dilate cerebral arteries [140,141]. ANP- and AVP-dilating effects on large pial arteries thereby counter cerebral vasospasm induced by endothelin following subarachnoid hemorrhage [142]. Such perfusion-supporting actions by centrally up-regulated ANP curtail edema [143] by stabilizing the CP and cerebral vasculature threatened by ischemia and augmented CSFP. In chronic hydrocephalus, even moderate increments in CSFP can compromise CBF and metabolism. Intermittent changes in CSFP need a thorough analysis, particularly in regard to effects on regional hydrodynamics and hemodynamics. Clearly, prospective as well as retrospective studies [91] on CSFP are essential to advance treatment strategies for CSF diseases (Fig. 6).
3.5 Advances in measuring CSF waveformsCSFP wave analysis provides substantial insight on the state of CSF dynamics and is more reliable than assessments of cerebral perfusion pressure and mean ICP, especially when there are differences in baseline pressure [144]. CSF has a characteristic pressure pulse that varies in health and disease. Cardiovascular parameters markedly affect CSFP waves by contributing systolic and diastolic components of pulse amplitude and latency [145-148]. Arterial pressure pulsations are transmitted across CPs to ventricular fluid [114] and generate CSF pressure waves. It would be clinically useful in hydrocephalus [149] to characterize these pressure waves in the ventriculo-subarachnoid system. How is ICP recorded, and does it matter where sensors are placed, i.e., in the CSF, brain parenchyma or epidural space? Continuous ICP signals have been recorded with sensors such as the Camino OLM ICP and Codman ICP MicroSensor [144]. A study of brain parenchyma vs. epidural space monitoring revealed marked differences in recorded mean pressure, but not in the parameters of mean ICP wave amplitude and mean ICP wave latency [150]. Thus, epidural ICP recording (to estimate parenchymal pressure) is feasible for determining parameters such as single wave pulse pressure amplitude (dP) and single wave latency (dT, or rise time). Moreover, monitoring ICP in the cerebral ventricles, as waveform parameters, gives comparable results to pressure measurements done with the sensor in brain parenchyma [145]. Evidence is lacking for an appreciable pressure gradient between the parenchyma and ventricular CSF. Pulsatile components of CSFP will likely be more helpful than mean CSFP in evaluating intracranial compliance (Fig. 7). Eide introduced a method for continually recording ICP signals at 100 Hz, converting to digital data, and then processing in 6-s time windows [151]. An algorithm filters noise prior to accepting cardiac beat-induced single ICP waves for analysis of amplitude and latency. Wave amplitude analysis is also promising in pediatric hydrocephalus [152] because it is a better predictor of intracranial compliance than is mean pressure. Children with intracranial hypertension from hydrocephalus or craniosynostosis had a more successful outcome after surgery if the mean CSF wave amplitude pre-surgery was > 5 mm Hg [152]. To assure quality control of the waveforms processed, an algorithmic analysis screens out infarct-induced waves to improve diagnostic information [153].
ICP/CSF waveform analyses have predictive potential for outcome in adult patients with chronic hydrocephalus. Although patients with idiopathic NPH (iNPH) may have normal mean ICP, it is possible that they have altered single ICP waves. Higher values of mean ICP wave amplitudes were found in iNPH patients who eventually improved after shunting [154]. In one cohort, the mean CSFP wave amplitude was a better predictor than resistance to CSF outflow (Ro), in regard to positive clinical change a year after shunting [155]. Up to 60% of iNPH patients have augmented mean CSF wave amplitudes, and 90% of these individuals respond favorably to shunting [156]. Post-shunting cognitive outcomes [157] were better in iNPH patients with relatively high pre-operative mean ICP wave amplitudes (Fig. 7). The so-called B waves in CSF, especially in NPH patients, can predict post-surgical outcome in adult chronic hydrocephalus. Slow B waves, however, only weakly correlated with improvement after shunt surgery [158]. An alternative to B wave examination has been proposed. Accordingly, the relative pulse pressure coefficient (RPPC) combines the effects of pulsatory volume changes and elastance on CSFP [159]. RPPC reflects reallocation/storage rather than reabsorption of CSF because it relates pulse amplitude to mean CSFP. A worthy clinical goal is to ascertain absolute CSFP by methodology minimally disruptive to CSF or brain. CSF is contiguous with fluids in the ear, nose and eyes. The orbit vasculature, for example, is exposed to ambient CSFP. This should enable reliable CSFP determination from transocular sonographic and dynamometric data. An empirical index based on ocular arterial (blood flow) and venous (outflow pressure) measurements highly correlates (r = 0.95) with absolute CSFP [160]. Therefore this promising indirect ocular approach deserves refinement. Technical advances are also being made with directly measured CSFP. A novel technique minimizing CNS invasion utilizes a hollow mandrin. This ventricular probe allows precise cannulation of CSF and determination of opening CSFP without fluid loss along the penetrating catheter [161]. This refined mandrin approach consistently accesses the ventricles with a single puncture compared with occasional multiple penetrations in previous cannulation procedures to locate the CSF [161]. Overall, the aim of CSFP assessments is reliability by minimally perturbing the CSF-brain. To expedite CSF and hydrocephalus modeling, attention is being devoted to delineating CSFP signals. Highly precise signals for hemodynamic and hydrodynamic parameters facilitate CSFP analyses. Continuous signal inputs to multiple sensors (blood pressure and CSFP during infusions) are integrated by software [162] to evaluate fluid dynamics and predict steady-state responses to infusion tests. Computerized rheoencephalography non-invasively assesses NPH by analyzing changes in cerebral electrical impedance related to pulsatile blood flow [163]. Arterial compliance determined by rheoencephalography is evaluated from the regression of arterial pulse amplitude (aAMP) on mean CSFP. Patients with lower arterial compliance have higher slope values for aAMP vs. CSFP. Increasingly sophisticated analyses of CSFP against arterial pressure will improve predictive shunting. Models of fluid-structure interactions to predict pressure and flow within the ventricles [164] and transmittal of pressure into brain parenchyma [165,166] are advancing the theory of pulsatile fluid dynamics. 4 CSF flowCSF flow pathways need elucidation for both healthy and diseased brain. Choroidally secreted CSF flows down the neuraxis to the 4th ventricle and then out through hindbrain foramina into the cisterna magna and the subarachnoid space in basal regions. In addition to this classically-described pathway, new evidence indicates that ventricular CSF also flows by another route to the basal and midbrain cisterns, i.e., into subarachnoid extensions [167] of the velum interpositum (from dorsal 3rd ventricle) and superior medullary velum (rostral 4th ventricle). Additional evaluation is needed for the limited CSF flow from cisterna magna to cortical subarachnoid regions and arachnoid villi [168], and for the possible shunting of CSF bulk flow between the ventricles and injured/edematous brain parenchyma [169]. Insight gained on CSF distribution routes will benefit pharmaco-therapeutic regimens. 4.1 CSF flow and brain metabolismThere is increasing appreciation that reduced CSF flow adversely affects brain metabolism and fluid balance [3,18,19,118,119]. Historically in hydrocephalus investigations, CSF pressure and volume [170-173], not flow and composition, have been emphasized in animal models and shunt design. Consequently, considerable knowledge has accrued on pressure-volume relationships in the ventriculo-subarachnoid system. Evidence continues to accumulate, however, for the importance of CSF flow on cerebral metabolism. Because the CP-CSF supplies micronutrients and peptides to neuronal networks, and removes many catabolites, impeded CSF flow disturbs metabolism in early life [119] as well as in late stages [174]. 4.2 Flow effects on fetal germinal matrixInterference with CSF flow through the ventricles and aqueduct in fetal life profoundly retards brain development [118,119]. This is due partly to compromised transport of growth factors from secretory sites such as CP to subventricular germinative zones where stem cells become neurons. In the H-Tx hydrocephalic rat there is a congenital defect leading to tissue dysgenesis in the aqueductal region [175,176]. The H-Tx model [117-119] displays prenatal ventriculomegaly and distortions in CSF growth factor delivery via volume transmission even before intraventricular pressure rises. Prenatally-altered CSF flow thus causes maldevelopment in H-Tx due to faulty differentiation of neural precursor cells [118]. Because CP function is fundamental for CNS development [2], it is pertinent to assess how perturbed CSF flow and composition harm the growing brain. Non-invasive quantification of aqueductal CSF flow [177] during perinatal life would enhance insights into pediatric hydrocephalus. 4.3 Decreasing CSF flow in aging CNSCSF flow disruption in adult chronic hydrocephalus also devastates cerebral functions. Throughout aging, the ability of CP epithelium to manufacture CSF undergoes continual decline [2,3,57,79]. As CSF formation rate dwindles by 50% or more in senescence and disease [3,19], the sink action [33] of slower-flowing CSF is attenuated [9]. The concentration of potentially-toxic peptides and organic metabolites in CSF [174] and brain consequently builds up due to sluggish flow. Less favorable concentration gradients for catabolites diffusing from ISF to ventricular CSF, results in reduced clearance of harmful substances from brain. Pharmacological studies in old animals treated with flow inhibitors, e.g., acetazolamide [36,53], FGF2 [178,179], and kaolin [180] are needed to analyze the time course of elevated CSF protein concentration in acute vs. chronic states of curtailed flow. 4.4 Refinement of non-invasive flow measurementsDue to previous technological limitations, there has been a paucity of investigations to assess CSF flow in animal models. However several non-invasive studies involving magnetic resonance imaging (MRI) to quantify CSF flow have been carried out in humans. One of the earliest such analyses by Ridgway et al. [181] demonstrated that CSF flow is pulsatile, i.e., moving to and fro, alternately in cephalic and caudal directions. Thus, they used the MRI pulse sequence (gated from the R-wave of the electrocardiogram) to calculate CSF flow velocities (e.g., 2.9 cm/sec) and corresponding flow rates (e.g., 0.4–0.6 ml/min). Similarly, dynamic MRI of CSF flow, using a multi-slice spin echo approach, was used to compare aqueductal CSF flow rates before and after ventriculostomy to repair non-communicating hydrocephalus [182]. MR phase imaging has also been used to demonstrate a circadian variation in human CSF flow, the latter being twice as great at night as in daytime [183]. Recent advances have been made in the technology and algorithms for quantifying CSF flow non-invasively. Using phase-contrast MRI to calculate CSF and CBF curves over the cardiac cycle, Stoquart-Elsankari et al. [184] extracted data for several CSF parameters: mean and peak flows, latencies and stroke volume. They found that CSF stroke volume was reduced in the elderly, both at the aqueductal and cervical levels. Another new approach is the phase contrast balanced steady-state free precession (PC-bSSFP). It is advantageous over the gradient echo in that signal-to-noise ratio is improved and non-laminar CSF flows can be more efficiently analyzed [185]. PC-bSSFP has been more suitable than the gradient echo approach for quantifying turbulent CSF flow in the prepontine cistern and cervical subarachnoid space [184,185]. Application of refined imaging procedures to small animal models will be helpful in modeling flow pulsatility and the intra-cardiac cycle displacements of CSF volume. 5 CSF volumeMaintaining normal CSF volume is indispensable to brain health. CSF volume ranges from the greatly reduced spaces in slit ventricle syndrome to the ventriculomegaly of severe hydrocephalus. The dynamics of ventricular contraction and expansion are poorly understood but likely involve the interplay of three main factors: changes in brain tissue properties (e.g., compliance), CSF dynamics and vascular parameters. CSF volume can be significantly altered iatrogenically by suboptimal rate of CSF flow through shunts. Disorders that rupture the BBB and BCSFB also modify ventricular volume. Understanding CSF volume is important because of the impact on neuronal function exerted by changes in cerebral metabolism and blood flow. Therefore, information is needed on the rate and extent of regional CSF volume adjustments. Maintaining the appropriate size of the ventriculo-cisternal-subarachnoid compartments is biophysically and biochemically complex. CSF volume in adult mammals ranges from about 0.04 ml in mice [77] to approximately 150–160 ml in humans [3]. Over an organism's lifespan, the CSF volume is variably set to a higher or lower degree in response to stressors. Hypoperfusion of the plexuses [186-188] interrupts the O2 supply and severely compromises the BCSFB and ventricular integrity. Hyperthermia also devastates the CP-ventricle nexus. By way of osmotic and autonomic disruptions between the CP and CSF, hyperthermia causes an edematous expansion of the CNS parenchyma [189]. On the other hand, ventricular volume can contract as occurs in slit-ventricle syndrome [190]. Transgenic, hydrocephalic and hypertensive models inform on ontogenetic, physical and physiologic factors that alter ventricular volume. The discussion below treats the overlapping actions of vascular, hydrodynamic and neuroendocrine phenomena in regulating ventricle size. 5.1 Hemodynamic factorsCSF volume importantly adjusts to physiological variations in cerebral blood volume (CBV). Thus an increased amount of blood within the cerebrovascular system leads to a displacement, and to a reduced volume, of CSF. Conversely, a decrease in CBV can result in an augmented volume of CSF. This more-or-less reciprocal relationship between CBV and CSF volume reflects the fact that, according to the Munro-Kelly doctrine [191], the combined volume of blood, CSF and brain remains relatively constant in the intracranial space bounded by the rigid skull. Consequently, in order to regulate pressure within the CNS, the CSF is a useful physical buffer that helps to accommodate changes in brain blood supply. Physical aspects of choroidal hemodynamics also significantly affect CSF volume. There is a brisk, pulsating blood flow of 3–4 ml/g/min to the plexus [108,109]. This strong arterial pulse is transmitted across the choroidal epithelial membranes to CSF. Therefore nearly all CSF motion is pulsatile. It has long been known that CSF dynamics are markedly impacted by vascular pressure waves in CP [114]. Hyperdynamic upstream CP pulsations dilate the cerebral ventricles when there is increased impedance to the flow of CSF pulsations in the SAS [192]. As downstream CSF impedance rises, there is redistribution of CSF pulses from the subarachnoid compartment back to the ventricles and the capillary-venous circulation. Egnor and colleagues propose that communicating hydrocephalus with ventriculomegaly results from pulse redistribution within the cranial cavity [192]. 5.2 Hydrodynamic factorsHypo-secretion of CSF, presumably occurring consequent to disrupted bicarbonate transport in CP of SLC4 knockout mice, drastically reduces ventricular volume [193]. On the other hand, hypersecretion of CSF by an actively metabolizing CP papilloma [194], predisposes to ventricular expansion. Thus, altered transport and permeability at the choroidal blood-CSF interface significantly bears on the ventricular volume. The spontaneously hypertensive rat model (SHR) also reveals the significance of BCSFB transport and fluid formation in regulating fluid volume within the CNS interior. SHR displays a ventriculomegaly [127,195] that likely results from markedly transformed CP functions. Ions, water and non-electrolytes more readily penetrate the blood-CSF barrier of SHR compared with non-hypertensive Wistar-Kyoto (WKY) controls [196]. The CPe of SHR rats consistently has a greater number of mitochondria, increased Golgi processing and enhanced transport activity [197]. The higher permeability of the blood-CSF interface in SHR allows greater penetration of organic solutes such as sucrose from blood to CSF [196]. Increased activity of the Na+-K+-2Cl- cotransporter [198] which promotes fluid transfer in CP [1], also occurs in SHR. Greater permeability and secretion at the CP in SHR would promote faster transfer of fluid into the ventricles. This is consistent with the ventricular expansion in SHR [127,195]. According to the Egnor model [192], the larger pulse amplitude of the transmitted arterial pulse in the SHR would also be a factor causing ventriculomegaly. Other injury models of the blood-CSF barrier shed light on dysregulated ventricular volume. Acute arterial hypertension in adult rats transiently opens the BCSFB allowing plasma proteins to leak into the ventricles [199]. Pathological disturbances that enhance CP permeability lead to macromolecule accumulation in the normally low-protein CSF. This increases the osmotic pressure of CSF and draws water into the ventricles. Transient forebrain ischemia also disrupts choroidal ultrastructure and transporters [187], causing a temporary loss of CSF homeostasis. Further analyses of hypertensive and ischemic insults to the choroidal circulation should delineate repair mechanisms [125] that restore homeostasis of the CPe and ventricular volume. 5.3 Neuroendocrine factorsPeptidergically-regulated fluid transfer at the BCSFB and BBB [200,201] helps to set the volume and composition of CSF and brain ISF, respectively. Moreover the fine tuning of fluid exchange at the ependymal interface, mediated by neuropeptides [202] and growth factors [125], effects fluid balance between the ventricles and interstitium. When these coordinated homeostatic mechanisms at the transport interfaces are upset, the ventricles can either expand or contract. At the blood-CSF interface in CP, there is a complex interplay among ANP, AVP and FGF2 and their apical membrane receptors to control ion and water secretion into the ventricles. This trio of peptides down-regulates CSF formation via neuroendocrine effects on CPe [2,6,17,81-87]. ANP, AVP and FGF2 levels in the CP-CSF system are mainly under central control [6,98,203-208] and thus largely independent of plasma and peripheral effects. When the CNS is perturbed biochemically or physically, these peptidergic systems are activated to restore normal hydration and osmolality. By these mechanisms, extracellular as well as intracellular fluid volumes in CNS are stabilized [209]. Ventricle size is affected by peptide regulation of CSF output from CP. FGF2 has many physiological roles, but a newly appreciated one is fluid regulation. Exogenously administered FGF2 both in vivo and in vitro reduces CSF formation [178,179]. This FGF2-induced suppression of fluid generation is evidently promoted by the choroidal release of the CSF inhibitor, AVP [210]. FGF2 and AVP expression in the CPe, like that of the hypothalamus-pituitary axis, is sensitive to the water balance of the organism [208,211]. It is intriguing that in the growing SHR the continually declining FGF2 level in CPe (and perhaps a resultant diminishing inhibitory tone on CSF production) is temporally associated with progressively increasing ventricle size [195]. Collective evidence implicates choroidal FGF2 in ventricular volume regulation. ANP is also regarded as a volume-regulating peptide [212]. Several investigators report that choroidal ANP receptors in the ventriculomegalic SHR rat are down regulated [103,213-216]. Therefore, the reduced ANP tone lowers the generation of the CSF-inhibiting second messenger, cGMP, in the CPe of SHR [103]. A downloader of extracellular fluid volume in peripheral systems, ANP may have a similar function in the CNS. ANP receptor impoverishment in the CP of SHR rats [103,213-216] may cause less inhibition of CSF production and the related ability to maintain normal ventricular volume. Accordingly, the observed increase in CSF formation in the SHR [196], possibly due to attenuated natriuretic modulation, would be consistent with ventriculomegaly. The question is begged as to whether a genetic alteration in the ANP (or related neuroendocrine) systems in SHR rats precludes CSF volume down-regulation. To construct a global model of CSF-ISF volume homeostasis, more information is needed on how ANP, AVP and FGF2 work in concert to regulate fluid transfer across CP and BBB [200,201,209]. AVP also interacts with angiotensin II in the CP-CSF system to decrease fluid production [217]. Neuropeptidergic modulation at fluid reabsorption sites in the CNS importantly awaits elucidation. Gaining insights on peptidergic regulation of CSF flow in various regions may make feasible the use of natural ligands or their analogs and antagonists [17] to therapeutically correct aberrant ventricle size. 6 CSF turnover rateThe brain's ability to turn over or renew CSF is crucially important in maintaining metabolic balance in the CNS. This is because the brain lacks lymphatic capillaries. It therefore relies heavily on continual CSF convection to clear macromolecules and catabolites from the neuronal environment. Such clearance deficiency, as in states of CSF stagnation when turnover rate is severely compromised, results in catastrophic changes in the composition of the interstitium, vessel walls and meninges. Consequently, neurons incur damage. Pharmacotherapeutic strategies to stabilize the aging CNS might well include ways to maintain CSF formation and prevent ventricular enlargement. The CSF turnover rate is defined as the volume of CSF produced in 24 hours divided by the volume of the CSF space. In young adult rats, the total CSF volume is renewed about 11 times daily compared to 4 times/day in control humans (Table 4). Moreover, in both rodents and man, the rate of turnover of CSF declines with age and dementia progression (Table 4). Such dwindling of the CSF turnover rate is partly due to the declining ability of CP to form CSF in later stages of life [18,79]. Table 4. CSF dynamics and volume in aging and neurodegeneration 6.1 Adverse effects of ventriculomegalyAnother substantial factor in turnover rate is the volume of CSF. In young adults, there is a CSF space of 150–160 ml and a formation rate of about 0.4 ml/min [3]. The result is a normal turnover rate in man of about 4 volumes of CSF per 24 hours (Table 4). CSF volume or space however is augmented in senescence and dementia, often as an ex vacuo hydrocephalus secondary to atrophic loss of brain mass. Large ventricles inherently impair the CSF's ability to efficiently renew itself because turnover rate is inversely related to CSF volume (ventricles, cisterns and subarachnoid spaces). Accordingly, in aging, NPH and AD (Table 4), the CSF turnover rate can fall by 3–4-fold. Consequently as the ventricles enlarge in aging and disease [3], the purity of CSF is gradually lost due to less rapid turnover causing stagnation of extracellular fluid. 6.2 Attenuated CSF sink actionCSF disorders in both the young and old CNS often involve impoverished fluid turnover. CSF sink action to remove catabolites is a function of fluid formation and CSF volume relative to brain volume. In perinatal development when BCSFB transport capacity is less, the CP forms fluid at a slower rate per mass of tissue than in adults [33,106,107,110-113]. Moreover, in early life the ratio of CP-CSF volume to brain volume is relatively high [34]. These factors lessen the capability of immature brain to eliminate unneeded catabolites. The growing anabolic brain requires an optimally functioning CP-CSF to remove catabolites as well as provide micronutrients. Congenital hydrocephalus, with expanding ventricles, further reduces the already low degree of CSF sink action in the fetus [33,113]. Consequently, the low CSF turnover in infantile hydrocephalus makes the maturing CNS especially vulnerable to damage. In later life, CSF turnover rate is also markedly curtailed [2,3,9,18,19,79]. In senescence, NPH and AD, there is progressively lower CSF formation rate and expanded ventricular volume. The net result for all three states is diminished CSF turnover rate (Table 4). Such attenuated CSF sink action in aging, NPH and AD [3,19] alters CSF composition (see below) with deleterious consequences for brain. In aging, when dwindling fluid percolation and interstitial deposits hamper clearance of brain solutes, the curtailed flux of neurotransmitter metabolites (such as homovanillic acid) from interstitium to ventricles [218] likely reflects diminished bulk flow and diffusion between ISF and CSF. In a rat model that mimics NPH [219], beta amyloid peptide (Aβ) accumulates centrally as in NPH patients. In both cases Aβ clearance pathways are impaired (Fig. 8), by reduced transport of low-density lipophilic protein receptor related protein (LRP-1) at the BBB [219] and slower bulk flow from attenuated CSF dynamics [3,79]. Pharmacological intervention [11,12,15-17] in geriatric patients to maintain CSF formation and minimize ventricular dilation might prevent curtailed CSF turnover. A worthy goal is to provide trophic drugs or CP transplants [12,15] to minimize neurodegeneration by stabilizing CSF volume and content.
7 CSF compositionHistorically, CSF compositional analyses have been used widely to monitor distortions in brain metabolism, evaluate disruptions of barrier transport and permeability functions, obtain pharmacokinetic parameters for drugs targeting the brain parenchyma, and identify biomarkers for aiding the diagnosis and prognosis of CNS diseases. Thus the CSF contains valuable biochemical and cellular information that can be advantageous for more effective clinical management of brain complications. An appreciation of altered CSF composition, especially in relation to corresponding changes in plasma, is particularly useful in interpreting scientific and neurological data. 7.1 Kidney-like action of CP-CSF systemThe brain vitally depends upon the stability of CSF composition [220], similar to the way the body is dependent on plasma chemistry that is stabilized within tolerable limits. Acting like a kidney inside the CNS [34], the CP has a major role in homeostatically adjusting the brain extracellular fluid [1,18,27]. CSF constituents are exquisitely regulated by a complex array of transporters in the CP epithelium [1,18,46,68,220,221]. Substantial deviations in CSF concentration of ions and peptides require restoration to normality [17]. When CSF homeostasis fails, neuronal function becomes vulnerable [18,19,222]. A major translational challenge is to correct CSF solute distortions in aging, NPH and AD when both CP and BBB transport capacities are diminished [3,9,18,79,219,223]. Stabilizing the CSF composition is predicated largely on pharmacological manipulation of the barrier transporters and on restoration of a breached BCSFB or BBB [223-225]. To help manage certain CSF disorders, aberrant concentrations of proteins [226] and catabolites [174] in CSF need to be profiled and categorized for various stages of NPH and AD. 7.2 Altered CSF biochemistry in aging and diseaseBiochemical analysis of the CSF has immense potential for diagnostics and prognostics [227]. In disease states the CSF composition is transformed by invading immune cells, plasma cytokines and pathogens [5]; as well as by modified active secretions from CP. Therefore the CSF is clinically useful to evaluate: i) the nutritional and trophic status of the brain in patients with hydrocephalus or dementia [228]; ii) the purifying capacity of central anion and peptide reabsorptive systems in aging and AD [229], iii) the therapeutic or cytotoxic concentration of certain CSF-borne agents targeted to neurons or meninges [230], and iv) the presence of abnormal solutes [231], or normal molecules in atypical concentrations. Solute concentration profiles can define certain disease states and be used to evaluate the benefit of therapeutic intervention. To sustain the brain, the CSF provides a full complement of vitamins, peptides, nucleosides and growth factors [1,2,10,27,222,232]. Adequate nutritional/trophic support of neurons via CSF is compromised in senescence [79]. This may result from dietary deficiency coupled with reduced micronutrient delivery to brain by inefficient CP-CSF transport mechanisms [18,57,223]. Vitamins B and C are transported specifically across CP to CSF and adjacent neural tissue [222-234]. In aging, massive interstitial fibrosis of CP (Fig. 9) and oxidative damage to the epithelium [223] impair this essential transport route. Structural and biochemical disruptions may reduce not only CSF formation rates, but also the secretion of organic substances into CSF of AD subjects [228]. Overall then, CSF concentration data for the elderly should be interpreted in light of reduced bulk flow as well as altered metabolism [218].
Proteins in CSF can also become deficient in late life. Transthyretin (TTR) is extensively synthesized and secreted by CP into CSF. TTR is a useful CSF marker because it is manufactured mainly by CP [235] and only slightly if at all, by brain parenchyma [236]. One function of TTR is to bind Aβ, thus stabilizing it in a soluble form and preventing CNS peptide toxicity [223] that may occur when Aβ self-assembles into neurotoxic oligomers. CSF levels of TTR decrease in both aging and AD [237,238]. A CSF deficiency of TTR may predispose the brain interstitium to Aβ oligomer toxicity and plaque formation [223]. Strategies are needed to sustain TTR secretion by CP in the elderly, e.g., by nicotinic modulation [239]. Moreover the array of growth factors secreted by CP helps to repair injuries from forebrain ischemia or neurodegeneration [7,17,125,126]. Brain fitness requires a sustained choroidal secretion of a cocktail of peptides and proteins that effect a balanced metabolic homeostasis of the CSF and neuronal-glial networks. In addition to receiving productive secretions from the CP, the CSF is also a repository for catabolites diffusing out of brain. Excessive metabolite efflux from ISF to ventricles can toxify the CSF. Toxic catabolites in CSF, generated by peroxidative phenomena, increase with age and neurodegeneration [174]. Glycated proteins in CSF are elevated in AD [231]. The CP tissue that protects and nourishes the CSF-brain nexus, suffers from oxidative injury and disrupted metabolism in advanced age and AD [18,223,240,241]. A vicious cycle ensues as toxic neuronal products (e.g., Aβ) enter CSF from brain and inflict further harm to the CP already debilitated by aging [57,79]. The steady build up of Aβ in CP epithelium may disturb leptin transport from blood to CSF [242]. Such altered transport at the BCSFB could perturb neuroendocrine balance by interfering with hormone signal transfer to hypothalamus via the CSF. 7.3 Importance of clearance transportMaintaining ISF and CSF compositional purity is of prime importance and depends upon efficient clearance mechanisms. Because the CNS lacks lymphatic capillaries, the CSF-mediated removal of metabolites and toxins is essential for efficient neuronal function. The CP-CSF system, proximally and distally, plays a major role in removing harmful substances. This occurs three ways. First, reabsorptive transporters in the apical membrane of CP epithelium actively remove organic anions and peptides from ventricular CSF [1,17,243]. This choroidal clearance complements active reabsorption of unneeded metabolites from ISF into cerebral capillaries [229]; for a given catabolite, the proportional clearance across BBB vs. BCSFB [244] should be determined in both health and particular diseases. Secondly, the continually-elaborated nascent CSF streams through the brain interior acting as a sink for metabolites diffusing down concentration gradients into the ventricles [1-3,33]. These substances pass through the ventriculo-subarachnoid system by bulk flow to distal drainage sites [1,18]. A third aspect of toxin clearance is the downstream extrusion of metabolites via outward CSF flow at the arachnoidal-lymphatic-venous interfaces [1,7,245]. In healthy CSF these three disposal mechanisms work in concert to effect fluid homeostasis. Therefore, in chronic hydrocephalus (NPH) with decreased CSF turnover [3,19], distorted CSF chemistry may be rectified by enhancing CSF formation, flow and drainage. Metabolite clearance defects and toxicity must be considered along with known ischemic insults in NPH to obtain a complete picture of chronic hydrocephalus. Comprehensive analysis of CSF biochemistry helps to manage NPH, AD and other complications of senescence. Several animal models demonstrate inhibitory effects of neuropeptides and growth factors on CSF formation and reabsorption [178,246]. A logical extension is to analyze systematically the biochemistry of human CSF at stages of chronic hydrocephalus with and without neurodegeneration. CSF profiling of protein, peptides and organic metabolites (e.g., sphingomyelin derivatives) in aging patients will likely provide insight on how the failing barriers and brain metabolism are linked to deficient CSF dynamics. Elevated levels of ventricular CSF albumin, neuropeptide Y, va |
|
 |   | Log on / register BioMed Central home | Journals A-Z | Feedback | Support |
on Google Scholar
author email
corresponding author email
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.
Figure 9.