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

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.Outline1 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 CS...

The formation of cerebrospinal fluid: Nearly a hundred years of interpretations and misinterpretations

“…Choroid plexuses are the main site of CSF production (Dandy, 1919;Dandy and Blackfan, 1914;Davson, 1967;Davson et al, 1987;de Rougemont et al, 1960;Johanson et al, 2008;Masserman, 1934;Milhorat, 1987;Netsky and Shuangshoti, 1970;Rubin et al, 1966;Spector and Johanson, 1989;Welch, 1963;Welch, 1975), and other extrachoroidal sources also participate in maintaining the balance (Milhorat, 1987). According to Pollay and Curl (1967), another source of CSF is the ependyma lining the ventricles (Pollay and Curl, 1967).…”

“…The passage through the choroidal epithelium is an active metabolic process which transforms the ultrafiltrate into secretion (cerebrospinal fluid) (Brown et al, 2004;Davson et al, 1987;Johanson et al, 2008;Pollay et al, 1985;Segal and Pollay, 1977). Fluid secretion in epithelia has been found to be dependent on the unidirectional transport of ions, which creates an osmotic gradient inducing the movement of water (Figures 2, 3 and 4).…”

“…Based on literature (Bergsneider, 2001;Brodbelt and Stoodley, 2007;Brown et al, 2004;Davson et al, 1987;Johanson et al, 2008;Lyons and Meyer, 1990;Pollay 1977;Spector and Johanson, 1989), it could be generally shown that the net osmotic gradient across the choroid plexus is strictly regulated by the transport of Na + , Cl -, and HCO 3 -ions. The Na + /K + pump located on the CSFfacing (apical) membrane pumps Na + out of the choroid cells, driving down their intracellular Na + concentration (Figure 4).…”

“…There is an assumption that the CSF is formed mainly by the secretory activity of choroid plexuses in the brain ventricles, and that the majority of the remaining CSF is probably produced by the ependyma (Brown et al, 2004;Davson et al, 1987;Johanson et al, 2008;McComb, 1983;O'Connel, 1970). It is generally accepted that CSF flows/circulates unidirectional from the brain ventricles to the subarachnoid space with the exchange of various substances (more or less manifested) between the CSF and interstitial compartments (Davson, 1967;Davson et al, 1987;Johanson et al, 2008;Plum and Siesjö, 1975).…”

“…It is generally accepted that CSF flows/circulates unidirectional from the brain ventricles to the subarachnoid space with the exchange of various substances (more or less manifested) between the CSF and interstitial compartments (Davson, 1967;Davson et al, 1987;Johanson et al, 2008;Plum and Siesjö, 1975). There is a belief that arachnoid villi of the dural venous sinuses are primarily responsible for the drainage of CSF from the subarachnoid space to the cranial venous blood (Figs.…”