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...

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

ABSTRACTzheimer disease (AD) is characterized by deposits of an aggregated 42-amino-acid P-amyloid peptide (I3AP) in the brain and cerebrovasculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic .8AP slowly form fibrillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of soluble flAP in these in vitro assays is enhanced by addition ofsmall amounts ofpre-aggregated gamyloid "seed" material. We also have prepared these seeds by using a naturally occurring reaction between glucose and protein amino groups resulting in the formation of advanced "glycosylation" end products (AGEs) which chemically crosslink proteins. AGE-modified flAP-nucleation seeds further accelerated aggregation of soluble flAP compared to non-modiflied "seed" material. To better understand the factors which contribute to amyloid formation and stability, we have studied the in vitro aggregation of soluble synthetically prepared PAP monomers, a process which displays nucleation-dependent kinetics, especially at physiological (nanomolar) concentrations of monomer (refs. 9 and 10; this report). Although millimolar concentrations of (3AP exhibit extensive aggregation within minutes, micromolar and lower concentrations of monomer display a concentration-dependent lag period during which little or no measurable aggregate is formed, followed by a "growth" phase of more rapid aggregation (9-11). This lag period can be eliminated by adding trace amounts of preformed aggregate as "seed" material which serves to immediately induce aggregation (9). Seeding apparently eliminates the need for de novo formation of aggregation nuclei, a much slower process than the subsequent growth of nucleated aggregates. Thus, amyloid seeds can be seen to represent critical protein masses with special structural features capable of nucleating the formation of larger insoluble aggregates of amyloid from pools of soluble P3AP. The nature of these structural characteristics is unknown, but the net result of seeding is significant acceleration in the rate of aggregation compared with unseeded incubations of soluble PAP. By extrapolation from this simple in vitro model to the similar nanomolar concentrations of soluble fAP found in cerebrospinal fluid in vivo, it might be expected that the deposition and accumulation of PAP as amyloid plaques would reflect, in part, the amount or availability of seed material able to nucleate aggregation. Some cases of AD might correspondingly arise as a consequence of increased availability of nucleation seeds in the disease-prone brain relative to normal counterparts not destined to suffer AD at a similar chronological age.In the present communication, we explore the possibility that the formation or stability of amyloid structures which seed PAP aggregation may be enhanced by covalent crosslinks that chemically polymerize components of the aggregate. Under physiological conditions, long-lived proteins beco...