Cerebrospinal fluid

Senescent changes in cerebrospinal fluid circulatory physiology and their role in the pathogenesis of normal-tension glaucoma

Authors: Wostyn P, De Groot V, Van Dam D, Audenaert K, De Deyn PP.

PURPOSE: To evaluate the evidence supporting a role for senescent changes in cerebrospinal fluid (CSF) circulatory physiology in the pathogenesis of normal-tension glaucoma (NTG).
DESIGN: Literature review and personal perspective of the authors.
METHODS: Analysis of selected articles in the peer-reviewed literature with interpretation and perspective.
RESULTS: Recent studies have reported that intracranial pressure is lower in patients with NTG when compared with patients with primary open-angle glaucoma and nonglaucomatous control subjects. It has been suggested that a low intracranial pressure in patients with normal intraocular pressure could lead to glaucomatous damage. This low intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, could result in barotraumatically induced optic nerve damage at the lamina cribrosa. However, several experimental studies do not support the speculation that low intracranial pressure and the resulting pressure-dependent effects cause bowing back of the lamina cribrosa and optic disc cupping. On the other hand, CSF production and turnover have been shown to be decreased in aging and in pathologic conditions, such as Alzheimer disease and normal pressure hydrocephalus. Interestingly, recent studies have revealed that both Alzheimer disease patients and patients with normal pressure hydrocephalus may have a higher risk of developing glaucoma. Therefore, we believe that CSF circulatory failure, ultimately resulting in reduced neurotoxin clearance along the optic nerves, could be an alternative explanation as to why glaucoma develops in patients with low intracranial pressure.
CONCLUSIONS: On the basis of the evidence available from the peer-reviewed literature, our tentative conclusion is that age-related changes in CSF circulatory physiology and the subsequent decrease in CSF turnover, with diminished clearance of toxic substances, can account for, at least in part, the pathogenesis of NTG. It should be stressed that for the moment at least, the present hypothesis remains unproven. Further research will be necessary to determine the possible role of CSF circulatory dysfunction in NTG. If confirmed, this hypothesis could provide new, important insights into the pathogenesis of NTG.

"Compensated Hyperosmolarity" Of Cerebrospinal Fluid And The Development Of Hydrocephalus

Authors: Klarica M, Miše B, Vladić A, Radoš M, Orešković D.

Acute osmolar loading of cerebrospinal fluid within one lateral ventricle of dogs was examined as a cause of water extraction from the bloodstream and an increase in intracranial pressure. We have shown that a certain amount of 3H2O from the bloodstream enters osmotically loaded cerebrospinal fluid significantly faster, hence causing a significant increase in intracranial pressure. The noted phenomenon in which intracranial pressure still significantly increases, but in which the hyperosmolarity of the cerebrospinal fluid is no longer present, was named "compensated hyperosmolarity". In the case of the sub-chronic application of hyperosmolar solutions into cat ventricles, we observed an increase in cerebrospinal fluid volume and a more pronounced development of hydrocephalus in the area of application, but without significant increase in intracranial pressure and without blockage of cerebrospinal fluid pathways. These results support the newly proposed hypothesis of cerebrospinal fluid hydrodynamics and the ability to develop new strategies for the treatment of cerebrospinal fluid-related diseases.

Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

Authors: Wostyn P, Van Dam D, Audenaert K, De Deyn PP.

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na(+)-K(+) ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

Genes involved in cerebrospinal fluid production as candidate genes for late-onset Alzheimer's disease: a hypothesis

Authors: Wostyn P, van Dam D, Audenaert K, de Deyn PP.

In rare patients with autosomal dominant, early-onset Alzheimer's disease (AD), pathogenic mutations in the genes encoding β-amyloid precursor protein, and the γ-secretase-complex components presenilin-1 and presenilin-2 appear to result in β-amyloid (Aβ) overproduction. The pathological accumulation of Aβ in the far more common late-onset AD is more likely to be the result of deficient clearance of Aβ. There is evidence that production and turnover of cerebrospinal fluid (CSF) help to clear toxic molecules such as Aβ from the interstitial fluid space of the brain to the bloodstream. CSF production and turnover have been shown to be decreased in aging and in pathological conditions, such as normal pressure hydrocephalus and AD. Reduced formation of CSF, with diminished clearance of Aβ, may play an important role in the onset and progression of AD. If reduced CSF turnover is a risk factor for AD, then its incidence ought to be increased under conditions of CSF circulatory failure. In this paper, the authors hypothesize that genes and variations of genes involved in the CSF production and absorption may contribute to the pathogenesis of late-onset AD.

Cerebrospinal fluid dynamics in the human cranial subarachnoid space: an overlooked mediator of cerebral disease. I. Computational model

Authors: Gupta S, Soellinger M, Grzybowski DM, Boesiger P, Biddiscombe J, Poulikakos D, Kurtcuoglu V.

Abnormal cerebrospinal fluid (CSF) flow is suspected to be a contributor to the pathogenesis of neurodegenerative diseases such as Alzheimer's through the accumulation of toxic metabolites, and to the malfunction of intracranial pressure regulation, possibly through disruption of neuroendocrine communication. For the understanding of transport processes involved in either, knowledge of in vivo CSF dynamics is important. We present a three-dimensional, transient, subject-specific computational analysis of CSF flow in the human cranial subarachnoid space (SAS) based on in vivo magnetic resonance imaging. We observed large variations in the spatial distribution of flow velocities with a temporal peak of 5 cm s(-1) in the anterior SAS and less than 4 mm s(-1) in the superior part. This could reflect dissimilar flushing requirements of brain areas that may show differences in susceptibility to pathological CSF flow. Our methods can be used to compare the transport of metabolites and neuroendocrine substances in healthy and diseased brains.

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