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Choroidal Proteins Involved in Cerebrospinal Fluid Production may be Potential Drug Targets for Alzheimer’s Disease Therapy
Peter Wostyn, Kurt Audenaert and Peter Paul De Deyn
Perspectives in Medicinal Chemistry , 2012, DOI: 10.4137/PMC.S6509
Abstract: Alzheimer’s disease is known to be the most common form of dementia in the elderly. It is clinically characterized by impairment of cognitive functions, as well as changes in personality, behavioral disturbances and an impaired ability to perform activities of daily living. To date, there are no effective ways to cure or reverse the disease. Genetic studies of early-onset familial Alzheimer’s disease cases revealed causative mutations in the genes encoding β-amyloid precursor protein and the γ-secretase-complex components presenilin-1 and presenilin-2, supporting an important role of β-amyloid in the pathogenesis of Alzheimer’s disease. Compromised function of the choroid plexus and defective cerebrospinal fluid production and turnover, with diminished clearance of β-amyloid, may play an important role in late-onset forms of Alzheimer’s disease. If reduced cerebrospinal fluid turnover is a risk factor for Alzheimer’s disease, then therapeutic strategies to improve cerebrospinal fluid flow are reasonable. However, the role of deficient cerebrospinal fluid dynamics in Alzheimer’s disease and the relevance of choroidal proteins as potential therapeutic targets to enhance cerebrospinal fluid turnover have received relatively little research attention. In this paper, we discuss several choroidal proteins, such as Na+-K+ ATPase, carbonic anhydrase, and aquaporin 1, that may be targets for pharmacological up-regulation of cerebrospinal fluid formation. The search for potentially beneficial drugs useful to ameliorate Alzheimer’s disease by facilitating cerebrospinal fluid production and turnover may be an important area for future research. However, the ultimate utility of such modulators in the management of Alzheimer’s disease remains to be determined. Here, we hypothesize that caffeine, the most commonly used psychoactive drug in the world, may be an attractive therapeutic candidate for treatment of Alzheimer’s disease since long-term caffeine consumption may augment cerebrospinal fluid production. Other potential mechanisms of cognitive protection by caffeine have been suggested by recent studies.
Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease  [PDF]
Peter Wostyn,Debby Van Dam,Kurt Audenaert,Peter Paul De Deyn
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/617420
Abstract: 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. 1. Introduction Alzheimer’s disease (AD), the most common type of dementia among older people, is a progressive neurodegenerative disorder characterized clinically by a gradual decline in cognition and daily functioning and behavioural alterations [1]. Principal neuropathological hallmarks of AD include extracellular senile plaques containing β-amyloid (Aβ) derived from β-amyloid precursor protein (APP) after sequential cleavage by β-secretase and γ-secretase, and intracellular neurofibrillary tangles caused by abnormally phosphorylated tau protein [1]. Early-onset familial AD caused by mutations in the genes encoding APP and the γ-secretase-complex components presenilin-1 and presenilin-2 accounts for less than 5% of the total number of AD cases [2]. The discovery of pathogenic mutations in these three genes in rare patients with autosomal dominant, early-onset AD provided incontestable evidence that aberrant APP processing can be
The regulation of brain states by neuroactive substances distributed via the cerebrospinal fluid; a review
Jan G Veening, Henk P Barendregt
Fluids and Barriers of the CNS , 2010, DOI: 10.1186/1743-8454-7-1
Abstract: The cranial CSF displays a rapid caudally-directed ventricular flow followed by a slower rostrally-directed subarachnoid flow (mainly towards the cribriform plate and from there into the nasal lymphatics). Thus, many brain areas are exposed to and can be influenced by substances contained in the CSF. In this review we discuss the production and flow of the CSF, including the mechanisms involved in the regulation of its composition. In addition, the available evidence for the release of neuropeptides and other neuroactive substances into the CSF is reviewed, with particular attention to the selective effects of these on distant downstream receptive brain areas. As a conclusion we suggest that (1) the flowing CSF is involved in more than just nutrient and waste control, but is also used as a broadcasting system consisting of coordinated messages to a variety of nearby and distant brain areas; (2) this special form of volume transmission underlies changes in behavioral states.IntroductionProduction and circulation of CSFProduction and sources of CSFFlow and destiny of the CSFThe CSF circulation during development and aging of the CNSCSF composition: sources, targets and exchange with ECFSources of CSF contentsFlow-transport: speed and mechanismsExchange of substances between CSF and ECF; mechanisms and targets:Neuropeptides form an integral part of the CSF contentsBehavioral effects of CSF contentsConclusionsBehavioral observations as well as modern imaging techniques show that brain activity is an input-output process that depends on the physiological or behavioral state of the animal or subject. A state is a well-known concept in mathematical system theory and in computer science. A machine, but for that matter also an organism or even a human, is at moment t1 in the same state as at moment t2, if for all possible input, the resulting internal and external reactions are the same. The states will be different if there is a particular input resulting in different react
The Maze of the Cerebrospinal Fluid Discovery  [PDF]
Leszek Herbowski
Anatomy Research International , 2013, DOI: 10.1155/2013/596027
Abstract: The author analyzes a historical, long, and tortuous way to discover the cerebrospinal fluid. At least 35 physicians and anatomists described in the text have laid the fundamentals of recognition of this biological fluid’s presence. On the basis of crucial anatomical, experimental, and clinical works there are four greatest physicians who should be considered as equal cerebrospinal fluid’s discoverers: Egyptian Imhotep, Venetian Nicolo Massa, Italian Domenico Felice Cotugno, and French Fran?ois Magendie. 1. Introduction Cerebrospinal fluid (Latin: liquor cerebrospinalis) is a liquid occupying subarachnoid space (cavum subarachnoideale) and brain ventricles (ventricules cerebri) (see Figure 1). Cerebrospinal fluid was not really discovered in terms of its liquid state of matter until the early 16th century A.D. It took three more centuries for physicians to become aware of its cerebrospinal location. Previously, it was thought that cerebral ventricles contained “spiritus animalis” (spirit of the animal). According to Schaltenbrand, cerebrospinal fluid found in humans and other higher vertebrates replaced the ocean, where 3.5 billion years ago the life had begun [1, 2]. Robertson claims that cerebrospinal fluid comes from amniotic fluid by conversion of the colloidal molecules throughout the embryonic life [3]. It is known and generally accepted by medical historians that cerebrospinal fluid has been discovered by Domenico Cotugno. Figure 1: The MRI sagittal neural tube section. The cerebrospinal fluid surrounding the brain and the spine within subarachnoid space is red-colored on this image. 2. “Spiritus Animalis” Idea Resonating through Centuries From the ancient times to the 16th century, based on the beliefs of Hippocrates from Kos (460–370 B.C.) and Claudius Galen from Pergamon (130–200 A.D.), it was thought that “pneuma psychikon” (Greek: πνε?μα ?ψυχικóv, Latin: spiritus animalis) with its mental functions was located within the cerebral ventricles [4–7]. As far as Galen’s role in the history of medicine is undoubted, not necessarily all the scientists analyzed his texts literally. It was Irani who referring to the research of Torack ascribed the description of the cerebrospinal fluid to Galen [8]. Torack, in turn, gave full credit to Galen for the discovery of the choroid plexus as a site of production of cerebrospinal fluid in his publication of 1982, based on On the usefulness of parts of the body, Galen’s work translated into English in 1968 [9]. According to Conly and Ronald (although without providing the sources) it was Galen who described
Predictors of Caffeine Consumption among Young Women
Ahmed A. Al-Shoshan
Pakistan Journal of Nutrition , 2007,
Abstract: Designing a meaningful nutritional educational massages and introducing a real changes in food behaviors need to address predictors determining consumption. In the subject of caffeine teratogenic effects on the health of women at childbearing age, important factors such as the women's knowledge, attitude and practices which may influence the level of caffeine consumption need to be investigated. This study involved 112 Saudi non-pregnant young women with main age of 26& plusmn;1.85 years whom were reported as heavy coffee and soda drinkers. All study participants consume more than 100mg/day of caffeine with a mean range of 258±156 - 305±204 mg/day. Soft drinks provide the highest amount of caffeine, 401±113 - 540±60 mg, for around 56-81% of the studied group. The caffeine consumption data were gathered and calculated using the 24-hour recalls and the beverage-frequency methods. The results indicated that the two methods were significantly correlated (Pearson r = 076, P ~ 0.01). An attitude concerning the difficulty associated with limiting coffee consumption was the strongest predictor of caffeine consumption but a weak positive correlation between caffeine consumption and other attitude related to caffeine use during pregnancy. No correlation between caffeine consumption and knowledge about caffeine and a negative association existed between knowledge about caffeine and attitude toward use of caffeine during pregnancy. No relationship between knowledge about caffeine and attitude toward the importance of dietary awareness.
Cerebrospinal Fluid Shunt Infections and Treatment  [cached]
ümit ?elik,Emre Alhan
Cocuk Enfeksiyon Dergisi , 2009,
Abstract: Cerebrospinal fluid shunts play a major role in the management of hydrocephalus. Cerebrospinal fluid shunt infection is one of the leading causes of cerebrospinal infection in childhood and if not adequately managed, may result in increased mortality and morbidity. Despite the fact that the modern valve controlled shunt has been used for nearly four decades, many questions remain about the prevention and management of cerebrospinal fluid shunt infections. In this review, the risk factors, diagnosis and treatment of shunt infections were discussed.
Cortisol in plasma and cerebrospinal fluid of patients with brain ischemia
Selakovi? Vesna M.
Medicinski Pregled , 2004, DOI: 10.2298/mpns0408354s
Abstract: Introduction One of the reactions to ischemia is increased release of glucocorticoid hormones, included in regulation of effects of numerous mediators/modulators that could be released in the acute phase of brain ischemia. The aim of our investigation was to define temporal dynamics of cortisol concentrations in plasma and cerebrospinal fluid of patients with different types of ischemic brain disease. Material and methods The study included 263 patients of both sexes, aged 55-68 years. History, clinical examination and cerebral computerized tomography were performed to establish the diagnosis. 97 patients had brain infarction, 66 had a reversible ischemic attack, 66 had a transient ischemic attack, and 34 patients had chronic encephalopathy. The control group included 22 age- and sex- matched patients, subjected to diagnostic lumbar radiculography, without disturbances in the cerebrospinal fluid passage. Cortisol concentrations were measured by direct radioimmunoassay. Results and discussion Results obtained in this research showed that in acute brain ischemic period there was a significant increase of cortisol concentration in plasma and cerebrospinal fluid. The increase was highest in patients with brain infarction, somewhat lower in reversible ischemic attack, and the lowest in transient ischemic attack compared to controls (331.7±92.8 pmol/ml of plasma and 2.5±1.1 pmol/ml of cerebrospinal fluid). Maximum concentrations were found during the first two days after insult. The main potentially protective effects of increased cortisol concentrations in patients with acute stroke could be the decrease of effects of deleterious reactions induced by ischemia. This mechanism might be an attempt of organism to compensate for disturbed homeostasis. Conclusion Measurement of cortisol in plasma and cerebrospinal fluid in patients with acute stroke is significant for monitoring the intensity of response of an organism to acute brain damage.
Atrial fibrillation in healthy adolescents after highly caffeinated beverage consumption: two case reports
Jennifer R Di Rocco, Adelaide During, Peter J Morelli, Marybeth Heyden, Thomas A Biancaniello
Journal of Medical Case Reports , 2011, DOI: 10.1186/1752-1947-5-18
Abstract: We report the cases of two Caucasian adolescent boys of 14 and 16 years of age at the time of presentation, each without a significant cardiac history, who presented with palpitations or vague chest discomfort or both after a recent history of excessive caffeine consumption. Both were found to have atrial fibrillation on electrocardiogram; one patient required digoxin to restore a normal sinus rhythm, and the other self-converted after intravenous fluid administration.With the increasing popularity of energy drinks in the pediatric and adolescent population, physicians should be aware of the arrhythmogenic potential associated with highly caffeinated beverage consumption. It is important for pediatricians to understand the lack of regulation in the caffeine content and other ingredients of these high-energy beverages and their complications so that parents and children can be educated about the risk of cardiac arrhythmias with excessive energy drink consumption.Atrial fibrillation is extremely rare in the pediatric population, almost always occurring in association with structural heart disease, such as rheumatic mitral valve disease, congenital heart disease with dilated atria, and rarely, as a complication of intra-atrial surgery [1]. Patients may present with palpitations, dyspnea, fatigue, light-headedness, or syncope. The electrocardiogram is characterized by disorganized atrial activity without discrete P waves. The ventricular response is often irregularly irregular. Without a prior cardiac or family history, other inciting causes such as thyrotoxicosis, infectious pericarditis, and pulmonary emboli should be considered in the previously healthy child presenting with new-onset atrial fibrillation [2].Exogenous causes of atrial fibrillation through a substrate such as caffeine have not been widely reported in the literature, especially in the pediatric population. A large-scale Danish study evaluating adult human caffeine consumption and arrhythmias did not fi
Cerebrospinal Fluid Shunt Infections  [cached]
Serkan ?ncü
Klimik Journal , 2010,
Abstract: Shunt is the most common approach among medical and surgical treatment modalities for treating hydrocephalus. The main purpose of the shunt is to reduce intracranial pressure by draining the cerebrospinal fluid (CSF) from the ventricles. Infection is one of the serious complications and it develops in approximately 5-15% of the inserted devices. The microorganisms responsible for the shunt infection usually arise from the normal flora of the skin. During the surgical procedure and healing period, microorganisms residing in skin may adhere to the shunt and start the infection. The clinical symptoms may differ according to the type of shunt used. Abdominal pain is the most common complaint in patients with infected ventriculo-peritoneal (VP) shunt. On the other hand, fever is the leading symptom in ventriculo-atrial (VA) shunt infection. Other than clinical signs, biochemical and microbiological analysis of CSF are necessary to diagnose shunt infection. The gold standard of treatment is the usage of antibiotics with shunt revision. In addition to parenteral antibiotics, intraventricular administration of antibiotics may be an essential part of the treatment. The most efficient way to avoid shunt infection is to follow the strict rules for preventing surgical site infections.
Cerebrospinal fluid in multiple sclerosis
Rammohan Kottil
Annals of Indian Academy of Neurology , 2009,
Abstract: Background: Technological advances have made it possible to examine the human cerebrospinal fluid (CSF) in a manner that was previously impossible. CSF provides a window into the changes that occur in the central nervous system (CNS) in health and disease. Through analysis of the CSF, we discern indirectly the state of health of the CNS, and correctly or incorrectly, draw conclusions regarding mechanisms of CNS injury and repair. Objective, Materials and Methods: To review the current state of knowledge of changes in the CSF in multiple sclerosis. Discussion: Establishing CSF markers that permit evaluation of the various biological processes in multiple sclerosis remains a challenge. Of all the biological processes, inflammatory markers are probably the best identified. Detection of oligoclonal immunoglobulin bands in the CSF is now established as the single most useful laboratory marker in the CSF to aid in the diagnosis of multiple sclerosis. Markers of demyelination, remyelination, neuro-axonal loss, neural repair and regeneration, and astrogliosis are only now being recognized. A good surrogate for any of these pathophysiological processes has not been defined to date. Conclusion: The goal of future research is not only to define surrogate markers in the CSF for each of the above functions, but also to extend it to other more readily accessible body fluids like blood and urine. A synopsis of the current literature in most of these areas of CSF evaluation pertaining to multiple sclerosis is presented in this article.
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