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Sleep is a physiological process that preserves the integrity of the neuro-immune-endocrine network to maintain homeostasis. Sleep regulates the production and secretion of hormones, neurotransmitters, cytokines and other inflammatory mediators, both at the central nervous system (CNS) and at the periphery. Sleep promotes the removal of potentially toxic metabolites out of the brain through specialized systems such as the glymphatic system, as well as the expression of specific transporters in the blood-brain barrier. The blood-brain barrier maintains CNS homeostasis by selectively transporting metabolic substrates and nutrients into the brain, by regulating the efflux of metabolic waste products, and maintaining bidirectional communication between the periphery and the CNS. All those processes are disrupted during sleep loss. Brain endothelial cells express the blood-brain barrier phenotype, which arises after cell-to-cell interactions with mural cells, like pericytes, and after the release of soluble factors by astroglial endfeet. Astroglia, pericytes and brain endothelial cells respond differently to sleep loss; evidence has shown that sleep loss induces a chronic low-grade inflammatory state at the CNS, which is associated with blood-brain barrier dysfunction. In animal models, blood-brain barrier dysfunction is characterized by increased blood-brain barrier permeability, decreased tight junction protein expression and pericyte detachment from the capillary wall. Blood-brain barrier dysfunction may promote defects in brain clearance of potentially neurotoxic metabolites and byproducts of neural physiology, which may eventually contribute to neurodegenerative diseases. This chapter aims to describe the cellular and molecular mechanisms by which sleep loss modifies the function of the blood-brain barrier.

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Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that is typically sporadic and has a high social and economic cost. We utilized the intracerebroventricular administration of streptozotocin (STZ), an established preclinical model for sporadic AD, to investigate hippocampal astroglial changes during the first 4 weeks post-STZ, a period during which amyloid deposition has yet to occur. Astroglial proteins aquaporin 4 (AQP-4) and connexin-43 (Cx-43) were evaluated, as well as claudins, which are tight junction (TJ) proteins in brain barriers, to try to identify changes in the glymphatic system and brain barrier during the pre-amyloid phase. Glial commitment, glucose hypometabolism and cognitive impairment were characterized during this phase. Astroglial involvement was confirmed by an increase in glial fibrillary acidic protein (GFAP); concurrent proteolysis was also observed, possibly mediated by calpain. Levels of AQP-4 and Cx-43 were elevated in the fourth week post-STZ, possibly accelerating the clearance of extracellular proteins, since these proteins actively participate in the glymphatic system. Moreover, although we did not see a functional disruption of the blood-brain barrier (BBB) at this time, claudin 5 (present in the TJ of the BBB) and claudin 2 (present in the TJ of the blood-cerebrospinal fluid barrier) were reduced. Taken together, data support a role for astrocytes in STZ brain damage, and suggest that astroglial dysfunction accompanies or precedes neuronal damage in AD.

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Objective: To evaluate the impact of a multicomponent physical exercise program on clinical variables associated with the glymphatic clearance system, sleep-awake patterns, and cognitive function in individuals with mild cognitive impairment or mild Alzheimer's disease. Methods: This is a single-center parallel randomized controlled trial involving pre- and post-intervention assessments. The intervention consists of a 12 (±3)-week multicomponent aerobic and resistance physical exercise program of moderate intensity divided into 2 groups: an experimental group (undergoing multicomponent training) and a control group (no intervention). Eligible participants are those diagnosed with probable mild cognitive impairment or mild Alzheimer's disease. Expected results: Anticipated outcomes suggest that the multicomponent training protocol, incorporating both aerobic and resistance physical exercises at a moderate intensity, will yield improvements in glymphatic clearance dynamics, sleep-awake parameters, and performance on cognitive, functional, and behavioral tasks among eligible patients. Relevance: The need to move beyond cognitive clinical testing justifies our trial, which proposes an assessment employing neuroimaging techniques and the analysis of biomarkers present in cerebrospinal fluid in conjunction with clinical tests for physical and cognitive assessment. (AU)

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BACKGROUND AND PURPOSE: Recent studies have suggested an association between dysfunction of the choroid plexus and the glymphatic system. However, information is inconclusive. Following a population-based study design, we aimed to assess the association between choroid plexus calcifications (CPCs)-as a surrogate of choroid plexus dysfunction-and severity and progression of putative markers of glymphatic dysfunction, including white matter hyperintensities (WMH) of presumed vascular origin and abnormally enlarged basal ganglia perivascular spaces (BG-PVS). METHODS: This study recruited community-dwellers aged ≥40 years living in neighboring Ecuadorian villages. Participants who had baseline head CTs and brain MRIs were included in cross-sectional analyses and those who additional had follow-up MRIs (after a mean of 6.4 ± 1.5 years) were included in longitudinal analyses. Logistic and Poisson regression models, adjusted for demographics and cardiovascular risk factors, were fitted to assess associations between CPCs and WMH and enlarged BG-PVS severity and progression. RESULTS: A total of 590 individuals were included in the cross-sectional component of the study, and 215 in the longitudinal component. At baseline, 25% of participants had moderate-to-severe WMH and 27% had abnormally enlarged BG-PVS. At follow-up, 36% and 20% of participants had WMH and enlarged BG-PVS progression, respectively. Logistic regression models showed no significant differences between CPCs volumes stratified in quartiles and severity of WMH and enlarged BG-PVS. Poisson regression models showed no association between the exposure and WMH and enlarged BG-PVS progression. Baseline age remained significant in these models. CONCLUSIONS: Choroid plexus calcifications are not associated with putative markers of glymphatic system dysfunction.

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S100B is a 21-kDa protein that is produced and secreted by astrocytes and widely used as a marker of brain injury in clinical and experimental studies. The majority of these studies are based on measurements in blood serum, assuming an associated increase in cerebrospinal fluid and a rupture of the blood-brain barrier (BBB). Moreover, extracerebral sources of S100B are often underestimated. Herein, we will review these interpretations and discuss the routes by which S100B, produced by astrocytes, reaches the circulatory system. We discuss the concept of S100B as an alarmin and its dual activity as an inflammatory and neurotrophic molecule. Furthermore, we emphasize the lack of data supporting the idea that S100B acts as a marker of BBB rupture, and the need to include the glymphatic system in the interpretations of serum changes of S100B. The review is also dedicated to valorizing extracerebral sources of S100B, particularly adipocytes. Furthermore, S100B per se may have direct and indirect modulating roles in brain barriers: on the tight junctions that regulate paracellular transport; on the expression of its receptor, RAGE, which is involved in transcellular protein transport; and on aquaporin-4, a key protein in the glymphatic system that is responsible for the clearance of extracellular proteins from the central nervous system. We hope that the data on S100B, discussed here, will be useful and that it will translate into further health benefits in medical practice.

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PURPOSE: Hydrocephalus is a multifactorial neurological disorder and one of the most common neurosurgical conditions characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain's ventricles. It can result in dilatation of the ventricular system caused by the inadequate passage of CSF from its point of production within the ventricles to its point of absorption into the systemic circulation. Recent findings on the genetics and molecular studies of hydrocephalus have the potential to improve treatment and quality of life. METHODS: Review of literature on the novel studies of the pathogenesis of hydrocephalus. CONCLUSION: Molecular studies on the pathogenesis of hydrocephalus have provided a means to improve the treatment and follow-up of patients with hydrocephalus.

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Pneumococcal meningitis, inflammation of the meninges due to an infection of the Central Nervous System caused by Streptococcus pneumoniae (the pneumococcus), is the most common form of community-acquired bacterial meningitis globally. Aquaporin 4 (AQP4) water channels on astrocytic end feet regulate the solute transport of the glymphatic system, facilitating the exchange of compounds between the brain parenchyma and the cerebrospinal fluid (CSF), which is important for the clearance of waste away from the brain. Wistar rats, subjected to either pneumococcal meningitis or artificial CSF (sham control), received Evans blue-albumin (EBA) intracisternally. Overall, the meningitis group presented a significant impairment of the glymphatic system by retaining the EBA in the CSF compartments compared to the uninfected sham group. Our results clearly showed that during pneumococcal meningitis, the glymphatic system does not function because of a detachment of the astrocytic end feet from the blood-brain barrier (BBB) vascular endothelium, which leads to misplacement of AQP4 with the consequent loss of the AQP4 water channel's functionality. IMPORTANCE The lack of solute drainage due to a dysfunctional glymphatic system leads to an increase of the neurotoxic bacterial material in the CSF compartments of the brain, ultimately leading to brain-wide neuroinflammation and neuronal damage with consequent impairment of neurological functions. The loss of function of the glymphatic system can therefore be a leading cause of the neurological sequelae developing post-bacterial meningitis.

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Resumen La hidrocefalia es un problema de salud frecuente en pediatría, en particular durante el primer mes de vida. La incidencia en América Latina es una de las más altas del mundo. En Colombia no existen datos representativos sobre la incidencia real de esta enfermedad. Recientes hallazgos relacionados con la dinámica del líquido cefalorraquídeo permitieron proponer nuevos modelos sobre la fisiopatología de la hidrocefalia que, junto con los hallazgos en la Resonancia Magnética, han llevado a tener una mejor comprensión de la enfermedad. El objetivo de este articulo es realizar una revisión de la información disponible en la literatura sobre los avances en la fisiopatología de la enfermedad y los hallazgos en neuroimágenes, además de realizar una breve revisión sobre el papel de estas en el diagnóstico y seguimiento de los pacientes. Se realizó una revisión bibliográfica con términos MeSH, en las bases de datos de PUBMED, OVID y SCOPUS con artículos publicados en los últimos 6 años, seleccionado un total de 30 artículos que abordaron el tema de forma integral. Los nuevos hallazgos descritos como lo son el sistema glinfático y el papel de las AQP4 y los avances en las neuroimágenes, sobre todo de la resonancia magnética, han ayudado a comprender mejor esta entidad, apoyando el desarrollo de un nuevo modelo de la dinámica del líquido cefalorraquídeo y a partir de él diferentes explicaciones sobre la fisiopatología. MÉD.UIS.2022;35(1): 17-29.

Abstract Hydrocephalus is a frequent health problem in pediatrics, particularly during the first month of life. The incidence in Latin America is one of the highest in the world. In Colombia there are no representative data. Recent findings related to the dynamics of cerebrospinal fluid allowed proposals of new models on the pathophysiology of hydrocephalus that, along with new findings on MRI, have led to a better understanding of the disease. The aim of this work is to review the information available in the literature about the progress in the pathophysiology of the disease and neuroimaging findings, in addition to conducting a brief review on the role of these in the diagnosis and follow-up of patients. A bibliographic review with MeSH terms was carried out in PUBMED, OVID and SCOPUS databases, with articles published in the last 6 years. 30 articles that dealt with the theme in a comprehensive way were included. New findings described as the glymphatic system and the role of AQP4, along with advances in neuroimaging, especially MRI, have helped to better understand hydrocephalus, supporting the development of a new model of cerebrospinal fluid dynamics, and based on it, different explanations regarding its pathophysiology. MÉD.UIS.2022;35(1): 17-29.

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BACKGROUND: An important feature of hydrocephalus is the alteration of the cerebral spinal fluid (CSF) homeostasis. New insights in the understanding of production, secretion, and absorption of CSF, along with the discovery of the glymphatic system (GS), can be useful for a better understanding and treatment of hydrocephalus in disorders with CSF overproduction. CASE DESCRIPTION: A 1-year-old patient was diagnosed with communicating hydrocephalus; ventricle peritoneal shunt (VPS) is installed and ascites developed. VPS is exposed, yielding volumes of 1000-1200ml/day CSF per day. MRI is performed showing generalized choroidal plexus hyperplasia. Bilateral endoscopic coagulation of thechoroid plexus was performed in 2 stages (CPC) however the high rate of CSF production persisted, needing a bilateral plexectomy through septostomy, which finally decreased the CSF outflow. DISCUSSION: New knowledge about the CSF physiology will help to propose better treatment depending on the cause of the hydrocephalus. The GS is becoming an additional reason to better study and develop new therapies focused of the modulation of alternative CSF reabsorption. CONCLUSION: Despite the current knowledge about hydrocephalus, we remain without a complete understanding of the pathophysiology of this condition. GS could be more important than conventional concept of reabsorption of CSF in the arachnoid villi, therefore GS could be a new key point, which will guide future investigations.

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This article discusses the role that melatonin may have in the prevention and treatment of Parkinson's disease (PD). In parkinsonian patients circulating melatonin levels are consistently disrupted and the potential therapeutic value of melatonin on sleep disorders in PD was examined in a limited number of clinical studies using 2-5 mg/day melatonin at bedtime. The low levels of melatonin MT1 and MT2 receptor density in substantia nigra and amygdala found in PD patients supported the hypothesis that the altered sleep/wake cycle seen in PD could be due to a disrupted melatonergic system. Motor symptomatology is seen in PD patients when about 75% of the dopaminergic cells in the substantia nigra pars compacta region degenerate. Nevertheless, symptoms like rapid eye movement (REM) sleep behavior disorder (RBD), hyposmia or depression may precede the onset of motor symptoms in PD for years and are index of worse prognosis. Indeed, RBD patients may evolve to an α-synucleinopathy within 10 years of RBD onset. Daily bedtime administration of 3-12 mg of melatonin has been demonstrated effective in RDB treatment and may halt neurodegeneration to PD. In studies on animal models of PD melatonin was effective to curtail symptomatology in doses that allometrically projected to humans were in the 40-100 mg/day range, rarely employed clinically. Therefore, double-blind, placebo-controlled clinical studies are urgently needed in this respect.

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Sleep occupies roughly one-third of human lives, yet it is still not entirely scientifically clear about its purpose or function. However, the latest research achievement concluded that sleeping has much more effect on the brain than formerly believed. Much of these studies are about the effects of sleep deprivation, and the glymphatic pathway initially identified in the rodent brain. In this paper, it is presented some of the theories about sleep functions, besides a review of some physiologic function of sleep. Now, it is accepted that sleep is involved with cleaning the brain toxins, physical restoration, information processing and recall, regulation, besides strengthening the immune system. Sleep implies in a neuronal activity markedly different along with its phases. It is regulated by two parallel mechanisms, homeostatic and circadian. Besides, the sleep-waking cycle involves diverse brain circuits and neurotransmitters and their interaction is explained using a flip-flop model. Several theories may help clarify the reasons human beings spend an important part of their lives sleeping such as those of Inactivity, Energy Conservation, Restorative, and Brain Plasticity. Recently, it was emphasized the importance of the glymphatic system that is a waste clearence system that acts mainly during sleep support efficient removal of soluble proteins and metabolites from the central nervous system. Indeed, sleep meet the needs of higher brain functions along with basic vital processes.

O sono ocupa cerca de um terço da vida humana, mas ainda não é totalmente claro cientificamente o seu propósito ou função. No entanto, a mais recente pesquisa concluiu que dormir tem muito mais efeito no cérebro do que se pensava anteriormente. Muitos desses estudos são sobre os efeitos da privação do sono e o sistema glinfático inicialmente identificada no cérebro de roedores. Neste artigo, são apresentadas algumas das teorias sobre as funções do sono, além de uma revisão de algumas funções fisiológicas do sono. Agora, aceita-se que o sono esteja envolvido com a limpeza de toxinas cerebrais, restauração física, processamento e memorização de informações, regulação do humor, além de fortalecer o sistema imunológico. O sono implica em uma atividade neuronal marcadamente diferente ao longo de suas fases. É regulado por dois mecanismos paralelos, homeostático e circadiano. Além disso, o ciclo de vigília envolve diversos circuitos cerebrais e neurotransmissores e sua interação é explicada por meio de um modelo de flip-flop. Várias teorias podem ajudar a esclarecer as razões pelas quais o ser humano passa uma parte importante de suas vidas dormindo, como as de inatividade, conservação de energia, restauração e plasticidade cerebral. Recentemente, enfatizou-se a importância do sistema glinfático agir principalmente durante o sono, que é um sistema de eliminação de resíduos para apoiar a remoção eficiente de proteínas e metabólitos solúveis do sistema nervoso central. De fato, o sono atende às necessidades de funções cerebrais superiores, juntamente com processos vitais básicos.

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Prevention of neurodegenerative diseases is presently a major goal for our Society and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. Melatonin combines both chronobiotic and cytoprotective properties. As a chronobiotic, melatonin can modify phase and amplitude of biological rhythms. As a cytoprotective molecule, melatonin reverses the low degree inflammatory damage seen in neurodegenerative disorders and aging. Low levels of melatonin in blood characterizes advancing age. In experimental models of Alzheimer's disease (AD) and Parkinson's disease (PD) the neurodegeneration observed is prevented by melatonin. Melatonin also increased removal of toxic proteins by the brain glymphatic system. A limited number of clinical trials endorse melatonin's potentiality in AD and PD, particularly at an early stage of disease. Calculations derived from animal studies indicate cytoprotective melatonin doses in the 40-100 mg/day range. Hence, controlled studies employing melatonin doses in this range are urgently needed. The off-label use of melatonin is discussed.

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The brain represents 2% of the adult body mass; conversely, it is responsible for 20% to 25% of the glucose and 20% of the oxygen consumption, receiving 15% of the cardiac output. This substantial metabolic rate is associated with a significant production of biological debris, which is potentially toxic. Therefore, a complex and efficient clearance system is required to prevent the accumulation of byproducts and ensure optimal function. However, until today, there is little knowledge about this topic. The glymphatic system, also known as perivascular pathway, is a recently described glialdependent network that is responsible for the clearance of metabolites from the central nervous system (CNS), playing a role equivalent to the one played by the lymphatic vessels present in other organs. Studies have demonstrated that the glymphatic pathway has a paramount role in protein homeostasis, and that the malfunction of this system may be related to the development of neurodegenerative disorders such as Alzheimer disease and normal pressure hydrocephalus. They also showed that body posture, exercise and the state of consciousness influence the glymphatic transport. In this context, the understanding of this clearance system could not only clarify the pathophysiology of several diseases, but also contribute to future therapeutic interventions. In the present article, we will evaluate the glymphatic pathway, focusing on the factors that regulate its flow, as well as on its role in CNS physiology and in disease initiation and progression, including dementia, hydrocephalus, glaucoma and traumatic brain injury. Ultimately, this review also aims to encourage further research on novel therapeutic targets.

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In contrast to virtually all organ systems of the body, the central nervous system was until recently believed to be devoid of a lymphatic system. The demonstration of a complex system of paravascular channels formed by the endfeet of astroglial cells ultimately draining into the venous sinuses has radically changed this idea. The system is subsidized by the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma along paravascular spaces (PVSs) and by exchanges with the interstitial fluid (IF). Aquaporin-4 channels are the chief transporters of water through these compartments. This article hypothesizes that glymphatic dysfunction is a major pathogenetic mechanism underpinning idiopathic intracranial hypertension (IIH). The rationale for the hypothesis springs from MRI studies, which have shown many signs related to IIH without evidence of overproduction of CSF. We propose that diffuse retention of IF is a direct consequence of an imbalance of glymphatic flow. This imbalance, in turn, may result from an augmented flow from the arterial PVS into the IF, by impaired outflow of the IF into the paravenous spaces, or both. Our hypothesis is supported by the facts that (i) visual loss, one of the main complications of IIH, is secondary to the impaired drainage of the optic nerve, a nerve richly surrounded by water channels and with a long extracranial course in its meningeal sheath; (ii) there is a high association between IIH and obesity, a condition related to paravascular inflammation and lymphatic disturbance, and (iii) glymphatic dysfunction has been related to the deposition of ß-amyloid in Alzheimer's disease. We conclude that the concept of glymphatic dysfunction provides a new perspective for understanding the pathophysiology of IIH; it may likewise entice the development of novel therapeutic approaches aiming at enhancing the flow between the CSF, the glymphatic system, and the dural sinuses.