Effects of physical exercise on cognition and glymphatic system of patients with mild cognitive impairment or Alzheimer's disease ­ study protocol

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)

Updated Understanding of the Glial-Vascular Unit in Central Nervous System Disorders / 神经科学通报·英文版

The concept of the glial-vascular unit (GVU) was raised recently to emphasize the close associations between brain cells and cerebral vessels, and their coordinated reactions to diverse neurological insults from a "glio-centric" view. GVU is a multicellular structure composed of glial cells, perivascular cells, and perivascular space. Each component is closely linked, collectively forming the GVU. The central roles of glial and perivascular cells and their multi-level interconnections in the GVU under normal conditions and in central nervous system (CNS) disorders have not been elucidated in detail. Here, we comprehensively review the intensive interactions between glial cells and perivascular cells in the niche of perivascular space, which take part in the modulation of cerebral blood flow and angiogenesis, formation of the blood-brain barrier, and clearance of neurotoxic wastes. Next, we discuss dysfunctions of the GVU in various neurological diseases, including ischemic stroke, spinal cord injury, Alzheimer's disease, and major depression disorder. In addition, we highlight the possible therapies targeting the GVU, which may have potential clinical applications.

The Exploration of Glymphatic System Alteration in Pediatric Acute Lymphoblastic Leukemia Using DTI-ALPS Method / 中山大学学报(医学科学版)

ObjectiveThe glymphatic system regulates cerebral spinal fluid and interstitial fluid transport which might be one of the pathways of central nervous system （CNS） leukemia at the early stage. This study aimed to investigate the alteration of glymphatic system based on diffusion tensor image-analysis along the perivascular space （DTI-ALPS） in pediatric acute lymphoblastic leukemia （ALL） without clinically diagnosed CNS infiltration. MethodsTwenty-five ALL and typically developing （TD） children were prospectively recruited， and all subjects underwent DTI. Group differences in brain water diffusivities and ALPS-index were evaluated using the analysis of covariance. The Spearman correlation analysis was used to evaluate the relationship between biological characteristics and significant parameters in pediatric ALL. ResultsCompared with TDs， decreased Dxassoc value （PFDR-corrected = 0.048） and increased Dzassoc value （PFDR-corrected = 0.033） were found in pediatric ALL. Hence， lower ALPS-index was found in children with ALL （PFDR-corrected < 0.001）. ALPS-index was negatively associated with the risk classification （rs = -0.47， P = 0.018） as well as immunophenotype （rs = -0.40， P = 0.046） in pediatric ALL. ConclusionsOur results show dysfunction of the glymphatic system is presented in pediatric ALL without clinically diagnosed CNS infiltration， which suggests that the glymphatic system might be one of pathway in the early-stage of ALL CNS infiltration. The DTI-ALPS method can be used to evaluate the change of glymphatic system， providing a new method for exploring the underlying mechanisms and early detection of pediatric ALL CNS infiltration.

Study on the correlation between cerebral glymphatic system dysfunction and motor dysfunction in patient with ischemic stroke / 实用放射学杂志

Objective To evaluate the activity of the cerebral glymphatic system during recovery in ischemic stroke(IS)patients with motor dysfunction,and to explore its association with motor function scores and corticospinal tract(CST)integrity via.Methods A total of 20 patients with IS(stroke group)and 20 healthy volunteer(control group)were recruited.There was a single lesion located at the left cerebral hemisphere in the stroke group.Demographic and clinical data of all participants were recorded.All participants underwent brain MRI scans,including diffusion tensor imaging(DTI)and T2WI.Diffusion tensor image analysis along the perivascular space(DTI-ALPS)index at lateral ventricle level,fractional anisotropy(FA)and axial diffusivity(AD)of CST were calculated and the differences of each index between the two groups were compared.The correlation between DTI-ALPS index and Fugl-Meyer score and integrity of CST were analyzed in stroke group,respectively.Results The DTI-ALPS index in the stroke group was significantly lower than that in the control group(t=-3.88,P＜0.001).The DTI-ALPS index in the stroke group was positively correlated with motor function score(P=0.019),motor function grading(P=0.024)and sensory score(P=0.048),respectively.The DTI-ALPS index was negatively correlated with FA(r=-0.60,P=0.009)and AD(r=-0.67,P=0.002)of healthy side CST.Conclusion The decrease of DTI-ALPS index in patients with IS indicates the damage of cerebral glymphatic system.DTI-ALPS index may be a potential MRI biomarker for motor dysfunction in patients with IS,and a new idea is proposed for the study of the pathophysiological mechanism of IS.

Glymphatic system functional changes of bilateral cerebral hemispheres in early-stage Parkinson disease patients complicated with unilateral limb motor symptoms / 中国医学影像技术

Objective To observe the glymphatic system functional changes of bilateral cerebral hemispheres in early-stage Parkinson disease(PD)patients complicated with unilateral limb motor symptoms.Methods A total of 52 early-stage PD patients complicated with unilateral limb motor symptoms were prospectively enrolled,including 21 cases of left-onset PD(LPD group),31 cases of right-onset PD(RPD group).Meanwhile,28 healthy individuals were recruited as healthy controls(HC group).Clinical data and indices of diffusion tensor imaging analysis along the perivascular space(DTI-ALPS)were compared among 3 groups and between each 2 groups.The correlations of DTI-ALPS indices and clinical scales were analyzed.Results Significant difference of Hamilton depression scale(HAMD)score was found among 3 groups(P＜0.05).HAMD score of LPD group and RPD group were higher than that of HC group(both P＜0.017).There were significant differences of left and right cerebral hemispheres DTI-ALPS(DTI-ALPS_L,DTI-ALPS_R)indices among 3 groups(both P＜0.05).DTI_ALPS_R in LPD group was lower than that in HC group(P＜0.017),and DTI_ALPS_L in RPD group was lower than that in HC group(P＜0.017).No obvious correlation of bilateral cerebral hemisphere DTI-ALPS indices with clinical scales was detected in PD patients(all P＞0.05).Conclusion Like that of motor symptoms,glymphatic system dysfunction of PD patients had characteristics of laterality,manifested as DTI_ALPS_R decreased in LPD patients while DTI_ALPS_L decreased in RPD patients.

Diffusion tensor imaging analysis along the perivascular space derived intracerebral glymphatic system circulatory function on neuromyelitis optica spectrum disorder: a follow-up study for curative effect / 中华放射学杂志

Objective:To evaluate the value of curative effect in neuromyelitis spectrum disease (NMOSD) based on circulatory function evaluation of intracerebral glymphatic system by using diffusion tensor imaging analysis along the perivascular space.Methods:The clinical and imaging data of 23 patients diagnosed with NMOSD at Tianjin Medical University General Hospital from March 2018 to December 2019 were retrospectively analyzed in this study. The clinical data included expanded disability status scale (EDSS), average relapse rate (ARR) and retinal nerve fiber layer (RNFL) thickness at baseline and 1 year follow-up after treatment. Among the 23 NMOSD patients, there were 22 females and 1 male, aged from 21 to 71 (45±13) years old. All the patients underwent MR scans at both baseline and 1 year after treatment, and the scanning sequences included cerebral 3D-T 1WI, T 2WI, diffusion tensor imaging and cervical spinal sagittal 3D-T 2WI, and the cervical spinal cord volume and bilateral diffusion tensor imaging analysis along the perivascular space index (ALPS index) were calculated. The partial correlation test was used to analyze the correlations between ALPS index and the clinical indicators such as EDSS, ARR, and bilateral RNFL, with the control variables as gender, age, years of education and course of disease. The multiple linear regression model was used to analyze the independent predictors for ALPS index and EDSS after treatment. Receiver operating characteristic curve (ROC) and area under the curve (AUC) were used to evaluate the diagnostic value of NMOSD treatment outcome by using ALPS index. Results:When controlling for gender, age, years of education and course of disease, there were significant negative correlations between right ALPS index and EDSS ( r=-0.50, P=0.048), bilateral average ALPS index and EDSS ( r=-0.53, P=0.034), left ALPS index and ARR ( r=-0.58, P=0.018), while there was significant positive correlations between right ALPS index and RNFL ( r=0.88, P=0.008) at 1 year follow-up after treatment. Multiple linear regression analysis showed that cervical spinal cord volume was an independent impact factor of bilateral average ALPS indexes (β=0.24, 95%CI 0.10-0.38, P=0.002), and bilateral average ALPS indexes (β=-3.22, 95%CI -5.97--0.48, P=0.024) and right RNFL (β=-0.05, 95%CI -0.08--0.02, P=0.002) at baseline were the independent impact factors of EDSS after treatment. ROC curve analysis showed that the bilateral average ALPS index at baseline had the best efficacy in predicting the curative effect of NMOSD patients with AUC=0.92. Conclusions:After treatment, NMOSD patients with severe clinical disability, high frequency of disease attack, poor visual performance, and severe cervical spinal cord atrophy have more serious impairment of intracerebral glymphatic system circulatory function. The ALPS index could help in predicting the clinical curative effect of NMOSD patients.

Effect of sleep on brain clearing metabolites: thinking based on lymphoid system / 中华神经科杂志

Disruption of the structure of regular sleep is a common cause of neurodegenerative diseases such as Alzheimer′s disease and Parkinson′s disease, and its pathogenesis may be related to the deposition of waste products in the central nervous system. The glymphatic pathway, which is essentially a periarterial cerebrospinal fluid inflow pathway and peripheral venous clearance pathway, is functionally dependent on interstitial bulk flow coupling supported by aquaporin-4 on the astrocyte end-foot, also known as the lymphoid glial system. The glymphatic pathway, which removes waste proteins from the brain, is active primarily during sleep, and sleep quality declines with age, while the glymphatic pathway system also deteriorates with age, suggesting a relationship between sleep disturbances and symptom progression in neurodegeneration, and glymphatic system as a link closely links the two. The interaction of sleep, aging, metabolic waste and glymphatic pathway reticulation provides new clues to the pathogenesis of central nervous system degenerative diseases, and the glymphatic pathway may constitute a new target on treatment. The recent research progress on the effects of sleep and sleep disorders on the circulation of the glymphatic system, and proposes the possibility of sleep intervention to slow down the impairment of the lymphoid system function or even restore the function of the lymphoid system and thus improve the disease development process were reviewed in this paper.

Research progress in the evaluation of glymphatic system function by the DTI-ALPS method / 中南大学学报(医学版)

The glymphatic system can remove metabolic wastes from the brain, which plays a significant role in maintaining the homeostasis of the central nervous system. It is an important basis for advanced cognitive functions such as learning and memory. Studies have analyzed the function of glymphatic system by diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) recently. Compared with other invasive examinations that require fluorescent tracer technique or the injection of contrast agents, DTI-ALPS can evaluate the hydromechanics of the glymphatic system via quantifying the diffusion rate of water molecules in different directions, which turns out to be a non-invasive in vivo neuroimaging method. The ALPS-index calculated by the DTI-ALPS method is significantly correlated with the cognitive function in diseases of central nervous system and other system and can reflect the dynamic changes of diseases. In general, ALPS-index is expected to become a novel neuroimaging biomarker for predicting prognosis and clinical effects.

Peripheral origin exosomal microRNAs aggravate glymphatic system dysfunction in diabetic cognitive impairment

Cognitive dysfunction is one of the common central nervous systems (CNS) complications of diabetes mellitus, which seriously affects the quality of life of patients and results in a huge economic burden. The glymphatic system dysfunction mediated by aquaporin-4 (AQP4) loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment (DCI). However, the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear. Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators. Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus, and skeletal muscle, liver and adipose tissue are the key target insulin resistance organs. In this review, the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed. We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet, which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI. Furthermore, the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized, which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.

Avances recientes en el diagnóstico imagenológico de la hidrocefalia en niños. Revisión de la literatura de los últimos seis años / Recent advances of the imagological diagnosis of hydrocephalus in children. Review of the literature of the last six years

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.

Glymphatic system in Parkinson′s disease / 中华神经科杂志

Parkinson′s disease is a degenerative disease of the central nervous system with abnormal protein deposition in the brain as the main pathological changes. The onset of Parkinson′s disease is related to abnormal deposition protein removal disorders, and the relevant mechanisms are still unclear. The glymphatic system is a metabolic waste and abnormal protein deposition removal system in the brain. In recent years, studies have shown that the changes of aquaporin 4, perivascular space and dural lymphatic vessels in Parkinson′s disease are closely related to the level of relevant pathological proteins in cerebrospinal fluid, leading to the occurrence and development of Parkinson′s disease. The researches on structure and biomarkers of the glymphatic system in Parkinson′s disease in recent years are reviewed in this article.

Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion / 神经科学通报·英文版

The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.

Glymphatic system and cerebral edema after ischemic stroke / 国际脑血管病杂志

Glymphatic system is a fluid transport and material clearance system found in recent years. It promotes the flow and exchange of cerebrospinal fluid and interstitial fluid, remove metabolic waste, and maintain the stability of the internal environment of the brain through the perivascular space and aquaporin 4 on astrocytes. Recent studies have shown that the glymphatic system plays an important role in the intake and discharge of the fluid in brain, and the changes of glymphatic system may be an important reason for brain edema after ischemic stroke. This article reviews the pathophysiological mechanism and related therapeutic targets of glymphatic system in the formation of cerebral edema after ischemic stroke, in order to provide new ideas for the treatment of cerebral edema after ischemic stroke.

Recent advance in application of neuroimaging techniques in the glymphatic system / 中华神经医学杂志

The glymphatic system is a fluid dynamics network that is important for maintaining homeostasis of the brain, and it is also a new target for the treatment of various central nervous system diseases. The crucial point regarding research into the glymphatic system is the microhydrodynamics of the cerebrospinal fluid tracer. This review summarizes the emerging technologies, such as magnetic resonance technology, two photon microscopic imaging technology, near infrared fluorescence imaging technology, and transcranial macroscopic imaging, and summarizes its research applications and technical advantages to provide methodological strategies for basic and clinical research on glymphatic system function.

Recent advance in quantitative MRI in glymphatic systems of the brain / 中华神经医学杂志

The glymphatic system, as "waste" clearance pathway in the brain, plays a critical role in maintaining the homeostasis of the brain cell microenvironment. It has been found that changes in the glymphatic system are common in many neurological diseases. MRI is currently the only technology that can achieve human glymphatic imaging, and has the advantages of high soft tissue resolution and sensitivity to tracers. Quantitative MRI can objectively evaluate the changes of inflow and outflow of glymphatic system. Therefore, in this review, we introduce the application of quantitative MRI technology in the glymphatic system in detail, aiming to provide help for the diagnosis and treatment of diseases related to glymphatic system.

Recent advance in role of glymphatic system in diabetes-related cognitive dysfunction / 中华神经医学杂志

Recently, an increasing number of studies have shown that the glymphatic system is damaged in diabetes and is closely associated with diabetes-related cognitive dysfunction. In this review, we describe the direct and indirect effects of diabetes on the glymphatic system and summarize the relevant evidence in imaging studies in order to promote the understanding of this field.

Evaluation of brain glymphatic system function in patients with multiple sclerosis based on diffusion tensor imaging / 中华神经医学杂志

Objective:To investigate the changes of glymphatic system function at relapse and remission phases in patients with relapsing remitting multiple sclerosis (RRMS) and their relations with clinical parameters.Methods:Sixteen patients with RRMS at relapsing phase and 25 patients with RRMS at remitting phase, admitted to Department of Neurology, First Affiliated Hospital of Nanchang University from September 2012 to December 2020, were enrolled; and 29 normal controls were recruited at the same period in Physical Examination Center the same hospital. The diffusion tensor imaging data were analyzed retrospectively, and the along perivascular space (ALPS) index was calculated. The differences in clinical data and ALPS index among the 3 groups were compared, and the correlations between ALPS index and clinical parameters in RRMS patients were analyzed.Results:The scores of expanded disability status scale (EDSS) and modified fatigue impact scale (MFIS) in patients at relapsing phase were significantly higher than those in patients at remitting phase ( P<0.05). The ALPS index in bilateral cerebral hemispheres in the control group was significantly higher than that in RRMS patients at relapse and remission phases ( P<0.05). In patients with RRMS at relapse phase, the ALPS index in the left cerebral hemisphere was negatively correlated with disease duration and EDSS scores ( r=-0.536, P=0.032; r=-0.573, P=0.020). Conclusion:Patients with RRMS have glymphatic system dysfunction; this dysfunction may be the potential pathological basis of clinical dysfunction in patients with RRMS at relapsing phase.

The process in research of anatomy of brain lymphatic system and the relationship between it and Alzheimer's disease / 中华显微外科杂志

Conventional wisdom holds that the central nervous system (CNS) does not have lymphatic vessels or lymphatic circulation, and it lacks lymphatic pathways to clear brain metabolites. However, with the development of study in intracranial clearance, it has been discovered that there are lymphatic systems in CNS, including glymphatic pathway and it meningeal lymphatic vessels. It further reveals the exchange system between cerebrospinal fluid (CSF) and interstitial fluid (ISF). It also closely relates to the development of neurodegenerative diseases, age-related changes of brain, traumatic brain injury, circulatory diseases and tumors. In the past 10 years, the research in CNS has been a hot spot in life sciences. This article aims to explain the research progress from the aspects of the discovery of glymphatic system, anatomical structure and function, and relationship with Alzheimer's disease (AD).

The glymphatic system: a new exploration of the clearance of alpha-synuclein in Parkinson′s disease / 中华神经科杂志

Parkinson′s disease (PD) is a common neurodegenerative disease. Impaired balance between deposition and clearance of α-synuclein lies at the core of PD pathogenesis. The glymphatic system is a highly organized fluid transport system that is capable of removing brain waste. Emerging evidence revealed that glymphatic dysfunction plays a critical role in the pathogenesis of neurodegenerative diseases, yet study on its implication in PD is at its early stage. An in-depth study of the relationship between the function of the glymphatic system and α-synuclein clearance in PD may shed light on the pathogenesis and therapeutics of the disease.

Recent advance of aquaporin-4 in neurodegenerative diseases / 中华神经科杂志

Neurodegenerative disease is a type of disease characterized by the progressive loss of neurons, the cause of which is not clear. Aquaporin-4 (AQP4) is a member of the aquaporin family, which plays an important role in maintaining water homeostasis in the brain. In recent years, researchers found that AQP4 has the functions of draining brain metabolic wastes and participating in material exchange through the glmphatic system. This review aims to summarize the current researches of AQP4 in the pathogenesis and progression of neurodegenerative diseases such as Parkinson′s disease and Alzheimer′s disease, and to propose future research directions.