scholarly journals Glial Associated Impairment of the Glymphatic System in Experimental Neonatal Hydrocephalus

2021 ◽  
Author(s):  
Joseph Tyler Vasas ◽  
James Pat McAllister ◽  
Ramin Eskandari
Keyword(s):  
Immunofluorescent Staining ◽  
Perivascular Spaces ◽  
Glymphatic System ◽  
Aqp4 Expression ◽  
Treatment Groups ◽  
Gfap Expression ◽  
Kaolin Injection ◽  
Late Treatment ◽  
Feline Model ◽  
Glial Scarring

Abstract Background Changes in aquaporin-4 (AQP4) and glial fibrillary acid protein (GFAP) expression by astrocytes have been observed in several pathologies. It is hypothesized that prolonged exposure to pathologically elevated intracranial pressure (ICP) may be linked to impaired glymphatic pathways. In this study we explore histological consequences of prolonged pressure-induced injury in a feline model of neonatal hydrocephalus through changes in AQP4 and GFAP expression. We discuss the implications this may have in gaining a better understanding of the underlying mechanisms of hydrocephalus (HCP). Methods Using a neonatal feline model, obstructive HCP was induced through kaolin injection into the cisterna magna. Time between injection and intervention via ventricular reservoir placement was used to divide groups into early and late treatment groups. Early and late animals received reservoirs at 1- and 2-weeks post kaolin injection, respectively. Controls underwent sham operations (saline injection instead of kaolin). Animals were sacrificed at 4 months allowing for a chronic treated hydrocephalic model at time of brain harvest. Immunofluorescent staining for GFAP, AQP4 and DAPI was performed on histological brain sections from each group, and densitometry was used to quantify the relative signal of protein expression. Results Hydrocephalus was seen in all animals receiving kaolin injection as demonstrated by magnetic resonance imaging, clinical examination and neurological sequelae. Hydrocephalic animals demonstrated lower levels of perivascular AQP4 expression, increased diffuse AQP4 expression and increased glial scarring of perivascular, ependymal and subependymal spaces. Cerebral microvasculature of early treatment groups demonstrated increased astrocytic processes in the perivascular spaces, while late treatment groups demonstrated increased glial scar formation. Overall, the glymphatic system was severely disrupted in chronic treated hydrocephalus compared to controls. Conclusions Reactive astrogliosis and AQP4 mislocation are evident in early and late reservoir-treated HCP. Glial scarring in the perivascular, ependymal and subependymal spaces concurrent with AQP4 internalization from the perivascular region are prominent in HCP conditions present within the neonatal period. Delay in treatment by 1 week demonstrates quantifiable increases in perivascular and ependymal glial scarring at 4 months of age. Further investigation is needed to correlate glymphatic disruption with impaired CSF absorption and its role in promoting progressive hydrocephalus.

scholarly journals Diffusion Tensor Imaging Along the Perivascular Space Index in Different Stages of Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Xinxin Ma ◽  
Shuhua Li ◽  
Chunmei Li ◽  
Rui Wang ◽  
Min Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Diffusion Tensor ◽  
Multivariate Logistic Regression Analysis ◽  
Perivascular Space ◽  
Periventricular White Matter ◽  
Perivascular Spaces ◽  
Glymphatic System ◽  
Multiple Variables ◽  
Association Fibers

Background: The aim of this study was to evaluate the glymphatic system activity in patients with Parkinson’s disease (PD) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) methods.Methods: In total, 71 patients with idiopathic PD and 36 age- and sex-matched normal controls (NCs) were involved. Patients with PD were divided into early (n = 35) and late (n = 36) subgroups, based on Hoehn and Yahr (HY) stages. We calculated the diffusivity along the perivascular spaces (ALPS), as well as projection fibers and association fibers separately, to acquire the ALPS index. Enlarged perivascular spaces (EPVS) and periventricular white matter hyperintensities were also rated. Differences in ALPS index between the PD group and NCs and between two PD subgroups and NCs were compared. In addition, a multivariate logistic regression analysis was conducted to investigate the association between ALPS index and clinical variables.Results: Patients with PD revealed lower ALPS index than NCs (p = 0.010). The late PD group exhibited significantly lower ALPS index than NCs (p = 0.006). However, there were no marked differences noticed in ALPS index between NCs and early PD group and between the two PD subgroups. In the early PD group, there was a significantly positive correlation between ALPS index and Mini-Mental State Examination (MMSE) score (β = 0.021, p = 0.029) and a negative correlation between ALPS index and EPVS score (β = −0.050, p = 0.034), after controlling for multiple variables. In the late PD group, ALPS index was inversely associated with age (β = −0.012, p = 0.004).Conclusion: Impairment of the glymphatic system is involved in PD. DTI-ALPS index could be a promising biomarker of glymphatic system in PD.

scholarly journals Vitamin D and Calcium Milk Fortification in Pregnant Women with Periodontitis: A Feasibility Trial

2020 ◽  
Vol 17 (21) ◽  
pp. 8023
Author(s):  
Amanda Rodrigues Amorim Adegboye ◽  
Danilo Dias Santana ◽  
Paula Guedes Cocate ◽  
Camila Benaim ◽  
Pedro Paulo Teixeira dos Santos ◽  
...  
Keyword(s):  
Vitamin D ◽  
Pregnant Women ◽  
Low Income ◽  
Retention Rate ◽  
Recruitment Rate ◽  
Feasibility Trial ◽  
Random Allocation ◽  
Treatment Groups ◽  
Late Treatment ◽  
Participant Flow

This study aims to assess the acceptability, adherence, and retention of a feasibility trial on milk fortification with calcium and vitamin D (Ca + VitD) and periodontal therapy (PT) among low income Brazilian pregnant women with periodontitis (IMPROVE trial). This 2 × 2 factorial feasibility trial used a mixed-methods evaluation. In total, 69 pregnant women were randomly allocated to four groups: 1. fortified sachet with Ca+VitD and milk plus early PT (throughout gestation); 2. placebo and milk plus early PT; 3. fortified sachet with Ca+VitD and milk plus late PT after childbirth; 4. placebo and milk plus late PT. Data were collected via questionnaires, field notes, participant flow logs, treatment diary, and focal group discussions. Quantitative and qualitative data were analysed using appropriate descriptive statistics and content analysis, respectively. Eligibility rate (12%) was below the target of 15%, but participation (76.1%) and recruitment rate (2 women/week) exceeded the targets. Retention rate (78.6%) was slightly below the target (80%). Adherence to the PT was significantly higher in the early treatment groups (98.8%) compared to the late treatment groups (29%). All women accepted the random allocation, and baseline groups were balanced. There was no report of adverse events. This multi-component intervention is acceptable, well-tolerated, and feasible among low-risk pregnant women in Brazil.

MO216PRELIMINARY STUDY OF THE GLYMPHATIC SYSTEM IN CKD

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Veronica Buonincontri ◽  
Davide Viggiano ◽  
Giovambattista Capasso
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Diffusion Tensor ◽  
Human Subjects ◽  
Water Diffusion ◽  
Perivascular Spaces ◽  
Glymphatic System ◽  
Ckd Stage

Abstract Background and Aims The glymphatic system is a network of extracellular spaces between neurons, glial cells, and capillaries that promotes the elimination of soluble molecules from the brain. Its dysfunction is probably relevant for neurodegenerative diseases such as Alzheimer's disease (AD). It is widely accepted that cognitive impairment accompanies chronic kidney disease (CKD). CKD is also a risk factor for dementia. However, the role of the glymphatic system in this process is unknown. A recent method to study the glymphatic system in human subjects has been proposed based on Diffusion Tensor Imaging (DTI) data and water diffusion calculation along with perivascular spaces. This approach is based on calculating a diffusion index named ALPS and showed that the glymphatic flow is reduced in MCI. Method To analyze the role of glymphatic system in CKD patients, we took advantage of the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI is a longitudinal multicenter study helping researchers to monitor Alzheimer's disease and Mild Cognitive Impairment (MCI) progression. This database has a cohort of control patients and MCI patients, among which several patients with CKD stage II-III were identifiable from the creatinine values. Patients with Alzheimer's disease were excluded for this study. Among the control and MCI patients, we identified 12 CKD patients and pair-matched 12 non-CKD patients comparable for age, gender, and MoCA score. Magnetic resonance data with DTI sequences were retrieved for all patients, and the glymphatic system was characterized by the ALPS index. Tensor values were calculated using the FSL software; the diffusion values were calculated on tensor images using the ImageJ software. Differences in ALPS between CKD and non-CKD patients with and without MCI were tested. Results Analysis of DTI data confirmed that control patients without CKD had lower ALPS values when MCI was present compared to the non-MCI patients, suggesting a reduction of water diffusion in the glymphatic system. However, the presence of CKD had a different effect: in the absence of MCI, CKD did not modify ALPS values compared to non-CKD patients. At variance, in patients with MCI, CKD resulted in a significant increase of water diffusion in the glymphatic system compared to the controls. Conclusion In this preliminary study, MCI and CKD exerted opposite effects on the diffusion of water within the glymphatic system: MCI was accompanied by a reduction of water diffusion whereas CKD by an increased diffusion in the glymphatic spaces. It is possible that small modification of water balance in CKD may be responsible for the increased diffusion of water in glymphatics in CKD. Further studies are needed to verify whether this unexpected phenomenon may modify cognitive function with a mechanism rather different from Alzheimer's disease.

Cervical Central Canal Occlusion Induces Noncommunicating Syringomyelia

Neurosurgery ◽  
2012 ◽  
Vol 71 (1) ◽  
pp. 126-137 ◽  
Author(s):  
Yongjie Zhang ◽  
Yi Ping Zhang ◽  
Lisa B.E. Shields ◽  
Yiyan Zheng ◽  
Xiao-Ming Xu ◽  
...  
Keyword(s):  
Cervical Spinal Cord ◽  
Central Canal ◽  
Single Site ◽  
Aquaporin 4 ◽  
Therapeutic Interventions ◽  
Sprague Dawley ◽  
Adult Rats ◽  
Aqp4 Expression ◽  
Kaolin Injection ◽  
Dorsal Columns

Abstract BACKGROUND: Mechanisms underlying the development of noncommunicating syringomyelia are poorly understood. OBJECTIVE: To assess the influence of focal arachnoiditis and central canal (CC) occlusion (CCO) on the formation of noncommunicating syringomyelia in the adult rat cervical spinal cord. Expression of pericanalicular aquaporin-4 is also examined. METHODS: Sprague-Dawley rats were subjected to circumferential or dorsal arachnoiditis (n = 34). Rats undergoing CCO (n = 69) were divided into 4 groups: group A, kaolin injection at a single site in the dorsal columns near the CC; group B, kaolin injection at multiple sites in the dorsal columns near the CC; group C, saline injection at multiple sites in the dorsal columns near the CC; or group D, controls. Rats were killed at 1, 4, 8, and 12 weeks. The CC area and aquaporin-4 (AQP4) expression were measured at the level of maximal CC enlargement. RESULTS: Circumferential and dorsal arachnoiditis induced a mild increase in the CC area at 12 weeks. Single-site CCO induced slight CC enlargement. In contrast, multiple sites of CCO in proximity frequently induced a major expansion of the CC area (up to 50 times). Increased AQP4 expression was observed in pericanalicular astrocytes proportional to the degree of CC expansion. CONCLUSION: Multiple sites of CCO created a model of noncommunicating syringomyelia in adult rats. Increased astrocytic AQP4 expression was proportional to the degree of CC expansion. Modulation of aquaporin expression may be a novel target for therapeutic interventions to prevent syringomyelia.

scholarly journals Associations Among Diffusion Tensor Image Along the Perivascular Space (DTI-ALPS), Enlarged Perivascular Space (ePVS), and Cognitive Functions in Asymptomatic Patients With Carotid Plaque

2022 ◽  
Vol 12 ◽  
Author(s):  
Hui Liu ◽  
Shuai Yang ◽  
Wei He ◽  
Xiaojuan Liu ◽  
Shanyi Sun ◽  
...  
Keyword(s):  
Cerebrovascular Disease ◽  
Carotid Plaque ◽  
Diffusion Tensor ◽  
Perivascular Space ◽  
Diffusion Tensor Image ◽  
Perivascular Spaces ◽  
Glymphatic System ◽  
Significant Difference ◽  
The Brain ◽  
Normal Controls

Background and Aim: Carotid atherosclerosis (CAS) is a common pathogenesis of cerebrovascular disease closely related to stroke and silent cerebrovascular disease (SCD), while the insufficient brain perfusion mechanism cannot quite explain the mechanism. The purpose of this study was to utilize diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate the glymphatic system activity and correlated DTI-ALPS with enlarged perivascular spaces (ePVS), carotid intima-media thickening (CIMT), mini-mental state examination (MMSE), and serological indicator in individuals with carotid plaque.Methods: Routine MRI and diffusion tensor images scan of the brain, carotid ultrasound, and blood examination were conducted on 74 individuals (52 carotid plaque subjects, 22 non-carotid plaque subjects), whose demographic and clinical characteristics were also recorded. DTI-ALPS index between patients with carotid plaque and normal controls were acquired and the correlations with other variables were analyzed.Results: The values of ALPS-index in the carotid plaque group was significantly lower compared to normal controls (2.12 ± 0.39, 1.95 ± 0.28, respectively, p = 0.034). The ALPS-index was negatively correlated with the basal ganglia (BG)-ePVS score (r = −0.242, p = 0.038) while there was no significant difference in the centrum semiovale (CSO)-ePVS score. Further analysis showed that there are more high-grade ePVS in the BG compared to the carotid plaque group than in the non-carotid plaque group (84.6% vs. 40.9%, p = 0.001).Conclusions: ALPS-index reflects the glymphatic system of the brain, which is associated with early high-risk cerebrovascular diseases. There may be damage in the function of the glymphatic system which induces the expansion of the perivascular space (PVS) in the BG in individuals with carotid plaque.

scholarly journals Aquaporin-4 dependent glymphatic solute transport in rodent brain

2017 ◽  
Author(s):  
Humberto Mestre ◽  
Benjamin T. Kress ◽  
Wenyan Zou ◽  
Tinglin Pu ◽  
Giridhar Murlidharan ◽  
...  
Keyword(s):  
Solute Transport ◽  
Healthy Aging ◽  
Fluid Transport ◽  
Water Channel ◽  
Amyloid Β ◽  
Aquaporin 4 ◽  
Tau Proteins ◽  
Glymphatic System ◽  
Aqp4 Expression ◽  
Transgenic Lines

AbstractThe glymphatic system is a brain-wide metabolite clearance pathway, impairment of which in post-traumatic and ischemic brain or healthy aging is proposed to contribute to intracerebral accumulation of amyloid-β and tau proteins. Glymphatic perivascular influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent publication that failed to find an effect of Aqp4 knockout on perivascular CSF tracer influx and interstitial fluid (ISF) tracer dispersion, four independent research groups have herein re-examined the importance of Aqp4 in glymphatic fluid transport. We concur in finding that CSF tracer influx, as well as fluorescently-tagged amyloid-β efflux, are significantly faster in wild-type mice than in three different transgenic lines featuring disruption of the Aqp4 gene and one line in which AQP4 expression lacks the critical perivascular localization (Snta1 knockout). These data validate the role of AQP4 in supporting fluid and solute transport and efflux in brain in accordance with the glymphatic system model.

scholarly journals Acute systemic LPS-exposure impairs perivascular CSF distribution in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Oscar Manouchehrian ◽  
Marta Ramos ◽  
Sara Bachiller ◽  
Iben Lundgaard ◽  
Tomas Deierborg
Keyword(s):  
Heart Rate ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Acute Inflammation ◽  
Western Blots ◽  
Doppler Flowmetry ◽  
Glymphatic System ◽  
Aqp4 Expression ◽  
The Brain

Abstract Background The exchange of cerebrospinal (CSF) and interstitial fluid is believed to be vital for waste clearance in the brain. The sleep-dependent glymphatic system, which is comprised of perivascular flow of CSF and is largely dependent on arterial pulsatility and astrocytic aquaporin-4 (AQP4) expression, facilitates much of this brain clearance. During the last decade, several observations have indicated that impaired glymphatic function goes hand in hand with neurodegenerative diseases. Since pathologies of the brain carry inflammatory components, we wanted to know how acute inflammation, e.g., with lipopolysaccharide (LPS) injections, would affect the glymphatic system. In this study, we aim to measure the effect of LPS on perivascular CSF distribution as a measure of glymphatic function. Methods Three hours after injection of LPS (1 mg/kg i.p.), C57bl/6 mice were (1) imaged for two CSF tracers, injected into cisterna magna, (2) transcardially perfused with buffer, or (3) used for physiological readouts. Tracer flow was imaged using a low magnification microscope on fixed brains, as well as using vibratome-cut slices for measuring tracer penetration in the brain. Cytokines, glial, and BBB-permeability markers were measured with ELISAs, Western blots, and immunohistochemistry. Cerebral blood flow was approximated using laser Doppler flowmetry, respiration and heart rate with a surgical monitor, and AQP4-polarization was quantified using confocal microscopy of immunolabeled brain sections. Results LPS-injections significantly lowered perivascular CSF tracer flow and penetration into the parenchyma. No differences in AQP4 polarization, cytokines, astroglial and BBB markers, cerebral blood flow, or respiration were detected in LPS-injected mice, although LPS did elevate cortical Iba1+ area and heart rate. Conclusions This study reports another physiological response after acute exposure to the bacterial endotoxin LPS, namely the statistically significant decrease in perivascular distribution of CSF. These observations may benefit our understanding of the role of systemic inflammation in brain clearance.

scholarly journals The Glymphatic System (En)during Inflammation

2021 ◽  
Vol 22 (14) ◽  
pp. 7491
Author(s):  
Frida Lind-Holm Mogensen ◽  
Christine Delle ◽  
Maiken Nedergaard
Keyword(s):  
Fluid Transport ◽  
Neurological Diseases ◽  
Lymphatic Vessels ◽  
Perivascular Spaces ◽  
Fluid Exchange ◽  
Glymphatic System ◽  
The Central Nervous System ◽  
The Brain ◽  
Privileged Site ◽  
Vascular Compartment

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

scholarly journals Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia

2019 ◽  
Vol 5 (2) ◽  
pp. eaav5447 ◽  
Author(s):  
Lauren M. Hablitz ◽  
Hanna S. Vinitsky ◽  
Qian Sun ◽  
Frederik Filip Stæger ◽  
Björn Sigurdsson ◽  
...  
Keyword(s):  
Heart Rate ◽  
Perivascular Spaces ◽  
Wild Type ◽  
Glymphatic System ◽  
Delta Power ◽  
Beta Power ◽  
Eeg Power ◽  
Eeg Recordings ◽  
Electroencephalogram Eeg ◽  
The Brain

The glymphatic system is responsible for brain-wide delivery of nutrients and clearance of waste via influx of cerebrospinal fluid (CSF) alongside perivascular spaces and through the brain. Glymphatic system activity increases during sleep or ketamine/xylazine (K/X) anesthesia, yet the mechanism(s) facilitating CSF influx are poorly understood. Here, we correlated influx of a CSF tracer into the brain with electroencephalogram (EEG) power, heart rate, blood pressure, and respiratory rate in wild-type mice under six different anesthesia regimens. We found that glymphatic CSF tracer influx was highest under K/X followed by isoflurane (ISO) supplemented with dexmedetomidine and pentobarbital. Mice anesthetized with α-chloralose, Avertin, or ISO exhibited low CSF tracer influx. This is the first study to show that glymphatic influx correlates positively with cortical delta power in EEG recordings and negatively with beta power and heart rate.

scholarly journals A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Yohei Doi ◽  
Masaya Hibino ◽  
Ryota Hase ◽  
Michiko Yamamoto ◽  
Yu Kasamatsu ◽  
...  
Keyword(s):  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Multicenter Trial ◽  
Viral Clearance ◽  
Open Label ◽  
Ecog Performance Status ◽  
Treatment Groups ◽  
Reverse Transcription Pcr ◽  
Adolescents And Adults ◽  
Late Treatment

ABSTRACT Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.)

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