Glymphatic Drainage Research Articles

Perivascular space dysfunction in cerebral small vessel disease is related to neuroinflammation

Abstract Enlarged perivascular spaces are a feature of cerebral small vessel disease, and it has been hypothesized that they may reflect impaired glymphatic drainage. The mechanisms underlying perivascular spaces enlargement are not fully understood, but both increased inflammation and blood brain barrier permeability have been hypothesized to play a role. We investigated the relationship between perivascular spaces and both CNS and peripheral inflammation, as well as blood brain barrier permeability, in cerebral small vessel disease. Fifty-four symptomatic sporadic cerebral small vessel disease patients were studied. perivascular spaces were quantified using both a visual rating scale, and by measurement of perivascular spaces volume, in both the white matter and basal ganglia. PET-MRI was used to simultaneously measure microglial activation using the radioligand 11C-PK11195, and blood brain barrier permeability was acquired using dynamic contrast enhanced MRI. We determined 11C-PK11195 binding and blood brain barrier permeability in the local vicinity of individual perivascular spaces in concentric shells surrounding perivascular spaces. In addition, both mean 11C-PK11195 binding and blood brain barrier permeability in both the white matter and basal ganglia were determined. To assess systemic inflammation a panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured. Within the white matter tissue in closest proximity to perivascular spaces displayed greater 11C-PK11195 binding (p < 0.001), in the vicinity of perivascular spaces. Higher white matter perivascular spaces burden on the visual rating scale was associated with higher white matter 11C-PK11195 binding (rho = 0.469, FDR-p =0.009); values for perivascular spaces volume showed a similar trend. In contrast there were no associations between basal ganglia perivascular spaces burden and 11C-PK11195 binding. No perivascular spaces marker correlated with blood brain barrier permeability. There was no association between perivascular spaces markers and systemic inflammation blood biomarkers. Our findings demonstrate that white matter perivascular spaces are associated with increased 11C-PK11195 binding, consistent with neuroinflammation playing a role in white matter perivascular spaces enlargement. Further longitudinal and intervention studies and required to determine whether the relationship between neuroinflammation with enlarged perivascular spaces is causal.

Unveiling connections between venous disruption and cerebral small vessel disease using diffusion tensor image analysis along perivascular space (DTI-ALPS): A 7-T MRI study.

Cerebral venous disruption is one of the characteristic findings in cerebral small vessel disease (CSVD), and its disruption may impede perivascular glymphatic drainage. And lower diffusivity along perivascular space (DTI-ALPS) index has been suggested to be with the presence and severity of CSVD. However, the relationships between venous disruption, DTI-ALPS index, and CSVD neuroimaging features remain unclear. To investigate the association between venous integrity and perivascular diffusion activity, and explore the mediating role of DTI-ALPS index between venous disruption and CSVD imaging features. In this cross-sectional study, 31 patients (mean age, 59.0 ± 9.9 years) were prospectively enrolled and underwent 7-T magnetic resonance (MR) imaging. DTI-ALPS index was measured to quantify the perivascular diffusivity. The visibility and continuity of deep medullary veins (DMVs) were evaluated based on a brain region-based visual score on high-resolution susceptibility-weighted imaging. White matter hyperintensity (WMH) and perivascular space (PVS) were assessed using qualitative and quantitative methods. Linear regression and mediation analysis were performed to analyze the relationships among DMV scores, DTI-ALPS index, and CSVD features. The DTI-ALPS index was significantly associated with the parietal DMV score (β = -0.573, p corrected = 0.004). Parietal DMV score was associated with WMH volume (β = 0.463, p corrected = 0.013) and PVS volume in basal ganglia (β = 0.415, p corrected = 0.028). Mediation analyses showed that DTI-ALPS index manifested a full mediating effect on the association between parietal DMV score and WMH (indirect effect = 0.115, Pm = 43.1%), as well as between parietal DMV score and PVS volume in basal ganglia (indirect effect = 0.161, Pm = 42.8%). Cerebral venous disruption is associated with glymphatic activity, and with WMH and PVS volumes. Our results suggest cerebral venous integrity may play a critical role in preserving perivascular glymphatic activity; while disruption of small veins may impair the perivascular diffusivity, thereby contributing to the development of WMH and PVS enlargement.

A Histopathologic Correlation Study Evaluating Glymphatic Function in Brain Tumors by Multiparametric MRI.

This study aimed to elucidate the impact of brain tumors on cerebral edema and glymphatic drainage by leveraging advanced MRI techniques to explore the relationships among tumor characteristics, glymphatic function, and aquaporin-4 (AQP4) expression levels. In a prospective cohort from March 2022 to April 2023, patients with glioblastoma, brain metastases, and aggressive meningiomas, alongside age- and sex-matched healthy controls, underwent 3.0T MRI, including diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index and multiparametric MRI for quantitative brain mapping. Tumor and peritumor tissues were analyzed for AQP4 expression levels via immunofluorescence. Correlations among MRI parameters, glymphatic function (DTI-ALPS index), and AQP4 expression levels were statistically assessed. Among 84 patients (mean age: 55 ± 12 years; 38 males) and 59 controls (mean age: 54 ± 8 years; 23 males), patients with brain tumor exhibited significantly reduced glymphatic function (DTI-ALPS index: 2.315 vs. 2.879; P = 0.001) and increased cerebrospinal fluid volume (201.376 cm³ vs. 115.957 cm³; P = 0.001). A negative correlation was observed between tumor volume and the DTI-ALPS index (r: -0.715, P < 0.001), whereas AQP4 expression levels correlated positively with peritumoral brain edema volume (r: 0.989, P < 0.001) and negatively with proton density in peritumoral brain edema areas (ρ: -0.506, P < 0.001). Our findings highlight the interplay among tumor-induced compression, glymphatic dysfunction, and altered fluid dynamics, demonstrating the utility of DTI-ALPS and multiparametric MRI in understanding the pathophysiology of tumor-related cerebral edema. These insights provide a radiological foundation for further neuro-oncological investigations into the glymphatic system. See related commentary by Surov and Borggrefe, p. 4813.

May Glymphatic Drainage Improve Life Quality in Progressive Multiple Sclerosis Outpatients?

The cerebral fluid-dynamic system plays a critical role in maintaining brain health and function. Recent studies identify the glymphatic system as primarily responsible for removing waste products and toxins from brain tissue. In recent years, we have achieved beneficial improvements in MS patients' symptoms and lifestyle using a specific Fluid Dynamic Intensive MAM (FD-MAM) protocol. We treated 40 outpatients with progressive MS, aged 45-55 years and with EDSS scores from 6 to 9. We applied FD-MAM in 10 daily sessions over two weeks. Before and after glymphatic drainage by FD-MAM, we assessed each patient's clinical status and quality of life using six validated questionnaires. Data from the six validated questionnaires administered to the 40 MS patients show an improvement in 83% of the scores. At the same time, we observed a shift from pathological to physiological values in 50% of the pathological scores after 10 sessions of FD-MAM protocol. This study confirms the positive improvements on life quality in outpatients with progressive multiple sclerosis after one cycle of Fluid Dynamic Intensive MAM (FD-MAM) protocol. Initial follow-up on few patients treated with the FD-MAM protocol suggests that the results persist for six to ten months post-treatment. Future detailed studies, on MS outpatients' larger cohort, are essential to assess the duration of results and its effect on glymphatic system.

The Regulation of Cerebral Lymphatic Drainage in the Transverse Sinus Region of the Mouse Brain.

Cerebral lymphatic drainage is an important pathway for metabolic waste clearance in the brain, which plays a crucial role in the progression of central nervous system diseases. Recent studies have shown that norepinephrine (NE) is involved in the regulation of cerebral lymphatic drainage function, but the modulation mechanism remains unknown. In this study, we confirmed that NE rapidly reduced glymphatic influx and enhanced meningeal lymphatic clearance. Moreover, the transverse sinus (TS) was the vital region of cerebral lymphatic drainage regulation by NE. Further analysis revealed that NE inhibition could simultaneously enhance glymphatic drainage and dorsal meningeal lymphatic drainage, mainly acting on the TS region. This study demonstrated that the cerebral lymphatic drainage system can be regulated by NE, with the TS region serving as the primary modulating site. The findings provide a potential regulatory target for the amelioration of neurological diseases associated with cerebral lymphatic drainage function.

Deep sleep improved by a manual therapy aimed at aiding glymphatic drainage in long COVID: a case study

ABSTRACT Introduction: Long Covid remains a global health challenge. We report here the case of a 55-year-old female who contracted acute COVID-19 (SARS-CoV-2) in March 2020 with symptoms including a high fever for 15 days. She subsequently reported fatigue-related symptoms compatible with Long Covid. Methods: Treatment was aimed at aiding glymphatic drainage. The patient captured information about her sleep quality which is presented here together with her Profile of Fatigue-Related Symptoms Scale (PFRS) scores. Results: Following the 16 treatments, the patient's PFRS Score reduced to 85, in keeping with a marked decline in symptom severity. Specifically, somatic symptoms, fatigue and cognitive scores showed a reduction in severity compared to the initial score. Conclusion: There was an overall benefit in relation to Long Covid symptom reduction achieved following this therapy.

Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems.

Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.

Dystrophin 71 deficiency causes impaired aquaporin-4 polarization contributing to glymphatic dysfunction and brain edema in cerebral ischemia

ObjectiveThe glymphatic system serves as a perivascular pathway that aids in clearing liquid and solute waste from the brain, thereby enhancing neurological function. Disorders in glymphatic drainage contribute to the development of vasogenic edema following cerebral ischemia, although the molecular mechanisms involved remain poorly understood. This study aims to determine whether a deficiency in dystrophin 71 (DP71) leads to aquaporin-4 (AQP4) depolarization, contributing to glymphatic dysfunction in cerebral ischemia and resulting in brain edema. MethodsA mice model of middle cerebral artery occlusion and reperfusion was used. A fluorescence tracer was injected into the cortex and evaluated glymphatic clearance. To investigate the role of DP71 in maintaining AQP4 polarization, an adeno-associated virus with the astrocyte promoter was used to overexpress Dp71. The expression and distribution of DP71 and AQP4 were analyzed using immunoblotting, immunofluorescence, and co-immunoprecipitation techniques. The behavior ability of mice was evaluated by open field test. Open-access transcriptome sequencing data were used to analyze the functional changes of astrocytes after cerebral ischemia. MG132 was used to inhibit the ubiquitin-proteasome system. The ubiquitination of DP71 was detected by immunoblotting and co-immunoprecipitation. ResultsDuring the vasogenic edema stage following cerebral ischemia, a decline in the efflux of interstitial fluid tracer was observed. DP71 and AQP4 were co-localized and interacted with each other in the perivascular astrocyte endfeet. After cerebral ischemia, there was a notable reduction in DP71 protein expression, accompanied by AQP4 depolarization and proliferation of reactive astrocytes. Increased DP71 expression restored glymphatic drainage and reduced brain edema. AQP4 depolarization, reactive astrocyte proliferation, and the behavior of mice were improved. After cerebral ischemia, DP71 was degraded by ubiquitination, and MG132 inhibited the decrease of DP71 protein level. ConclusionAQP4 depolarization after cerebral ischemia leads to glymphatic clearance disorder and aggravates cerebral edema. DP71 plays a pivotal role in regulating AQP4 polarization and consequently influences glymphatic function. Changes in DP71 expression are associated with the ubiquitin-proteasome system. This study offers a novel perspective on the pathogenesis of brain edema following cerebral ischemia.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

Enlarged perivascular spaces in alcohol-related brain damage induced by dyslipidemia

Perivascular spaces (PVSs) as the anatomical basis of the glymphatic system, are increasingly recognized as potential imaging biomarkers of neurological conditions. However, it is not clear whether enlarged PVSs are associated with alcohol-related brain damage (ARBD). We aimed to investigate the effect of long-term alcohol exposure on dyslipidemia and the glymphatic system in ARBD. We found that patients with ARBD exhibited significantly enlargement of PVSs in the frontal cortex and basal ganglia, as well as a notable increased levels of total cholesterol (TC) and triglycerides (TG). The anatomical changes of the glymphatic drainage system mentioned above were positively associated with TC and TG. To further explore whether enlarged PVSs affects the function of the glymphatic system in ARBD, we constructed long alcohol exposure and high fat diet mice models. The mouse model of long alcohol exposure exhibited increased levels of TC and TG, enlarged PVSs, the loss of aquaporin-4 polarity caused by reactive astrocytes and impaired glymphatic drainage function which ultimately caused cognitive deficits, in a similar way as high fat diet leading to impairment in glymphatic drainage. Our study highlights the contribution of dyslipidemia due to long-term alcohol abuse in the impairment of the glymphatic drainage system.

The Anatomy and Physiology of the Glymphatic System and Its Role in Craniectomies and Syndrome of the Trephined

Background: The glymphatic system, a relatively recently discovered system for transport of cerebrospinal fluid (CSF) and waste products in the central nervous system, has been implicated in several neurologic disorders. Altered CSF dynamics are seen after decompressive craniectomy, suggesting this procedure may impact glymphatic function. We aimed to systematically review the current literature to understand the effect of the glymphatic system on patients with decompressive craniectomies and Syndrome of the Trephined (SoT). Methods: PubMed and Embase were searched for preclinical and clinical studies investigating the glymphatic system and craniectomy, cranioplasty, or SoT in years 2012 to 2023. Results: Sixty-three studies were identified for review. Intracranial oscillations, cerebral perfusion, and arterial pulsations have been identified as major drivers of glymphatic influx. Each of these processes are diminished following craniectomy, suggesting craniectomy may impair glymphatic function. Reductions in brain pulsatility and alterations in glymphatic drainage after craniectomy were accompanied by impaired functional outcomes, as seen in SoT. Radiologically, CSF flow alterations are seen after craniectomies, which improve with cranioplasty. Conclusions: Glymphatic system dysfunction after craniectomy and in SoT may be a potential therapeutic target for patients with iatrogenically altered cranial vault anatomy.

Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches.

Clearance of amyloid-beta (Aβ) from the brain is impaired in both early-onset and late-onset Alzheimer's disease (AD). Mechanisms for clearing cerebral Aβ include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aβ. Mechanisms suggested for ABC transporter-mediated lowering of brain Aβ, in addition to exporting of Aβ across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aβ into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aβ levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aβ may slow the clinical progression of AD merits further consideration.

Segmentation and quantification of venous structures and perivascular spaces in the thalamus in epilepsy using 7 Tesla MRI

Background and purposeEpilepsy is a complex neurological disorder affecting 50 million people worldwide. Persistent seizures may correlate with neural network, microstructural, and vascular changes within the thalamus. These thalamic changes may result from seizure activity or broader alterations involving neuronal vasculature and neuroinflammatory processes linked to glymphatic drainage. Improved resolution with Ultra-high field (UHF) magnetic resonance imaging (MRI) may be useful in identifying possible thalamic vascular abnormalities not otherwise detectable at lower field strengths. Materials and methodsWe outline a novel method which leverages UHF neuroimaging for detection and quantification of vessels and perivascular spaces (PVS) within the thalamus in 25 epilepsy patients and 16 controls, to uncover possible underlying imaging biomarkers of epilepsy. In our analysis, we optimize a MATLAB-based Frangi-based detection tool called Perivascular Space Semi-Automated Segmentation (PVSSAS) to detect thalamic PVSs, and additionally use a second Frangi-based segmentation tool method to automate detection of vascular structures in the thalamus. The resulting PVS and vessel masks were used to quantify differences in the number of vessels, PVS, overlaps, and number of PVS overlaps per vessel detected between groups, using a Hessian detection filter linked on an 18-connected network. ResultsWe found significantly more thalamic PVS (p = 0.0307) and a significant increase in the number of thalamic vessels (p = 0.038) in patients compared to controls. ConclusionHere we have developed a novel process which leverages UHF MRI to quantify and detect thalamic vessels and PVS that may provide a potential neuroimaging biomarker of epilepsy. Statement of SignificanceWe use 7T, ultra-high field MRI and employed an innovative combination of semi-automated perivascular space segmentation and automated vessel segmentation to visualize and quantify vessels and perivascular spaces (PVS) within the thalamus, a highly cited region of interest in epilepsy. To our knowledge, this is the first study to semi-automatically visualize and segment PVS in the thalamus and automatically detect thalamic vessels. We uncovered detectable differences in thalamic vasculature and PVS. These findings suggests that increases in the number of thalamic PVS and vessels may be a potential neuroimaging biomarker in epilepsy. This tool may be useful in the detection of subtle vascular changes in other regions of the brain related to epilepsy or can be employed in other neurological conditions.

Impaired glymphatic system revealed by DTI-ALPS in cerebral palsy due to periventricular leukomalacia: relation with brain lesion burden and hand dysfunction

PurposePreterm children with cerebral palsy (CP) often have varying hand dysfunction, while the specific brain injury with periventricular leukomalacia (PVL) cannot quite explain its mechanism. We aimed to investigate glymphatic activity using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and evaluate its association with brain lesion burden and hand dysfunction in children with CP secondary to PVL.MethodsWe retrospectively enrolled 18 children with bilateral spastic CP due to PVL and 29 age- and sex-matched typically developing controls. The Manual Ability Classification System (MACS) was used to assess severity of hand dysfunction in CP. A mediation model was performed to explore the relationship among the DTI-ALPS index, brain lesion burden, and the MACS level in children with CP.ResultsThere were significant differences in the DTI-ALPS index between children with CP and their typically developing peers. The DTI-ALPS index of the children with CP was lower than that of the controls (1.448 vs. 1.625, P = 0.003). The mediation analysis showed that the DTI-ALPS index fully mediated the relationship between brain lesion burden and the MACS level (c′ = 0.061, P = 0.665), explaining 80% of the effect.ConclusionThis study provides new insights into the neural basis of hand dysfunction in children with CP, demonstrating an important role of glymphatic impairment in such patients. These results suggest that PVL might affect hand function in children with CP by disrupting glymphatic drainage.

Boosting glymphatic drainage via adrenergic receptor inhibition protects the injured brain.

Boosting glymphatic drainage via adrenergic receptor inhibition protects the injured brain.

STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals

IntroductionCerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective...

Yuanzhi powder facilitated Aβ clearance in APP/PS1 mice: Target to the drainage of glymphatic system and meningeal lymphatic vessels

Ethnopharmacological relevanceYuanzhi Powder (YZP) is a classical Chinese medicine prescription, which is suitable for the treatment of dementia by “dispelling phlegm and opening orifice”. The therapeutic efficacy of YZP on Alzheimer's disease (AD) has been previously reported in our work. However, it remains unclear whether the neuroprotective effect of YZP is linked to β-amyloid(Aβ) clearance through cerebral lymphatic drainage. Aim of the studyThe aim was to determine the protective efficacy of YZP against AD and investigate the potential mechanism for eliminating excessive Aβ deposition. Materials and methodsAPP/PS1 mice were divided into four groups of 8 mice each: APP/PS1 group, DONE group, L-YZP group, and H-YZP group. Additionally, 8 wild-type littermates were assigned to the control group (WT group). After 8 weeks of consecutive intragastric administration, behavioral tests, including the open field test, novel object recognition test and Morris Water Maze test, were employed to assess the cognitive abilities of all groups of mice. Nissl staining, immunohistochemistry, and western blotting were utilized to evaluate clearance of excessive Aβ deposition and pathological changes. Furthermore, immunofluorescence was applied to visualize the drainage of the cerebral lymphatic system after fluorescent tracer injection in the cisterna magna. ResultsThe administration of YZP significantly attenuated cognitive deficits, cleared excessive Aβ deposition, and improved pathological damage in APP/PS1 mice. Furthermore, YZP effectively enhanced glymphatic system drainage by restoring AQP4 polarization and inhibiting reactive astrogliosis. Additionally, YZP facilitated the drainage of meningeal lymphatic vessels (MLVs) by augmenting their diameter and coverage. Lastly, YZP promoted the elimination of Aβ from the brain to deep cervical lymph nodes. ConclusionsThe administration of YZP may ameliorate the cognitive deficits and pathological damage in APP/PS1 mice by effectively clearing excessive Aβ deposition. The underlying mechanisms potentially involve Aβ clearance through the cerebral lymphatic system, which includes the glymphatic system and MLVs.

Investigation of Association between Alzheimer Disease and Glymphatic System

Novel studies indicated that brain metabolic derivatives clearance is provided by s system called glymphatic (glia+lymphatic) system. Glymphatic system drainage works thanks to arterial pulsation and clear out brain wastes via AQP4 channels localized at astrocytes endfeet. Dysfunction of this system associated with senescence and several pathologies. One of those disease is Alzheimer’s Disease. This study objected to determine the relation between glymphatic system and Alzheimer’s Disease in accordance with previous studies. Method: Data was collected from “Google Scholar” and “Pubmed” publishments drafted by related professionals between 2011-2023 years. Results: Our results indicated that Alzheimer’s Disease and glymphatic system tightly associated each other. It was observed that during Alzheimer’s Disease glymphatic flux diminished and AQP4 expression levels were decreased, and localization disrupted. Thus, we suggest that glymphatic system inducing treatment or methods might be beneficial for preventive of Alzheimer’s Disease.

GABA promotes interstitial fluid clearance in an AQP4-dependent manner by activating the GABAA R.

The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin-4 (AQP4) expressed on the perivascular astrocytic end-feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ-aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABAA R) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation-continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4-dependent manner by activating the GABAA R. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition-related diseases.

Neurofluids and the glymphatic system: anatomy, physiology, and imaging.

First described in 2012, the glymphatic system is responsible for maintaining homeostasis within the central nervous system, including nutrient delivery, waste clearance, and consistency of the ionic microenvironment. It is comprised of glial cells and barrier systems that modulate neurofluid production, circulation, and exchange. Experimental interrogation of neurofluid dynamics is restricted to ex vivo and in vitro studies in animals and humans, therefore diagnostic imaging plays an important role in minimally invasive evaluation. This review article will synthesize current knowledge and theories regarding neurofluid circulation and implications for neuroimaging. First, we will discuss the anatomy of the neurogliovascular unit, including paravascular and perivascular pathways of fluid exchange. In addition, we will summarize the structure and function of barrier systems including the blood-brain, blood-cerebrospinal fluid, and brain-cerebrospinal fluid barriers. Next, we will mention physiologic factors that yield normal variations in neurofluid circulation, and how various disease pathologies can disrupt glymphatic drainage pathways. Lastly, we will cover the spectrum of diagnostic imaging and interventional techniques with relevance to glymphatic structure, flow, and function. We conclude by highlighting current barriers and future directions for translational imaging and applications to neurologic disorders.