The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

Lv, Tao; Zhao, Bing; Hu, Qin; Zhang, Xiaohua

doi:10.3389/fnagi.2021.689098

Cited by 55 publications

(49 citation statements)

References 213 publications

(243 reference statements)

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“…In patients with normal pressure hydrocephalus, there is a significant decrease in the ALPS index ( Yokota et al, 2019 ; Bae et al, 2021 ). In this study, the ALPS index was significantly decreased in cerebral hemispheres with infarct and that may imply impaired glymphatic function and reduced interstitial fluid clearance, similar to that observed in animal studies ( Ji et al, 2021 ; Lv et al, 2021 ).…”

Section: Discussionsupporting

confidence: 87%

“…reduced interstitial fluid clearance, similar to that observed in animal studies (Ji et al, 2021;Lv et al, 2021).…”

Section: Discussionsupporting

confidence: 87%

“…It is widely accepted that interstitial fluid clearance is reduced after ischemic stroke in animal studies ( Lv et al, 2021 ). Impaired CSF circulation in the glymphatic system after ischemic stroke has been a consistent finding ( Gaberel et al, 2014 ; Yang et al, 2015 ; Lin et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although infarct volume ( Vogt et al, 2012 ), infarct ADC ( Nagaraja, 2021 ), infarct FA ( Sotak, 2002 ; Moura et al, 2019 ), and hemorrhagic change ( Kastrup et al, 2008 ) may predict outcomes of patients with ischemic stroke, they were not associated with the glymphatic function in our study. Rather, other factors such as Aquaporin-4 and meningeal lymphatics may have more significant roles in regulating the function of the glymphatic system ( Lv et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Rodent experiments have provided some insights into the changes in glymphatic function associated with ischemic stroke. It is widely accepted that interstitial fluid clearance in the glymphatic system is reduced after ischemic infarct ( Ji et al, 2021 ; Lv et al, 2021 ). Despite that substantial knowledge has been gained from animal studies, further research is necessary to confirm if findings regarding the glymphatic system of animals apply to humans.…”

Section: Introductionmentioning

confidence: 99%

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Glymphatic Dysfunction in Patients With Ischemic Stroke

Toh

Siow

2021

Front. Aging Neurosci.

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Objectives: Rodent experiments have provided some insight into the changes of glymphatic function in ischemic stroke. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method offers an opportunity for the noninvasive investigation of the glymphatic system in patients with ischemic stroke. We aimed to investigate the changes of glymphatic function in ischemic stroke and the factors associated with the changes.Materials and Methods: A total of 50 patients (mean age 56.7 years; 30 men) and 44 normal subjects (mean age 53.3 years; 23 men) who had preoperative diffusion-tensor imaging for calculation of the analysis along the perivascular space (ALPS) index were retrospectively included. Information collected from each patient included sex, age, time since stroke onset, infarct location, hemorrhagic change, infarct volume, infarct apparent diffusion coefficient (ADC), infarct fractional anisotropy (FA), and ALPS index of both hemispheres. Interhemispheric differences in ALPS index (infarct side vs. contralateral normal side) were assessed with a paired t-test in all patients. ALPS index was normalized by calculating ALPS ratios (right-to-left and left-to-right) for comparisons between patients and normal subjects. Comparisons of ALPS ratios between patients and normal subjects were performed using analysis of covariance with adjustments for age and sex. Linear regression analyses were performed to identify factors associated with the ALPS index.Results: In patients, the mean ALPS index ipsilateral to infarct was 1.162 ± 0.126, significantly lower (P < 0.001) than that of the contralateral side (1.335 ± 0.160). The right-to-left ALPS index ratio of patients with right cerebral infarct was 0.84 ± 0.08, significantly lower (P < 0.001) than that of normal subjects (0.95 ± 0.07). The left-to-right ALPS ratio of patients with left cerebral infarct was 0.92 ± 0.09, significantly (P < 0.001) lower than that of normal subjects (1.05 ± 0.08). On multiple linear regression analysis, time since stroke onset (β = 0.794, P < 0.001) was the only factor associated with the ALPS index.Conclusion: The ALPS index showed lower values in ischemic stroke suggesting impaired glymphatic function. Following initial impairment, the ALPS index increased with the time since stroke onset, which is suggestive of glymphatic function recovery.

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Section: Discussionsupporting

confidence: 87%

“…reduced interstitial fluid clearance, similar to that observed in animal studies (Ji et al, 2021;Lv et al, 2021).…”

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glymphatic Dysfunction in Patients With Ischemic Stroke

Toh

Siow

2021

Front. Aging Neurosci.

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Aquaporin‐4 activation facilitates glymphatic system function and hematoma clearance post‐intracerebral hemorrhage

Chen,

Liang,

Peng

et al. 2024

Glia

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Efficient clearance of hematomas is crucial for improving clinical outcomes in patients with intracerebral hemorrhage (ICH). The glymphatic system, facilitated by aquaporin‐4 (AQP4), plays a crucial role in cerebrospinal fluid (CSF) entry and metabolic waste clearance. This study examined the role of the glymphatic system in ICH pathology, with a focus on AQP4. Collagenase‐induced ICH models were established, with AQP4 expression regulated through mifepristone as an agonist, TGN‐020 as an inhibitor, and Aqp4 gene knockout. Fluorescence tracing and multimodal magnetic resonance imaging (MRI) were employed to observe glymphatic system functionality, hematoma, and edema volumes. Neurological deficit scoring was performed using the modified Garcia Scale. AQP4 expression was quantified using RT‐qPCR and Western blotting, and cellular localization was explored using immunofluorescence. The brain tissue sections were examined for neuronal morphology, degenerative changes, and iron deposition. Three days post‐ICH, the AQP4 agonist group showed increased AQP4 protein expression and perivascular polarization, decreased hemoglobin levels, and reduced iron deposition. Conversely, the inhibition group exhibited contrasting trends. AQP4 activation improved glymphatic system function, leading to a wider distribution, improved neurological function, and reduced hematoma. Pharmacological inhibition and genetic knockout of AQP4 have opposing effects. The glymphatic system, facilitated by AQP4, plays a crucial role in hematoma clearance following cerebral hemorrhage. Upregulation of AQP4 improves glymphatic system function, facilitates hematoma clearance, and promotes brain tissue recovery.

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Glymphatic System Impairment in the Advanced Stage of Moyamoya Disease

Jin,

Hu,

Han

et al. 2024

J of Neuroscience Research

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Assessing the glymphatic system activity using diffusion tensor imaging analysis along with the perivascular space (DTI‐ALPS) may be helpful to understand the pathophysiology of moyamoya disease (MMD). 63 adult patients with MMD and 20 healthy controls (HCs) were included for T1‐weighted images, T2‐FLAIR, pseudocontinuous arterial spin labeling, and DTI. 60 patients had digital subtraction angiography more than 6 months after combined revascularization. The Suzuki stage, postoperative Matsushima grade, periventricular anastomoses (PA), enlarged perivascular spaces (EPVS), deep and subcortical white matter hyperintensities (DSWMH), DTI‐ALPS, cerebral blood flow (CBF), and cognitive scales of MMD patients were assessed. MMD patients were divided into early and advanced stage based on the Suzuki stage. We detected lower DTI‐ALPS in patients with advanced stage relative to HCs (p = 0.046) and patients with early stage (p = 0.004), hemorrhagic MMD compared with ischemic MMD (p = 0.048), and PA Grade 2 compared with Grade 0 (p = 0.010). DTI‐ALPS was correlated with the EPVS in basal ganglia (r = −0.686, p < 0.001), Suzuki stage (r = −0.465, p < 0.001), DSWMH (r = −0.423, p = 0.001), and global CBF (r = 0.300, p = 0.017) and cognitive scores (r = 0.343, p = 0.018). The DTI‐ALPS of patients with good postoperative collateral formation was higher compared to those with poor postoperative collateral formation (p = 0.038). In conclusion, the glymphatic system was impaired in advanced MMD patients and may affected cognitive function and postoperative neoangiogenesis.

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The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

Cited by 55 publications

References 213 publications

Glymphatic Dysfunction in Patients With Ischemic Stroke

Glymphatic Dysfunction in Patients With Ischemic Stroke

Aquaporin‐4 activation facilitates glymphatic system function and hematoma clearance post‐intracerebral hemorrhage

Glymphatic System Impairment in the Advanced Stage of Moyamoya Disease

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