The excessive buildup of neurotoxicα-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease,highlighting the urgent need for innovative therapeutic strategies to promoteα-synuclein clearance,p...The excessive buildup of neurotoxicα-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease,highlighting the urgent need for innovative therapeutic strategies to promoteα-synuclein clearance,particularly given the current lack of disease-modifying treatments.The glymphatic system,a recently identified perivascular fluid transport network,is crucial for clearing neurotoxic proteins.This review aims to synthesize current knowledge on the role of the glymphatic system inα-synuclein clearance and its implications for the pathology of Parkinson's disease while emphasizing potential therapeutic strategies and areas for future research.The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance.It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson's disease,as well as the effect of glymphatic dysfunction onα-synuclein accumulation in Parkinson's disease models.Subsequently,the review summarizes the mechanisms of glymphatic system impairment in Parkinson's disease,including sleep disturbances,aquaporin-4 impairment,and mitochondrial dysfunction,all of which diminish glymphatic system efficiency.This creates a vicious cycle that exacerbatesα-synuclein accumulation and worsens Parkinson's disease.The therapeutic perspectives section outlines strategies for enhancing glymphatic activity,such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization.Promising interventions include deep brain stimulation,melatonin supplementation,γ-aminobutyric acid modulation,and non-invasive methods(such as exercise and bright-light therapy),multisensoryγstimulation,and ultrasound therapy.Moreover,identifying neuroimaging biomarkers to assess glymphatic flow as an indicator ofα-synuclein burden could refine Parkinson's disease diagnosis and track disease progression.In conclusion,the review highlights the critical role of the glymphatic system inα-synuclein clearance and its potential as a therapeutic target in Parkinson's disease.It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfoldedα-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson's disease.Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducingα-synuclein deposits and mitigating the progression of Parkinson's disease.展开更多
Cerebral small vessel disease encompasses a group of neurological disorders characterized by injury to small blood vessels,often leading to stroke and dementia.Due to its diverse etiologies and complex pathological me...Cerebral small vessel disease encompasses a group of neurological disorders characterized by injury to small blood vessels,often leading to stroke and dementia.Due to its diverse etiologies and complex pathological mechanisms,preventing and treating cerebral small vessel vasculopathy is challenging.Recent studies have shown that the glymphatic system plays a crucial role in interstitial solute clearance and the maintenance of brain homeostasis.Increasing evidence also suggests that dysfunction in glymphatic clearance is a key factor in the progression of cerebral small vessel disease.This review begins with a comprehensive introduction to the structure,function,and driving factors of the glymphatic system,highlighting its essential role in brain waste clearance.Afterwards,cerebral small vessel disease was reviewed from the perspective of the glymphatic system,after which the mechanisms underlying their correlation were summarized.Glymphatic dysfunction may lead to the accumulation of metabolic waste in the brain,thereby exacerbating the pathological processes associated with cerebral small vessel disease.The review also discussed the direct evidence of glymphatic dysfunction in patients and animal models exhibiting two subtypes of cerebral small vessel disease:arteriolosclerosis-related cerebral small vessel disease and amyloid-related cerebral small vessel disease.Diffusion tensor image analysis along the perivascular space is an important non-invasive tool for assessing the clearance function of the glymphatic system.However,the effectiveness of its parameters needs to be enhanced.Among various nervous system diseases,including cerebral small vessel disease,glymphatic failure may be a common final pathway toward dementia.Overall,this review summarizes prevention and treatment strategies that target glymphatic drainage and will offer valuable insight for developing novel treatments for cerebral small vessel disease.展开更多
Glymphatic flow has been proposed to clear brain waste while we sleep.Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma,with subsequent cerebrospinal fluid drainage to dural lymph...Glymphatic flow has been proposed to clear brain waste while we sleep.Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma,with subsequent cerebrospinal fluid drainage to dural lymphatics.Glymphatic disruption is associated with neurological conditions such as Alzheimer’s disease and traumatic brain injury.Therefore,investigating its structure and function may improve understanding of pathophysiology.The recent controversy on whether glymphatic flow increases or decreases during sleep demonstrates that the glymphatic hypothesis remains contentious.However,discrepancies between different studies could be due to limitations of the specific techniques used and confounding factors.Here,we review the methods used to study glymphatic function and provide a toolkit from which researchers can choose.We conclude that tracer analysis has been useful,ex vivo techniques are unreliable,and in vivo imaging is still limited.Finally,we explore the potential for future methods and highlight the need for in vitro models,such as microfluidic devices,which may address technique limitations and enable progression of the field.展开更多
Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals an...Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.展开更多
Cerebral edema is characterized by fluid accumulation,and the glymphatic system(GS)plays a pivotal role in regulating fluid transport.Using the Tenecteplase system,magnesium salt of salvianolic acid B/ginsenoside Rg1(...Cerebral edema is characterized by fluid accumulation,and the glymphatic system(GS)plays a pivotal role in regulating fluid transport.Using the Tenecteplase system,magnesium salt of salvianolic acid B/ginsenoside Rg1(SalB/Rg1)was injected intravenously into mice 4.5 h after middle cerebral artery occlusion and once every 24 h for the following 72 h.GS function was assessed by Evans blue imaging,near-infrared fluorescence region II(NIR-II)imaging,and magnetic resonance imaging(MRI).SalB/Rg1 had significant effects on reducing the infarct volume and hemorrhagic transformation score,improving neurobehavioral function,and protecting tissue structure,especially inhibiting cerebral edema.Meanwhile,the influx/efflux drainage of GS was enhanced by SalB/Rg1 according to NIR-II imaging and MRI.SalB/Rg1 inhibited matrix metalloproteinase-9(MMP-9)activity,reduced cleavedβ-dystroglycan(β-DG),and stabilized aquaporin-4(AQP4)polarity,which was verified by colocalization with CD31.Our findings indicated that SalB/Rg1 treatment enhances GS function and attenuates cerebral edema,accompanying the regulation of the MMP9/β-DG/AQP4 pathway.展开更多
The glymphatic system,a recently discovered cerebrospinal fluid-mediated pathway,plays a crucial role in fluid exchange and waste clearance in the brain.Its dysfunction has been implicated in various neurological diso...The glymphatic system,a recently discovered cerebrospinal fluid-mediated pathway,plays a crucial role in fluid exchange and waste clearance in the brain.Its dysfunction has been implicated in various neurological disorders,including Alzheimer's disease and traumatic brain injury.Recent studies suggest that alcohol intake has a biphasic effect on the glymphatic system:Low doses of alcohol enhance glymphatic function,whereas high doses lead to glymphatic suppression and cognitive decline,mirroring patterns seen in alcohol-related dementia,providing valuable insights into the dose-dependent effects of alcohol on glymphatic function,but significant gaps persist,particularly regarding the mechanistic understanding and the influence of confounding factors such as sex,age,blood pressure,and wakefulness.Here,we synthesize and critically evaluate the important research findings within this field to gauge its progress and identify new research opportunities.We discuss the specific mechanisms by which alcohol affects the glymphatic system,including how alcohol influences cerebrospinal fluid-interstitial fluid exchange and waste removal.We also discuss the potential of the glymphatic system as a new target,such as through pharmacological or lifestyle interventions aimed at enhancing glymphatic function to treat alcohol use disorder and other neurological disorders associated with glymphatic dysfunction.展开更多
Various pathological mechanisms represent distinct therapeutic targets for cognitive disorders,but a balance between clearance and production is essential for maintaining the stability of the brain's internal envi...Various pathological mechanisms represent distinct therapeutic targets for cognitive disorders,but a balance between clearance and production is essential for maintaining the stability of the brain's internal environment.Thus,the glymphatic system may represent a common pathway by which to address cognitive disorders.Using the established model of the glymphatic system as our foundation,this review disentangles and analyzes the components of its clearance mechanism,including the initial inflow of cerebrospinal fluid,the mixing of cerebrospinal fluid with interstitial fluid,and the outflow of the mixed fluid and the clearance.Each section summarizes evidence from experimental animal models and human studies,highlighting the normal physiological properties of key structures alongside their pathological manifestations in cognitive disorders.The same pathologic manifestations of different cognitive disorders appearing in the glymphatic system and the same upstream influences are main points of interest of this review.We conclude this article by discussing new findings and outlining the limitations identified in current research progress.展开更多
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 m...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 glym・phatic 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.展开更多
The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the brain.Accumulating evidence indicates thatglymphatic function is impaired not only in central nervous system disord...The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the brain.Accumulating evidence indicates thatglymphatic function is impaired not only in central nervous system disorders but also in systemic diseases.Systemic diseases can trigger the inflammatory responses in the central nervous system,occasionally leading to sustained inflammation and functional disturbance of the central nervous system.This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation.In addition,we discuss the hypothesis that disease conditions initially associated with peripheral inflammation ove rwhelm the performance of the glymphatic system,thereby triggering central nervous system dysfun ction,chronic neuroinflammation,and neurodegeneration.Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.展开更多
Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired eli...Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.展开更多
BACKGROUND Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized.AIM To investigate the function of the glymphatic s...BACKGROUND Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized.AIM To investigate the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states,the present study employed diffusion tensor imaging along the perivascular space(DTI-ALPS)index.METHODS Sample size was calculated using the pwr package in R software.This crosssectional study enrolled 22 patients with normal glucose metabolism(NGM),20 patients with prediabetes,and 22 patients with type 2 diabetes mellitus(T2DM).A 3.0T magnetic resonance imaging was used to evaluate the function of the glymphatic system.The mini-mental state examination(MMSE)was used to assess general cognitive function.The DTI-ALPS index of bilateral basal ganglia and the mean DTI-ALPS index was calculated.Further,the correlation between DTI-ALPS and clinical features was assessed.RESULTS The left-side,right-side,and mean DTI-ALPS index in the T2DM group were significantly lower than that in the NGM group.The right-side DTI-ALPS and mean DTI-ALPS index in the T2DM group were significantly lower than those in the prediabetes group.DTI-ALPS index lateralization was not observed.The MMSE score in the T2DM group was significantly lower than that in the NGM and prediabetes group.After controlling for sex,the left-side DTI-ALPS and mean DTI-ALPS index in the prediabetes group were positively correlated with 2-hour postprandial blood glucose level;the left-side DTI-ALPS index was negatively correlated with total cholesterol and low-density lipoprotein level.The right-side DTI-ALPS and mean DTI-ALPS index were negatively correlated with the glycosylated hemoglobin level and waist-to-hip ratio in the prediabetes group.The left-side,right-side,and mean DTI-ALPS index in the T2DM group were positively correlated with height.The left-side and mean DTIALPS index in the T2DM group were negatively correlated with high-density lipoprotein levels.CONCLUSION Cerebral glymphatic system dysfunction may mainly occur in the T2DM stage.Various clinical variables were found to affect the DTI-ALPS index in different glucose metabolism states.This study enhances our understanding of the pathophysiology of diabetic brain damage and provides some potential biological evidence for its early diagnosis.展开更多
Following intrathecal injection of fluorescent tracers,ex vivo imaging of brain vibratome slices has been widely used to study the glymphatic system in the rodent brain.Tracer penetration into the brain is usually qua...Following intrathecal injection of fluorescent tracers,ex vivo imaging of brain vibratome slices has been widely used to study the glymphatic system in the rodent brain.Tracer penetration into the brain is usually quantified by image-processing,even though this approach requires much time and manual operation.Here,we illustrate a simple protocol for the quantitative determination of glymphatic activity using spectrophotofluorometry.At specific time-points following intracisternal or intrastriatal injection of fluorescent tracers,certain brain regions and the spinal cord were harvested and tracers were extracted from the tissue.The intensity of tracers was analyzed spectrophotometrically and their concentrations were quantified from standard curves.Using this approach,the regional and dynamic delivery of subarachnoid CSF tracers into the brain parenchyma was assessed,and the clearance of tracers from the brain was also determined.Furthermore,the impairment of glymphatic influx in the brains of old mice was confirmed using our approach.Our method is more accurate and efficient than the imaging approach in terms of the quantitative determination of glymphatic activity,and this will be useful in preclinical studies.展开更多
Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Re...Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Recently,it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases.The ability to clear metabolic waste is essential for tissue homeostasis in mammals,including humans.While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions,there is growing evidence of a glymphatic system in the central nervous system,which structurally includes the optic nerve.Named to acknowledge the supportive role of astroglial cells,this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system.Herein,we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve.We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents,aquaporin 4-null rodents,and humans;glymphatic imaging studies in diseases where the optic nerve is impaired;and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health.We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.展开更多
The glymphatic system(GS)is a newly discovered brain anatomy.Its discovery improves our understanding of brain fluid flow and waste removal paths and provides an anatomical basis for the flow of cerebral interstitial ...The glymphatic system(GS)is a newly discovered brain anatomy.Its discovery improves our understanding of brain fluid flow and waste removal paths and provides an anatomical basis for the flow of cerebral interstitial fluid(ISF)and cerebrospinal fluid(CSF).GS occurs through a normal exchange within perivascular space(PVS),facilitating the elimination of metabolic wastes generated by nerve cells from the brain.Therefore,the GS is mainly responsible for the removal of metabolic waste.Reduced GS activity has been observed to be associated with central nervous system disorders such as cerebral small vessel disease(CSVD)and neurodegenerative diseases.Its activity is expected to be an indicator for diagnosing diseases and predicting their prognosis.This review introduces the magnetic resonance imaging(MRI)technology related to the GS suitable for clinical use and the difference in the system's activity in normal and abnormal states.Through a summary of previous research,imaging methods suitable for monitoring the activity of the GS in the clinic were proposed,and their diagnostic effect on different brain disorders was analyzed.This review aims to clarify ideas for the clinical translation of basic research focusing on GS and provide future clinical research directions and perspectives.展开更多
Diabetes is one of the most devastating medical dilemmas impacting every region of the world severely.The study by Tian et al investigates glymphatic system dys-function in the context of glucose metabolism and diabet...Diabetes is one of the most devastating medical dilemmas impacting every region of the world severely.The study by Tian et al investigates glymphatic system dys-function in the context of glucose metabolism and diabetes,using diffusion tensor imaging along the perivascular space.The study evaluated individuals with type 2 diabetes mellitus(T2DM),prediabetes,and normal glucose metabolism.It found that prediabetic and T2DM groups had significantly impaired glymphatic func-tion.Glymphatic dysfunction may serve as an early indicator of cognitive deteri-oration in diabetes due to the correlations shown between these abnormalities and clinical factors as well as cognitive performance.The study has some positives,such as thorough evaluations and novel imaging methods,but its cross-sectional design and limited sample size restrict its applicability.More extensive,long-term research is required to verify these results.Furthermore,there are significant cli-nical implications.Patients with diabetes may benefit from immediate therapies to prevent microvascular and macrovascular damage if glymphatic dysfunction is identified early.The study promotes comprehensive diabetes care with a focus on maintaining cognitive function.In conclusion,the work of Tian et al is crucial because it opens the door to better treatment and diagnostic strategies for dia-betes-related cognitive deterioration.展开更多
The rising prevalence of diabetes and prediabetes globally necessitates a deeper understanding of associated complications,including glymphatic system dysfunction.The glymphatic system,crucial for brain waste clearanc...The rising prevalence of diabetes and prediabetes globally necessitates a deeper understanding of associated complications,including glymphatic system dysfunction.The glymphatic system,crucial for brain waste clearance,is implicated in cognitive decline and neurodegenerative diseases like Alzheimer’s disease.This letter explores recent research on glymphatic function across different glucose metabolism states.Tian et al’s study reveals significant glymphatic dysfunction in type 2 diabetes mellitus patients,evidenced by lower diffusion tensor imaging analysis along perivascular space indices compared to those with normal glucose metabolism and prediabetes.The research also reveals a link between glymphatic dysfunction and cognitive impairment.Additional research underscores the role of glymphatic impairment in neurodegenerative diseases.These findings highlight the importance of integrating glymphatic health into diabetes management and suggest potential biomarkers for early diagnosis and targeted therapeutic interventions.展开更多
In this article,we comment on an original article published in a recent issue of the World Journal of Diabetes.That observational cross-sectional study focused on investigating the function of the glymphatic system an...In this article,we comment on an original article published in a recent issue of the World Journal of Diabetes.That observational cross-sectional study focused on investigating the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states by using diffusion tensor imaging along the perivascular space(DTI-ALPS)index.It was shown that the cerebral glymphatic system may be dysfunctional in patients with type 2 diabetes.Various clinical variables affected the DTI-ALPS index in different glucose metabolism states.In conclusion,the study by Tian et al improves the under-standing of the pathophysiology of diabetes-associated brain damage and pro-vides insights for early diagnosis.展开更多
Identification of the glymphatic system,defined as a perivascular network that facilitates the clearance of metabolic waste through the exchange of cerebrospinal fluid(CSF)and interstitial fluid(ISF),has reshaped pers...Identification of the glymphatic system,defined as a perivascular network that facilitates the clearance of metabolic waste through the exchange of cerebrospinal fluid(CSF)and interstitial fluid(ISF),has reshaped perspectives on cerebral homeostasis and its implications for health and disease[1].According to the Global Burden of Disease Study 2019,psychiatric disorders accounted for approximately 4.9%of global disability-adjusted life years[2],highlighting the urgent need for targeted interventions.展开更多
Neurons are the main organizers of neurological activities in the brain.However,its role remains largely unknown in regulating waste clearance in the brain.This issue is addressed in a recent study published in Nature...Neurons are the main organizers of neurological activities in the brain.However,its role remains largely unknown in regulating waste clearance in the brain.This issue is addressed in a recent study published in Nature on neuronal dynamics in control of waste removal through cerebrospinal fluid perfusion1.Brain contains billions of neurons that are connected through synapses for precise spatial coordination and high-speed operation in support of functions like thoughts,emotions,and body movements in a dynamic manner.展开更多
基金supported by the National Natural Science Foundation of China,No.81971031(to ZL)the National Key Research and Development Program of China,No.2022YFE0210100(to JFC)+7 种基金the National Natural Science Foundation of China(Original Exploration Project),No.82151308(to JFC)the National Natural Science Foundation of China(Research Fund for International Senior Scientists),No.82150710558(to JFC)Science&Technology Initiative STI2030-Major Projects,No.2021ZD0203400(to JFC)Key Research and Development Program of Zhejiang Province,No.2023C03079(to JFC)Scientific Research Starting Foundation of Oujiang Laboratory(Zhejiang Laboratory for Regenerative Medicine,Vision and Brain Health),No.OJQDSP2022007(to JFC)Project of State Key Laboratory of Ophthalmology,Optometry and Visual Science,Wenzhou Medical University,No.J01-20190101(to JFC)Scientific Research Starting Foundation of Wenzhou Medical University,No.QTJ12003(to JFC)Department of Science and Technology of Zhejiang Province,No.2023ZY1011(to JFC)。
文摘The excessive buildup of neurotoxicα-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease,highlighting the urgent need for innovative therapeutic strategies to promoteα-synuclein clearance,particularly given the current lack of disease-modifying treatments.The glymphatic system,a recently identified perivascular fluid transport network,is crucial for clearing neurotoxic proteins.This review aims to synthesize current knowledge on the role of the glymphatic system inα-synuclein clearance and its implications for the pathology of Parkinson's disease while emphasizing potential therapeutic strategies and areas for future research.The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance.It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson's disease,as well as the effect of glymphatic dysfunction onα-synuclein accumulation in Parkinson's disease models.Subsequently,the review summarizes the mechanisms of glymphatic system impairment in Parkinson's disease,including sleep disturbances,aquaporin-4 impairment,and mitochondrial dysfunction,all of which diminish glymphatic system efficiency.This creates a vicious cycle that exacerbatesα-synuclein accumulation and worsens Parkinson's disease.The therapeutic perspectives section outlines strategies for enhancing glymphatic activity,such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization.Promising interventions include deep brain stimulation,melatonin supplementation,γ-aminobutyric acid modulation,and non-invasive methods(such as exercise and bright-light therapy),multisensoryγstimulation,and ultrasound therapy.Moreover,identifying neuroimaging biomarkers to assess glymphatic flow as an indicator ofα-synuclein burden could refine Parkinson's disease diagnosis and track disease progression.In conclusion,the review highlights the critical role of the glymphatic system inα-synuclein clearance and its potential as a therapeutic target in Parkinson's disease.It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfoldedα-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson's disease.Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducingα-synuclein deposits and mitigating the progression of Parkinson's disease.
基金supported by the National Natural Science Foundation of China,No.82274304(to YH)the Major Clinical Study Projects of Shanghai Shenkang Hospital Development Center,No.SHDC2020CR2046B(to YH)Shanghai Municipal Health Commission Talent Plan,No.2022LJ010(to YH).
文摘Cerebral small vessel disease encompasses a group of neurological disorders characterized by injury to small blood vessels,often leading to stroke and dementia.Due to its diverse etiologies and complex pathological mechanisms,preventing and treating cerebral small vessel vasculopathy is challenging.Recent studies have shown that the glymphatic system plays a crucial role in interstitial solute clearance and the maintenance of brain homeostasis.Increasing evidence also suggests that dysfunction in glymphatic clearance is a key factor in the progression of cerebral small vessel disease.This review begins with a comprehensive introduction to the structure,function,and driving factors of the glymphatic system,highlighting its essential role in brain waste clearance.Afterwards,cerebral small vessel disease was reviewed from the perspective of the glymphatic system,after which the mechanisms underlying their correlation were summarized.Glymphatic dysfunction may lead to the accumulation of metabolic waste in the brain,thereby exacerbating the pathological processes associated with cerebral small vessel disease.The review also discussed the direct evidence of glymphatic dysfunction in patients and animal models exhibiting two subtypes of cerebral small vessel disease:arteriolosclerosis-related cerebral small vessel disease and amyloid-related cerebral small vessel disease.Diffusion tensor image analysis along the perivascular space is an important non-invasive tool for assessing the clearance function of the glymphatic system.However,the effectiveness of its parameters needs to be enhanced.Among various nervous system diseases,including cerebral small vessel disease,glymphatic failure may be a common final pathway toward dementia.Overall,this review summarizes prevention and treatment strategies that target glymphatic drainage and will offer valuable insight for developing novel treatments for cerebral small vessel disease.
基金supported by the European Union Horizon 2020 Research and Innovation Programme(Marie Skłodowska-Curie grant agreement No 847419)supported by the Biotechnology and Biological Sciences Research Council via a Discovery Fellowship(BB/W00934X/1)+6 种基金the Aston University RKE Pump Priming Programmefunded by UKRI’s Research England as part of their Expanding Excellence in England(E3)fundsupported by a UKRI Frontier Research Grant EP/Y023684/1(following assessment as an ERC Advanced grant,FORTIFY,ERC-2022-ADG-101096882 under the UK Government Guarantee scheme)acknowledged a Biotechnology and Biological Sciences Research Council Pioneer Award(BB/Y512874/1)MMS was supported by a Medical Research Council Career Development Award(MR/W027119/1)acknowledged support from the BHF Centre of Research Excellence,University of Oxford(grant code:RE/24/130024)a Biotechnology and Biological Sciences Research Council Pioneer Award(BB/Y512874/1).
文摘Glymphatic flow has been proposed to clear brain waste while we sleep.Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma,with subsequent cerebrospinal fluid drainage to dural lymphatics.Glymphatic disruption is associated with neurological conditions such as Alzheimer’s disease and traumatic brain injury.Therefore,investigating its structure and function may improve understanding of pathophysiology.The recent controversy on whether glymphatic flow increases or decreases during sleep demonstrates that the glymphatic hypothesis remains contentious.However,discrepancies between different studies could be due to limitations of the specific techniques used and confounding factors.Here,we review the methods used to study glymphatic function and provide a toolkit from which researchers can choose.We conclude that tracer analysis has been useful,ex vivo techniques are unreliable,and in vivo imaging is still limited.Finally,we explore the potential for future methods and highlight the need for in vitro models,such as microfluidic devices,which may address technique limitations and enable progression of the field.
基金Supported by American Diabetes AssociationAmerican Heart Association+3 种基金NIH NIEHSNIH NIANIH NINDSand NIH ARRA.
文摘Diabetes mellitus(DM)is a debilitating disorder that impacts all systems of the body and has been increasing in prevalence throughout the globe.DM represents a significant clinical challenge to care for individuals and prevent the onset of chronic disability and ultimately death.Underlying cellular mechanisms for the onset and development of DM are multi-factorial in origin and involve pathways associated with the production of reactive oxygen species and the generation of oxidative stress as well as the dysfunction of mitochondrial cellular organelles,programmed cell death,and circadian rhythm impairments.These pathways can ultimately involve failure in the glymphatic pathway of the brain that is linked to circadian rhythms disorders during the loss of metabolic homeostasis.New studies incorporate a number of promising techniques to examine patients with metabolic disorders that can include machine learning and artificial intelligence pathways to potentially predict the onset of metabolic dysfunction.
基金supported by Zhao Guoping Academician Workstation(Hangzhou Academician Workstation)of Zhejiang Chinese Medical University,Chinese Academy of Sciences-the Alliance of National and International Science Organizations for the Belt and Road Regions Fellowship(CAS-ANSO-FP-2024-06)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB1060000)the Science and Technology Commission of Shanghai Municipality(No.YDZX20233100004032001,China).
文摘Cerebral edema is characterized by fluid accumulation,and the glymphatic system(GS)plays a pivotal role in regulating fluid transport.Using the Tenecteplase system,magnesium salt of salvianolic acid B/ginsenoside Rg1(SalB/Rg1)was injected intravenously into mice 4.5 h after middle cerebral artery occlusion and once every 24 h for the following 72 h.GS function was assessed by Evans blue imaging,near-infrared fluorescence region II(NIR-II)imaging,and magnetic resonance imaging(MRI).SalB/Rg1 had significant effects on reducing the infarct volume and hemorrhagic transformation score,improving neurobehavioral function,and protecting tissue structure,especially inhibiting cerebral edema.Meanwhile,the influx/efflux drainage of GS was enhanced by SalB/Rg1 according to NIR-II imaging and MRI.SalB/Rg1 inhibited matrix metalloproteinase-9(MMP-9)activity,reduced cleavedβ-dystroglycan(β-DG),and stabilized aquaporin-4(AQP4)polarity,which was verified by colocalization with CD31.Our findings indicated that SalB/Rg1 treatment enhances GS function and attenuates cerebral edema,accompanying the regulation of the MMP9/β-DG/AQP4 pathway.
文摘The glymphatic system,a recently discovered cerebrospinal fluid-mediated pathway,plays a crucial role in fluid exchange and waste clearance in the brain.Its dysfunction has been implicated in various neurological disorders,including Alzheimer's disease and traumatic brain injury.Recent studies suggest that alcohol intake has a biphasic effect on the glymphatic system:Low doses of alcohol enhance glymphatic function,whereas high doses lead to glymphatic suppression and cognitive decline,mirroring patterns seen in alcohol-related dementia,providing valuable insights into the dose-dependent effects of alcohol on glymphatic function,but significant gaps persist,particularly regarding the mechanistic understanding and the influence of confounding factors such as sex,age,blood pressure,and wakefulness.Here,we synthesize and critically evaluate the important research findings within this field to gauge its progress and identify new research opportunities.We discuss the specific mechanisms by which alcohol affects the glymphatic system,including how alcohol influences cerebrospinal fluid-interstitial fluid exchange and waste removal.We also discuss the potential of the glymphatic system as a new target,such as through pharmacological or lifestyle interventions aimed at enhancing glymphatic function to treat alcohol use disorder and other neurological disorders associated with glymphatic dysfunction.
基金supported by Zhejiang Provincial Medical and Health Science and Technology Project,Nos.2022KY008(to JW),2023KY001(to JW),2023KY006(to QL)Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project,No.2023ZL220(to QL)。
文摘Various pathological mechanisms represent distinct therapeutic targets for cognitive disorders,but a balance between clearance and production is essential for maintaining the stability of the brain's internal environment.Thus,the glymphatic system may represent a common pathway by which to address cognitive disorders.Using the established model of the glymphatic system as our foundation,this review disentangles and analyzes the components of its clearance mechanism,including the initial inflow of cerebrospinal fluid,the mixing of cerebrospinal fluid with interstitial fluid,and the outflow of the mixed fluid and the clearance.Each section summarizes evidence from experimental animal models and human studies,highlighting the normal physiological properties of key structures alongside their pathological manifestations in cognitive disorders.The same pathologic manifestations of different cognitive disorders appearing in the glymphatic system and the same upstream influences are main points of interest of this review.We conclude this article by discussing new findings and outlining the limitations identified in current research progress.
基金supported by Grants from the National Natural Science Foundation of China(81873749 and 81801072)。
文摘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 glym・phatic 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.
基金supported by the National Natural Science Foundation of China,Nos.82071249 and 81771207 (both to CH)。
文摘The glymphatic system is a relatively recently identified fluid exchange and transpo rt system in the brain.Accumulating evidence indicates thatglymphatic function is impaired not only in central nervous system disorders but also in systemic diseases.Systemic diseases can trigger the inflammatory responses in the central nervous system,occasionally leading to sustained inflammation and functional disturbance of the central nervous system.This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation.In addition,we discuss the hypothesis that disease conditions initially associated with peripheral inflammation ove rwhelm the performance of the glymphatic system,thereby triggering central nervous system dysfun ction,chronic neuroinflammation,and neurodegeneration.Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.
基金supported by the National Key R&D Program of China,No.2021YFF0702203(to HYL)the National Natural Science Foundation of China,No.82101323(to TS)Preferred Foundation of Zhejiang Postdoctors,No.ZJ2021152(to TS).
文摘Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.
文摘BACKGROUND Dysfunction of the glymphatic system in the brain in different stages of altered glucose metabolism and its influencing factors are not well characterized.AIM To investigate the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states,the present study employed diffusion tensor imaging along the perivascular space(DTI-ALPS)index.METHODS Sample size was calculated using the pwr package in R software.This crosssectional study enrolled 22 patients with normal glucose metabolism(NGM),20 patients with prediabetes,and 22 patients with type 2 diabetes mellitus(T2DM).A 3.0T magnetic resonance imaging was used to evaluate the function of the glymphatic system.The mini-mental state examination(MMSE)was used to assess general cognitive function.The DTI-ALPS index of bilateral basal ganglia and the mean DTI-ALPS index was calculated.Further,the correlation between DTI-ALPS and clinical features was assessed.RESULTS The left-side,right-side,and mean DTI-ALPS index in the T2DM group were significantly lower than that in the NGM group.The right-side DTI-ALPS and mean DTI-ALPS index in the T2DM group were significantly lower than those in the prediabetes group.DTI-ALPS index lateralization was not observed.The MMSE score in the T2DM group was significantly lower than that in the NGM and prediabetes group.After controlling for sex,the left-side DTI-ALPS and mean DTI-ALPS index in the prediabetes group were positively correlated with 2-hour postprandial blood glucose level;the left-side DTI-ALPS index was negatively correlated with total cholesterol and low-density lipoprotein level.The right-side DTI-ALPS and mean DTI-ALPS index were negatively correlated with the glycosylated hemoglobin level and waist-to-hip ratio in the prediabetes group.The left-side,right-side,and mean DTI-ALPS index in the T2DM group were positively correlated with height.The left-side and mean DTIALPS index in the T2DM group were negatively correlated with high-density lipoprotein levels.CONCLUSION Cerebral glymphatic system dysfunction may mainly occur in the T2DM stage.Various clinical variables were found to affect the DTI-ALPS index in different glucose metabolism states.This study enhances our understanding of the pathophysiology of diabetic brain damage and provides some potential biological evidence for its early diagnosis.
基金the National Natural Science Foundation of China(31871167 and 81920108016)China Postdoctoral Science Foundation(2016M601882)+2 种基金Suzhou Science and Technology Research Project(SYS201669 and SYS201709)Postdoctoral Science Foundation of Jiangsu Province,China(1601083C)Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Following intrathecal injection of fluorescent tracers,ex vivo imaging of brain vibratome slices has been widely used to study the glymphatic system in the rodent brain.Tracer penetration into the brain is usually quantified by image-processing,even though this approach requires much time and manual operation.Here,we illustrate a simple protocol for the quantitative determination of glymphatic activity using spectrophotofluorometry.At specific time-points following intracisternal or intrastriatal injection of fluorescent tracers,certain brain regions and the spinal cord were harvested and tracers were extracted from the tissue.The intensity of tracers was analyzed spectrophotometrically and their concentrations were quantified from standard curves.Using this approach,the regional and dynamic delivery of subarachnoid CSF tracers into the brain parenchyma was assessed,and the clearance of tracers from the brain was also determined.Furthermore,the impairment of glymphatic influx in the brains of old mice was confirmed using our approach.Our method is more accurate and efficient than the imaging approach in terms of the quantitative determination of glymphatic activity,and this will be useful in preclinical studies.
基金supported by National Institutes of Health,No.R01-EY028125Bright Focus Foundation,No.G2019103+2 种基金Feldstein Medical FoundationResearch to Prevent Blindness/Stavros Niarchos Foundation International Research Collaborators Awardan unrestricted grant from Research to Prevent Blindness to NYU Langone Health Department of Ophthalmology(to KCC)。
文摘Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Recently,it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases.The ability to clear metabolic waste is essential for tissue homeostasis in mammals,including humans.While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions,there is growing evidence of a glymphatic system in the central nervous system,which structurally includes the optic nerve.Named to acknowledge the supportive role of astroglial cells,this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system.Herein,we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve.We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents,aquaporin 4-null rodents,and humans;glymphatic imaging studies in diseases where the optic nerve is impaired;and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health.We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.
基金supported by grants from the National Natural Science Foundation of China(82327803,82151309,81825012 to X.L,82271952 to J.H.L)the National Key Research and Development Program of China(2022YFC2410005 to J.H.L.).
文摘The glymphatic system(GS)is a newly discovered brain anatomy.Its discovery improves our understanding of brain fluid flow and waste removal paths and provides an anatomical basis for the flow of cerebral interstitial fluid(ISF)and cerebrospinal fluid(CSF).GS occurs through a normal exchange within perivascular space(PVS),facilitating the elimination of metabolic wastes generated by nerve cells from the brain.Therefore,the GS is mainly responsible for the removal of metabolic waste.Reduced GS activity has been observed to be associated with central nervous system disorders such as cerebral small vessel disease(CSVD)and neurodegenerative diseases.Its activity is expected to be an indicator for diagnosing diseases and predicting their prognosis.This review introduces the magnetic resonance imaging(MRI)technology related to the GS suitable for clinical use and the difference in the system's activity in normal and abnormal states.Through a summary of previous research,imaging methods suitable for monitoring the activity of the GS in the clinic were proposed,and their diagnostic effect on different brain disorders was analyzed.This review aims to clarify ideas for the clinical translation of basic research focusing on GS and provide future clinical research directions and perspectives.
文摘Diabetes is one of the most devastating medical dilemmas impacting every region of the world severely.The study by Tian et al investigates glymphatic system dys-function in the context of glucose metabolism and diabetes,using diffusion tensor imaging along the perivascular space.The study evaluated individuals with type 2 diabetes mellitus(T2DM),prediabetes,and normal glucose metabolism.It found that prediabetic and T2DM groups had significantly impaired glymphatic func-tion.Glymphatic dysfunction may serve as an early indicator of cognitive deteri-oration in diabetes due to the correlations shown between these abnormalities and clinical factors as well as cognitive performance.The study has some positives,such as thorough evaluations and novel imaging methods,but its cross-sectional design and limited sample size restrict its applicability.More extensive,long-term research is required to verify these results.Furthermore,there are significant cli-nical implications.Patients with diabetes may benefit from immediate therapies to prevent microvascular and macrovascular damage if glymphatic dysfunction is identified early.The study promotes comprehensive diabetes care with a focus on maintaining cognitive function.In conclusion,the work of Tian et al is crucial because it opens the door to better treatment and diagnostic strategies for dia-betes-related cognitive deterioration.
基金Supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education,No.RS-2023-00237287 and No.2021S1A5A8062526Local Government-University Cooperation-Based Regional Innovation Projects,No.2021RIS-003.
文摘The rising prevalence of diabetes and prediabetes globally necessitates a deeper understanding of associated complications,including glymphatic system dysfunction.The glymphatic system,crucial for brain waste clearance,is implicated in cognitive decline and neurodegenerative diseases like Alzheimer’s disease.This letter explores recent research on glymphatic function across different glucose metabolism states.Tian et al’s study reveals significant glymphatic dysfunction in type 2 diabetes mellitus patients,evidenced by lower diffusion tensor imaging analysis along perivascular space indices compared to those with normal glucose metabolism and prediabetes.The research also reveals a link between glymphatic dysfunction and cognitive impairment.Additional research underscores the role of glymphatic impairment in neurodegenerative diseases.These findings highlight the importance of integrating glymphatic health into diabetes management and suggest potential biomarkers for early diagnosis and targeted therapeutic interventions.
基金Supported by European Union-Next Generation EU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘In this article,we comment on an original article published in a recent issue of the World Journal of Diabetes.That observational cross-sectional study focused on investigating the function of the glymphatic system and its clinical correlates in patients with different glucose metabolism states by using diffusion tensor imaging along the perivascular space(DTI-ALPS)index.It was shown that the cerebral glymphatic system may be dysfunctional in patients with type 2 diabetes.Various clinical variables affected the DTI-ALPS index in different glucose metabolism states.In conclusion,the study by Tian et al improves the under-standing of the pathophysiology of diabetes-associated brain damage and pro-vides insights for early diagnosis.
基金supported by the STI2030-Major Projects(2021ZD0200800)the National Natural Science Foundation of China(82288101)Joint Innovation Team for Clinical&Basic Research of Shandong First Medical University(202404).
文摘Identification of the glymphatic system,defined as a perivascular network that facilitates the clearance of metabolic waste through the exchange of cerebrospinal fluid(CSF)and interstitial fluid(ISF),has reshaped perspectives on cerebral homeostasis and its implications for health and disease[1].According to the Global Burden of Disease Study 2019,psychiatric disorders accounted for approximately 4.9%of global disability-adjusted life years[2],highlighting the urgent need for targeted interventions.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘Neurons are the main organizers of neurological activities in the brain.However,its role remains largely unknown in regulating waste clearance in the brain.This issue is addressed in a recent study published in Nature on neuronal dynamics in control of waste removal through cerebrospinal fluid perfusion1.Brain contains billions of neurons that are connected through synapses for precise spatial coordination and high-speed operation in support of functions like thoughts,emotions,and body movements in a dynamic manner.
