Function Of Glymphatic System Research Articles

Promotion of neuroinflammation by the glymphatic system: a new insight into ethanol extracts from Alisma orientale in alleviating obesity-associated cognitive impairment.

Obesity is one of the critical risk factors for cognitive dysfunction. The glymphatic system (GS) plays a key role in the pathogenesis of cognitive deficits. Alisma orientale has been shown to have anti-inflammatory and antihyperlipidemic effects, whereas its effects and underlying mechanisms on obesity-associated cognitive impairment (OACI) are unclear. This work aims to decipher the mechanism of ethanol extracts from Alisma orientale (EEAO) in restoring cognitive impairment in HFD-induced obese mice through a GS approach. The restoration of abnormal glucose/lipid metabolism and excess adipose deposition by EEAO were assayed by biochemical analysis and visually displayed by a micro-CT scanner and Oil Red O staining. Biochemical assays and Western blotting (WB) were used to measure cerebral blood flow (CBF), free fatty acid (FFAs) levels and the structural integrity of the blood-brain barrier (BBB). Microglial activation and neuroinflammation were assessed with immunohistochemistry staining, ELISA and WB. Moreover, GS function was determined by immunofluorescence staining, fluorescence tracer imaging and WB. Finally, the neuropathological features and cognitive functions were detested with immunohistochemistry staining, immunofluorescence and Morris Water Maze. EEAO not only alleviated body weight, cerebral lipid accumulation and serum FFAs in HFD-induced obese mice, but also increased CBF and BBB integrity. EEAO suppressed microglial activation and lipid deposition in the hippocampus and reduced the level of inflammatory cytokines including IL-6, IL-1β and TNF-α in brain tissue. Interestingly, long-term HFD-induced GS dysfunction was significantly restored after EEAO intervention, and neuropathological lesions and cognitive deficits were also markedly rescued. EEAO rescued the cognitive deficits of OACI by inhibiting neuroinflammation and restoring GS dysfunction, indicating a potential remedy for OACI.

Therapeutic approaches to CNS diseases via the meningeal lymphatic and glymphatic system: prospects and challenges.

The brain has traditionally been considered an "immune-privileged" organ lacking a lymphatic system. However, recent studies have challenged this view by identifying the presence of the glymphatic system and meningeal lymphatic vessels (MLVs). These discoveries offer new opportunities for waste clearance and treatment of central nervous system (CNS) diseases. Various strategies have been developed based on these pathways, including modulation of glymphatic system function, enhancement of meningeal lymphatic drainage, and utilization of these routes for drug delivery. Consequently, this review explores the developmental features and physiological roles of the cerebral lymphatic system as well as its significance in various CNS disorders. Notably, strategies for ameliorating CNS diseases have been discussed with a focus on enhancing glymphatic system and MLVs functionality through modulation of physiological factors along with implementing pharmacological and physical treatments. Additionally, emphasis is placed on the potential use of the CNS lymphatic system in drug delivery while envisioning future directions in terms of mechanisms, applications, and translational research.

MRI study of traditional Chinese medicinal physiotherapy to promote glymphatic system function in patients with insomnia

MRI study of traditional Chinese medicinal physiotherapy to promote glymphatic system function in patients with insomnia

Cross vendor test‐retest validation of diffusion tensor analysis along the perivascular space (DTI‐ALPS) method for evaluating glymphatic system function in vascular cognitive impairment and dementia (VCID)

AbstractBackgroundGlymphatic system (GS) is a recently discovered brain‐wide perivascular fluid transport system in the cerebral nervous system (CNS)(Benveniste H et al., 2019) The impairment of glymphatic transport has been demonstrated to be associated with several neurological diseases, in particular the vascular cognitive impairment and dementia (VCID)(Tang J et al., 2022). The diffusion tensor analysis along the perivascular space (DTI‐ALPS) was proposed to non‐invasively evaluate the GS clearance dysfunction which has been used to investigate the GS in various pathologies(Taoka T et al., 2017, Hsu JL et al., 2022). However, studies on the cross‐vendor and test‐retest reliability of DTI‐ALPS method are lacking. The current study aimed to perform cross‐vendor, inter‐rater and test‐retest validations of DTI‐ALPS method by using a cohort from the MarkVCID consortium.MethodFifty participants’ DTI data from the MarkVCID consortium (consists of 7 sites) were included in this study: 15 participants were scanned on four MRI scanners; 35 participants underwent two MR scans within 14 days. The DTI data were acquired used a single shell, b = 1000s/mm2, 40‐direction with a voxel size of 2.02.02.0mm3 and six b = 0 s/mm2 on 3T MR scanners from seven sites, including two Siemens systems, one Philips system and one GE system. Two pipelines by using DSI studio and FSL software were developed for data processing and ALPS index calculation (Figure 1). The mean ALPS (mALPS) index was obtained by the average of bilateral ALPS index and was used for testing the inter‐rater, cross‐vendor and test‐retest reliability. The association between mALPS index and Montreal Cognitive assessment (MoCA) scores were evaluated using a general linear model with age and gender as covariate.ResultThe Bland‐Altman plot and scatterplot illustrated the validation results of the mALPS index analyzed using DSI studio and FSL pipelines (Figure 2). The mALPS index demonstrated favorable inter‐scanner reproducibility (ICC = 0.77 to 0.95, P< 0.001), inter‐rater reliability (ICC = 0.96 to 1, P< 0.001) and test‐retest repeatability (ICC = 0.89 to 0.95, P< 0.001). A significantly positive correlation was observed between mALPS index and MoCA scores (r = 0.502, P< 0.01) (Figure 3).ConclusionThe mALPS index offers a robust potential biomarker for evaluating GS clearance function in VCID.

Multivalent Display of Erythropoietin on Quantum Dots Enhances Aquaporin-4 Expression and Water Transport in Human Astrocytes In Vitro.

In mammalian cells, growth factor-induced intracellular signaling and protein synthesis play a critical role in cellular physiology and homeostasis. In the brain's glymphatic system (GS), the water-conducting activity of aquaporin-4 (AQPN-4) membrane channels (expressed in polarized fashion on astrocyte end-feet) mediates the clearance of wastes through the convective transport of fluid and solutes through the perivascular space. The glycoprotein erythropoietin (EPO) has been shown to induce the astrocyte expression of AQPN-4 via signaling through the EPO receptor and the JAK/STAT signaling pathway. Here, we self-assemble EPO in a multivalent fashion onto the surface of semiconductor quantum dots (QDs) (driven by polyhistidine-based self-assembly) to drive the interaction of the bioconjugates with EPOR on human astrocytes (HA). This results in a 2-fold augmentation of JAK/STAT signaling activity and a 1.8-fold enhancement in the expression of AQPN-4 in cultured primary HA compared to free EPO. This translates into a 2-fold increase in the water transport rate in HA cells as measured by the calcein AM water transport assay. Importantly, EPO-QD-induced augmented AQPN-4 expression does not elicit any deleterious effect on the astrocyte viability. We discuss our results in the context of the implications of EPO-nanoparticle (NP) bioconjugates for use as research tools to understand the GS and their potential as therapeutics for the modulation of GS function. More generally, our results illustrate the utility of NP bioconjugates for the controlled modulation of growth factor-induced intracellular signaling.

Structural connectivity as a predictive factor for responsiveness to levetiracetam treatment in epilepsy.

To investigate whether structural connectivity or glymphatic system function is a potential predictive factor for levetiracetam (LEV) response in patients with newly diagnosed epilepsy. We enrolled patients with newly diagnosed epilepsy who were administered LEV as initial monotherapy and underwent diffusion tensor imaging (DTI) at diagnosis. We categorized the patients into drug response. We used graph theory to calculate the network measures for structural connectivity based on the DTI scans in patients with epilepsy. Additionally, we evaluated glymphatic system function by calculating the DTI analysis along the perivascular space (DTI-ALPS) index based on DTI scans. We enrolled 84 patients with epilepsy. The clinical factors and DTI-ALPS index did not differ between the groups. However, some of the structural connectivity measures significantly differ between the groups. The poor responders exhibited a higher mean clustering coefficient, global efficiency, and small-worldness index than the good responders (p = 0.003, p = 0.048, and p = 0.038, respectively). In the receiver operating characteristic curve analysis, the mean clustering coefficient exhibited the highest performance in predicting the responsiveness to LEV (area under the curve of 0.677). In the multiple logistic regression analysis, the mean clustering coefficient of the structural connectivity measures was the only significant predictor of LEV response (p = 0.014). Furthermore, in the survival analysis, the mean clustering coefficient was the only significant predictor of LEV response (p = 0.026). We demonstrated that structural connectivity is a potential predictive factor for responsiveness to LEV treatment in patients with newly diagnosed epilepsy.

Exploring the Association Linking Head Position and Sleep Architecture to Motor Impairment in Parkinson's Disease: An Exploratory Study.

Patients with Parkinson's disease (PD) tend to sleep more frequently in the supine position and less often change head and body position during sleep. Besides sleep quality and continuity, head and body positions are crucial for glymphatic system (GS) activity. This pilot study evaluated sleep architecture and head position during each sleep stage in idiopathic PD patients without cognitive impairment, correlating sleep data to patients' motor and non-motor symptoms (NMS). All patients underwent the multi-night recordings, which were acquired using the Sleep Profiler headband. Sleep parameters, sleep time in each head position, and percentage of slow wave activity (SWA) in sleep, stage 3 of non-REM sleep (N3), and REM sleep in the supine position were extracted. Lastly, correlations with motor impairment and NMS were performed. Twenty PD patients (65.7 ± 8.6 y.o, ten women) were included. Sleep architecture did not change across the different nights of recording and showed the prevalence of sleep performed in the supine position. In addition, SWA and N3 were more frequently in the supine head position, and N3 in the supine decubitus correlated with REM sleep performed in the same position; this latter correlated with the disease duration (correlation coefficient = 0.48, p-value = 0.03) and motor impairment (correlation coefficient = 0.53, p-value = 0.02). These preliminary results demonstrated the importance of monitoring sleep in PD patients, supporting the need for preventive strategies in clinical practice for maintaining the lateral head position during the crucial sleep stages (SWA, N3, REM), essential for permitting the GS function and activity and ensuring brain health.

Mechanism of anti-AD action of OAB-14 by enhancing the function of glymphatic system

The number of patients with Alzheimer's disease is increasing year by year, but only a few medications are available. We found that OAB-14, a new small molecule, can improve cognitive deficits in various mouse AD models. The structure and mechanism of OAB-14 are distinct from anti-AD medications that have been unsuccessful in recent clinical trials. OAB-14 can effectively reduce the accumulation of Aβ in the brain, but has no inhibitory effect on Aβ production enzymes. Reportedly, Aβ can be drained into the systemic circulation to be metabolized through the glymphatic system and meningeal lymphatic vessels. Our research has shown that OAB-14 is capable of enhancing the glymphatic system function by promoting the influx and efflux of the CSF tracers to the brain and deep cervical lymph nodes, respectively. After blocking the central lymphatic drainage, the effect of OAB-14 in improving cognitive impairments disappeared. Furthermore, OAB-14 may up-regulate AQP4 expression by acting on PPARγ-P2X7r-AQP4 pathway and protect the polarity of AQP4 by upregulating the expression of SNTA1, Agrin, and Abca1, which are closely associated with the proper functioning of the glymphatic system. In summary, OAB-14 can promote the clearance of brain Aβ through the glymphatic system and improve cognitive impairment.

Anti-seizure medication response and the glymphatic system in patients with focal epilepsy.

We aimed to evaluate (i) glymphatic system function in patients with focal epilepsy in comparison with healthy controls, and (ii) the association between anti-seizure medication (ASM) response and glymphatic system function by using diffusion tensor image analysis along the perivascular space (DTI-ALPS). We retrospectively enrolled 100 patients with focal epilepsy who had normal brain magnetic resonance imaging (MRI) findings, and classified them as "poor" or "good" ASM responders according to their seizure control at the time of brain MRI. We also included 79 age- and sex-matched healthy controls. All patients and healthy controls underwent conventional brain MRI and diffusion tensor imaging. The DTI-ALPS index was calculated using the DSI studio program. Of the 100 patients with focal epilepsy, 38 and 62 were poor and good ASM responders, respectively. The DTI-ALPS index differed significantly between patients with focal epilepsy and healthy controls and was significantly lower in patients with focal epilepsy (1.55 vs. 1.70; p < 0.001). The DTI-ALPS index also differed significantly according to ASM response and was lower in poor ASM responders (1.48 vs. 1.59; p = 0.047). Furthermore, the DTI-ALPS index was negatively correlated with age (r = -0.234, p = 0.019) and duration of epilepsy (r = -0.240, p = 0.016) in patients with focal epilepsy. Our study is the first to identify, in focal epilepsy patients, a greater reduction in glymphatic system function among poor ASM responders compared to good responders. To confirm our results, further prospective multicenter studies with large sample sizes are needed.

Melatonin alleviates depression-like behaviors and cognitive dysfunction in mice by regulating the circadian rhythm of AQP4 polarization

Depression is a common chronic psychiatric illness, which is resistant to medical treatments. While melatonin may alleviate certain depression symptoms, evidence for its efficacy against core symptoms is lacking. Here, we tested a mechanism whereby melatonin rescues the behavioral outcomes of the chronic unpredictable mild stress (CUMS) mouse model of depression. CUMS mice showed depressive behaviors to tail suspension, open field behavior, and sucrose preference test, and cognitive dysfunction in the Morris water maze. Impairments in these measures were relieved by melatonin treatment. Moreover, CUMS mice had impaired glymphatic function across the sleep-wake cycle due to the astrocytic loss and disturbance of circadian regulation of the polarized expression of aquaporin-4 (AQP4) water channels in perivascular astrocytes. EEG results in CUMS mice showed a reduced total sleep time and non-rapid eye movement (NREM) sleep, due to sleep fragmentation in the light phase. CUMS mice lost the normal rhythmic expressions of circadian proteins Per2, Cry2, Bmal1, Clock, and Per1. However, the melatonin treatment restored glymphatic system function and the polarization of AQP4, while improving sleep structure, and rectifying the abnormal expression of Per2, Bmal1, Clock, and Per1 in CUMS mice. Interestingly, Per2 expression correlated negatively with the polarization of AQP4. Further studies demonstrated that Per2 directed the location of AQP4 expression via interactions with the α-dystrobrevin (Dtna) subunit of AQP4 in primary cultured astrocytes. In conclusion, we report a new mechanism whereby melatonin improves depression outcomes by regulating the expression of the circadian protein Per2, maintaining the circadian rhythm of astrocytic AQP4 polarization, and restoring glymphatic function.

Changes in the glymphatic system before and after dialysis initiation in patients with end-stage kidney disease

Introduction The aims of this study were to evaluate 1) glymphatic system function in patients with end-stage kidney disease (ESKD) before initiating dialysis compared to healthy controls, and 2) changes in the glymphatic system function after kidney replacement therapy including dialysis in patients with ESKD using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. Materials and methods This study was prospectively conducted at a single hospital. We enrolled 14 neurologically asymptomatic patients who first initiated hemodialysis or peritoneal dialysis for ESKD and 17 healthy controls. Patients had magnetic resonance imaging scans before initiating dialysis and again 3 months after initiating dialysis and the DTI-ALPS index was calculated. We compared the DTI-ALPS index before and after the initiation of dialysis and compared the DTI-ALPS index between the patients with ESKD and healthy control. Results There were differences in the DTI-ALPS index between ESKD patients before initiating dialysis and healthy controls (1.342 vs. 1.633, p = 0.003). DTI-ALPS index between ESKD patients before initiating dialysis and those after dialysis were not different (1.342 vs. 1.262, p = 0.386). There was a positive correlation between DTI-ALPS index and phosphate (r = 0.610, p = 0.020) in patients with ESKD. Conclusion We confirmed the presence of glymphatic dysfunction in patients with ESKD. However, there was no difference in the glymphatic system before and after dialysis initiation. This finding may be related to uremic toxins that are not removed by dialysis in patients with ESKD. This study can be used for the development of pathophysiology of patients with ESKD.

Application of Multimodal MRI in the Early Diagnosis of Autism Spectrum Disorders: A Review.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in children. Early diagnosis and intervention can remodel the neural structure of the brain and improve quality of life but may be inaccurate if based solely on clinical symptoms and assessment scales. Therefore, we aimed to analyze multimodal magnetic resonance imaging (MRI) data from the existing literature and review the abnormal changes in brain structural-functional networks, perfusion, neuronal metabolism, and the glymphatic system in children with ASD, which could help in early diagnosis and precise intervention. Structural MRI revealed morphological differences, abnormal developmental trajectories, and network connectivity changes in the brain at different ages. Functional MRI revealed disruption of functional networks, abnormal perfusion, and neurovascular decoupling associated with core ASD symptoms. Proton magnetic resonance spectroscopy revealed abnormal changes in the neuronal metabolites during different periods. Decreased diffusion tensor imaging signals along the perivascular space index reflected impaired glymphatic system function in children with ASD. Differences in age, subtype, degree of brain damage, and remodeling in children with ASD led to heterogeneity in research results. Multimodal MRI is expected to further assist in early and accurate clinical diagnosis of ASD through deep learning combined with genomics and artificial intelligence.

Characterizing cerebrospinal fluid mobility using heavily T2-weighted 3D fast spin echo (FSE) imaging with improved multi-directional diffusion-sensitized driven-equilibrium (iMDDSDE) preparation

Cerebrospinal fluid (CSF) flow patterns and their relationship with arterial pulsation can depict the function of glymphatic system (GS). We propose an improved multi-directional diffusion-sensitized driven-equilibrium (iMDDSDE) prepared heavily T2-weighted 3D FSE (iMDDSDE-HT2) magnetic resonance imaging (MRI) method to noninvasively assess the mobility (MO) of CSF distributed in the ventricles and perivascular spaces (PVS). This method could obtain 3D high resolution (1 mm isotropic) imaging of CSF MO with full brain coverage within five min and distinguish the CSF MO across different pulse phases using a peripheral pulse unit (PPU). The MO curves had the largest amplitude value in the PVS of middle cerebral artery (11.11 × 10−9 m2/s) and the largest amplitude growth rate in the posterior cerebral artery (189%). The average coefficient of variations (CVs) in non-pulse trigger and pulse phase 1 and 3 were 0.11, 0.10 and 0.09 respectively. The MO in older healthy participants was lower compared to the young participants, and the MO in cerebral major artery stenosis patients with acute ischemia stroke (AIS) were lower compared to those without AIS in several ventriclar ROIs (P < 0.05). This sequence is a clinically feasible method to effectively evaluate CSF flow patterns in human brain.

Glymphatic system dysfunction in restless legs syndrome: evidenced by diffusion tensor imaging along the perivascular space.

There is growing evidence pointing at glymphatic system dysfunction in diseases with circadian disruption, such as sleep disorders. Lower diffusivity in the direction of perivascular space has been shown in several neurological and sleep-related disorders; however, its role in restless legs syndrome (RLS) is unclear. We hypothesized that similarly, in RLS the diffusivity in glymphatic system is decreased. Here, we aimed to evaluate glymphatic system functionality in patients with RLS, compare it to healthy controls, and analyze the correlation between its function and clinical characteristics. Sixty-nine patients with primary RLS and 51 healthy controls were recruited at a tertiary hospital. All participants underwent diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI) using a 3T MRI scanner, and the DTI along the perivascular space (DTI-ALPS) index was calculated using DTI data. We compared the DTI-ALPS index between the patients with RLS and healthy controls. We also conducted the correlation analysis between the DTI-ALPS index and clinical characteristics, including age, age of onset, symptom duration, and RLS severity. DTI-ALPS index differed significantly between the patients with RLS and healthy controls; the DTI-ALPS index in the patients with RLS was lower than that in the healthy controls (1.48 vs. 0.60, p = 0.008). There was no significant correlation between the DTI-ALPS index and clinical characteristics. A significantly lower DTI-ALPS index in patients with RLS suggests that the glymphatic system function is impaired in patients with RLS.

Evaluation of glymphatic system activity by diffusion tensor image analysis along the perivascular space in presbycusis.

Previous studies have suggested that presbycusis (age-related hearing loss) is accompanied with cognitive decline and dementia. However, the neural mechanism underlying the cognitive decline in presbycusis remains unclear. This study aimed to evaluate the glymphatic system function in presbycusis patients compared to healthy controls using diffusion tensor imaging (DTI) with the perivascular space (DTI-ALPS) method. DTI scans were obtained from 30 presbycusis patients with cognitive decline (PCD), 30 presbycusis patients with no cognitive decline (PNCD) and 40 age-, gender-, and education-matched healthy controls (HCs). The DTI-ALPS index was calculated for each group. We evaluated the differences in the DTI-ALPS index among PCD, PNCD and HCs. In addition, we conducted a correlation analysis between the DTI-ALPS index and cognitive performance. There were significant differences of the DTI-ALPS index among three groups. Post-hoc analysis suggested that the DTI-ALPS index in PCD was significantly lower patients in relative to PNCD and HCs (1.49147 vs. 1.57441 vs. 1.62020, p < 0.001). After correcting for age, gender, and education, the DTI-ALPS index is positively correlated with the MoCA scores (rho = 0.426, p = 0.026). Presbycusis patients with cognitive impairment exhibited decreased glymphatic activity than those without cognitive impairment and HCs. The DTI-ALPS index may provide useful disease progression or treatment biomarkers for patients with presbycusis as an indicator of modulation of glymphatic activity.

Glymphatic-System Function Is Associated with Addiction and Relapse in Heroin Dependents Undergoing Methadone Maintenance Treatment.

This study investigates the impact of methadone maintenance treatment (MMT) on the brain glymphatic system (GS) in opioid addiction in China. A total of 51 male MMT patients, 48 demographically matched healthy controls (HCs), and 20 heroin dependents (HDs) were recruited for this study. The GS functioning was assessed using diffusion-tensor-imaging analysis along perivascular spaces (DTI-ALPS index) and the bilateral ALPS divergency (DivALPS). Group differences were analyzed utilizing ANOVA and two-sample t-tests. The relationship between DivALPS and relapse rate was explored using regression analysis. The DTI-ALPS index was significantly higher for the left-side brain than the right side in all three groups. There was a significant difference for the right side (p = 0.0098) between the groups. The MMT and HD groups showed significantly higher DTI-ALPS than the HC group (p = 0.018 and 0.016, respectively). The DivALPS varied significantly among the three groups (p = 0.04), with the HD group showing the lowest and the HC group the highest values. Significant negative relationships were found between relapse count, DivALPS (p < 0.0001, Exp(B) = 0.6047), and age (p < 0.0001, Exp(B) = 0.9142). The findings suggest that MMT may contribute to promoting brain GS recovery in heroin addicts, and modulation of the GS may serve as a potential biomarker for relapse risk, providing insights into novel therapeutic strategies.

Research progress in the evaluation of glymphatic system function by the DTI-ALPS method.

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

Glymphatic system impairment in Alzheimer's disease: associations with perivascular space volume and cognitive function.

To investigate glymphatic function in Alzheimer's disease (AD) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and to explore the associations between DTI-ALPS index and perivascular space (PVS) volume, as well as between DTI-ALPS index and cognitive function. Thirty patients with PET-CT-confirmed AD (15 AD dementia; 15 mild cognitive impairment due to AD) and 26 age- and sex-matched cognitively normal controls (NCs) were included in this study. All participants underwent neurological MRI and cognitive assessments. Bilateral DTI-ALPS indices were calculated. PVS volume fractions were quantitatively measured at three locations: basal ganglia (BG), centrum semiovale, and lateral ventricle body level. DTI-ALPS index and PVS volume fractions were compared among three groups; correlations among the DTI-ALPS index, PVS volume fraction, and cognitive scales were analyzed. Patients with AD dementia showed a significantly lower DTI-ALPS index in the whole brain (p = 0.009) and in the left hemisphere (p = 0.012) compared with NCs. The BG-PVS volume fraction in patients with AD was significantly larger than the fraction in NCs (p = 0.045); it was also negatively correlated with the DTI-ALPS index (r = - 0.433, p = 0.021). Lower DTI-ALPS index was correlated with worse performance in the Boston Naming Test (β = 0.515, p = 0.008), Trail Making Test A (β = - 0.391, p = 0.048), and Digit Span Test (β = 0.408, p = 0.038). The lower DTI-ALPS index was found in patients with AD dementia, which may suggest impaired glymphatic system function. DTI-ALPS index was correlated with BG-PVS enlargement and worse cognitive performance in certain cognitive domains. Diffusion tensor image analysis along the perivascular space index may be applied as a useful indicator to evaluate the glymphatic system function. The impaired glymphatic system in patients with Alzheimer's disease (AD) dementia may provide a new perspective for understanding the pathophysiology of AD. • Patients with Alzheimer's disease dementia displayed a lower diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, possibly indicating glymphatic impairment. • A lower DTI-ALPS index was associated with the enlargement of perivascular space and cognitive impairment. • DTI-ALPS index could be a promising biomarker of the glymphatic system in Alzheimer's disease dementia.

Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice.

We aimed to assess the effects of cerebral glucagon-like peptide-1 receptor (GLP-1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI). Immunofluorescence was employed to evaluate glymphatic system function. The blood-brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests. Cerebral GLP-1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN-020 abolished the protective effect of the GLP-1R agonist against cognitive impairment. Cerebral GLP-1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.

The asymmetry of glymphatic system dysfunction in patients with temporal lobe epilepsy: A DTI-ALPS study

Background and purposeWhile the occurrence of glymphatic system dysfunction has been observed in temporal lobe epilepsy (TLE), the potential asymmetry of this system has yet to be investigated in the TLE context. We aimed to investigate the glymphatic system function in both hemispheres and to analyze asymmetric features of the glymphatic system in TLE patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. Materials and methods43 patients (left TLE (LTLE), n = 20; right TLE (RTLE), n = 23) and 39 healthy controls (HC) were enrolled in this study. The DTI-ALPS index was calculated for the left (left ALPS index) and right (right ALPS index) hemispheres respectively. An asymmetry index (AI) was calculated by AI = (Right − Left)/ [(Right + Left)/2] to represent the asymmetric pattern. Independent two sample t-test, two-sample paired t-test or one-way ANOVA with Bonferroni correction were conducted to compare the differences in ALPS indices and AI among the groups. ResultsBoth left ALPS index (p = 0.040) and right ALPS index (p = 0.001) of RTLE patients were significantly decreased, while only left ALPS index of LTLE patients (p = 0.005) was reduced. Compared to contralateral ALPS index, the ipsilateral ALPS index was significantly decreased in TLE (p = 0.008) and RTLE (p = 0.009) patients. Leftward asymmetry of the glymphatic system was found in HC (p = 0.045) and RTLE (p = 0.009) patients. The LTLE patients presented reduced asymmetric traits when compared to RTLE patients (p = 0.029). ConclusionThe TLE patients exhibited altered ALPS indices, which could be triggered by glymphatic system dysfunction. Altered ALPS indices were more severe in ipsilateral than in the contralateral hemisphere. Moreover, LTLE and RTLE patients exhibited different change patterns of the glymphatic system. In addition, glymphatic system function presented asymmetric patterns in both normal adult brain and RTLE patients.