Involvement of the glymphatic/meningeal lymphatic system in Alzheimer's disease: insights into proteostasis and future directions.

BACKGROUND:  Alzheimer's disease (AD) is pathologically characterized by the abnormal accumulation of Aß and tau proteins. There has long been a keen interest among researchers in understanding how Aß and tau are ultimately cleared in the brain. The discovery of this glymphatic system introduced a novel perspective on protein clearance and it gained recognition as one of the major brain clearance pathways for clearing these pathogenic proteins in AD. This finding has sparked interest in exploring the potential contribution of the glymphatic/meningeal lymphatic system in AD. Furthermore, there is a growing emphasis and discussion regarding the possibility that activating the glymphatic/meningeal lymphatic system could serve as a novel therapeutic strategy against AD. OBJECTIVES:  Given this current research trend, the primary focus of this comprehensive review is to highlight the role of the glymphatic/meningeal lymphatic system in the pathogenesis of AD. The discussion will encompass future research directions and prospects for treatment in relation to the glymphatic/meningeal lymphatic system.

Imaging of brain barrier inflammation and brain fluid drainage in human neurological diseases.

The intricate relationship between the central nervous system (CNS) and the immune system plays a crucial role in the pathogenesis of various neurological diseases. Understanding the interactions among the immunopathological processes at the brain borders is essential for advancing our knowledge of disease mechanisms and developing novel diagnostic and therapeutic approaches. In this review, we explore the emerging role of neuroimaging in providing valuable insights into brain barrier inflammation and brain fluid drainage in human neurological diseases. Neuroimaging techniques have enabled us not only to visualize and assess brain structures, but also to study the dynamics of the CNS in health and disease in vivo. By analyzing imaging findings, we can gain a deeper understanding of the immunopathology observed at the brain-immune interface barriers, which serve as critical gatekeepers that regulate immune cell trafficking, cytokine release, and clearance of waste products from the brain. This review explores the integration of neuroimaging data with immunopathological findings, providing valuable insights into brain barrier integrity and immune responses in neurological diseases. Such integration may lead to the development of novel diagnostic markers and targeted therapeutic approaches that can benefit patients with neurological disorders.

The glymphatic system and Amyotrophic lateral sclerosis.

The glymphatic system and the meningeal lymphatic vessels provide a pathway for transport of solutes and clearance of toxic material from the brain. Of specific relevance to ALS, this is applicable for TDP-43 and glutamate, both major elements in disease pathogenesis. Flow is propelled by arterial pulsation, respiration, posture, as well as the positioning and proportion of aquaporin-4 channels (AQP4). Non-REM slow wave sleep is the is key to glymphatic drainage which discontinues during wakefulness. In Parkinson's disease and Alzheimer's disease, sleep impairment is known to predate the development of characteristic clinical features by several years and is associated with progressive accumulation of toxic proteinaceous products. While sleep issues are well described in ALS, consideration of preclinical sleep impairment or the potential of a failing glymphatic system in ALS has rarely been considered. Here we review how the glymphatic system may impact ALS. Preclinical sleep impairment as an unrecognized major risk factor for ALS is considered, while potential therapeutic options to improve glymphatic flow are explored.

The glymphatic system as a potential biomarker and therapeutic target in secondary progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a refractory immune-mediated inflammatory disease of the central nervous system, and some cases of the major subtype, relapsing-remitting (RR), transition to secondary progressive (SP). However, the detailed pathogenesis, biomarkers, and effective treatment strategies for secondary progressive multiple sclerosis have not been established. The glymphatic system, which is responsible for waste clearance in the brain, is an intriguing avenue for investigation and is primarily studied through diffusion tensor image analysis along the perivascular space (DTI-ALPS). This study aimed to compare DTI-ALPS indices between patients with RRMS and SPMS to uncover potential differences in their pathologies and evaluate the utility of the glymphatic system as a possible biomarker. METHODS: A cohort of 26 patients with MS (13 RRMS and 13 SPMS) who met specific criteria were enrolled in this prospective study. Magnetic resonance imaging (MRI), including diffusion MRI, 3D T1-weighted imaging, and relaxation time quantification, was conducted. The ALPS index, a measure of glymphatic function, was calculated using diffusion-weighted imaging data. Demographic variables, MRI metrics, and ALPS indices were compared between patients with RRMS and those with SPMS. RESULTS: The ALPS index was significantly lower in the SPMS group. Patients with SPMS exhibited longer disease duration and higher Expanded Disability Status Scale (EDSS) scores than those with RRMS. Despite these differences, the correlations between the EDSS score, disease duration, and ALPS index were minimal, suggesting that the impact of these clinical variables on ALPS index variations was negligible. DISCUSSION: Our study revealed the potential microstructural and functional differences between RRMS and SPMS related to glymphatic system impairment. Although disease severity and duration vary among subtypes, their influence on ALPS index differences appears to be limited. This highlights the stronger association between SP conversion and changes in the ALPS index. These findings align with those of previous research, indicating the involvement of the glymphatic system in the progression of MS. CONCLUSION: Although the causality remains uncertain, our study suggests that a reduced ALPS index, reflecting glymphatic system dysfunction, may contribute to MS progression, particularly in SPMS. This suggests the potential of the ALPS index as a diagnostic biomarker for SPMS and underscores the potential of the glymphatic system as a therapeutic target to mitigate MS progression. Future studies with larger cohorts and pathological validation are necessary to confirm these findings. This study provides new insights into the pathogenesis of SPMS and the potential for innovative therapeutic strategies.

Magnetic Resonance Imaging Diagnosis in Normal Pressure Hydrocephalus.

BACKGROUND: Idiopatic normal pressure hydrocephalus (iNPH) is a progressive neurologic syndrome featured by the triad of gait disturbance, mental deterioration and urinary incontinence, associated with ventriculomegaly and normal cerebrospinal fluid (CSF) pressure. The clinical presentation may be atypical or incomplete, or mimicked by other diseases, so conventional neuroradiologic imaging plays an important role in defining this pathology. iNPH pathophysiologic mechanisms have not yet been fully elucidated, although several studies have demonstrated the involvement of the glymphatic system, a highly organized fluid transport system, the malfunction of which is involved in the pathogenesis of several disorders including normotensive hydrocephalus. METHODS: Recent studies have shown how crucial in the diagnosis of this pathology is the definition of morphologic biomarkers, such as ventricular enlargement disproportionate to cerebral atrophy and associated ballooning of frontal horns; periventricular hyperintensities; and corpus callosum thinning and elevation, with callosal angle <90 degrees. RESULTS: Another interesting feature that is becoming a well-recognized factor to look for and useful for the diagnosis of iNPH is disproportionately enlarged subarachnoid space hydrocephalus, which includes enlarged ventricles, tight high-convexity and medial surface subarachnoid spaces, and expanded Sylvian fissures. A correct choice of MRI sequences is important for a proper characterization identification of others diseases that may underlie this pathology. Magnetic resonance imaging allows us to evaluate CSF flow, enabling us to define qualitative and quantitative parameters necessary for the purpose of accurate iNPH diagnosis. CONCLUSIONS: iNPH can represent a real diagnostic challenge; a proper correlation among clinical features, traditional MRI, and CSF dynamics analysis can lead to a correct diagnosis.

Role of the glymphatic system and perivascular spaces as a potential biomarker for post-stroke epilepsy.

Stroke is one of the most common causes of acquired epilepsy, which can also result in disability and increased mortality rates particularly in elderly patients. No preventive treatment for post-stroke epilepsy is currently available. Development of such treatments has been greatly limited by the lack of biomarkers to reliably identify high-risk patients. The glymphatic system, including perivascular spaces (PVS), is the brain's waste clearance system, and enlargement or asymmetry of PVS (ePVS) is hypothesized to play a significant role in the pathogenesis of several neurological conditions. In this article, we discuss potential mechanisms for the role of perivascular spaces in the development of post-stroke epilepsy. Using advanced MR-imaging techniques, it has been shown that there is asymmetry and impairment of glymphatic function in the setting of ischemic stroke. Furthermore, studies have described a dysfunction of PVS in patients with different focal and generalized epilepsy syndromes. It is thought that inflammatory processes involving PVS and the blood-brain barrier, impairment of waste clearance, and sustained hypertension affecting the glymphatic system during a seizure may play a crucial role in epileptogenesis post-stroke. We hypothesize that impairment of the glymphatic system and asymmetry and dynamics of ePVS in the course of a stroke contribute to the development of PSE. Automated ePVS detection in stroke patients might thus assist in the identification of high-risk patients for post-stroke epilepsy trials. PLAIN LANGUAGE SUMMARY: Stroke often leads to epilepsy and is one of the main causes of epilepsy in elderly patients, with no preventative treatment available. The brain's waste removal system, called the glymphatic system which consists of perivascular spaces, may be involved. Enlargement or asymmetry of perivascular spaces could play a role in this and can be visualised with advanced brain imaging after a stroke. Detecting enlarged perivascular spaces in stroke patients could help identify those at risk for post-stroke epilepsy.

Increased perivascular space volume in white matter and basal ganglia is associated with cognition in Parkinson's Disease.

Perivascular spaces (PVS), fluid-filled compartments surrounding brain vasculature, are an essential component of the glymphatic system responsible for transport of waste and nutrients. Glymphatic system impairment may underlie cognitive deficits in Parkinson's disease (PD). Studies have focused on the role of basal ganglia PVS with cognition in PD, but the role of white matter PVS is unknown. This study examined the relationship of white matter and basal ganglia PVS with domain-specific and global cognition in individuals with PD. Fifty individuals with PD underwent 3T T1w magnetic resonance imaging (MRI) to determine PVS volume fraction, defined as PVS volume normalized to total regional volume, within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of global cognitive function (Montreal Cognitive Assessment, and global cognitive composite score), and cognitive-specific domains (executive function, memory, visuospatial function, attention, and language). Higher white matter rostral middle frontal PVS was associated with lower scores in both global cognitive and visuospatial function. In the basal ganglia higher PVS was associated with lower scores for memory with a trend towards lower global cognitive composite score. While previous reports have shown that greater amount of PVS in the basal ganglia is associated with decline in global cognition in PD, our findings suggest that increased white matter PVS volume may also underlie changes in cognition.

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

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

[Perifocal edema and glymphatic system dysfunction: quantitative assessment based on diffusion tensor magnetic resonance imaging]. / Peritumoroznyi otek i disfunktsiya glimfaticheskoi sistemy golovnogo mozga: kolichestvennaya otsenka na osnove diffuzionno-tenzornoi MRT.

BACKGROUND: Pathogenesis of peritumoral cerebral edema is unclear and potentially associated with glymphatic system dysfunction. Diffusion tensor MRI (DT-MRI) with analysis of ALPS (Analysis along the Perivascular Space) index may be valuable for assessment of edema. This approach visualizes fluid flow along perivascular spaces of deep cerebral veins. OBJECTIVE: To assess glymphatic system function in supratentorial tumors and healthy volunteers using DT-MRI. MATERIAL AND METHODS: There were 52 patients (59% men) aged 43 (28-64) years with supratentorial tumors (meningioma - 20, grade 3-4 glioma - 15, metastases - 9, lymphoma - 8). Tumors and perifocal edema did not involve deep cerebral veins. The control group included 6 healthy volunteers aged 34-66 years. MRI protocol (Signa HDxt, 3 T) contained standard T1, T2, T2FLAIR, DWI and post-contrast T1 (3D BRAVO). DT-MRI had the following parameters: TR=10 000 ms, TEmin=102 ms, FOV=240 mm, isotropic voxel size 3×3×3 mm3, 60 directions of diffusion gradients. Measurements were carried out at b-factor 0 and 1000 s/mm2. Analysis was carried out in the ReadyView software. RESULTS: Right- and left-sided ALPS indices were similar in the control group (p=0.917). Perifocal edema (regardless of histological type of tumor) in the ipsilateral hemisphere was accompanied by significantly lower ALPS index (p<0.005), while these values in contralateral (intact) hemisphere were similar in both groups (p=0.7). CONCLUSION: We found significantly lower ALPS index in deep parts of the affected hemisphere in patients with perifocal edema. These data can indicate the role of glymphatic system dysfunction in pathogenesis of this pathology.

Associations of Enlarged Perivascular Spaces With Brain Lesions, Brain Age, and Clinical Outcomes in Chronic Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Enlarged perivascular spaces (ePVS) have been identified as a key signature of glymphatic system dysfunction in neurologic conditions. The incidence and clinical implications of ePVS after traumatic brain injury (TBI) are not yet understood. We investigated whether individuals with chronic moderate-to-severe TBI had an increased burden of ePVS and whether ePVS burden is modulated by the presence of focal lesions, older brain age, and poorer sleep quality. We examined whether an increased burden of ePVS was associated with poorer cognitive and emotional outcomes. METHODS: Using a cross-sectional design, participants with a single moderate-to-severe chronic TBI (sustained ≥10 years ago) were recruited from an inpatient rehabilitation program. Control participants were recruited from the community. Participants underwent 3T brain MRI, neuropsychological assessment, and clinical evaluations. ePVS burden in white matter was quantified using automated segmentation. The relationship between the number of ePVS, group membership, focal lesions, brain age, current sleep quality, and outcome was modeled using negative binomial and linear regressions. RESULTS: This study included 100 participants with TBI (70% male; mean age = 56.8 years) and 75 control participants (54.3% male; mean age = 59.8 years). The TBI group had a significantly greater burden of ePVS (prevalence ratio rate [PRR] = 1.29, p = 0.013, 95% CI 1.05-1.57). The presence of bilateral lesions was associated with greater ePVS burden (PRR = 1.41, p = 0.021, 95% CI 1.05-1.90). There was no association between ePVS burden, sleep quality (PRR = 1.01, p = 0.491, 95% CI 0.98-1.048), and sleep duration (PRR = 1.03, p = 0.556, 95% CI 0.92-1.16). ePVS was associated with verbal memory (ß = -0.42, p = 0.006, 95% CI -0.72 to -0.12), but not with other cognitive domains. The burden of ePVS was not associated with emotional distress (ß = -0.70, p = 0.461, 95% CI -2.57 to 1.17) or brain age (PRR = 1.00, p = 0.665, 95% CI 0.99-1.02). DISCUSSION: TBI is associated with a greater burden of ePVS, especially when there have been bilateral brain lesions. ePVS was associated with reduced verbal memory performance. ePVS may indicate ongoing impairments in glymphatic system function in the chronic postinjury period.

Leveraging the glymphatic and meningeal lymphatic systems as therapeutic strategies in Alzheimer's disease: an updated overview of nonpharmacological therapies.

Understanding and treating Alzheimer's disease (AD) has been a remarkable challenge for both scientists and physicians. Although the amyloid-beta and tau protein hypothesis have largely explained the key pathological features of the disease, the mechanisms by which such proteins accumulate and lead to disease progression are still unknown. Such lack of understanding disrupts the development of disease-modifying interventions, leaving a therapeutic gap that remains unsolved. Nonetheless, the recent discoveries of the glymphatic pathway and the meningeal lymphatic system as key components driving central solute clearance revealed another mechanism underlying AD pathogenesis. In this regard, this narrative review integrates the glymphatic and meningeal lymphatic systems as essential components involved in AD pathogenesis. Moreover, it discusses the emerging evidence suggesting that nutritional supplementation, non-invasive brain stimulation, and traditional Chinese medicine can improve the pathophysiology of the disease by increasing glymphatic and/or meningeal lymphatic function. Given that physical exercise is a well-regarded preventive and pro-cognitive intervention for dementia, we summarize the evidence suggesting the glymphatic system as a mediating mechanism of the physical exercise therapeutic effects in AD. Targeting these central solute clearance systems holds the promise of more effective treatment strategies.

The effect of aquaporin-4 mis-localization on Aß deposition in mice.

The reduced clearance of amyloid-ß (Aß) is thought to contribute to the development of the pathology associated with Alzheimer's disease (AD), which is characterized by the deposition of Aß plaques. Previous studies have shown that Aß is cleared via the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is dependent upon the water channel aquaporin-4 (AQP4), localized at astrocytic endfeet. While prior studies have shown that both the loss and mislocalization of AQP4 slow Aß clearance and promote Aß plaque formation, the relative impact of the loss or mislocalization of AQP4 on Aß deposition has never been directly compared. In this study, we evaluated how the deposition of Aß plaques within the 5XFAD mouse line is impacted by either Aqp4 gene deletion or the loss of AQP4 localization in the α-syntrophin (Snta1) knockout mouse. We observed that both the absence (Aqp4 KO) and mislocalization (Snta1 KO) of AQP4 significantly increases the parenchymal Aß plaque and microvascular Aß deposition across the brain, when compared with 5XFAD littermate controls. Further, the mislocalization of AQP4 had a more pronounced impact on Aß plaque deposition than did global Aqp4 gene deletion, perhaps pointing to a key role that mislocalization of perivascular AQP4 plays in AD pathogenesis.

Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method.

BACKGROUND AND OBJECTIVE: Central nervous system (CNS) infiltration commonly occurs in children with acute lymphoblastic leukemia (ALL). Nevertheless, CNS infiltration is rarely detected at the initial diagnosis. The glymphatic system, which regulates cerebrospinal fluid (CSF) and interstitial fluid transport, is considered one of the possible routes of CNS infiltration by leukemia cells. In this study, we used diffusion tensor image analysis along the perivascular space (DTI-ALPS) method to investigate glymphatic system function and obtained CSF volume using synthetic magnetic resonance imaging (SyMRI) in pediatric ALL without clinically diagnosed CNS infiltration. MATERIALS AND METHODS: Twenty-nine ALL and 29 typically developing (TD) children were prospectively recruited (age 4-16 years) in the present study. Group differences in brain volumetric parameters, brain water diffusivities, and the ALPS index were evaluated after controlling for age, gender, and handedness. Furthermore, significant group-different parameters were correlated with clinical information using partial correlations analysis. RESULTS: Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). Moreover, the ALPS index was negatively associated with the risk classification (r = - 0.59, pFDR-corrected = 0.04) in pediatric ALL. CONCLUSIONS: Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration. These novel findings suggested that the glymphatic system might be essential in the early-stage process of ALL CNS infiltration, which provides a new direction for exploring underlying mechanisms and early detection of pediatric ALL CNS infiltration. KEY POINTS: • Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all pFDR-corrected < 0.05). • The ALPS index was negatively associated with the risk classification (r = -0.59, pFDR-corrected = 0.04) in pediatric ALL. • Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration, which suggested that the ALPS index and CSF volume might be promising imaging markers for early detection of pediatric ALL CNS infiltration.

Glymphatic pathway in sporadic cerebral small vessel diseases: From bench to bedside.

Cerebral small vessel diseases (CSVD) consist of a group of diseases with high heterogeneity induced by pathologies of intracranial small blood vessels. Endothelium dysfunction, bloodbrain barrier leakage and the inflammatory response are traditionally considered to participate in the pathogenesis of CSVD. However, these features cannot fully explain the complex syndrome and related neuroimaging characteristics. In recent years, the glymphatic pathway has been discovered to play a pivotal role in clearing perivascular fluid and metabolic solutes, which has provided novel insights into neurological disorders. Researchers have also explored the potential role of perivascular clearance dysfunction in CSVD. In this review, we presented a brief overview of CSVD and the glymphatic pathway. In addition, we elucidated CSVD pathogenesis from the perspective of glymphatic failure, including basic animal models and clinical neuroimaging markers. Finally, we proposed forthcoming clinical applications targeting the glymphatic pathway, hoping to provide novel ideas on promising therapies and preventions of CSVD.

Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models.

Alzheimer's disease (AD) is characterized by genetic and multifactorial risk factors. Many studies correlate AD to sleep disorders. In this study, we performed and validated a mouse model of AD and sleep fragmentation, which properly mimics a real condition of intermittent awakening. We noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to aquaporin-4 (AQP4) modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects aquaporin-4 channel (AQP4) expression according to the stage of the disease, with an up-regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4. Nevertheless, an in-depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms.

Glymphatic system evaluation using diffusion tensor imaging in patients with traumatic brain injury.

PURPOSE: Glymphatic system dysfunction has been reported in animal models of traumatic brain injury (TBI). This study aimed to evaluate the activity of the human glymphatic system using the non-invasive Diffusion Tensor Image-Analysis aLong the Perivascular Space (DTI-ALPS) method in patients with TBI. METHODS: A total of 89 patients with TBI (June 2018 to May 2020) were retrospectively enrolled, and 34 healthy volunteers were included who had no previous medical or neurological disease. Magnetic resonance imaging (MRI) with DTI was performed, and the ALPS index was calculated to evaluate the glymphatic system's activity. Wilcoxon rank-sum test was used to compare the ALPS index between patients with TBI and healthy controls. ANOVA was done to compare the ALPS index among controls and patients with mild/moderate-to-severe TBI. Multivariate logistic regression analyses were used to identify independent clinical and radiological factors associated with the ALPS index. The correlation between Glasgow Coma Scale (GCS) score and the ALPS index was also assessed. RESULTS: The ALPS index was significantly lower in patients with TBI than in healthy controls (median, 1.317 vs. 1.456, P < 0.0001). There were significant differences in the ALPS index between healthy controls and patients with mild/moderate-to-severe TBI (ANOVA, P < 0.001). The presence of subarachnoid hemorrhage (P = 0.004) and diffuse axonal injury (P = 0.001) was correlated with a lower ALPS index in the multivariate analysis. There was a weak positive correlation between the ALPS index and GCS scores (r = 0.242, P = 0.023). CONCLUSIONS: The DTI-ALPS method is useful for evaluating glymphatic system impairment and quantifying its activity in patients with TBI.

Conserved meningeal lymphatic drainage circuits in mice and humans.

Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune surveillance of brain tissues. Whether MLVs exist in the anterior part of the murine and human skull and how they connect with the glymphatic system and extracranial lymphatics remained unclear. Here, we used light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations after OVA-A555 tracer injection into the cerebrospinal fluid (CSF) and performed real-time vessel-wall (VW) magnetic resonance imaging (VW-MRI) after systemic injection of gadobutrol in patients with neurological pathologies. We observed a conserved three-dimensional anatomy of MLVs in mice and humans that aligned with dural venous sinuses but not with nasal CSF outflow, and we discovered an extended anterior MLV network around the cavernous sinus, with exit routes through the foramina of emissary veins. VW-MRI may provide a diagnostic tool for patients with CSF drainage defects and neurological diseases.

Characterization of perivascular space pathology in a rat model of cerebral small vessel disease by in vivo magnetic resonance imaging.

One of the most common causes of dementia is cerebral small vessel disease (SVD), which is associated with enlarged perivascular spaces (PVS). Clinically, PVS are visible as hyperintensities on T2-weighted (T2w) magnetic resonance images (MRI). While rodent SVD models exhibit arteriolosclerosis, PVS have not been robustly documented by MRI casting doubts on their clinical relevance. Here we established that the severity of SVD in spontaneously hypertensive stroke prone (SHRSP) rats correlated to 'moderate' SVD in human post-mortem tissue. We then developed two approaches for detecting PVS in SHRSP rats: 1) T2w imaging and 2) T1-weighted imaging with administration of gadoteric acid into cerebrospinal fluid. We applied the two protocols to six Wistar-Kyoto (WKY) control rats and thirteen SHRSP rats at ∼12 month of age. The primary endpoint was the number of hyperintense lesions. We found more hyperintensities on T2w MRI in the SHRSP compared to WKY rats (p-value = 0.023). CSF enhancement with gadoteric acid increased the visibility of PVS-like lesions in SHRSP rats. In some of the SHRSP rats, the MRI hyperintensities corresponded to enlarged PVS on histopathology. The finding of PVS-like hyperintensities on T2w MRI support the SHRSP rat's clinical relevance for studying the underlying pathophysiology of SVD.

Normal glymphatic system function in patients with migraine: A pilot study.

OBJECTIVE: No studies have evaluated the glymphatic system function in patients with migraine. In this pilot study, we evaluated and compared the alterations in the glymphatic system function in patients with migraine with healthy controls using a diffusion tensor imaging (DTI) analysis along the perivascular space (DTI-ALPS) method. We also investigated the differences in the glymphatic system function table between patients with migraine with and without aura using the ALPS method. METHODS: This field study used a cross-sectional study design. We prospectively enrolled patients with migraine and healthy controls. All brain magnetic resonance imaging (MRI), including DTI, in participants, patients with migraine, and healthy controls were obtained using the same MRI scanner. We calculated and compared the ALPS index between patients with migraine and healthy controls, and between patients with migraine with and without aura. In addition, we investigated the association between the glymphatic system function and the clinical characteristics of migraine. RESULTS: We enrolled 92 patients with migraine and 80 healthy controls. There were no significant differences in the ALPS index between patients with migraine and healthy controls (1.655 ± 0.335 [patients with migraine] vs. 1.713 ± 0.297 [controls], difference = 0.058, 95% confidence interval [CI] of difference = -0.037 to 0.154, p = 0.233), and between patients with migraine with and without aura (1.690 ± 0.380 [with aura] vs. 1.645 ± 0.323 [without aura], difference = -0.044, 95% CI of difference = -0.213 to 0.124, p = 0.601). There was no significant correlation between the ALPS index and clinical characteristics of migraine, including age (r = -0.07, p = 0.507), age at onset (r = 0.07, p = 0.552), disease duration (r = -0.12, p = 0.306), attack frequency (r = -0.05, p = 0.668), and headache intensity (r = 0.00, p = 0.976). CONCLUSIONS: There was no glymphatic system dysfunction in patients with migraine. Moreover, there were no differences in the glymphatic system function between patients with migraine with and without aura. We also demonstrated the feasibility of the ALPS method, which can be used for research on various neurological diseases. Further studies are needed to confirm our findings.