The association between glymphatic system dysfunction and alterations in cerebral function and structure in patients with white matter hyperintensities.

The objective of this study is to explore the relationship between the glymphatic system and alterations in the structure and function of the brain in white matter hyperintensity (WMH) patients. MRI data were collected from 27 WMH patients and 23 healthy controls. We calculated the along perivascular space (ALPS) indices, the anterior corner distance of the lateral ventricle, and the width of the third ventricle for each subject. The DPABISurf tool was used to calculate the cortical thickness and cortical area. In addition, data processing assistant for resting-state fMRI was used to calculate regional homogeneity, degree centrality, amplitude low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuation (fALFF), and voxel-mirrored homotopic connectivity (VMHC). In addition, each WMH patient was evaluated on the Fazekas scale. Finally, the correlation analysis of structural indicators and functional indicators with bilateral ALPS indices was investigated using Spearman correlation analysis. The ALPS indices of WMH patients were lower than those of healthy controls (left: t = -4.949, P < 0.001; right: t = -3.840, P < 0.001). This study found that ALFF, fALFF, regional homogeneity, degree centrality, and VMHC values in some brain regions of WMH patients were alternated (AlphaSim corrected, P < 0.005, cluster size > 26 voxel, rmm value = 5), and the cortical thickness and cortical area of WMH patients showed trend changes (P < 0.01, cluster size > 20 mm2, uncorrected). Interestingly, we found significantly positive correlations between the left ALPS indices and degree centrality values in the superior temporal gyrus (r = 0.494, P = 0.009, P × 5 < 0.05, Bonferroni correction). Our results suggest that glymphatic system impairment is related to the functional centrality of local connections in patients with WMH. This provides a new perspective for understanding the pathological mechanisms of cognitive impairment in the WMH population.

Comparative analysis of glymphatic system alterations in multiple sclerosis and neuromyelitis optica spectrum disorder using MRI indices from diffusion tensor imaging.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Glymphatic system dysfunction has been observed in both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), indicating the role of neuroinflammation in the glymphatic system. However, little is known about how the two diseases differently affect the human glymphatic system. The present study aims to evaluate the diffusion MRI-based measures of the glymphatic system by contrasting MS and NMOSD. METHODS: This prospective study included 63 patients with NMOSD (n = 21) and MS (n = 42) who underwent DTI. The fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging (DTI) along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. Age and EDSS scores were adjusted. RESULTS: Using Bayesian hypothesis testing, we show that the present data substantially favor the null model of no differences between MS and NMOSD for the diffusion MRI-based measures of the glymphatic system. The inclusion Bayes factor (BF10) of model-averaged probabilities of the group (MS, NMOSD) was 0.280 for FW and 0.236 for the ALPS index. CONCLUSION: Together, these findings suggest that glymphatic alteration associated with MS and NMOSD might be similar and common as an eventual result, albeit the disease etiologies differ. PRACTITIONER POINTS: Previous literature indicates important glymphatic system alteration in MS and NMOSD. We explore the difference between MS and NMOSD using diffusion MRI-based measures of the glymphatic system. We show support for the null hypothesis of no difference between MS and NMOSD. This suggests that glymphatic alteration associated with MS and NMOSD might be similar and common etiology.

The glymphatic system in migraine and other headaches.

Glymphatic system is an emerging pathway of removing metabolic waste products and toxic solutes from the brain tissue. It is made of a network of perivascular spaces, filled in cerebrospinal and interstitial fluid, encompassing penetrating and pial vessels and communicating with the subarachnoid space. It is separated from vessels by the blood brain barrier and from brain tissue by the endfeet of the astrocytes rich in aquaporin 4, a membrane protein which controls the water flow along the perivascular space. Animal models and magnetic resonance (MR) studies allowed to characterize the glymphatic system function and determine how its impairment could lead to numerous neurological disorders (e.g. Alzheimer's disease, stroke, sleep disturbances, migraine, idiopathic normal pressure hydrocephalus). This review aims to summarize the role of the glymphatic system in the pathophysiology of migraine in order to provide new ways of approaching to this disease and to its therapy.

Glymphatic system dysfunction in neurodegenerative diseases.

PURPOSE OF REVIEW: Purpose of this review is to update the ongoing work in the field of glymphatic and neurodegenerative research and to highlight focus areas that are particularly promising. RECENT FINDINGS: Multiple reports have over the past decade documented that glymphatic fluid transport is broadly suppressed in neurodegenerative diseases. Most studies have focused on Alzheimer's disease using a variety of preclinical disease models, whereas the clinical work is based on various neuroimaging approaches. It has consistently been reported that brain fluid transport is impaired in patients suffering from Alzheimer's disease compared with age-matched control subjects. SUMMARY: An open question in the field is to define the mechanistic underpinning of why glymphatic function is suppressed. Other questions include the opportunities for using glymphatic imaging for diagnostic purposes and in treatment intended to prevent or slow Alzheimer disease progression.

Glymphatic system dysfunction in middle-aged and elderly chronic insomnia patients with cognitive impairment evidenced by diffusion tensor imaging along the perivascular space (DTI-ALPS).

BACKGROUND: Chronic insomnia impairs the glymphatic system and may lead to cognitive impairment and dementia in elderly population. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been proposed as a non-invasive method to measure the activity of human brain glymphatic. We aim to explore whether glymphatic function is impaired in middle-aged and elderly chronic insomnia individuals and to identify the relationships between glymphatic dysfunction and cognitive impairment. METHODS: A total of 33 chronic insomnia patients (57.36 ± 5.44 years, 30 females) and 20 age- and sex-matched healthy controls (57.95 ± 5.78 years, 16 females) were prospectively enrolled between May 2022 and January 2023. All participants completed MRI screening, cognition and sleep assessments, and DTI-ALPS index analysis. RESULTS: Our findings revealed that the DTI-ALPS index was significantly difference among the chronic insomnia patients with impaired cognition group (1.32 ± 0.14), with normal cognition group (1.46 ± 0.09), and healthy controls (1.61 ± 0.16) (p = 0.0012, p < 0.0001, p = 0.0008, respectively). Mini-Mental State Examination (MMSE) scores of chronic insomnia patients with cognitive impairment were positively correlated with the DTI-ALPS index (Partial correlation analyses after correction for age, sex, education level and duration of chronic insomnia: r = 0.78, p = 0.002). DTI-ALPS had moderate accuracy in distinguishing chronic insomnia patients with cognitive impairment from those with normal cognition. DATA CONCLUSION: The glymphatic system dysfunction is involved in chronic insomnia among middle-aged and elderly individuals, and it has been found to be correlated with cognitive decline.

Diffusion-Weighted Imaging Reveals Impaired Glymphatic Clearance in Idiopathic Intracranial Hypertension.

BACKGROUND AND PURPOSE: The pathophysiology underlying idiopathic intracranial hypertension (IIH) remains incompletely understood. While one theory postulates impaired cerebral glymphatic clearance in IIH, there is a paucity of methods to quantify glymphatic activity in human brains. The purpose of this study was to use advanced diffusion-weighed imaging to evaluate the glymphatic clearance of IIH patients and how it may relate to clinical severity. MATERIALS AND METHODS: DWI was used to separately evaluate the diffusivity along the cerebral perivascular spaces and lateral association and projection fibers, with the degree of diffusivity used as a surrogate for glymphatic function (diffusion tensor image analysis along the perivascular space. Patients with IIH were compared with normal controls. Glymphatic clearance was correlated with several clinical metrics, including lumbar puncture opening pressure and Frisen papilledema grade (low grade: 0-2; high grade: 3-5). RESULTS: In total, 99 patients with IIH were identified and compared with 6 healthy controls. Overall, patients with IIH had significantly lower glymphatic clearance based on DWI-derived diffusivity compared with controls (P = .005). Additionally, in patients with IIH, there was a significant association between declining glymphatic clearance and increasing Frisen papilledema grade (P = .046) but no correlation between opening pressure and glymphatic clearance (P = .27). Furthermore, healthy controls had significantly higher glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .015) and high-grade papilledema (P = .002). Lastly, patients with IIH and high-grade papilledema had lower glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .005). CONCLUSIONS: Patients with IIH possess impaired glymphatic clearance, which is directly related to the extent of clinical severity. The DWI-derived parameters can be used for clinical diagnosis or to assess response to treatment.

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.

Higher intracranial arterial pulsatility is associated with presumed imaging markers of the glymphatic system: An explorative study.

BACKGROUND: Arterial pulsation has been suggested as a key driver of paravascular cerebrospinal fluid flow, which is the foundation of glymphatic clearance. However, whether intracranial arterial pulsatility is associated with glymphatic markers in humans has not yet been studied. METHODS: Seventy-three community participants were enrolled in the study. 4D phase-contrast magnetic resonance imaging (MRI) was used to quantify the hemodynamic parameters including flow pulsatility index (PIflow) and area pulsatility index (PIarea) from 13 major intracerebral arterial segments. Three presumed neuroimaging markers of the glymphatic system were measured: including dilation of perivascular space (PVS), diffusivity along the perivascular space (ALPS), and volume fraction of free water (FW) in white matter. We explored the relationships between PIarea, PIflow, and the presumed glymphatic markers, controlling for related covariates. RESULTS: PIflow in the internal carotid artery (ICA) C2 segment (OR, 1.05; 95 % CI, 1.01-1.10, per 0.01 increase in PI) and C4 segment (OR, 1.05; 95 % CI, 1.01-1.09) was positively associated with the dilation of basal ganglia PVS, and PIflow in the ICA C4 segment (OR, 1.06, 95 % CI, 1.02-1.10) was correlated with the dilation of PVS in the white matter. ALPS was associated with PIflow in the basilar artery (ß, -0.273, p, 0.046) and PIarea in the ICA C2 (ß, -0.239, p, 0.041) and C7 segments (ß, -0.238, p, 0.037). CONCLUSIONS: Intracranial arterial pulsatility was associated with presumed neuroimaging markers of the glymphatic system, but the results were not consistent across different markers. Further studies are warranted to confirm these findings.

Automatic Quantification of Enlarged Perivascular Space in Patients With Traumatic Brain Injury Using Super-Resolution of T2-Weighted Images.

The perivascular space (PVS) is important to brain waste clearance and brain metabolic homeostasis. Enlarged PVS (ePVS) becomes visible on magnetic resonance imaging (MRI) and is best appreciated on T2-weighted (T2w) images. However, quantification of ePVS is challenging because standard-of-care T1-weighted (T1w) and T2w images are often obtained via two-dimensional (2D) acquisition, whereas accurate quantification of ePVS normally requires high-resolution volumetric three-dimensional (3D) T1w and T2w images. The purpose of this study was to investigate the use of a deep-learning-based super-resolution (SR) technique to improve ePVS quantification from 2D T2w images for application in patients with traumatic brain injury (TBI). We prospectively recruited 26 volunteers (age: 31 ± 12 years, 12 male/14 female) where both 2D T2w and 3D T2w images were acquired along with 3D T1w images to validate the ePVS quantification using SR T2w images. We then applied the SR method to retrospectively acquired 2D T2w images in 41 patients with chronic TBI (age: 41 ± 16 years, 32 male/9 female). ePVS volumes were automatically quantified within the whole-brain white matter and major brain lobes (temporal, parietal, frontal, occipital) in all subjects. Pittsburgh Sleep Quality Index (PSQI) scores were obtained on all patients with TBI. Compared with the silver standard (3D T2w), in the validation study, the SR T2w provided similar whole-brain white matter ePVS volume (r = 0.98, p < 0.0001), and similar age-related ePVS burden increase (r = 0.80, p < 0.0001). In the patient study, patients with TBI with poor sleep showed a higher age-related ePVS burden increase than those with good sleep. Sleep status is a significant interaction factor in the whole brain (p = 0.047) and the frontal lobe (p = 0.027). We demonstrate that images produced by SR of 2D T2w images can be automatically analyzed to produce results comparable to those obtained by 3D T2 volumes. Reliable age-related ePVS burden across the whole-brain white matter was observed in all subjects. Poor sleep, affecting the glymphatic function, may contribute to the accelerated increase of ePVS burden following TBI.

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.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (ß = 0.515, p = 0.008), Trail Making Test A (ß = - 0.391, p = 0.048), and Digit Span Test (ß = 0.408, p = 0.038). CONCLUSIONS: 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. CLINICAL RELEVANCE STATEMENT: 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. KEY POINTS: • 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.

Correlation of glymphatic system abnormalities with Parkinson's disease progression: a clinical study based on non-invasive fMRI.

BACKGROUND: The glymphatic system is reportedly involved in Parkinson's disease (PD). Based on previous studies, we aimed to confirm the correlation between the glymphatic system and PD progression by combining two imaging parameters, diffusion tensor image analysis along the perivascular space (DTI-ALPS), and enlarged perivascular spaces (EPVS). METHODS: Fifty-one PD patients and fifty healthy control (HC) were included. Based on the Hoehn-Yahr scale, the PD group was divided into early-stage and medium-to late-stage. All PD patients were scored using the Unified PD Rating Scale (UPDRS). We assessed the DTI-ALPS indices in the bilateral hemispheres and EPVS numbers in bilateral centrum semiovale (CSO), basal ganglia (BG), and midbrain. RESULTS: The DTI-ALPS indices were significantly lower bilaterally in PD patients than in the HC group, and EPVS numbers in any of the bilateral CSO, BG, and midbrain were significantly higher, especially for the medium- to late-stage group and the BG region. In PD patients, the DTI-ALPS index was significantly negatively correlated with age, while the BG-EPVS numbers were significantly positively correlated with age. Furthermore, the DTI-ALPS index was negatively correlated with UPDRS II and III scores, while the BG-EPVS numbers were positively correlated with UPDRS II and III scores. Similarly, the correlation was more pronounced in the medium- to late-stage group. CONCLUSION: The DTI-ALPS index and EPVS numbers (especially in the BG region) are closely related to age and PD progression and can serve as non-invasive assessments for glymphatic dysfunction and its interventions in clinical studies.

The Glymphatic System in Humans: Investigations With Magnetic Resonance Imaging.

ABSTRACT: The concept of the glymphatic system was proposed more than a decade ago as a mechanism for interstitial fluid flow and waste removal in the central nervous system. The function of the glymphatic system has been shown to be particularly activated during sleep. Dysfunction of the glymphatic system has been implicated in several neurodegenerative diseases. Noninvasive in vivo imaging of the glymphatic system is expected to be useful in elucidating the pathophysiology of these diseases. Currently, magnetic resonance imaging is the most commonly used technique to evaluate the glymphatic system in humans, and a large number of studies have been reported. This review provides a comprehensive overview of investigations of the human glymphatic system function using magnetic resonance imaging. The studies can be divided into 3 categories, including imaging without gadolinium-based contrast agents (GBCAs), imaging with intrathecal administration of GBCAs, and imaging with intravenous administration of GBCAs. The purpose of these studies has been to examine not only the interstitial fluid movement in the brain parenchyma, but also the fluid dynamics in the perivascular and subarachnoid spaces, as well as the parasagittal dura and meningeal lymphatics. Recent research has even extended to include the glymphatic system of the eye and the inner ear. This review serves as an important update and a useful guide for future research directions.

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

BACKGROUND AND PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A Novel Diffusion Tensor Image Analysis Along the Perivascular Space Method to Evaluate Glymphatic Alterations in Alzheimer's Disease.

Alzheimer 's disease (AD) is the most prevalent neurodegenerative disorder worldwide. The glymphatic system is considered to be associated with the pathogenesis of AD. However, the alterations of glymphatic system along the AD continuum are still unknown. In this study, we used a novel DTI analysis method, diffusion tensor image analysis along the perivascular space (DTI-ALPS), to evaluate the difference in the activity of the glymphatic system among normal control (NC) subjects, mild cognitive impairment (MCI) and AD patients. The data utilized in the study was obtained from Tongji Hospital in Shanghai, China, including 65 NCs, 58 MCIs and 36 ADs. First, we calculated the ALPS-index to evaluate the activity of the glymphatic system. Then, analysis of variance (ANOVA) was used to find the differences of ALPS-index among different groups, and to explore the correlation between ALPS-index and the three clinical scales: Minimum Mental State Examination (MMSE), Montreal Cognitive Assessment-Basic (MoCA-B) and Instrumental Activity of Daily Living (IADL). Receiver operating characteristic curve (ROC) analysis was used to evaluate the role of the ALPS-index in disease classification. The findings indicated a significant difference in the ALPS-index between the groups of participants with normal cognition, MCI, and AD. In addition, we found that ALPS-index was significantly correlated with the scores of the three clinical scales (with MoCA-B: r=0.233, p=0.001). Furthermore, with ALPS-index, Fractional Anisotropy (FA) values achieved best classification results (AUC=0.8899). Cognitive dysfunction is closely associated with the activity of the glymphatic system, and ALPS-index can be used as a biomarker for alterations along the AD continuum.

Enlarged Perivascular Space and Index for Diffusivity Along the Perivascular Space as Emerging Neuroimaging Biomarkers of Neurological Diseases.

The existence of lymphatic vessels or similar clearance systems in the central nervous system (CNS) that transport nutrients and remove cellular waste is a neuroscientific question of great significance. As the brain is the most metabolically active organ in the body, there is likely to be a potential correlation between its clearance system and the pathological state of the CNS. Until recently the successive discoveries of the glymphatic system and the meningeal lymphatics solved this puzzle. This article reviews the basic anatomy and physiology of the glymphatic system. Imaging techniques to visualize the function of the glymphatic system mainly including post-contrast imaging techniques, indirect lymphatic assessment by detecting increased perivascular space, and diffusion tensor image analysis along the perivascular space (DTI-ALPS) are discussed. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders. The pathological link between glymphatic system dysfunction and neurological disorders is the key point, focusing on the enlarged perivascular space (EPVS) and the index for of diffusivity along the perivascular space (ALPS index), which may represent the activity of the glymphatic system as possible clinical neuroimaging biomarkers of neurological disorders.

Imaging of brain clearance pathways via MRI assessment of the glymphatic system.

Glymphatic clearance dysfunction may play an important role in a variety of neurodegenerative diseases and the progression of ageing. However, in vivo imaging of the glymphatic system is challenging. In this study, we describe an MRI method based on chemical exchange saturation transfer (CEST) of the Angiopep-2 probe to visualize the clearance function of the glymphatic system. We injected rats with Angiopep-2 via the tail vein and performed in vivo MRI at 7 T to track differences in Angiopep-2 signal changes; we then applied the same principles in a bilateral deep cervical lymph node ligation rat model and in ageing rats. We demonstrated the feasibility of Angiopep-2 CEST for visualizing the clearance function of the glymphatic system. Finally, a pathological assessment was performed. Within the model group, the deep cervical lymph node ligation group and the ageing group showed higher CEST signal than the control group. We conclude that this new MRI method can visualize clearance in the glymphatic system.

Increased glymphatic system activity in migraine chronification by diffusion tensor image analysis along the perivascular space.

BACKGROUND: Preliminary evidence suggests that several headache disorders may be associated with glymphatic dysfunction. However, no studies have been conducted to examine the glymphatic activity in migraine chronification. PURPOSES: To investigate the glymphatic activity of migraine chronification in patients with episodic migraine (EM) and chronic migraine (CM) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. METHODS: In this cross-sectional study, patients with EM, CM, and healthy controls (HCs) were included. All participants underwent a standard brain magnetic resonance imaging (MRI) examination. Bilateral DTI-ALPS indexes were calculated for all participants and compared among EM, CM, and HC groups. Correlations between the DTI-ALPS index and clinical characteristics were analyzed. RESULTS: A total of 32 patients with EM, 24 patients with CM, and 41 age- and sex-matched HCs were included in the analysis. Significant differences were found in the right DTI-ALPS index among the three groups (p = 0.011), with CM showing significantly higher values than EM (p = 0.033) and HCs (p = 0.015). The right DTI-ALPS index of CM group was significantly higher than the left DTI-ALPS index (p = 0.005). And the headache intensity was correlated to DTI-ALPS index both in the left hemisphere (r = 0.371, p = 0.011) and in the right hemisphere (r = 0.307, p = 0.038), but there were no correlations after Bonferroni correction. CONCLUSIONS: Glymphatic system activity is shown to be increased instead of impaired during migraine chronification. The mechanism behind this observation suggests that increased glymphatic activity is more likely to be a concomitant phenomenon of altered vascular reactivity associated with migraine pathophysiology rather than a risk factor of migraine chronification.

Imaging glymphatic response to glioblastoma.

BACKGROUND: The glymphatic system actively exchanges cerebrospinal fluid (CSF) and interstitial fluid (ISF) to eliminate toxic interstitial waste solutes from the brain parenchyma. Impairment of the glymphatic system has been linked to several neurological conditions. Glioblastoma, also known as Glioblastoma multiforme (GBM) is a highly aggressive form of malignant brain cancer within the glioma category. However, the impact of GBM on the functioning of the glymphatic system has not been investigated. Using dynamic contrast-enhanced magnetic resonance imaging (CE-MRI) and advanced kinetic modeling, we examined the changes in the glymphatic system in rats with GBM. METHODS: Dynamic 3D contrast-enhanced T1-weighted imaging (T1WI) with intra-cisterna magna (ICM) infusion of paramagnetic Gd-DTPA contrast agent was used for MRI glymphatic measurements in both GBM-induced and control rats. Glymphatic flow in the whole brain and the olfactory bulb was analyzed using model-derived parameters of arrival time, infusion rate, clearance rate, and residual that describe the dynamics of CSF tracer over time. RESULTS: 3D dynamic T1WI data identified reduced glymphatic influx and clearance, indicating an impaired glymphatic system due to GBM. Kinetic modeling and quantitative analyses consistently indicated significantly reduced infusion rate, clearance rate, and increased residual of CSF tracer in GBM rats compared to control rats, suggesting restricted glymphatic flow in the brain with GBM. In addition, our results identified compromised perineural pathway along the optic nerves in GBM rats. CONCLUSIONS: Our study demonstrates the presence of GBM-impaired glymphatic response in the rat brain and impaired perineural pathway along the optic nerves. Reduced glymphatic waste clearance may lead to the accumulation of toxic waste solutes and pro-inflammatory signaling molecules which may affect the progression of the GBM.