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Perivascular spaces include a variety of passageways around arterioles, capillaries and venules in the brain, along which a range of substances can move. Although perivascular spaces were first identified over 150 years ago, they have come to prominence recently owing to advances in knowledge of their roles in clearance of interstitial fluid and waste from the brain, particularly during sleep, and in the pathogenesis of small vessel disease, Alzheimer disease and other neurodegenerative and inflammatory disorders. Experimental advances have facilitated in vivo studies of perivascular space function in intact rodent models during wakefulness and sleep, and MRI in humans has enabled perivascular space morphology to be related to cognitive function, vascular risk factors, vascular and neurodegenerative brain lesions, sleep patterns and cerebral haemodynamics. Many questions about perivascular spaces remain, but what is now clear is that normal perivascular space function is important for maintaining brain health. Here, we review perivascular space anatomy, physiology and pathology, particularly as seen with MRI in humans, and consider translation from models to humans to highlight knowns, unknowns, controversies and clinical relevance.In this Review, Wardlaw et al. discuss the anatomy, physiology and pathology of perivascular spaces, particularly as seen with MRI in humans, and consider translation from models to humans to highlight knowns, unknowns, controversies and clinical relevance.

•Dynamic contrast-enhanced MRI (DCE-MRI) revealed glymphatic dysfunction in the hypoxic-ischemic encephalopathy (HIE) mouse model.•Fluorescent cerebrospinal fluid (CSF) tracer demonstrated that hypoxic-ischemic encephalopathy (HIE) caused glymphatic dysfunction and impacted glymphatic system development in mice.•Decreased polarization of Aquaporin-4 (AQP4) is closely associated with glymphatic dysfunction. Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal brain injury. The glymphatic system aids in waste clearance via perivascular pathways and is crucial in maintaining brain functions. While studies have shown that diseases such as stroke and traumatic brain injury disrupt glymphatic function, the impact of HIE on this system remains largely unexplored. We utilized an HIE mouse model with dynamic contrast-enhanced MRI (DCE-MRI) to conduct both qualitative and quantitative assessment of glymphatic transports dysfunction in different brain regions. Fluorescent cerebrospinal fluid (CSF) tracers were used to investigate the effects of HIE on glymphatic system development. Mice brain sections were subjected to Aquaporin-4 (AQP4) immunohistochemical staining, allowing for detailed morphological assessment of AQP4 polarization in affected brain regions. HIE mice exhibited delayed glymphatic transport dynamics, with prolonged time-to-peak tracer enhancement and increased retention in olfactory bulb, basal forebrain, and hypothalamus regions. Quantitative kinetic analysis showed significant reductions in Kf (CSF-to-perivascular space transfer constants) and Ks (perivascular-to-parenchyma transfer constants), alongside elevated Vf (perivascular volume fractions) across cortical and subcortical structures. Fluorescent CSF tracer analysis indicates that HIE impaired glymphatic system maturation in neonatal mice. This impairment progressed to persistent glymphatic dysfunction. Histologically validated via immunofluorescence, HIE-induced astrocytic AQP4 mis-polarization directly correlates with glymphatic transport dysfunction, underscoring AQP4′s critical role in glymphatic system integrity. Our multimodal imaging study combining DCE-MRI and CSF tracer analysis indicates that HIE can cause regional impairments of glymphatic function and adversely affect brain development.

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

Defined by the World Health Organization as a neurological disorder, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness, affecting millions of people worldwide. First reported in the early nineteenth century, ME/CFS is uniquely characterized by a wide array of symptoms, including fatigue, brain fog, post-exertional malaise (PEM), sleep dysfunction, and orthostatic intolerance (OI). Despite decades of extensive research, there are no effective medical treatments or simple diagnostics for ME/CFS, with an estimated 90% of patients remaining undiagnosed. The recently discovered glymphatic system, a lymphatic analog of the brain, is believed to be responsible for the removal of toxic metabolic wastes accumulated in the course of daily activities, primarily during sleep. A link between glymphatic dysfunction and some neurological disorders such as Alzheimer’s disease has already been established, raising the possibility of its involvement in ME/CFS. Accordingly, we believe the ME/CFS medical/scientific community will be interested in seriously considering GD an important contributor to its pathophysiology. If so, therapeutics that modulate glymphatic function may also benefit patients with ME/CFS.

•An improved sub-voxel QSM separation method was applied to calculate WMH iron burden.•Multimodal neuroimaging was applied to explore the pathological mechanism of CSVD.•WMH iron overload mediates glymphatic dysfunction and cognitive impairment in CSVD. Glymphatic system function has been increasingly linked to cognition in cerebral small vessel disease (CSVD), although the underlying pathological mechanisms related to brain metabolism remain to be fully clarified. Iron overload within white matter hyperintensity (WMH), potentially reflecting metabolic abnormalities, may play a pivotal role in this process. This study investigated whether WMH iron burden mediates the association between glymphatic dysfunction and cognitive impairment in CSVD. A total of 102 patients with CSVD and 29 matched healthy controls (HCs) underwent brain MRI and cognitive assessments. WMH iron burden was quantified using a sub-voxel quantitative approach, while glymphatic function was assessed with the Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS) index. Correlation and mediation analyses were then conducted to evaluate relationships among WMH iron burden, DTI-ALPS index, and cognitive scores. Compared with HCs, CSVD patients exhibited significantly higher WMH iron burden, lower DTI-ALPS index, and poorer cognitive performances. Elevated WMH iron burden was associated with deficits in attention-executive (att-exe), memory, and visual-spatial domains, whereas reduced DTI-ALPS index correlated with impaired att-exe and memory function. Importantly, WMH iron burden fully mediated the link between DTI-ALPS index and both att-exe function (p < 0.001) and memory (p = 0.02) in the CSVD group. These findings noninvasively identify WMH iron overload, a probable representative of microglial activation, as a key mediator between glymphatic dysfunction and cognitive decline in CSVD, prompting a potential therapeutic target for disease management.

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste. Arterial pulsations are thought to drive flow, but this has never been quantitatively shown. We used particle tracking to quantify CSF flow velocities in PVSs of live mice. CSF flow is pulsatile and driven primarily by the cardiac cycle. The speed of the arterial wall matches that of the CSF, suggesting arterial wall motion is the principal driving mechanism, via a process known as perivascular pumping. Increasing blood pressure leaves the artery diameter unchanged but changes the pulsations of the arterial wall, increasing backflow and thereby reducing net flow in the PVS. Perfusion-fixation alters the normal flow direction and causes a 10-fold reduction in PVS size. We conclude that particle tracking velocimetry enables the study of CSF flow in unprecedented detail and that studying the PVS in vivo avoids fixation artifacts. Arterial pulsations are thought to drive CSF flow through perivascular spaces (PVSs), but this has never been quantitatively shown. Using particle tracking to quantify CSF flow velocities in PVSs of live mice, the authors show that flow speeds match the instantaneous speeds of the pulsing artery walls that form the inner boundaries of the PVSs.

The glymphatic system is a fluid transport network of cerebrospinal fluid (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial fluid (ISF), ultimately establishing directional clearance of interstitial solutes. CSF transport is facilitated by the expression of aquaporin-4 (AQP4) water channels on the perivascular endfeet of astrocytes. Mice with genetic deletion of AQP4 (AQP4 KO) exhibit abnormalities in the brain structure and molecular water transport. Yet, no studies have systematically examined how these abnormalities in structure and water transport correlate with glymphatic function. Here, we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) along with intravoxel-incoherent motion (IVIM) DWI, while evaluating glymphatic function using a standard dynamic contrast-enhanced MR imaging to better understand how water transport and glymphatic function is disrupted after genetic deletion of AQP4. AQP4 KO mice had larger interstitial spaces and total brain volumes resulting in higher water content and reduced CSF space volumes, despite similar CSF production rates and vascular density compared to wildtype mice. The larger interstitial fluid volume likely resulted in increased slow but not fast MR diffusion measures and coincided with reduced glymphatic influx. This markedly altered brain fluid transport in AQP4 KO mice may result from a reduction in glymphatic clearance, leading to enlargement and stagnation of fluid in the interstitial space. Overall, diffusion MR is a useful tool to evaluate glymphatic function and may serve as valuable translational biomarker to study glymphatics in human disease.

Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure, which can be accompanied by functional impairment of or organic damage to the heart, brain, kidney and other organs. Hypertensive emergencies occur when significant increases in blood pressure result in persistent target organ damage. Hypertensive encephalopathy is a rare hypertensive emergency. Glymphatic system dysfunction is significantly correlated with the occurrence and development of hypertensive encephalopathy. We found that SHRs had a longer duration of peak contrast intensity and a slower clearance of contrast in the brain compared with WKY rats. Of note, in SHRs, there was a clear difference in contrast signal intensity between the hippocampus and the aqueduct. The results of cluster analysis showed that shr and WKY rats exhibited different patterns of voxel clustering. Progressively expanding brain clusters were observed from the posterior part of the brain near the cisterna magna (CM) to the anterior part of the brain, olfactory bulb, and dorsal cortical areas. In addition, shr showed a significant peak delay within some clusters and a slower rate of signal decay with time. Ex vivo imaging of ISF efflux showed that ISF efflux was also significantly reduced in shr. In vitro studies have shown decreased AQP4 expression in the brainstem and olfactory bulb of shr, accompanied by extensive astrogliosis, which may affect CSF circulation.Our study highlights the changes in glymphatic system function in a hypertension model and provides an important theoretical basis for further elucidating the mechanisms underlying the development and progression of hypertensive encephalopathy.

Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research.

INTRODUCTION Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. METHODS Whole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative. RESULTS ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid‐positive transition and clinical progression, and faster rates of amyloid‐ and neurodegeneration‐related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. DISCUSSION Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. Highlights The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aβ) positron emission tomography (PET) burden and Aβ‐positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aβ42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aβ PET and brain atrophy mediated the link of ALPS index with cognitive decline.