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The glymphatic (glial-lymphatic) pathway is a fluid-clearance pathway identified in the rodent brain in 2012. This pathway subserves the flow of CSF into the brain along arterial perivascular spaces and subsequently into the brain interstitium, facilitated by aquaporin 4 (AQP4) water channels. The pathway then directs flow towards the venous perivascular and perineuronal spaces, ultimately clearing solutes from the neuropil into meningeal and cervical lymphatic drainage vessels. In rodents, the glymphatic pathway is predominantly active during sleep, when the clearance of harmful metabolites such as amyloid β (Aβ) increases two-fold relative to the waking state. Glymphatic dysfunction, probably related to perturbed AQP4 expression, has been shown in animal models of traumatic brain injury, Alzheimer's disease, and stroke. The recent characterisations of the glymphatic and meningeal lymphatic systems in rodents and in humans call for revaluation of the anatomical routes for CSF–interstitial fluid flow and the physiological role that these pathways play in CNS health. Several features of the glymphatic and meningeal lymphatic systems have been shown to be present in humans. MRI scans with intrathecally administered contrast agent show that CSF flows along pathways that closely resemble the glymphatic system outlined in rodents. Furthermore, PET studies have revealed that Aβ accumulates in the healthy brain after a single night of sleep deprivation, suggesting that the human glymphatic pathway might also be primarily active during sleep. Other PET studies have shown that CSF clearance of Aβ and tau tracers is reduced in patients with Alzheimer's disease compared with healthy controls. The observed reduction in CSF clearance was associated with increasing grey-matter concentrations of Aβ in the human brain, consistent with findings in mice showing that decreased glymphatic function leads to Aβ accumulation. Altered AQP4 expression is also evident in brain tissue from patients with Alzheimer's disease or normal pressure hydrocephalus; glymphatic MRI scans of patients with normal pressure hydrocephalus show reduced CSF tracer entry and clearance. Research is needed to confirm whether specific factors driving glymphatic flow in rodents also apply to humans. Longitudinal imaging studies evaluating human CSF dynamics will determine whether a causal link exists between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or traumatic brain injury could identify whether this function correlates with neurological recovery. New insights into how behaviour and genetics modify glymphatic function, and how this function decompensates in disease, should lead to the development of new preventive and diagnostic tools and novel therapeutic targets.

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.

Background Slowed clearance of amyloid β (Aβ) is believed to underlie the development of Aβ plaques that characterize Alzheimer’s disease (AD). Aβ is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aβ clearance, and promotes Aβ plaque formation. Methods To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the α-syntrophin ( Snta1 ) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid β levels. Results In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing Aβ and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid β levels. Conclusions These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations.

In the majority of patients multiple sclerosis starts with a relapsing remitting course (RRMS), which may at later times transform into secondary progressive disease (SPMS). In a minority of patients the relapsing remitting disease is skipped and the patients show progression from the onset (primary progressive MS, PPMS). Evidence obtained so far indicate major differences between RRMS and progressive MS, but no essential differences between SPMS and PPMS, with the exception of a lower incidence in the global load of focal white matter lesions and in particular in the presence of classical active plaques in PPMS. We suggest that in MS patients two types of inflammation occur, which develop in parallel but partially independent from each other. The first is the focal bulk invasion of T- and B-lymphocytes with profound blood brain barrier leakage, which predominately affects the white matter, and which gives rise to classical active demyelinated plaques. The other type of inflammation is a slow accumulation of T-cells and B-cells in the absence of major blood brain barrier damage in the connective tissue spaces of the brain, such as the meninges and the large perivascular Virchow Robin spaces, where they may form aggregates or in most severe cases structures in part resembling tertiary lymph follicles. This type of inflammation is associated with the formation of subpial demyelinated lesions in the cerebral and cerebellar cortex, with slow expansion of pre-existing lesions in the white matter and with diffuse neurodegeneration in the normal appearing white or gray matter. The first type of inflammation dominates in acute and relapsing MS. The second type of inflammation is already present in early stages of MS, but gradually increases with disease duration and patient age. It is suggested that CD8 T-lymphocytes remain in the brain and spinal cord as tissue resident cells, which may focally propagate neuroinflammation, when they re-encounter their cognate antigen. B-lymphocytes may propagate demyelination and neurodegeneration, most likely by producing soluble neurotoxic factors. Whether lymphocytes within the brain tissue of MS lesions have also regulatory functions is presently unknown. Key open questions in MS research are the identification of the target antigen recognized by tissue resident CD8 T-cells and B-cells and the molecular nature of the soluble inflammatory mediators, which may trigger tissue damage.

Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI. Traumatic brain injury (TBI) is a serious and poorly understood medical condition. Here, the authors show that TBI induces long-lasting deficits in brain lymphatic drainage. They report that defects in this drainage pathway provoke severe TBI pathogenesis that can be rescued with VEGF-C treatment.

•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.

•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.

The glymphatic system (GS) hypothesis states that advective driven cerebrospinal fluid (CSF) influx from the perivascular spaces into the interstitial fluid space rapidly transport solutes and clear waste from brain. However, the presence of advection in neuropil is contested and solutes are claimed to be transported by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of GS transport revealed that solute speed was faster in CSF compared to grey and white matter. Further, rOMT analysis also demonstrated 2-fold differences in regional solute speed within the brain. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to GS transport in parenchyma. In a rat model of cerebral small vessel disease (cSVD), solute transport in the perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normal rats. Thus, the analytical framework of rOMT provides novel insights in the local dynamics of GS transport that may have implications for neurodegenerative diseases. Future studies should apply the rOMT analysis approach to confirm GS transport reductions in humans with cSVD.

Abstract Poor sleep quality might contribute to the risk and progression of neurodegenerative disorders via deficient cerebral waste clearance functions during sleep. In this retrospective cross-sectional study, we explore the link between enlarged perivascular spaces (PVS), a putative marker of sleep-dependent glymphatic clearance, with sleep quality and motor symptoms in patients with Parkinson’s disease (PD). T2-weighted magnetic resonance imaging (MRI) images of 20 patients and 17 healthy control participants were estimated visually for PVS in the basal ganglia (BG) and centrum semiovale (CSO). The patient group additionally underwent a single-night polysomnography. Readouts included polysomnographic sleep features and slow-wave activity (SWA), a quantitative EEG marker of sleep depth. Associations between PVS counts, PD symptoms (MDS-UPDRS scores), and sleep parameters were evaluated using correlation and regression analyses. Intra- and inter-rater reproducibility was assessed with weighted Cohen`s kappa coefficient. BG and CSO PVS counts in both patients and controls did not differ significantly between groups. In patients, PVS in both brain regions was negatively associated with SWA (1–2 Hz; BG: r(15) = −.58, padj = .015 and CSO: r(15) = −.6, padj = .015). Basal ganglia PVS counts were positively associated with motor symptoms of daily living (IRR = 1.05, CI [1.01, 1.09], p = .007, padj = .026) and antidepressant use (IRR = 1.37, CI [1.05, 1.80], p = .021, padj = .043) after controlling for age. Centrum Semiovale PVS counts in patients were positively associated with a diagnosis of REM sleep behavior disorder (IRR = 1.39, CI [1.06, 1.84], p = .018, padj = .11). These results add to evidence that sleep deterioration may play a role in impairing glymphatic clearance via altered perivascular function, potentially contributing to disease severity in PD patients. Graphical Abstract Graphical Abstract

The pathological hallmarks of Parkinson’s disease (PD), a neurodegenerative disorder, are the selective loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and the presence of α-synuclein (α-syn) aggregates in the form of Lewy bodies/Lewy neurites (LBs/LNs) in neurons. Recent studies have indicated that aquaporin 4 (AQP4), as a predominant water channel protein in the brain, is involved in the progression of Parkinson’s disease (PD). However, it remains unclear whether AQP4 expression affects α-syn pathology in Parkinson’s disease. In this study, we established a progressive PD model by subjecting AQP4 null (AQP4+/−) mice to bilateral intrastriatal injection of α-syn preformed fibrils (PFFs) and investigated the effect of decreased AQP4 expression on the development of PD. We found that decreased expression of AQP4 accelerated pathologic deposition of α-syn and facilitated the loss of dopamine neurons and behavioral disorders. Draining of macromolecules from the brain via the glymphatic pathway was slowed due to decreased AQP4 expression. Taken together, these findings indicate that decreased AQP4 expression may aggravate PD-like pathology, possibly via impairment of the glymphatic pathway.