Modeling of brain efflux: Constraints of brain surfaces.

Fluid efflux from the brain plays an important role in solute waste clearance. Current experimental approaches provide little spatial information, and data collection is limited due to short duration or low frequency of sampling. One approach shows tracer efflux to be independent of molecular size, indicating bulk flow, yet also decelerating like simple membrane diffusion. In an apparent contradiction to this report, other studies point to tracer efflux acceleration. We here develop a one-dimensional advection-diffusion model to gain insight into brain efflux principles. The model is characterized by nine physiological constants and three efflux parameters for which we quantify prior uncertainty. Using Bayes' rule and the two efflux studies, we validate the model and calculate data-informed parameter distributions. The apparent contradictions in the efflux studies are resolved by brain surface boundaries being bottlenecks for efflux. To critically test the model, a custom MRI efflux assay measuring solute dispersion in tissue and release to cerebrospinal fluid was employed. The model passed the test with tissue bulk flow velocities in the range 60 to 190 [Formula: see text]m/h. Dimensional analysis identified three principal determinants of efflux, highlighting brain surfaces as a restricting factor for metabolite solute clearance.

Immune dynamics in the CNS and its barriers during homeostasis and disease.

The central nervous system (CNS) has historically been viewed as an immunologically privileged site, but recent studies have uncovered a vast landscape of immune cells that reside primarily along its borders. While microglia are largely responsible for surveying the parenchyma, CNS barrier sites are inhabited by a plethora of different innate and adaptive immune cells that participate in everything from the defense against microbes to the maintenance of neural function. Static and dynamic imaging studies have revolutionized the field of neuroimmunology by providing detailed maps of CNS immune cells as well as information about how these cells move, organize, and interact during steady-state and inflammatory conditions. These studies have also redefined our understanding of neural-immune interactions at a cellular level and reshaped our conceptual view of immune privilege in this specialized compartment. This review will focus on insights gained using imaging techniques in the field of neuroimmunology, with an emphasis on anatomy and CNS immune dynamics during homeostasis, infectious diseases, injuries, and aging.

Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies.

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

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.

Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood.

Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the "EU Joint Programme - Neurodegenerative Disease Research (JPND)" consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration-time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.

Dynamic changes in glymphatic function in reversible cerebral vasoconstriction syndrome.

BACKGROUND: The pathophysiology of the reversible cerebral vasoconstriction syndrome (RCVS) remains enigmatic and the role of glymphatics in RCVS pathophysiology has not been evaluated. We aimed to investigate RCVS glymphatic dynamics and its clinical correlates. METHODS: We prospectively evaluated the glymphatic function in RCVS patients, with RCVS subjects and healthy controls (HCs) recruited between August 2020 and November 2023, by calculating diffusion-tensor imaging along the perivascular space (DTI-ALPS) index under a 3-T MRI. Clinical and vascular (transcranial color-coded duplex sonography) investigations were conducted in RCVS subjects. RCVS participants were separated into acute (≤ 30 days) and remission (≥ 90 days) groups by disease onset to MRI interval. The time-trend, acute stage and longitudinal analyses of the DTI-ALPS index were conducted. Correlations between DTI-ALPS index and vascular and clinical parameters were performed. Bonferroni correction was applied to vascular investigations (q = 0.05/11). RESULTS: A total of 138 RCVS patients (mean age, 46.8 years ± 11.8; 128 women) and 42 HCs (mean age, 46.0 years ± 4.5; 35 women) were evaluated. Acute RCVS demonstrated lower DTI-ALPS index than HCs (p < 0.001) and remission RCVS (p < 0.001). A continuously increasing DTI-ALPS trend after disease onset was demonstrated. The DTI-ALPS was lower when the internal carotid arteries resistance index and six-item Headache Impact test scores were higher. In contrast, during 50-100 days after disease onset, the DTI-ALPS index was higher when the middle cerebral artery flow velocity was higher. CONCLUSIONS: Glymphatic function in patients with RCVS exhibited a unique dynamic evolution that was temporally coupled to different vascular indices and headache-related disabilities along the disease course. These findings may provide novel insights into the complex interactions between glymphatic transport, vasomotor control and pain modulation.

Fluid dynamics in aging-related dementias.

Recent human and animal model experimental studies revealed novel pathways for fluid movement, immune cell trafficking and metabolic waste clearance in CNS. These studies raise the intriguing possibility that the newly discovered pathways, including the glymphatic system, lymphatic meningeal vessels and skull-brain communication channels, are impaired in aging and neurovascular and neurodegenerative diseases associated with dementia, including Alzheimer's disease (AD) and AD-related dementia. We provide an overview of the glymphatic and dural meningeal lymphatic systems, review current methods and approaches used to study glymphatic flow in humans and animals, and discuss current evidence and controversies related to its role in CNS flow homeostasis under physiological and pathophysiological conditions. Non-invasive imaging approaches are needed to fully understand the mechanisms and pathways driving fluid movement in CNS and their roles across lifespan including healthy aging and aging-related dementia.

An optimized b-value sampling for the quantification of interstitial fluid using diffusion-weighted MRI, a genetic algorithm approach.

PURPOSE: Multi-b-value diffusion-weighted MRI techniques can simultaneously measure the parenchymal diffusivity, microvascular perfusion, and a third, intermediate diffusion component. This component is related to the interstitial fluid in the brain parenchyma. However, simultaneously estimating three diffusion components from multi-b-value data is difficult and has strong dependence on SNR and chosen b-values. As the number of acquired b-values is limited due to scanning time, it is important to know which b-values are most effective to be included. Therefore, this study evaluates an optimized b-value sampling for interstitial fluid estimation. METHOD: The optimized b-value sampling scheme is determined using a genetic algorithm. Subsequently, the performance of this optimized sampling is assessed by comparing it with a linear, logarithmic, and previously proposed sampling scheme, in terms of the RMS error (RMSE) for the intermediate component estimation. The in vivo performance of the optimized sampling is assessed using 7T data with 101 equally spaced b-values ranging from 0 to 1000 s/mm2 . In this case, the RMSE was determined by comparing the fit that includes all b-values. RESULTS: The optimized b-value sampling for estimating the intermediate component was reported to be [0, 30, 90, 210, 280, 350, 580, 620, 660, 680, 720, 760, 980, 990, 1000] s/mm2 . For computer simulations, the optimized sampling had a lower RMSE, compared with the other samplings for varying levels of SNR. For the in vivo data, the voxel-wise RMSE of the optimized sampling was lower compared with other sampling schemes. CONCLUSION: The genetic algorithm-optimized b-value scheme improves the quantification of the diffusion component related to interstitial fluid in terms of a lower RMSE.

Arterial spin labeling signal in the CSF: Implications for partial volume correction and blood-CSF barrier characterization.

For better quantification of perfusion with arterial spin labeling (ASL), partial volume correction (PVC) is used to disentangle the signals from gray matter (GM) and white matter within any voxel. Based on physiological considerations, PVC algorithms typically assume zero signal in the cerebrospinal fluid (CSF). Recent measurements, however, have shown that CSF-ASL signal can exceed 10% of GM signal, even when using recommended ASL labeling parameters. CSF signal is expected to particularly affect PVC results in the choroid plexus. This study aims to measure the impact of CSF signal on PVC perfusion measurements, and to investigate the potential use of PVC to retrieve pure CSF-ASL signal for blood-CSF barrier characterization. In vivo imaging included six pCASL sequences with variable label duration and post-labeling delay (PLD), and an eight-echo 3D-GRASE readout. A dataset was simulated to estimate the effect of CSF-PVC with known ground-truth parameters. Differences between the results of CSF-PVC and non-CSF-PVC were estimated for regions of interest (ROIs) based on GM probability, and a separate ROI isolating the choroid plexus. In vivo, the suitability of PVC-CSF signal as an estimate of pure CSF was investigated by comparing its time course with the long-TE CSF signal. Results from both simulation and in vivo data indicated that including the CSF signal in PVC improves quantification of GM CBF by approximately 10%. In simulated data, this improvement was greater for multi-PLD (model fitting) quantification than for single PLD (~1-5% difference). In the choroid plexus, the difference between CSF-PVC and non-CSF-PVC was much larger, averaging around 30%. Long-TE (pure) CSF signal could not be estimated from PVC CSF signal as it followed a different time course, indicating the presence of residual macrovascular signal in the PVC. The inclusion of CSF adds value to PVC for more accurate measurements of GM perfusion, and especially for quantification of perfusion in the choroid plexus and study of the glymphatic system.

Perivascular clearance of blood proteins after blood-brain barrier disruption in a rat model of microinfarcts.

Microinfarcts result in a transient loss of the blood-brain barrier (BBB) in the ischemic territory. This leads to the extravasation of blood proteins into the brain parenchyma. It is not clear how these proteins are removed. Here we studied the role of perivascular spaces in brain clearance from extravasated blood proteins. Male and female Wistar rats were infused with microspheres of either 15, 25, or 50 µm in diameter (n = 6 rats per group) via the left carotid artery. We infused either 25,000 microspheres of 15 µm, 5500 of 25 µm, or 1000 of 50 µm. One day later, rats were infused with lectin and hypoxyprobe to label perfused blood vessels and hypoxic areas, respectively. Rats were then euthanized and perfusion-fixed. Brains were excised, sectioned, and analyzed using immunostaining and confocal imaging. Microspheres induced a size-dependent increase in ischemic volume per territory, but the cumulative ischemic volume was similar in all groups. The total volumes of ischemia, hypoxia and infarction affected 1-2 % of the left hemisphere. Immunoglobulins (IgG) were present in ischemic brain tissue surrounding lodged microspheres in all groups. In addition, staining for IgG was found in perivascular spaces of blood vessels nearby areas of BBB disruption. About 2/3 of these vessels were arteries, while the remaining 1/3 of these vessels were veins. The subarachnoid space (SAS) of the affected hemisphere stained stronger for IgG than the contralateral hemisphere in all groups: +27 %, +44 % and +27 % respectively. Microspheres of various sizes induce a local loss of BBB integrity, evidenced by parenchymal IgG staining. The presence of IgG in perivascular spaces of both arteries and veins distinct from the ischemic territories suggests that both contribute to the removal of blood proteins. The strong staining for IgG in the SAS of the affected hemisphere suggests that this perivascular route egresses via the CSF. Perivascular spaces therefore play a previously unrecognized role in tissue clearance of fluid and extravasated proteins after BBB disruption induced by microinfarcts.

MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and secondary brain edema in a mouse model of intracerebral hemorrhage.

BACKGROUND: The functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH-SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood-brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH-SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH-SBI. METHODS: We used a whole-blood injection model in mice, to systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7-Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average-intensity-mapping. RESULTS: We identified a pronounced early response of the choroid plexus (CP) peaking at 12-24 h that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96 h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24 h after whole-blood injection. CONCLUSIONS: We report a biphasic brain reaction pattern after ICH with a MyD88-TLR4-dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP activation might harbor the potential to modulate the development of ICH-SBI.

Photomodulation of Lymphatic Delivery of Bevacizumab to the Brain: The Role of Singlet Oxygen.

The blood-brain barrier (BBB) poses a significant challenge for drug delivery to the brain. Therefore, the development of safe methods for an effective delivery of medications to the brain can be a revolutionary step in overcoming this limitation. Using a quantum-dot-based 1267 nm laser (photosensitiser-free generation of singlet oxygen), we clearly show the photostimulation of lymphatic delivery of bevacizumab (BMZ) to the brain tissues and the meninges. These pilot findings open promising perspectives for photomodulation of a lymphatic brain drug delivery bypassing the BBB, and potentially enabling a breakthrough strategy in therapy of glioma using BMZ and other chemotherapy drugs.

Ultra-long-TE arterial spin labeling reveals rapid and brain-wide blood-to-CSF water transport in humans.

The study of brain clearance mechanisms is an active area of research. While we know that the cerebrospinal fluid (CSF) plays a central role in one of the main existing clearance pathways, the exact processes for the secretion of CSF and the removal of waste products from tissue are under debate. CSF is thought to be created by the exchange of water and ions from the blood, which is believed to mainly occur in the choroid plexus. This exchange has not been thoroughly studied in vivo. We propose a modified arterial spin labeling (ASL) MRI sequence and image analysis to track blood water as it is transported to the CSF, and to characterize its exchange from blood to CSF. We acquired six pseudo-continuous ASL sequences with varying labeling duration (LD) and post-labeling delay (PLD) and a segmented 3D-GRASE readout with a long echo train (8 echo times (TE)) which allowed separation of the very long-T2 CSF signal. ASL signal was observed at long TEs (793 ms and higher), indicating presence of labeled water transported from blood to CSF. This signal appeared both in the CSF proximal to the choroid plexus and in the subarachnoid space surrounding the cortex. ASL signal was separated into its blood, gray matter and CSF components by fitting a triexponential function with T2s taken from literature. A two-compartment dynamic model was introduced to describe the exchange of water through time and TE. From this, a water exchange time from the blood to the CSF (Tbl->CSF) was mapped, with an order of magnitude of approximately 60 s.

Idiopathic intracranial hypertension pathogenesis: The jugular hypothesis.

In spite of expanding research, idiopathic intracranial hypertension (IIH) and its spectrum conditions remain challenging to treat. The failure to develop effective treatment strategies is largely due to poor agreement on a coherent disease pathogenesis model. Herein we provide a hypothesis of a unifying model centered around the internal jugular veins (IJV) to explain the development of IIH, which contends the following: (1) the IJV are prone to both physiological and pathological compression throughout their course, including compression near C1 and the styloid process, dynamic muscular/carotid compression from C3 to C6, and lymphatic compression; (2) severe dynamic IJV stenosis with developments of large cervical gradients is common in IIH-spectrum patients and significantly impacts intracranial venous and cerebrospinal fluid (CSF) pressures; (3) pre-existing IJV stenosis may be exacerbated by infectious/inflammatory etiologies that induce retromandibular cervical lymphatic hypertrophy; (4) extra-jugular venous collaterals dilate with chronic use but are insufficient resulting in impaired aggregate cerebral venous outflow; (5) poor IJV outflow initiates, or in conjunction with other factors, contributes to intracranial venous hypertension and congestion leading to higher CSF pressures and intracranial pressure (ICP); (6) glymphatic congestion occurs but is insufficient to compensate and this pathway becomes overwhelmed; and (7) elevated intracranial CSF pressures triggers extramural venous sinus stenosis in susceptible individuals that amplifies ICP elevation producing severe clinical manifestations. Future studies must focus on establishing norms for dynamic cerebral venous outflow and IJV physiology in the absence of disease so that we may better understand and define the diseased state.

Large molecules from the cerebrospinal fluid enter the optic nerve but not the retina of mice.

It has been proposed that cerebrospinal fluid (CSF) can enter and leave the retina and optic nerve along perivascular spaces surrounding the central retinal vessels as part of an aquaporin-4 (AQP4) dependent ocular 'glymphatic' system. Here, we injected fluorescent dextrans and antibodies into the CSF of mice at the cisterna magna and measured their distribution in the optic nerve and retina. We found that uptake of dextrans in the perivascular spaces and parenchyma of the optic nerve is highly sensitive to the cisternal injection rate, where high injection rates, in which dextran disperses fully in the sub-arachnoid space, led to uptake along the full length of the optic nerve. Accumulation of dextrans in the optic nerve did not differ significantly in wild-type and AQP4 knockout mice. Dextrans did not enter the retina, even when intracranial pressure was greatly increased over intraocular pressure. However, elevation of intraocular pressure reduced accumulation of fluorescent dextrans in the optic nerve head, and intravitreally injected dextrans left the retina via perivascular spaces surrounding the central retinal vessels. Human IgG distributed throughout the perivascular and parenchymal areas of the optic nerve to a similar extent as dextran following cisternal injection. However, uptake of a cisternally injected AQP4-IgG antibody, derived from a seropositive neuromyelitis optica spectrum disorder subject, was limited by AQP4 binding. We conclude that large molecules injected in the CSF can accumulate along the length of the optic nerve if they are fully dispersed in the optic nerve sub-arachnoid space but that they do not enter the retina.

Perivascular spaces around arteries exceed perivenous spaces in the mouse brain.

The perivascular space (PVS) surrounds cerebral blood vessels and plays an important role in clearing waste products from the brain. Their anatomy and function have been described for arteries, but PVS around veins remain poorly characterized. Using in vivo 2-photon imaging in mice, we determined the size of the PVS around arteries and veins, and their connection with the subarachnoid space. After infusion of 70 kD FITC-dextran into the cerebrospinal fluid via the cisterna magna, labeled PVS were evident around arteries, but veins showed less frequent labeling of the PVS. The size of the PVS correlated with blood vessel size for both pial arteries and veins, but not for penetrating vessels. The PVS around pial arteries and veins was separated from the subarachnoid space by a thin meningeal layer, which did not form a barrier for the tracer. In vivo, FITC-dextran signal was observed adjacent to the vessel wall, but minimally within the wall itself. Post-mortem, there was a significant shift in the tracer's location within the arterial wall, extending into the smooth muscle layer. Taken together, these findings suggest that the PVS around veins has a limited role in the exchange of solutes between CSF and brain parenchyma.

Integrative MR Imaging Interpretation in Cognitive Impairment with Alzheimer's Disease, Small Vessel Disease, and Glymphatic Function-Related MR Parameters.

RATIONALE AND OBJECTIVES: The role of MR imaging in patients with cognitive impairment is to evaluate each component of Alzheimer's disease (AD), small vessel disease (SVD), and glymphatic function. We want to validate the diagnostic performance of the comprehensive interpretation of these parameters to predict the cognitive impairment stage. MATERIALS AND METHODS: This retrospective single-center study included 359 patients with cognitive impairment who had undergone MRI (FLAIR, T2WI, 3D-T1WI, susceptibility-weighted imaging, and diffusion tensor imaging [DTI]) and a neuropsychological screening battery between January 2020 and July 2022. Each AD and SVD-related MR parameter was visually evaluated, and DTI analysis along the perivascular space (ALPS) index was calculated. Volumetry analysis was performed using Neurophet AQUA AI-based software. Using logistic regression analysis, four types of models were developed and compared by adding the components in the following order: (1) clinical factors and AD, (2) SVD, (3) glymphatic function-related MR parameters, and (4) volumetric data. Chi-square automatic interaction detection algorithm was used to develop diagnostic tree analysis (DTA) model to predict late-stage cognitive impairment. RESULTS: APOE4 status, years of education, medial temporal lobe atrophy score, Fazekas scale score, DTI-ALPS index, and white matter hyperintensity were significant predictors of late-stage cognitive impairment. The performance of the prediction model increased from Model 1 to Model 4 (AUC: 0.880, 0.899, 0.914, and 0.945, respectively). The overall accuracy of the DTA model was 87.47%. CONCLUSION: Integrative brain MRI assessments in patients with cognitive impairment, AD, SVD, and glymphatic function-related MR parameters, improve the prediction of late-stage cognitive impairment.

Brain Lymphatics: Rediscovery and New Insights into Lymphatic Involvement in Diseases of Human Brains.

The brain's lymphatic system is comprised of a glymphatic-meningeal-cervical lymphatic vessel pathway. The study of its mechanism and pathophysiology in neurodegenerative disease has been one of the most exciting topics in basic and translational neuroscience of the last decade. However, while there has been some debate about when the meningeal lymphatics were discovered, it cannot be denied that studies in preclinical models and humans in this century represent a monumental step forward in our understanding of how the brain removes metabolic waste, the role this system plays in neurodegenerative disease, and, most importantly, its potential as a novel therapeutic target. This is a summary of the history, functional anatomy, and role of the brain's lymphatics in neurodegenerative disease.

Nasal turbinate lymphatic obstruction: a proposed new paradigm in the etiology of essential hypertension.

Hypertension affects an estimated 1.3 billion people worldwide and is considered the number one contributor to mortality via stroke, heart failure, renal failure, and dementia. Although the physiologic mechanisms leading to the development of essential hypertension are poorly understood, the regulation of cerebral perfusion has been proposed as a primary cause. This article proposes a novel etiology for essential hypertension. Our hypothesis developed from a review of nuclear medicine scans, where the authors observed a significantly abnormal increase in nasal turbinate vasodilation in hypertensive patients using quantitative region of interest analysis. The authors propose that nasal turbinate vasodilation and resultant blood pooling obstruct the flow of cerebrospinal fluid passing through nasal turbinate lymphatics, thereby increasing intracranial pressure. The authors discuss the glymphatic/lymphatic clearance system which is impaired with age, and at which time hypertension also develops. The increased intracranial pressure leads to compensatory hypertension via Cushing's mechanism, i.e., the selfish brain hypothesis. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs simultaneously along with the well-established increased sympathetic activity of the cardiovascular system. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of processed food. This hypothesis explains the rapid worldwide rise in essential hypertension in the last 50 years and offers a novel mechanism and a new paradigm for the etiology of essential hypertension. This new paradigm offers compelling evidence for the modulation of parasympathetic nervous system activity as a novel treatment strategy, specifically targeting nasal turbinate regulation, to treat diseases such as hypertension, idiopathic intracranial hypertension, and degenerative brain diseases. The proposed mechanism of essential hypertension presented in this paper is a working hypothesis and confirmatory studies will be needed.