Cerebrospinal fluid CXCL10 is associated with the presence of low level CSF HIV during suppressive antiretroviral therapy

Surrogate markers of HIV central nervous system (CNS) persistence are needed because direct HIV measurements from the CNS require specialized protocols and are not always detectable or quantifiable. We analyzed paired plasma and CSF samples from people with HIV (PWH) on suppressive therapy (ART) with a validated HIV single copy RNA assay. Two potential markers of CNS persistence were measured (CXCL10 and sCD30). We then examined associations with CSF HIV RNA positivity in univariable and multivariable analyses. Among 66 individuals, 18.2% had detectable CSF HIV. Individuals who had detectable HIV in CSF had higher CSF CXCL10 concentrations (median 514 pg/ml versus median 317 pg/ml, p = 0.019), but did not have significantly different CSF sCD30 concentrations (median 7.5 ng/ml versus median 7.6 ng/ml, p = 0.78). In the multiple logistic analysis, both higher CSF CXCL10 (p = 0.038) and plasma HIV detectability (p = 0.035) were significantly associated with detectable CSF HIV. Both sCD30 and CXCL10 correlated positively with NfL and NSE, two neuronal markers. This study demonstrates that CSF CXCL10 concentrations reflect low level HIV CNS persistence despite virologic suppression on ART. Given that it is readily detectable and quantifiable, this chemokine may be a promising biomarker to evaluate HIV eradication therapies that target the CNS

Glymphatic transport is reduced in rats with spontaneous pituitary tumor

BACKGROUND AND OBJECTIVE: Pituitary tumor in patients induces adverse alterations in the brain, accompanied by cognitive deficits. Dysfunction of glymphatic waste clearance results in accumulation of neurotoxic products within the brain, leading to cognitive impairment. However, the status of glymphatic function in the brain with pituitary tumor is unknown. Using magnetic resonance imaging (MRI) and an advanced mathematical modeling, we investigated the changes of glymphatic transport in the rats carrying spontaneous pituitary tumor. METHODS: Rats (22-24 months, female, Wistar) with and without pituitary tumor (n = 7/per group) underwent the identical experimental protocol. MRI measurements, including T2-weighted imaging and dynamic 3D T1-weighted imaging with intracisternal administration of contrast agent, were performed on each animal. The contrast-induced enhancement in the circle of Willis and in the glymphatic influx nodes were observed on the dynamic images and verified with time-signal-curves (TSCs). Model-derived parameters of infusion rate and clearance rate that characterize the kinetics of glymphatic tracer transport were evaluated in multiple representative brain regions. RESULTS: Our imaging data demonstrated a higher incidence of partially enhanced circle of Willis (86 vs. 14%; p \u3c 0.033) and a lower incidence of enhancement in glymphatic influx nodes of pituitary (71 vs. 100%) and pineal (57 vs. 86%) recesses in the rats with pituitary tumor than in the rats with normal appearance of pituitary gland, indicating an intensification of impaired peri-vascular pathway and impeded glymphatic transport due to the presence of pituitary tumor. Consistently, our kinetic modeling and regional cerebral tissue quantification revealed significantly lower infusion and clearance rates in all examined regions in rats with spontaneous pituitary tumor than in non-tumor rats, representing a suppressed glymphatic transport in the brain with pituitary tumor. CONCLUSION: Our study demonstrates the compromised glymphatic transport in the rat brain with spontaneous pituitary tumor. The reduced efficiency in cerebral waste clearance increases the risk for neurodegeneration in the brain that may underlie the cognitive impairment commonly seen in patients with pituitary tumors

Integrated understanding of hydrocephalus — a practical approach for a complex disease

Most of childhood hydrocephalus are originating during infancy. It is considered to be a complex disease since it is developed on the basis of heterogeneous pathophysiological mechanisms and different pathological conditions as well as during different age groups. Hence, it is of relevant importance to have a practical concept in mind, how to categorize hydrocephalus to surgically better approach this disease. The current review should offer further basis of discussion on a disease still most frequently seen in Pediatric Neurosurgery. Current literature on pathophysiology and classification of pediatric hydrocephalus has been reviewed to integrate the different published concepts of hydrocephalus for pediatric neurosurgeons. The current understanding of infant and childhood hydrocephalus pathophysiology is summarized. A simplified concept based on seven factors of CSF dynamics is elaborated and discussed in the context of recent discussions. The seven factors such as pulsatility, CSF production, major CSF pathways, minor CSF pathways, CSF absorption, venous outflow, and respiration may have different relevance and may also overlap for the individual hydrocephalic condition. The surgical options available for pediatric neurosurgeons to approach hydrocephalus must be adapted to the individual condition. The heterogeneity of hydrocephalus causes mostly developing during infancy warrant a simplified overview and understanding for an everyday approach. The proposed guide may be a basis for further discussion and may serve for a more or less simple categorization to better approach hydrocephalus as a pathophysiological complex disease

Glymphatic transport is reduced in rats with spontaneous pituitary tumor

Background and objectivePituitary tumor in patients induces adverse alterations in the brain, accompanied by cognitive deficits. Dysfunction of glymphatic waste clearance results in accumulation of neurotoxic products within the brain, leading to cognitive impairment. However, the status of glymphatic function in the brain with pituitary tumor is unknown. Using magnetic resonance imaging (MRI) and an advanced mathematical modeling, we investigated the changes of glymphatic transport in the rats carrying spontaneous pituitary tumor.MethodsRats (22–24 months, female, Wistar) with and without pituitary tumor (n = 7/per group) underwent the identical experimental protocol. MRI measurements, including T2-weighted imaging and dynamic 3D T1-weighted imaging with intracisternal administration of contrast agent, were performed on each animal. The contrast-induced enhancement in the circle of Willis and in the glymphatic influx nodes were observed on the dynamic images and verified with time-signal-curves (TSCs). Model-derived parameters of infusion rate and clearance rate that characterize the kinetics of glymphatic tracer transport were evaluated in multiple representative brain regions.ResultsOur imaging data demonstrated a higher incidence of partially enhanced circle of Willis (86 vs. 14%; p < 0.033) and a lower incidence of enhancement in glymphatic influx nodes of pituitary (71 vs. 100%) and pineal (57 vs. 86%) recesses in the rats with pituitary tumor than in the rats with normal appearance of pituitary gland, indicating an intensification of impaired peri-vascular pathway and impeded glymphatic transport due to the presence of pituitary tumor. Consistently, our kinetic modeling and regional cerebral tissue quantification revealed significantly lower infusion and clearance rates in all examined regions in rats with spontaneous pituitary tumor than in non-tumor rats, representing a suppressed glymphatic transport in the brain with pituitary tumor.ConclusionOur study demonstrates the compromised glymphatic transport in the rat brain with spontaneous pituitary tumor. The reduced efficiency in cerebral waste clearance increases the risk for neurodegeneration in the brain that may underlie the cognitive impairment commonly seen in patients with pituitary tumors

Optimal Mass Transport with Lagrangian Workflow Reveals Advective and Diffusion Driven Solute Transport in the Glymphatic System

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

Understanding the role of the perivascular space in cerebral small vessel disease

Small vessel diseases are a group of disorders that result from pathological alteration of the small blood vessels in the brain, including the small arteries, capillaries and veins. Of the 35-36 million people that are estimated to suffer from dementia worldwide, up to 65% have an SVD component. Furthermore, SVD causes 20-25% of strokes, worsens outcome after stroke and is a leading cause of disability, cognitive impairment and poor mobility. Yet the underlying cause(s) of SVD are not fully understood.Magnetic resonance imaging (MRI) has confirmed enlarged perivascular spaces (PVS) as a hallmark feature of SVD. In healthy tissue, these spaces are proposed to form part of a complex brain fluid drainage system which supports interstitial fluid exchange and may also facilitate clearance of waste products from the brain. The pathophysiological signature of PVS, and what this infers about their function and interaction with cerebral microcirculation, plus subsequent downstream effects on lesion development in the brain has not been established. Here we discuss the potential of enlarged PVS to be a unique biomarker for SVD and related brain disorders with a vascular component. We propose that widening of PVS suggests presence of peri-vascular cell debris and other waste products that forms part of a vicious cycle involving impaired cerebrovascular reactivity (CVR), blood-brain barrier (BBB) dysfunction, perivascular inflammation and ultimately impaired clearance of waste proteins from the interstitial fluid (ISF) space, leading to accumulation of toxins, hypoxia and tissue damage.Here, we outline current knowledge, questions and hypotheses regarding understanding the brain fluid dynamics underpinning dementia and stroke through the common denominator of SVD

Opportunities in posthemorrhagic hydrocephalus research: outcomes of the Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop

Abstract The Hydrocephalus Association Posthemorrhagic Hydrocephalus Workshop was held on July 25 and 26, 2016 at the National Institutes of Health. The workshop brought together a diverse group of researchers including pediatric neurosurgeons, neurologists, and neuropsychologists with scientists in the fields of brain injury and development, cerebrospinal and interstitial fluid dynamics, and the blood–brain and blood–CSF barriers. The goals of the workshop were to identify areas of opportunity in posthemorrhagic hydrocephalus research and encourage scientific collaboration across a diverse set of fields. This report details the major themes discussed during the workshop and research opportunities identified for posthemorrhagic hydrocephalus. The primary areas include (1) preventing intraventricular hemorrhage, (2) stopping primary and secondary brain damage, (3) preventing hydrocephalus, (4) repairing brain damage, and (5) improving neurodevelopment outcomes in posthemorrhagic hydrocephalus.https://deepblue.lib.umich.edu/bitstream/2027.42/142869/1/12987_2018_Article_96.pd

Perivascular spaces in the brain:anatomy, physiology and pathology

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