The Brain's Glymphatic System: Current Controversies.

The glymphatic system is a glial-dependent waste clearance pathway in the brain, in place of lymphatic vessels, dedicated to drain away soluble waste proteins and metabolic products. Specifically, the glymphatic network serves as a "front end" for waste clearance, and is connected downstream to an authentic lymphatic network, associated with dura covering the brain as well as cranial nerves and large vessels at the skull exits. The anatomical and functional interconnections between these two networks are not completely understood. Several key physiological processes have been identified that control glymphatic transport function and waste clearance from brain. In this review, we aim to provide an overview and discussion of the concept behind the glymphatic system, current evidence, and controversies, while specifically focusing on the consequences of aging and evidence of its existence in human brain. Discovering novel strategies for optimizing and maintaining efficient brain waste clearance across the lifespan may in the future prove to be important for preventing cognitive decline and sustaining healthy aging.

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The Glymphatic System and Waste Clearance with Brain Aging: A Review

Small vessel diseases (SVDs) 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 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 form part of a vicious cycle involving impaired cerebrovascular reactivity, blood-brain barrier dysfunction, perivascular inflammation and ultimately impaired clearance of waste proteins from the interstitial fluid 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.

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

Background:The glymphatic pathway transports cerebrospinal fluid through the brain, thereby facilitating waste removal A unique aspect of this pathway is that its function depends on the state of consciousness of the brain and is associated with norepinephrine activity A current view is that all a

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Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane.

The relationships between cerebrospinal fluid (CSF) and brain interstitial fluid are still being elucidated. It has been proposed that CSF within the subarachnoid space will enter paravascular spaces along arteries to flush through the parenchyma of the brain. However, CSF also directly exits the subarachnoid space through the cribriform plate and other perineural routes to reach the lymphatic system. In this study, we aimed to elucidate the functional relationship between CSF efflux through lymphatics and the potential influx into the brain by assessment of the distribution of CSF-infused tracers in awake and anesthetized mice. Using near-infrared fluorescence imaging, we showed that tracers quickly exited the subarachnoid space by transport through the lymphatic system to the systemic circulation in awake mice, significantly limiting their spread to the paravascular spaces of the brain. Magnetic resonance imaging and fluorescence microscopy through the skull under anesthetized conditions indicated that tracers remained confined to paravascular spaces on the surface of the brain. Immediately after death, a substantial influx of tracers occurred along paravascular spaces extending into the brain parenchyma. We conclude that under normal conditions a rapid CSF turnover through lymphatics precludes significant bulk flow into the brain.

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Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain

Purpose
We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived.

Methods
We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms. Normal Wistar rats underwent Gd-DOTA infusion into CSF via the cisterna magna and continuous MRI for approximately 130 min using T1-weighted imaging. Dynamic Gd-DOTA concentration maps were calculated and parenchymal uptake was estimated.

Results
In the phantom study, T1 discrepancies between the VFA-SPGR and IR-RARE sequences were approximately 6% with a transmit coil inhomogeneity correction. In the in vivo study, contrast transport profiles indicated maximal parenchymal retention of approximately 19% relative to the total amount delivered into the cisterna magna.

Conclusion
Imaging strategies for accurate 3D contrast concentration mapping at 9.4T were developed and whole brain dynamic concentration maps were derived to study solute transport via the glymphatic system. The newly developed approach will enable future quantitative studies of the glymphatic system in health and disease states. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

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Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T

The stimulation phase of electroconvulsive therapy (ECT) induces bradycardia. We evaluated the effect of this bradycardia on cerebral perfusion and oxygenation by administration of the anticholinergic drug glycopyrrolate (Glp). Cerebral perfusion was estimated by transcranial ultrasound in the middle cerebral artery reporting the mean flow velocity (middle cerebral artery [MCA] V(mean)), and cerebral oxygenation was determined by near-infrared spectroscopy of the frontal lobe. Before ECT, heart rate (HR) was 84 beats min(-1) (66-113; median and range) and decreased to 17 (7-85) beats min(-1) during the stimulation phase of ECT (P < 0.001). Middle cerebral artery V(mean) decreased 43% (9%-71%; P < 0.001), and frontal lobe oxyhemoglobin (O(2)Hb) concentration decreased from 0.6 (0.0-25.3) to 0.1 (-1.9 to 7.6) microM, whereas the deoxyhemoglobin concentration increased from -0.2 (-13.9 to 0.8) to 0.0 (-4.2 to 0.8) microM (P < 0.001). Pretreatment with Glp largely eliminated these effects during the stimulation phase of ECT, maintaining HR at 78 (40-94) beats min(-1), MCA V(mean) at 53 (37-77) cm s(-1), and O(2)Hb at 5.6 (10.6-38.5) microM (P < 0.05). After ECT, HR, cerebral perfusion and oxygenation normalized over approximately 3 minutes, whereas the electroencephalogram was unaffected by Glp. The results demonstrate that ECT is associated with hemodynamic effects severe enough to affect cerebral oxygenation and perfusion, and that these effects can be attenuated by Glp treatment.

Glycopyrrolate prevents extreme bradycardia and cerebral deoxygenation during electroconvulsive therapy.

Designing effective and safe tuberculosis (TB) subunit vaccines for inhalation requires identification of appropriate antigens and adjuvants and definition of the specific areas to target in the lungs. Magnetic resonance imaging (MRI) enables high spatial resolution, but real-time anatomical and functional MRI of lungs is challenging. Here, we describe the design of a novel gadoteridol-loaded cationic adjuvant formulation 01 (CAF01) for MRI-guided vaccine delivery of the clinically tested TB subunit vaccine candidate H56/CAF01. Gadoteridol-loaded CAF01 liposomes were engineered by using a quality-by-design approach to (i) increase the mechanistic understanding of formulation factors governing the loading of gadoteridol and (ii) maximize the loading of gadoteridol in CAF01, which was confirmed by cryotransmission electron microscopy. The encapsulation efficiency and loading of gadoteridol were highly dependent on the buffer pH due to strong attractive electrostatic interactions between gadoteridol and the cationic lipid component. Optimal gadoteridol loading of CAF01 liposomes showed good in vivo stability and safety upon intrapulmonary administration into mice while generating 1.5-fold MRI signal enhancement associated with approximately 30% T1 relaxation change. This formulation principle and imaging approach can potentially be used for other mucosal nanoparticle-based formulations, species, and lung pathologies, which can readily be translated for clinical use.

Palle Koch

Papers

Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T

Glycopyrrolate prevents extreme bradycardia and cerebral deoxygenation during electroconvulsive therapy.

Design of Gadoteridol-Loaded Cationic Liposomal Adjuvant CAF01 for MRI of Lung Deposition of Intrapulmonary Administered Particles.