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The glymphatic concept along with the discovery of meningeal lymphatic vessels have, in recent years, highlighted that fluid is directionally transported within the central nervous system (CNS). Imaging studies, as well as manipulations of fluid transport, point to a key role of the glymphatic–lymphatic system in clearance of amyloid-β and other proteins. As such, the glymphatic–lymphatic system represents a new target in combating neurodegenerative diseases. Not unexpectedly, introduction of a new plumbing system in the brain has stirred controversies. This opinion article will highlight what we know about the brain's fluid transport systems, where experimental data are lacking, and what is still debated. Several global models of brain fluid transport have been proposed. When assessing these models, it is imperative that they are based on observations in live animals. Cerebrospinal fluid (CSF) tracer distribution in histological sections mostly reflects nonphysiological events triggered after death. The literature suggests that diffusion and convective flow both contribute to clearance of CNS solutes. Experiments that are aimed at defining the relative contribution of diffusion versus convection are difficult to interpret because minor changes in physiological variables, such as body posture or respiratory rate, can significantly affect both pathways. Invasive procedures, such as tracer injection, will primarily suppress convective flow. The glymphatic system drives CSF into the brain along periarterial spaces and interstitial fluid (ISF) out along perivenous spaces. Aquaporin-4 (AQP4) water channels, densely expressed at the vascular endfeet of astrocytes, facilitate glymphatic transport, based on all studies on this topic (with one exception). Glymphatic–lymphatic efflux of amyloid-β contributes to diurnal variations in amyloid-β concentration in murine Alzheimer's disease models and represents a potential therapeutic target for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Astrocytes have been presumed to be uninteresting for the better part of a century. Recent findings suggest unexpected new functions for these cells and highlight the importance of viewing most brain activities as a collaboration between astrocytes and neurons. Astrocytes have been implicated in dynamic regulation of neuron production, synaptic network formation, neuron electrical activity and specific neurological diseases. We are only at the threshold of understanding fully the nature and consequences of these new astrocyte functions, and there is still much to be learned about the older and better-known roles. But now, at last, astrocytes have our attention. [Copyright &y& Elsevier]

Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brain-barrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used α 2 -adrenergic agonist dexmedetomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics. Unlabelled Image • The glymphatic system drives cerebrospinal fluid influx into brain tissue. • Glymphatic flow is increased by drugs that decrease brain noradrenergic tone. • Dexmedetomidine is a clinically used α 2 -adrenergic agonist sedative. • Dexmedetomidine increases the brain delivery of intrathecally administered drugs. • Glymphatic flow can be manipulated to enhance the CNS delivery of intrathecal therapeutics. [ABSTRACT FROM AUTHOR]

Abstract Cerebral small vessel disease(s) (SVD) results from pathological changes of the small blood vessels in the brain and is common in older people. The diagnostic features by which SVD manifests in brain includes white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and atrophy. In the present study, we use in vivo magnetic resonance imaging (MRI) to characterize brain morphometry and longitudinal relaxation time (T1) of spontaneously hypertensive rats (SHRs) to study the contribution of chronic hypertension to SVD relevant pathology. Male SHR and Wistar-Kyoto (WKY) rats underwent 3D variable flip angle spoiled gradient echo brain MRI at 9.4 T at early (seven weeks old) and established (19 weeks old) stages of hypertension. The derived proton density weighted and T1 images were utilized for morphometry and to characterize T1 properties in gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Custom tissue probability maps were constructed for accurate computerized whole brain tissue segmentations and voxel-wise analyses. Characteristic morphological differences between the two strains included enlarged ventricles, smaller corpus callosum (CC) volumes and general 'thinning' of CC in SHR compared to WKY rats at both age groups. While we did not observe parenchymal T1 differences, the T1 of CSF was elevated in SHR compared to controls. Collectively these findings indicate that SHRs develop WM atrophy which is a clinically robust MRI biomarker associated with WM degeneration. Highlights • VFA-SPGR MRI technique was applied in studying both morphology and longitudinal relaxation time. • SHRs exhibit enlarged ventricles and reduced corpus callosum volumes. • The longitudinal relaxation times in SHR and WKY rats were not significantly different in the brain. [ABSTRACT FROM AUTHOR]

One of the most distinguishing features of the adult human brain is the complexity and diversity of its cortical astrocytes. Human protoplasmic astrocytes manifest a threefold larger diameter and have tenfold more primary processes than those of rodents. In all mammals, protoplasmic astrocytes are organized into spatially non-overlapping domains that encompass both neurons and vasculature. Yet unique to humans and primates are additional populations of layer 1 interlaminar astrocytes that extend long (millimeter) fibers, and layer 5–6 polarized astrocytes that also project distinctive long processes. We propose that human cortical evolution has been accompanied by increasing complexity in the form and function of astrocytes, which reflects an expansion of their functional roles in synaptic modulation and cortical circuitry. [Copyright &y& Elsevier]