Sleep restoration is a likely MOA for the positive effect of 2-73 across multiple CNS diseases:
The Glymphatic System in Diabetes-Induced Dementia. Kim YK1,2, Nam KI3, Song J2,3. The glymphatic system has emerged as an important player in central nervous system (CNS) diseases, by regulating the vasculature impairment, effectively controlling the clearance of toxic peptides, modulating activity of astrocytes, and being involved in the circulation of neurotransmitters in the brain. Recently, several studies have indicated decreased activity of the glymphatic pathway under diabetes conditions such as in insulin resistance and hyperglycemia. Furthermore, diabetes leads to the disruption of the blood-brain barrier and decrease of apolipoprotein E (APOE) expression and the secretion of norepinephrine in the brain, involving the impairment of the glymphatic pathway and ultimately resulting in cognitive decline. Considering the increased prevalence of diabetes-induced dementia worldwide, the relationship between the glymphatic pathway and diabetes-induced dementia should be investigated and the mechanisms underlying their relationship should be discussed to promote the development of an effective therapeutic approach in the near future. Here, we have reviewed recent evidence for the relationship between glymphatic pathway dysfunction and diabetes. We highlight that the enhancement of the glymphatic system function during sleep may be beneficial to the attenuation of neuropathology in diabetes-induced dementia. Moreover, we suggest that improving glymphatic system activity may be a potential therapeutic strategy for the prevention of diabetes-induced dementia. cognitive decline; diabetes-induced dementia; glymphatic system; norepinephrine; sleep
Lancet Neurol. 2018 Nov;17(11):1016-1024. doi: 10.1016/S1474-4422(18)30318-1. The glymphatic pathway in neurological disorders. Rasmussen MK1, Mestre H2, Nedergaard M3. Author information Abstract BACKGROUND: 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 ß (Aß) 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.
RECENT DEVELOPMENTS: 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 Aß 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 Aß 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 Aß in the human brain, consistent with findings in mice showing that decreased glymphatic function leads to Aß 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. WHERE NEXT?: 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.
Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. Iliff JJ1, Lee H, Yu M, Feng T, Logan J, Nedergaard M, Benveniste H. Abstract The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid ß clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain. Link to complete article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582150/ The Effect of Body Posture on Brain Glymphatic Transport. Lee H1, Xie L2, Yu M3, Kang H2, Feng T4, Deane R2, Logan J5, Nedergaard M2, Benveniste H6.
Abstract The glymphatic pathway expedites clearance of waste, including soluble amyloid ß (Aß) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aß, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aß clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans.
SIGNIFICANCE STATEMENT: The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Aß, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Aß, because clinical studies have shown that sleep drives Aß clearance from the brain.
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