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Replies to post #173516 on Anavex Life Sciences Corp (AVXL)
1. Amyloid-b and Alzheimer’s disease pathogenesis Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment that is a current and growing public health crisis that only has minimally effective treatments. In 2010, more than 5 million Americans aged 65 years were living with AD, and this number is expected to increase to 13.5 million in 2050 (Alzheimer’s Association, 2010). A reliable, even modest reduction in the risk of AD would have a tremendous public health impact. Age is the greatest risk factor for AD, but the progression to cognitive impairment likely results from genetic (e.g., ApoE4) and environmental (e.g., exercise, diet, and sleep) factors that influence AD pathology (Mayeux and Stern, 2012). Recent evidence in both humans and animal models suggests a possible mechanism through which sleep, likely interacting with other genetic and environmental risk factors, may play a role in AD pathogenesis.
Deposition of extracellular amyloid-b (Ab) into insoluble plaques in the brain is a key early step in the pathogenesis of AD that is associated with the aggregation of tau into intracellular neurofibrillary tangles, synaptic dysfunction, neuronal loss, and cognitive impairment (Hardy and Selkoe, 2002; Jack et al., 2010). The Ab peptide is predominantly produced in the brain by neurons when amyloid precursor protein (APP) is cleaved by b- and gsecretases into multiple isoforms of different amino acid lengths (Strooper et al., 2010). More specifically, g-secretase cuts the C-terminal end of the Ab peptide to generate 3 major isoforms, that is, Ab38, Ab40, and Ab42. Ab isoforms are then secreted into the interstitial fluid (ISF) through synaptic vesicle exocytosis, which is a process influenced by synaptic activity (Cirrito et al., 2005). The contribution of Ab isoforms to plaque formation varies. Whereas Ab40 is produced at higher concentrations, Ab42 is more hydrophobic, neurotoxic, and prone to aggregate (Jarrett et al., 1993). Further, the aggregation of Ab into extracellular plaques has been found to be concentration dependent. In a mouse model study, neural cells were transplanted from APP23 transgenic mice into wild-type mice and Ab levels were measured both within the neural graft and the surrounding ISF. Ab concentrations were the highest within the graft and decreased as a function of the distance from the graft, and a similar gradient pattern was observed for amyloid plaques (Meyer-Luehmann et al., 2003). Since all the Ab deposition did not occur only within the grafts, it was suggested that Ab diffusion into surrounding neural tissue played a role in plaque formation.
Neuropathologic changes in AD, that is, extracellular amyloid plaques and intracellular neurofibrillary tangles of aggregatedtau, likely proceed in a sequential anatomic pattern involving the entorhinal cortex, hippocampus, and medial temporal lobe (Braak and Braak, 1991). Ab deposition is probably insufficient to result in cognitive decline because pathologic studies show that significant neuronal and synaptic loss has already occurred by the time clinical symptoms manifest. Further, amyloid deposition can be assessed in vivo in humans by positron emission tomography (PET) with an amyloid tracer, that is, Pittsburgh Compound B (PiB) that binds to amyloid, or by decreased cerebrospinal fluid (CSF) Ab42 concentrations. Approximately 25%e30% of individuals in their eight decade who were cognitively normal that were assessed by either of these methods have been found to have amyloid deposition (Mintun et al., 2006; Morris et al., 2009). The period of amyloid deposition with normal cognitive functioning has been described as “preclinical Alzheimer’s disease” (Jack et al., 2010; Sperling et al., 2011). Treatment of AD is hypothesized to be the most successful in this preclinical phase before Ab deposition into Ab-containing plaques and tau aggregation occurs, which causes significant cell loss leading to the onset of clinically detectable cognitive impairment (Morris, 2005).
Amyloid imaging has also shown that Ab deposition co-localizes anatomically with other imaging abnormalities associated with AD in many regions of the brain. Abnormalities that co-localize with PiB-PET include brain atrophy as shown on brain magnetic resonance imaging, hypometabolism measured by fluorodeoxyglucosePET, and dysfunction of the default mode network (DMN) as measured by functional magnetic resonance imaging (Bero et al., 2011; Buckner et al., 2005). The DMN is the resting state network most active in the absence of task performance (Raichle et al., 2000) and has been reported as the first network affected by AD (Greicius et al., 2004). The DMN is associated with episodic memory (Buckner, 2004), which is a cognitive domain that is impaired early in AD. Since the DMN is a resting state network and is therefore synaptically and metabolically more active than other regions of the brain, this co-localization with AD pathology may be because of increased Ab production and secretion into the ISF resulting in a higher local concentration and greater deposition. Additionally, decreased energy metabolism and atrophy in the brain have also been correlated with areas of amyloid deposition (Vlassenko et al., 2010). Because all these imaging abnormalities overlap, these findings suggest that increased synaptic activity leading to Ab aggregation into plaques progresses to decreased neuronal metabolic function and atrophy presumably through neuronal loss. This hypothesis is supported by findings in the dominantly inherited AD population (Bateman et al., 2012).
2. Sleep and AD Sleep serves a restorative function in the brain and is involved with memory retention. More specifically, slow-wave sleep (SWS) plays a critical role in the consolidation of long-term memory (Born and Wilhelm, 2012). Good quality sleep involves following a day and/or night (i.e., diurnal) pattern of alertness and activity during the day followed by quiescence at night. Cycling several times through the different sleep stages during the sleep period is also essential to restorative sleep. Scoring an individual as awake or in a specific sleep stage is primarily determined by changes on an electroencephalogram (EEG) recorded during polysomnography. In the awake state, the EEG shows low amplitude, high-frequency fluctuations because of neurons in the cerebral cortex firing irregularly. As wakefulness gives way to sleep, the low amplitude, highfrequency activity attenuates as cortical neurons undergo a slow oscillation (<1 Hz) in membrane potential between a hyperpolarized state with no neuronal firing to a depolarized state of intense firing (Massimini et al., 2004). This slow oscillation is the fundamental cellular process that organizes waveforms seen on EEG during sleep, that is, sleep spindles and slow waves.
There are 4 sleep stages. The EEG background in rapid eye movement sleep is similar to the awake state with low amplitude, mixed-frequency activity. Non-rapid eye movement (NREM) sleep is characterized by 3 stages that exhibit progressively increased slow wave activity (SWA): N1 or drowsiness, N2, and N3 or SWS. During the deeper stages of NREM sleep (N2 and N3) there are more high-amplitude slow waves, which likely accounts for the general decrease in regional synaptic activity during NREM sleep (Vyazovskiy et al., 2011). These periods of deeper NREM sleep with increased SWA are hypothesized to decrease synaptic strength to a level that is energetically sustainable and promotion of synaptic plasticity and memory (Tononi and Cirelli, 2006).
Nearly all people older than the age of 60 years have disrupted sleep architecture and decreased SWS (Redline et al., 2004). Further, aging has also been associated with regional brain atrophy involving the midline frontal lobe regions (Sowell et al., 2003) and cognitive decline (Buckner, 2004). These 3 factors have been independently associated with aging. However, a recent study found that age-related medial prefrontal cortex gray-matter atrophy was associated with reduced NREM SWA in older adults, the extent of which statistically accounted for the impairment of overnight sleep-dependent memory retention (Mander et al., 2013). These recent findings suggest an additional potential mechanism that may be linked to the sleep changes that have been observed in aging that may be contributing to cognitive decline in older individuals.
Sleep disturbances in individuals with AD are multifaceted and include increased or decreased total sleep time, nocturnal arousals, and reversal of the day and/or night sleep pattern (McCurry et al., 1999). However, these sleep disturbances have been measured in individuals already exhibiting cognitive impairment and are likely a manifestation of dementia. Sleep interventions at this stage of AD may be difficult to both implement and achieve positive benefits. For example, the incidence of sleep disorders (e.g., sleep apnea) is increased in patients with AD and continuous positive airway pressure (CPAP) therapy may slow or improve cognitive functioning in patients with AD and sleep disordered breathing (SDB) (AncoliIsrael et al., 2008; Cooke et al., 2009). However, both the diagnosis and treatment of sleep disorders (e.g., SDB) in patients with AD is challenging because of the patients’ underlying cognitive dysfunction impeding both the diagnosis via polysomnography and treatment with CPAP. Therefore, the efficacy of current therapies (e.g., CPAP) is difficult to assess in an AD patient population (Yesavage et al., 2003).
Recent research has focused on the risk of developing cognitive impairment in cognitively-normal individuals with long-term sleep disturbances. In multiple cross-sectional studies, changes in sleep duration have been associated with an increased risk of cognitive impairment. Tworoger et al. (2006) observed that selfreported difficulty sleeping and sleep duration 5 hours/night in older women was associated with poorer cognitive performance for general cognition, verbal memory, category fluency, and attention. Others have shown conflicting results including cognitive impairment associated with longer sleep times >11 hours/ night (Faubel et al., 2009) or 9 hours/night (Loerbroks et al., 2010), but not short sleep time or both short and long sleep time (Ferrie et al., 2011; Kronholm et al., 2009; Xu et al., 2011). Additional markers of poor sleep quality, that is, low sleep efficiency, prolonged sleep latency, increased wake after sleep onset, and increased napping, have all been associated with impaired cognitive function (Blackwell et al., 2006, 2011; Keage et al., 2012; Potvin et al., 2012).
4. Sleep, Ab, and Alzheimer’s disease pathophysiology: a proposed model
The diurnal Ab pattern is hypothesized to be related to higher neuronal activity during wakefulness and decreased neuronal activity during sleep, such as occurs in SWS (Nir et al., 2011). Synaptic activity has been shown to increase ISF Ab release from neurons in both the mouse and in humans (Brody et al., 2008; Cirrito et al., 2005). Loss of this diurnal pattern is likely because of sequestration of Ab in extracellular amyloid plaques (e.g., altered clearance) or altered neuronal firing (e.g., altered production). There is evidence to support Ab42 sequestration in plaques in older individuals with amyloid deposition that leads to decreased clearance and lower, less variable CSF Ab42 concentrations. Production of soluble Ab may be relatively increased during the sleep period by loss of SWS in the context of aging and/or sleep disturbances such as sleep apnea or insomnia. The net effect of these sleep changes is to increase wake time during the sleep period. More specifically, the DMN deactivates during sleep, particularly SWS (Samann et al., 2011). Therefore,decreased sleep efficiency and decreased SWS will lead to a lack of deactivation of the DMN, relative increases in synaptic and metabolic neuronal activity, increased soluble CSF Ab levels during the sleep period, increased Ab aggregation and sequestration into plaques, and attenuation of the Ab diurnal pattern.
Although changes in the sleep-wake cycle have been associated with markers of AD pathology such as amyloid deposition, the timing, role, and extent of these changes that are associated with increasing stages of AD neuropathology and cognitive dysfunction is unclear. Findings in animal models hint that driving Ab concentrations up or down with sleep deprivation or sleep induction, respectively, may affect amyloid aggregation into plaques. This finding has not been replicated in humans, but changes of Ab production by 25%e40% (Jonsson et al., 2012) can completely protect or cause AD in humans (Jonghe et al., 1999), which suggests that increasing SWS time may decrease or prevent Ab accumulation. Notably, a 25% change in Ab concentration has been found between wakefulness and sleep (Huang et al., 2012). An alternative explanation of the current data is that sleep changes are a marker for progression of AD pathology rather than a key event in AD pathogenesis. Further research is needed to differentiate between these hypotheses.
A model for the role of sleep in AD pathogenesis is proposed to test future hypothesis-driven research (Fig. 2). As previously discussed, there are numerous changes that occur during aging including regional brain atrophy (e.g., medial prefrontal cortex) and changes in sleep parameters, that is, increased wake after sleep onset, decreased sleep efficiency, decreased SWS, and an increased incidence of sleep disorders (e.g., SDB). These changes occur in individuals with genetic and environmental risk factors that affect overall risk of AD. In individuals prone to AD based on these risk factors, sleep may play a more or less significant role in the development of AD.
The net effect of disturbed sleep parameters in older adults is a relative increase in synaptic and metabolic activity in the brain during the sleep period compared with younger individuals. Therefore, the concentration of Ab in the CSF does not decrease during sleep as expected and results in attenuation of the Ab diurnal pattern. Ab concentrations during the sleep period are maintained at relatively high levels (25% higher than during sleep), which promotes amyloid deposition that may further feedback to disturb sleep and elevate Ab levels during sleep.
The regions of the brain most at risk for amyloid deposition in this proposed model are those that are metabolically most active, that is, the DMN. Ab deposition in brain regions is important because the DMN leads to network dysfunction, synaptic dysfunction, and impaired cognitive functioning. Impaired cognitive functioning and network dysfunction will manifest as hypometabolism or vice versa. Impaired cognitive function is associated with sleep disturbances, feeding back to the sleep changes associated with aging. The net effect is to increase Ab deposition that is a known marker for AD risk.
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.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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.
Copyright © 2015 the authors 0270-6474/15/3511034-11$15.00/0.
KEYWORDS:
CSF; brain; posture; sleep; unconsciousness; waste removal
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