A primary purpose of sleep for humans is to remove toxins and metabolic wastes from the brain (e.g., Aβ, tau, lactate) that would otherwise build up and compromise brain functionality. There are currently no drugs or devices that have been clinically shown in humans to enhance brain toxin removal, either during sleep or wakefulness. This perspective article focuses on a recently (re)discovered major route of toxin drainage from the human brain through meningeal lymphatic vessels (mLVs) and the primary enhancer of their flow-the cytokine Vascular Endothelial Growth Factor (VEGF). The purpose of this perspective article is to present pre-clinical and clinical evidence relevant to a new bioengineered technology (Transcranial Radiofrequency Treatment; TRFT) that appears to enhance mLV flow to increase brain toxin cleansing in humans during wakefulness. In being both safe and non-invasive, TRFT is administered in-home, presently through a device called "MemorEM". Two months of daily TRFT during wakefulness increased the typically low plasma/brain levels of VEGF in Alzheimer's Disease (AD) subjects, which was associated with increased Aβ and tau toxin removal from their brains during wakefulness-ostensibly through VEGF-increased mLV flow. Even irrespective of baseline VEGF levels, brain toxin cleansing was increased by TRFT in AD subjects, who also experienced a notable reversal of their cognitive impairment after TRFT. Additional clinical studies are nonetheless required to firmly establish TRFT's brain cleansing abilities during wakefulness. In performing a major duty of sleep, TRFT during wakefulness is proposed as a viable intervention to counter the decline in nighttime brain toxin cleansing that occurs with aging and in multiple brain diseases, most notably Alzheimer's Disease. The implications of TRFT for insomnia and for sleep deprivation are also discussed, as is the potential for TRFT to extend healthy human longevity.

Sleep deprivation (SD) contributes to cognitive impairment. Astrocytic cholesterol biosynthesis is crucial for brain cholesterol homeostasis and cognitive function. However, the underlying mechanism of astrocytic cholesterol metabolism in SD-induced cognitive impairment has not been fully explored. Trimethylamine N-oxide (TMAO), a product of liver flavin-containing monooxygenase-3 (FMO3), has been shown to be increased in the urine of sleep-deprived humans and implicated with peripheral cholesterol metabolism. Nevertheless, how TMAO affects brain cholesterol metabolism remains unclear. In our study, increased FMO3 and brain TMAO levels were observed in the SD mice, and elevated levels of TMAO were confirmed to lead to SD-induced cognitive dysfunction. In addition, we found that the expression of sterol regulatory element-binding protein 2 (SREBP2) is decreased in the brain of SD mice, resulting in the reduction in brain cholesterol content, which in turn causes synaptic damage. Moreover, we demonstrated that TMAO inhibits the expression of SREBP2. In contrast, FMO3 inhibitor 3,3'-diindolylmethane (DIM) alleviates SD-induced cognitive impairment by targeting the liver-brain axis. In conclusion, our study revealed that the TMAO pathway is involved in memory impairment in SD mice through deregulating astrocytic cholesterol metabolism.

A significant effort in biomedical sciences has been made to examine relationships between sex and the mechanisms underlying various disease states and behaviors, including sleep. Here, we investigated biological sex differences in sleep using male and female C57BL/6J mice (n = 267). Physiological parameters were recorded for 48-h using non-invasive piezoelectric cages to determine total sleep, non-rapid eye movement (NREM) sleep, rapid eye movement (REM)-like sleep, and wakefulness (WAKE). We fit hierarchical generalized linear mixed models with nonlinear time effects and found substantial sex differences in sleep. Female mice slept less overall, with less NREM sleep compared to males. Females also exhibited more REM-like sleep and WAKE and had shorter NREM sleep bout lengths. We also conducted a simulation exercise where we simulated a hypothetical treatment that altered the sleep of female mice, but not male mice. In models that included an appropriate sex by treatment interaction, a female-specific treatment response was accurately estimated when sample sizes were equal but was not detected when sample sizes were unequal, and females were underrepresented. Failure to include both sexes in experimental designs or appropriately account for sex during analysis could lead to inaccurate translational recommendations in pre-clinical sleep studies.

Sleep deficits are a possible risk factor for development of cognitive decline and dementia in older age. Research suggests that neuroinflammation may be a link between the two. This observational, cross-sectional study evaluated relationships between sleep architecture, neuroinflammation and cognitive functioning in healthy older adults. Twenty-two adults aged ≥60 years underwent whole-brain magnetic resonance spectroscopic imaging (in vivo method of visualizing increased brain temperatures as a proxy for neuroinflammation), supervised laboratory-based polysomnography, and comprehensive neurocognitive testing. Multiple regressions were used to assess relationships between magnetic resonance spectroscopic imaging-derived brain temperature and metabolites related to inflammation (choline; myo-inositol; N-acetylaspartate), sleep efficiency, time and % N3 sleep and cognitive performance. Choline, myo-inositol and N-acetylaspartate were associated with sleep efficiency and cognitive performance. Higher choline and myo-inositol in the bilateral frontal lobes were associated with slower processing speed and lower sleep efficiency. Higher choline and myo-inositol in bilateral frontoparietal regions were associated with better cognitive performance. Higher N-acetylaspartate around the temporoparietal junction and adjacent white matter was associated with better visuospatial function. Brain temperature was not related to cognitive or sleep outcomes. Our findings are consistent with the limited literature regarding neuroinflammation and its relationships with sleep and cognition in older age, which has implicated ageing microglia and astrocytes in circadian dysregulation, impaired glymphatic clearance and increased blood-brain barrier integrity, with downstream effects of neurodegeneration and cognitive decline. Inflammatory processes remain difficult to measure in the clinical setting, but magnetic resonance spectroscopic imaging may serve as a marker of the relationship between neuroinflammation, sleep and cognitive decline in older adults.

Rationale: Currently, there are occasional reports of health problems caused by sleep deprivation (SD). However, to date, there remains a lack of in-depth research regarding the effects of SD on the growth and development of oocytes in females. The present work aimed to investigate whether SD influences ovarian folliculogenesis in adolescent female mice. Methods: Using a dedicated device, SD conditions were established in 3-week old female mice (a critical stage of follicular development) for 6 weeks and gut microbiota and systemic metabolomics were analyzed. Analyses were related to parameters of folliculogenesis and reproductive performance of SD females. Results: We found that the gut microbiota and systemic metabolomics were severely altered in SD females and that these were associated with parameters of premature ovarian insufficiency (POI). These included increased granulosa cell apoptosis, reduced numbers of primordial follicles (PmFs), correlation with decreased AMH, E2, and increased LH in blood serum, and a parallel increased number of growing follicles and changes in protein expression compatible with PmF activation. SD also reduced oocyte maturation and reproductive performance. Notably, fecal microbial transplantation from SD females into normal females induced POI parameters in the latter while niacinamide (NAM) supplementation alleviated such symptoms in SD females. Conclusion: Gut microbiota and alterations in systemic metabolomics caused by SD induced POI features in juvenile females that could be counteracted with NAM supplementation.

Insomnia, commonly treated with benzodiazepine (BZD) receptor agonists, presents challenges due to associated serious side effects such as abuse and dependence. To address these concerns, many researches have been conducted to develop and advance both pharmacological and non-pharmacological interventions. Dual orexin receptor antagonists (DORAs), which include suvorexant, daridorexant and lemborexant, have recently been approved by United States Food and Drug Administration (US FDA) as a novel pharmacotherapeutic alternative. Unlike BZD receptor agonists that act as positive allosteric modulators of the gamma-aminobutyric acid type A subunit alpha 1 receptor, DORAs function by binding to both orexin receptor types 1 and 2, and inhibiting the action of the wake-promoting orexin neuropeptide. These drugs induce normal sleep without sleep stage change, do not impair attention and memory performance, and facilitate easier awakening. However, more real-world safety information is needed. Selective orexin-2 receptor antagonists (2-SORAs) is under clinical developments. This review provides an overview of the mechanism of action in relation to insomnia, pharmacokinetics, efficacy and safety information of DORAs and SORA. According to insomnia management guidelines, the first-line treatment for chronic insomnia is cognitive behavioral therapy for insomnia (CBT-I). Although it has proven effective in improving sleep-related quality of life, it has several restrictions limitations due to a face-to-face format. Recently, prescription digital therapy such as Somryst® was approved by US FDA. Somryst®, a smartphone app-based CBT-I, demonstrated meaningful responses in patients. However, digital limitations may impact scalability. Overall, these developments offer promising alternatives for insomnia treatment, emphasizing safety, efficacy, and accessibility.

As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer's Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated.

A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals.

In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction.

Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.

Alzheimer's disease (AD) is highly intertwined with sleep disturbances throughout its whole natural history. Sleep consists of a major compound of the functionality of the glymphatic system, as the synchronized slow-wave activity during NREM facilitates cerebrospinal and interstitial long-distance mixing.

The present study undertakes a scoping review of research on the involvement of the glymphatic system in AD-related sleep disturbances.

we searched Medline, Embase, PsychInfo and HEAL-link databases, without limitations on date and language, along with reference lists of relevant reviews and all included studies. We included in vivo, in vitro and post-mortem studies examining glymphatic implications of sleep disturbances in human populations with AD spectrum pathology. A thematic synthesis of evidence based on the extracted content was applied and presented in a narrative way.

In total, 70 original research articles were included and were grouped as following: a) Protein aggregation and toxicity, after sleep deprivation, along with its effects on sleep architecture, b) Glymphatic Sequalae in SDB, yielding potential glymphatic markers c) Circadian Dysregulation, d) Possible Interventions.

this review sought to provide insight into the role of sleep disturbances in AD pathogenesis, in the context of the glymphatic disruption.

Alzheimer's disease (AD) is a significant 21st-century public health challenge. This article delves into AD's neurodegenerative complexities, highlighting cognitive decline, memory impairment, and societal burdens. Mechanistically, protein misfolding, amyloid-beta (Aβ) pathway abnormalities, and genetic/environmental factors are discussed. The pivotal amyloid hypothesis is dissected, focusing on Aβ aggregation's role in synaptic dysfunction and neurodegeneration. The review showcases promising therapeutic strategies, including anti-amyloid antibodies and β/γ-secretase inhibitors targeting Aβ production. Notably, the FDA-approved Lecanemab signifies a breakthrough, slowing disease progression. Anti-Tau therapies' emergence is highlighted, addressing late-stage intervention. Tau aggregation blockers and anti-Tau antibodies offer potential against intracellular tau pathology. The review underscores collaborative efforts to uncover AD's secrets and pave the way for memory preservation.

Sleep deprivation is quite frequent in military during combat, intelligence gathering or peacekeeping operations. Even one night of sleep deprivation leads to accumulation of amyloid beta peptide burden that would lead to precipitation of Alzheimer's disease over the years. Thus, efforts are needed to slow down or neutralize accumulation of amyloid beta peptide (AβP) and associated Alzheimer's disease brain pathology including phosphorylated tau (p-tau) within the brain fluid environment. Sleep deprivation also alters serotonin (5-hydroxytryptamine) metabolism in the brain microenvironment and impair upregulation of several neurotrophic factors. Thus, blockade or neutralization of AβP, p-tau and serotonin in sleep deprivation may attenuate brain pathology. In this investigation this hypothesis is examined using nanodelivery of cerebrolysin- a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies against AβP, p-tau and serotonin (5-hydroxytryptamine, 5-HT). Our observations suggest that sleep deprivation induced pathophysiology is significantly reduced following nanodelivery of cerebrolysin together with monoclonal antibodies to AβP, p-tau and 5-HT, not reported earlier.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders among the older population. Sleep disruption and circadian rhythm disorders often develop in AD patients, and many experience sleeping difficulties requiring pharmacological and non-pharmacological interventions.

This review appraised the evidence from clinical studies on various pharmacological and non-pharmacological therapies for sleep disturbances in AD patients and proposed an algorithm to manage sleep disturbances in this population of patients.

Non-pharmacological interventions are generally preferred as the first-line approach to improve sleep-related symptoms in AD due to their favorable safety profile. However, when non-pharmacological interventions alone are insufficient, a range of pharmacological agents can be considered. Trazodone and melatonin are commonly used as adjunctive therapies, while Z-drugs including zopiclone and zolpidem are specifically employed to treat insomnia in patients with late-onset AD. Furthermore, a newer class of agents known as dual orexin receptor antagonists has emerged and gained approval for improving sleep onset and maintenance in AD patients.

Alzheimer's disease (AD)-related neurofibrillary tangles (NFT), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), limbic predominant TDP-43 proteinopathy (LATE), and amygdala-predominant Lewy body disease (LBD) are proteinopathies that, together with hippocampal sclerosis, progressively appear in the elderly affecting from 50% to 99% of individuals aged 80 years, depending on the disease. These disorders usually converge on the same subject and associate with additive cognitive impairment. Abnormal Tau, TDP-43, and α-synuclein pathologies progress following a pattern consistent with an active cell-to-cell transmission and abnormal protein processing in the host cell. However, cell vulnerability and transmission pathways are specific for each disorder, albeit abnormal proteins may co-localize in particular neurons. All these alterations are unique or highly prevalent in humans. They all affect, at first, the archicortex and paleocortex to extend at later stages to the neocortex and other regions of the telencephalon. These observations show that the phylogenetically oldest areas of the human cerebral cortex and amygdala are not designed to cope with the lifespan of actual humans. New strategies aimed at reducing the functional overload of the human telencephalon, including optimization of dream repair mechanisms and implementation of artificial circuit devices to surrogate specific brain functions, appear promising.

Gastrodin is the active ingredient in Gastrodia elata. Our previous studies demonstrated that gastrodin ameliorated cerebral ischemia-reperfusion and hypoperfusion injury and improved cognitive deficit in Alzheimer's disease. This study aims to examine the effects of gastrodin on REM sleep deprivation in rats. Gastrodin (100 and 150 mg/kg) was orally administered for 7 consecutive days before REM sleep deprivation. Seventy-two hours later, pentobarbital-induced sleep tests and a Morris water maze were performed to measure REM sleep quality and learning and memory ability. Histopathology was observed with hematoxylin-eosin staining, and the expression of the NF-κB and Wnt/β-catenin signaling pathways was examined using Western blot. After REM sleep deprivation, sleep latency increased and sleep duration decreased, and the ability of learning and memory was impaired. Neurons in the hippocampal CA1 region and the cortex were damaged. Gastrodin treatment significantly improved REM sleep-deprivation-induced sleep disturbance, cognitive deficits and neuron damage in the hippocampus CA1 region and cerebral cortex. A mechanism analysis revealed that the NF-κB pathway was activated and the Wnt/β-catenin pathway was inhibited after REM sleep deprivation, and gastrodin ameliorated these aberrant changes. Gastrodin improves REM sleep-deprivation-induced sleep disturbance and cognitive dysfunction by regulating the TLR4/NF-κB and Wnt/β-catenin signaling pathways and can be considered a potential candidate for the treatment of REM sleep deprivation.