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The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer’s disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

Background Known circadian variations in cerebrospinal fluid (CSF) flow and composition include fluctuations in electrolytes, hormones, and neurotransmitters. However, how commonly measured CSF constituents, such as protein and glucose, vary by time-of-day is understudied. Here, we identify and compare time-of-day differences in CSF protein and glucose from patients who underwent CSF collection during clinical care. Methods Patients with CSF collected between June 2018 and May 2023 at thirteen hospitals within our institution’s health system were identified. Clinical, demographic and laboratory results were recorded. CSF results were divided into 1- and 4-hour intervals based on time-of-day and patient age. Patients were excluded if there was evidence of CSF infection, bleeding, as well as age criteria excluding neonates. One-way ANOVA with post-hoc Tukey was used to analyze differences between means. Results 15,272 patients underwent 26,397 CSF collection encounters. After exclusion, 8,210 CSF glucose and 10,103 CSF protein values remained. The CSF/blood glucose ratio showed time-of-day fluctuations; the mean ratio was higher from 00:00–04:00 (0.660), 04:00–08:00 (0.651), 16:00–20:00 (0.619), and 20:00–00:00 (0.633) than from 08:00–12:00 (0.588) and 12:00–16:00 (0.599). This pattern was also observed when dividing the time-of-day into 1-hour intervals and in every age cohort except patients 80 years and older. Children also exhibited time-of-day differences in CSF/blood glucose ratios, but the phase of their time-of-day pattern is shifted earlier to peak at 00:00–04:00. No clear time-of-day patterns were observed for CSF protein; however there was a significant association of age with CSF protein (R 2  = 0.2182). There were no meaningful differences in CSF protein by time-of-day after separating patients by age. Conclusions Higher CSF glucose from 00:00–08:00 and 16:00–00:00 compared to 08:00–16:00 suggests diurnal fluctuations which may be driven by a circadian rhythm. A higher CSF protein concentration was strongly associated with increasing age, without clear time-of-day variations. These results have implications for clinical interpretation and future research of the role of CSF in health and disease.

The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processes. Kinetic parameters were estimated using: (1) MRI-derived brain volumes, (2) stable isotope labeling kinetics (SILK) of amyloid-β peptide (Aβ), and (3) lumbar CSF Aβ concentration during SILK. Here we show that changes in blood-brain barrier transport and/or proteolysis were largely responsible for the age-related decline in Aβ turnover rates. CSF-based clearance declined modestly in normal aging but became increasingly important due to the slowing of other processes. The magnitude of CSF-based clearance was also lower than that due to blood-brain barrier function plus proteolysis. These results suggest important roles for blood-brain barrier transport and proteolytic degradation of Aβ in the development Alzheimer’s Disease in humans. To understand if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques, Elbert et al. develop a non-steady state physiological model using MRI-derived brain volumes, stable isotope labeling kinetics of Aβ, and lumbar CSF Aβ concentration. Their model suggests an important role for blood-brain barrier transport and proteolytic degradation of Aβ in the development Alzheimer’s Disease in humans.

Henrietta Lacks died in 1951 of an aggressive adenocarcinoma of the cervix. A tissue biopsy obtained for diagnostic evaluation yielded additional tissue for Dr George O. Gey's tissue culture laboratory at Johns Hopkins (Baltimore, Maryland). The cancer cells, now called HeLa cells, grew rapidly in cell culture and became the first human cell line. HeLa cells were used by researchers around the world. However, 20 years after Henrietta Lacks' death, mounting evidence suggested that HeLa cells contaminated and overgrew other cell lines. Cultures, supposedly of tissues such as breast cancer or mouse, proved to be HeLa cells. We describe the history behind the development of HeLa cells, including the first published description of Ms Lacks' autopsy, and the cell culture contamination that resulted. The debate over cell culture contamination began in the 1970s and was not harmonious. Ultimately, the problem was not resolved and it continues today. Finally, we discuss the philosophical implications of the immortal HeLa cell line.

Background Amyloid beta protein (Aβ) is a treatment target in Alzheimer’s Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. Methods Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21–23 days, then underwent CSF catheter placement, intravenous infusion of 13 C 6 -leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. Results From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. Conclusions Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. Trial registration NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

To assess stages of Alzheimer's disease (AD) pathogenesis and the efficacy of drugs during clinical trials, there has been immense interest in the field to establish baseline cerebrospinal fluid (CSF) concentrations for potential AD biomarkers such as amyloid-β (Aβ) and tau. Significant within-person variations in CSF Aβ concentrations over time found that this variation followed the sleep-wake cycle. A recent paper in Molecular Neurodegeneration reported the absence of diurnal variations in multiple classical and candidate AD biomarkers, such as soluble APP, Aβ, tau, p-tau, YKL-40, VILIP-1, or apolipoprotein E. This commentary addresses these apparently discordant results regarding the diurnal variability of APP and Aβ compared with the literature. Despite our concerns, we appreciate the authors' interest in this important topic and contribution to improve our knowledge about the factors influencing Aβ diurnal variation.

Introduction We aimed to determine the independent association between sleep quality and Alzheimer's disease (AD) biomarkers, and whether the associations differ with age. Methods We included 1240 individuals aged ≥50, without dementia from the European Prevention of Alzheimer's Disease v1500.0 dataset. Linear regression was used to examine Pittsburgh Sleep Quality Index (PSQI) scores against cerebrospinal fluid (CSF) phosphorylated tau/β‐amyloid ratio (p‐tau/Aβ42) for the entire sample and via age tertiles. Models controlled for demographic, clinical, genetic, vascular, and neuroimaging variables. Results For the youngest age tertile, shorter sleep duration and higher sleep efficiency were associated with greater p‐tau/Aβ42 ratio. For the oldest tertile, longer sleep latency was associated with greater p‐tau/Aβ42. Discussion Differential relationships between sleep and AD pathology depend on age. Short sleep duration and sleep efficiency are relevant in middle age whereas time taken to fall asleep is more closely linked to AD biomarkers in later life. Highlights This study shows age differences in the link between sleep and AD biomarkers. Shorter sleep was associated with greater p‐tau/Aβ42 ratio in middle age. The association was independent of genetic, vascular, and neuroimaging markers of AD.

IntroductionLate-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series.Methods and analysisSWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2–6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion.Ethics and disseminationThe study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial.Trial registration numberNCT04680910.

IntroductionDelirium is a potentially preventable disorder characterised by acute disturbances in attention and cognition with fluctuating severity. Postoperative delirium is associated with prolonged intensive care unit and hospital stay, cognitive decline and mortality. The development of biomarkers for tracking delirium could potentially aid in the early detection, mitigation and assessment of response to interventions. Because sleep disruption has been posited as a contributor to the development of this syndrome, expression of abnormal electroencephalography (EEG) patterns during sleep and wakefulness may be informative. Here we hypothesise that abnormal EEG patterns of sleep and wakefulness may serve as predictive and diagnostic markers for postoperative delirium. Such abnormal EEG patterns would mechanistically link disrupted thalamocortical connectivity to this important clinical syndrome.Methods and analysisP-DROWS-E (Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography) is a 220-patient prospective observational study. Patient eligibility criteria include those who are English-speaking, age 60 years or older and undergoing elective cardiac surgery requiring cardiopulmonary bypass. EEG acquisition will occur 1–2 nights preoperatively, intraoperatively, and up to 7 days postoperatively. Concurrent with EEG recordings, two times per day postoperative Confusion Assessment Method (CAM) evaluations will quantify the presence and severity of delirium. EEG slow wave activity, sleep spindle density and peak frequency of the posterior dominant rhythm will be quantified. Linear mixed-effects models will be used to evaluate the relationships between delirium severity/duration and EEG measures as a function of time.Ethics and disseminationP-DROWS-E is approved by the ethics board at Washington University in St. Louis. Recruitment began in October 2018. Dissemination plans include presentations at scientific conferences, scientific publications and mass media.Trial registration numberNCT03291626.