Age differences in the association between sleep and Alzheimer\u27s disease biomarkers in the EPAD cohort

INTRODUCTION: We aimed to determine the independent association between sleep quality and Alzheimer\u27s disease (AD) biomarkers, and whether the associations differ with age. METHODS: We included 1240 individuals aged ≥50, without dementia from the 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

Teaching in the 21st century – Engaging students in active learning using student response systems

The prevalence of student response systems (hereafter SRS) in higher education has grown significantly in the last few years. Student classroom participation and student’s assessment of performance particularly in larger classes, has often been regarded as problematic in pedagogical research (Black and Wiliam, 1998; Fies and Marshall, 2006). Growth in technology, coupled with popularity of handheld devices has led to the development in SRS with the intention of increasing classroom participation and engaging students in the lecture setting (Denker, 2013). Studies identify benefits to students participating in the classroom using SRS including increased student involvement, attendance, learning and engagement (Heaslip et al., 2014; Van Daele et al., 2017). This research seeks to examine the effects of a SRS on student participation and engagement in large undergraduate economics modules at both an Irish and UK university during the academic year of 2018/19. We compare a control period (no SRS in place) with a trial period (SRS in place). The results show that the use of the SRS significantly increased student’s interaction with the lecturer and their ability to perform self-assessment in absolute terms and relative to their peers

Enhancing student engagement and self-evaluation using student response systems

Whilst previous studies are broadly in agreement on the effectiveness of student response systems (hereafter SRSs) in enhancing student engagement, there are gaps in the literature relating to study design and outcomes assessed. This study offers enhancements to study design. First, by collecting baseline data, engagement levels can be conditioned and changes in engagement attributable to the SRS detected. Second, it is one of the few studies that employs a comprehensive measure of student engagement. Third, analysis occurs at student level rather than class level. The study finds increased positive perceptions towards self-evaluation (both self and relative assessment) and ability to express opinion, in addition to strong student positivity towards the SRS

Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways

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\u27s Disease in humans

Comparison of single-channel EEG, actigraphy, and sleep diary in cognitively normal and mildly impaired older adults

STUDY OBJECTIVES: Multiple methods for monitoring sleep-wake activity have identified sleep disturbances as risk factors for Alzheimer disease (AD). In order to identify the level of agreement between different methods, we compared sleep parameters derived from single-channel EEG (scEEG), actigraphy, and sleep diaries in cognitively normal and mildly impaired older adults. METHODS: Two hundred ninety-three participants were monitored at home for up to six nights with scEEG, actigraphy, and sleep diaries. Total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), and wake after sleep onset (WASO) were calculated using each of these methods. In 109 of the 293 participants, the ratio of cerebrospinal fluid concentrations of phosphorylated tau (p-tau) and amyloid-β-42 (Aβ42) was used as a biomarker for AD pathology. RESULTS: Agreement was highest for TST across instruments, especially in cognitively normal older adults. Overall, scEEG and actigraphy appeared to have greater agreement for multiple sleep parameters than for scEEG and diary or actigraphy and diary. Levels of agreement between scEEG and actigraphy overall decreased in mildly impaired participants and those with biomarker evidence of AD pathology, especially for measurements of TST. CONCLUSIONS: Caution should be exercised when comparing scEEG and actigraphy in individuals with mild cognitive impairment or with AD pathology. Sleep diaries may capture different aspects of sleep compared to scEEG and actigraphy. Additional studies comparing different methods of measuring sleep-wake activity in older adults are necessary to allow for comparison between studies using different methods

Closed-loop acoustic stimulation during sedation with dexmedetomidine (CLASS-D): Protocol for a within-subject, crossover, controlled, interventional trial with healthy volunteers

Introduction: The relative power of slow-delta oscillations in the electroencephalogram (EEG), termed slow-wave activity (SWA), correlates with level of unconsciousness. Acoustic enhancement of SWA has been reported for sleep states, but it remains unknown if pharmacologically induced SWA can be enhanced using sound. Dexmedetomidine is a sedative whose EEG oscillations resemble those of natural sleep. This pilot study was designed to investigate whether SWA can be enhanced using closed-loop acoustic stimulation during sedation (CLASS) with dexmedetomidine. Methods: Closed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine (CLASS-D) is a within-subject, crossover, controlled, interventional trial with healthy volunteers. Each participant will be sedated with a dexmedetomidine target-controlled infusion (TCI). Participants will undergo three CLASS conditions in a multiple crossover design: in-phase (phase-locked to slow-wave upslopes), anti-phase (phase-locked to slow-wave downslopes) and sham (silence). High-density EEG recordings will assess the effects of CLASS across the scalp. A volitional behavioral task and sequential thermal arousals will assess the anesthetic effects of CLASS. Ambulatory sleep studies will be performed on nights immediately preceding and following the sedation session. EEG effects of CLASS will be assessed using linear mixed-effects models. The impacts of CLASS on behavior and arousal thresholds will be assessed using logistic regression modeling. Parametric modeling will determine differences in sleepiness and measures of sleep homeostasis before and after sedation. Results: The primary outcome of this pilot study is the effect of CLASS on EEG slow waves. Secondary outcomes include the effects of CLASS on the following: performance of a volitional task, arousal thresholds, and subsequent sleep. Discussion: This investigation will elucidate 1) the potential of exogenous sensory stimulation to potentiate SWA during sedation; 2) the physiologic significance of this intervention; and 3) the connection between EEG slow-waves observed during sleep and sedation

Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: Protocol for a phase I open label trial

INTRODUCTION: Late-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 ANALYSIS: SWIPED (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 DISSEMINATION: The 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 NUMBER: NCT04680910

Protocol for the Prognosticating Delirium Recovery Outcomes Using Wakefulness and Sleep Electroencephalography (P-DROWS-E) study: A prospective observational study of delirium in elderly cardiac surgical patients

INTRODUCTION: Delirium 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 ANALYSIS: P-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 DISSEMINATION: P-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 NUMBER: NCT03291626

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter

INTRODUCTION: Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time. METHODS: Grouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time. RESULTS: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors' studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection. CONCLUSIONS: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs