Faculty Bibliography

INTRODUCTION/BACKGROUND:Sleep and circadian rest-activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS-associated AD continuum remain uncharacterized. METHODS:We analyzed 7-day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group-specific associations. RESULTS:DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA. DISCUSSION/CONCLUSIONS:Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.

A recent case study reported a PSEN2 mutation carrier with high amyloid burden but unexpectedly restricted tau pathology and preserved cognition. While genetic and proteomic factors were explored, the patient's lifelong occupational heat exposure may represent an overlooked contributor to resilience. We highlight evidence from preclinical, clinical, and epidemiological studies suggesting that elevated body temperature promotes tau clearance via enhanced proteostasis. This observation invites deeper investigation into thermoregulation as a modifiable factor in tau homeostasis and Alzheimer's disease vulnerability, with implications for both biomarker interpretation and therapeutic strategies targeting tau-mediated neurodegeneration.

The locus coeruleus (LC) plays important roles in sleep/wake regulation and cognitive functions. LC neurons may be particularly sensitive to neural injury and serve as an early site of accumulation pathological tau in Alzheimer's disease. Obstructive sleep apnea (OSA) creates both chronic intermittent hypoxia and sleep fragmentation as potential insults to differentially sensitive neural populations including the locus coeruleus (LC). Using high field 7T imaging in cognitively normal older adults, we demonstrate that time spent with an oxygen saturation below 90% (T90), a measure of OSA's hypoxic burden, inversely correlates with LC structural integrity and explains significant variance in LC structural integrity after controlling for age, sex, and BMI. In contrast, other sleep variables such as the apnea-hypopnea index (AHI), total sleep time, and sleep efficiency did not contribute significant variance in LC structural integrity in this model. Thus, in the diagnosis of OSA, attention to hypoxic burden variables may be important in risk stratification for LC neural injury. This observation may inform future work determining whether mitigation of the hypoxemic burden from OSA can slow deterioration in LC integrity.

BACKGROUND:Comorbidity between alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) exacerbates symptom severity and worsens treatment outcomes. Limited clinical research suggests that cannabidiol (CBD) may have therapeutic effects on anxiety disorders and addictive behavior, but efficacy has not been established. METHODS:Two proof-of-concept trials of CBD were conducted simultaneously. In Study 1, 27 adults with moderate to severe AUD were randomized to CBD [600 mg/day for 4 weeks, then 1200 mg/day for 4 weeks] versus placebo. In Study 2, 30 adults with AUD plus DSM-5 PTSD or subthreshold post-traumatic stress disorder (PTSD) were randomized to CBD 600 mg/day vs. placebo for 6 weeks. The trials assessed CBD pharmacokinetics, safety and tolerability, alcohol consumption, craving, mood and anxiety symptoms, and, in Study 2, PTSD symptom severity. Efficacy analyses used mixed-effects models, and the primary drinking outcome was the average number of drinks per day during treatment. RESULTS:CBD was rapidly absorbed, achieving near-steady-state trough levels by week 1, with dose-dependent increases during weeks 5-8 in Study 1. Mean trough and estimated peak CBD levels at week 4 (n = 20) were 31.15 (SD: 21.22) ng/mL and 130.75 (SD: 152.57) ng/mL, respectively. Few safety concerns emerged, but 7/31 (22.6%) of participants assigned to CBD experienced dose-limiting side effects. In both studies, participants in both treatment groups showed large reductions in drinks per day and percentage heavy drinking days during treatment (Cohen's dz. > 0.9). Neither trial demonstrated superiority of CBD over placebo for drinking outcomes, craving, mood, anxiety, or PTSD symptoms. CONCLUSIONS:These findings support the feasibility and tolerability of twice-daily oral CBD up to 1200 mg/day in actively drinking individuals but do not demonstrate efficacy at the CBD levels that were achieved in this study. Further dose finding and larger, well-powered trials are needed to clarify CBD's therapeutic potential in AUD and comorbid PTSD.

INTRODUCTION/BACKGROUND:Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. METHODS:Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10-20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. RESULTS:Fourteen individuals with DS and five age-matched euploid controls were studied, with all DS cases showing HFOs. HFOs emerged before AD dementia and LOMEDS and showed hemispheric lateralization in asymptomatic but not symptomatic AD dementia cases. A trend toward increasing HFO rates with age in DS warrants further confirmation. DISCUSSION/CONCLUSIONS:HFOs are promising biomarkers that may predict symptomatic AD dementia in adults with DS. HIGHLIGHTS/CONCLUSIONS:Wideband polysomnography reveals a new electrical abnormality in DS. HFOs precede AD dementia in DS. The occurrence of HFOs in DS is independent of an epilepsy diagnosis. HFOs showed hemispheric lateralization in asymptomatic DS cases. A trend of increased HFO rate with advancing age warrants further investigation.

INTRODUCTION/BACKGROUND:Down syndrome (DS) is a genetic form of Alzheimer's disease (AD), with a high prevalence of sleep disorders, but data in adults with DS and dementia are lacking. We aim to assess sleep in adults with DS across the AD continuum. METHODS:We studied 78 healthy controls and 229 adults with DS (154 asymptomatic, 25 with prodromal AD, and 75 with AD) with subjective sleep measures and objective nocturnal polysomnography. RESULTS:Adults with DS presented worse sleep quality and higher prevalence of unnoticed obstructive sleep apnea (OSA) than controls. Sleep disruption and OSA severity increased across the AD continuum. Age-related decreases in slow-wave sleep and rapid eye movement sleep were more pronounced in the DS group. Subjective sleep measures did not capture sleep disorders. CONCLUSIONS:In DS, AD is linked to worse sleep disturbances and altered architecture. However, longitudinal studies are needed to clarify directionality and disease progression. HIGHLIGHTS/CONCLUSIONS:Down syndrome (DS) is associated with increased slow-wave sleep (SWS) and reduced rapid eye movement (REM) sleep. Obstructive sleep apnea prevalence increases along the Alzheimer's disease continuum in DS. Age-related decreases in SWS and REM sleep are accelerated in DS. Subjective sleep measures do not detect sleep disturbances in adults with DS.

Obstructive sleep apnea (OSA) exerts pathogenic effects through a combination of sleep fragmentation (SF) and intermittent hypoxia (IH). The mechanisms through which sleep disruption impacts memory might arise by investigating disruption of specific sleep stages and, when such disruption occurs through OSA, by evaluating the individual contributions of SF and IH. Given region-specific EEG slow activity during non-REM sleep has been associated with overnight declarative, motor and spatial memory formation, we investigated the effects of disrupting slow wave sleep (SWS) on a virtual maze navigation task. Thirty three participants (24 male, 56 years old [range 28-68 years] with OSA (baseline AHI4%>20/hour) who were habitually well-treated and adherent to CPAP completed 3 timed trials on a 3D spatial maze before and after polysomnographically (PSG) recorded sleep. We restricted CPAP withdrawal to SWS through real-time monitoring of the PSG under three conditions: 1) stable-SWS on therapeutic CPAP, 2) SWS-CPAP withdrawal containing SF and IH, and 3) SWS-CPAP withdrawal with supplemental oxygen containing SF with reduced IH. SWS-specific CPAP withdrawal (with or without supplemental oxygen) did not significantly impact EEG slow oscillation or spatial navigational memory, despite effectively reducing %SWS and SWS bout length. Greater regional EEG slow oscillation (0.6-1Hz), but not delta (1-4Hz) activity, was associated with improvements in overnight memory during stable SWS in the CPAP condition. These observations suggest that slow oscillations may be important for overnight memory processing, and sleep disruptions of sufficient magnitude to reduce slow oscillations may be required to capture demonstrable change in spatial navigation performance.

Sleep disturbance is bidirectionally associated with increased risks of Alzheimer's disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial given evidence indicates that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combine in vitro, in vivo and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, higher BT during wakefulness and sleep-deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway-I (UPS-I) components, including (i) intracellular tau dephosphorylation, (ii) caspase-3-mediated cleavage of tau (TauC3) and (iii) its membrane translocation through binding to PIP2 and syndecan-3. In humans, the increase in CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration, and the preventative potential of thermal interventions.