Dexmedetomidine Trial for Effects on Rhythms, Sleep Architecture, and Biomarker Dynamics in Older Adults

Dexmedetomidine Trial for Effects on Rhythms, Sleep Architecture, and Biomarker Dynamics - A Pilot Study (DEXTER)

The DEXTER study is a cross-over, double-blind, placebo-controlled pilot research study led by Dr. Peng Li. The goal of this project is to evaluate the safety, feasibility, and biological effects of a single dose of sublingual (under-the-tongue) dexmedetomidine (SL Dex) in older adults. Specifically, researchers want to see how this medication affects sleep patterns, internal 24-hour circadian rhythms, and the daily cycles of certain neurological proteins (specifically plasma p-tau217) associated with brain aging.

Circadian rhythms are fundamental regulators of human physiology, coordinating sleep-wake timing, neural activity, metabolic processes, and hormonal signaling across the 24-hour day. These endogenous rhythms are coordinated by the suprachiasmatic nucleus (SCN), the central circadian pacemaker in the hypothalamus that integrates environmental cues such as light to synchronize peripheral and central biological processes. In older adults, circadian rhythms often degrade, exhibiting reduced robustness and impaired alignment with behavioral cycles. Such alterations are closely linked to disrupted sleep architecture, particularly sleep fragmentation and loss of restorative non-rapid eye movement (NREM) sleep. Crucially, sleep and circadian dysfunction is increasingly recognized as a critical modulator of neurodegenerative biomarker dynamics. Experimental evidence suggests that fragmented sleep and reduced slow-wave sleep directly alter the production, release, and clearance of neurotoxic proteins, leading to elevated tau levels. These observations highlight a potential mechanistic pathway linking sleep-circadian dysfunction to neurodegeneration and underscore the need to understand how interventions that stabilize these systems influence the temporal profile of tau-related biomarkers. Dexmedetomidine, a highly selective alpha2-adrenergic receptor agonist, represents a unique pharmacologic probe for investigating the links between sleep architecture, circadian physiology, and tau biomarker dynamics. Unlike traditional sedatives, dexmedetomidine engages endogenous sleep-promoting pathways and produces a NREM-like state characterized by electrophysiologic features resembling natural sleep. Beyond its sleep-modulating properties, emerging preclinical evidence suggests that dexmedetomidine exerts potent chronobiotic effects (i.e., the ability to stabilize or entrain circadian rhythms). For instance, preclinical models indicate it activates vasoactive intestinal peptide (VIP) neurons within the SCN and modulates circadian entrainment processes. Clinical studies of thoracic surgery patients further suggest that dexmedetomidine may preserve endogenous circadian signaling, such as melatonin secretion, during the early postoperative period. The recent development of sublingual dexmedetomidine (SL Dex) provides a transformative, noninvasive formulation that enables controlled administration outside of intensive care settings, distinguishing it from traditional intravenous (IV) dexmedetomidine, which is typically limited to monitored environments. Preliminary studies have suggested that SL Dex produces measurable changes in sleep architecture, including increased slow-wave activity, shortened sleep latency, and prolonged REM sleep latency. However, the extent to which SL Dex influences circadian regulation, sleep architecture, and the temporal profile of tau biomarkers across the 24-hour sleep-wake cycle in humans has not been systematically characterized. Addressing this gap requires a rigorously controlled experimental approach capable of isolating the physiologic effects of SL Dex from environmental and behavioral confounders. Prior clinical studies have largely occurred in perioperative or other medically complex settings in which surgery, pain, inflammation, environmental disruption, concomitant medications, and irregular behaviors may confound interpretation of sleep and circadian outcomes. An in-laboratory protocol that standardizes light exposure, posture, feeding, activity, and sampling timing provides a necessary platform to isolate these effects. Determining whether SL Dex produces not only sleep-like sedation, but also measurable sleep/circadian effects and tau dynamics would provide important insights into the relationship between pharmacologic modulation of sleep-circadian biology and inform future translational studies in aging and neurobiology.

Specific Aims and Objectives: This study aims to evaluate the feasibility, safety, and physiologic effects of sublingual dexmedetomidine (SL Dex) on sleep architecture, circadian physiology, and tau biomarker dynamics in older adults under controlled laboratory conditions. SL Dex represents a novel, noninvasive approach to modulating sleep and circadian biology and provides a unique opportunity to examine downstream effects on neurodegenerative biomarkers. Specifically, this study aims to:

1. Assess the feasibility and safety of administering SL Dex within a controlled in-laboratory sleep and circadian protocol with ambulatory follow-up.
2. Quantify the acute effects of SL Dex on sleep architecture, circadian physiology, and tau dynamics under controlled experimental conditions.
3. Characterize the duration and trajectory of SL Dex-associated effects on sleep and circadian physiology during ambulatory follow-up.

Inclusion Criteria:

• Age 65 years or older
• Able to provide informed consent
• Willing and able to comply with all study procedures, including in-laboratory and ambulatory monitoring
• Able to provide informed consent using an IRB-approved translated consent document (when available) and complete study procedures with translated materials and/or qualified interpreter services, if needed- Stable residence and sleep schedule sufficient to complete study monitoring periods
• Able to safely discontinue or adjust medications that may interfere with study procedures or outcomes, as determined by the study investigator

Exclusion Criteria:

• Clinically significant sleep disorders including narcolepsy, severe obstructive sleep apnea, REM sleep behavior disorder, or periodic limb movement disorder
• Clinically significant cardiovascular disease including bradyarrhythmia, conduction abnormalities, heart failure, cardiomyopathy, ischemic heart disease, or conditions increasing risk with dexmedetomidine
• Known QT prolongation, clinically significant arrhythmias, symptomatic bradycardia, hypokalemia, hypomagnesemia, or concurrent use of QT-prolonging medications
• Contraindication or allergy to dexmedetomidine or study medications
• Severe hepatic impairment
• Neurologic, psychiatric, or substance use disorders that may interfere with participation or data interpretation
• Use of medications significantly affecting sleep, circadian rhythms, or cardiovascular function
• Gastrointestinal conditions increasing risk of capsule retention or bowel obstruction
• Swallowing disorders or aspiration risk
• Presence of implantable electronic medical devices
• Use of anticoagulant or antiplatelet medications increasing bleeding risk
• Pregnancy or breastfeeding
• Shift work or frequent travel across more than two time zones
• Participation in another interventional study that may interfere with study participation or interpretation of results
• Anticipated need for MRI during the period in which the ingestible telemetry capsule may remain in the body
• Inability to tolerate study procedures (blood draws, PSG, wearable devices, ingestible capsule)
• Unable to provide informed consent even with translated materials/interpreter support
• Previous participation in this trial
• Concurrent interventional studies that may interfere with participation