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

Circadian rhythms are fundamental regulators of human physiology, coordinating sleep‐waketiming, neural activity, metabolic processes, and hormonal signaling across the 24‐hourday. These endogenous rhythms are coordinated by the suprachiasmatic nucleus (SCN), thecentral circadian pacemaker in the hypothalamus that integrates environmental cues suchas light to synchronize peripheral and central biological processes. In older adults,circadian rhythms often degrade, exhibiting reduced robustness and impaired alignmentwith behavioral cycles. Such alterations are closely linked to disrupted sleeparchitecture, particularly sleep fragmentation and loss of restorative non‐rapid eyemovement (NREM) sleep. Crucially, sleep and circadian dysfunction is increasinglyrecognized as a critical modulator of neurodegenerative biomarker dynamics. Experimentalevidence suggests that fragmented sleep and reduced slow‐wave sleep directly alter theproduction, release, and clearance of neurotoxic proteins, leading to elevated taulevels. These observations highlight a potential mechanistic pathway linkingsleep‐circadian dysfunction to neurodegeneration and underscore the need to understandhow interventions that stabilize these systems influence the temporal profile oftau‐related biomarkers. Dexmedetomidine, a highly selective alpha2‐adrenergic receptoragonist, represents a unique pharmacologic probe for investigating the links betweensleep architecture, circadian physiology, and tau biomarker dynamics. Unlike traditionalsedatives, dexmedetomidine engages endogenous sleep‐promoting pathways and produces aNREM‐like state characterized by electrophysiologic features resembling natural sleep.Beyond its sleep‐modulating properties, emerging preclinical evidence suggests thatdexmedetomidine exerts potent chronobiotic effects (i.e., the ability to stabilize orentrain circadian rhythms). For instance, preclinical models indicate it activatesvasoactive intestinal peptide (VIP) neurons within the SCN and modulates circadianentrainment processes. Clinical studies of thoracic surgery patients further suggest thatdexmedetomidine may preserve endogenous circadian signaling, such as melatonin secretion,during the early postoperative period. The recent development of sublingualdexmedetomidine (SL Dex) provides a transformative, noninvasive formulation that enablescontrolled administration outside of intensive care settings, distinguishing it fromtraditional intravenous (IV) dexmedetomidine, which is typically limited to monitoredenvironments. Preliminary studies have suggested that SL Dex produces measurable changesin sleep architecture, including increased slow‐wave activity, shortened sleep latency,and prolonged REM sleep latency. However, the extent to which SL Dex influences circadianregulation, sleep architecture, and the temporal profile of tau biomarkers across the24‐hour sleep‐wake cycle in humans has not been systematically characterized. Addressingthis gap requires a rigorously controlled experimental approach capable of isolating thephysiologic effects of SL Dex from environmental and behavioral confounders. Priorclinical studies have largely occurred in perioperative or other medically complexsettings in which surgery, pain, inflammation, environmental disruption, concomitantmedications, and irregular behaviors may confound interpretation of sleep and circadianoutcomes. 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 measurablesleep/circadian effects and tau dynamics would provide important insights into therelationship between pharmacologic modulation of sleep‐circadian biology and informfuture translational studies in aging and neurobiology.Specific Aims and Objectives: This study aims to evaluate the feasibility, safety, andphysiologic effects of sublingual dexmedetomidine (SL Dex) on sleep architecture,circadian physiology, and tau biomarker dynamics in older adults under controlledlaboratory conditions. SL Dex represents a novel, noninvasive approach to modulatingsleep and circadian biology and provides a unique opportunity to examine downstreameffects on neurodegenerative biomarkers. Specifically, this study aims to: 1. Assess the feasibility and safety of administering SL Dex within a controlledin‐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 andcircadian physiology during ambulatory follow‐up.