Dysfunction of circadian and sleep rhythms is an early feature of many neurodegenerative diseases. Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in cognitive and psychiatric disturbances. Although it is largely unclear whether dysfunctions in sleep and circadian rhythms contribute to the etiology of AD or are a consequence of the disease, there is evidence that these conditions are involved in a complex self-reinforcing bidirectional relationship. According to the recent studies, dysregulation of the circadian clock already occurs during the asymptomatic stage of the disease and could promote neurodegeneration. Thus, restoration of sleep and circadian rhythms in preclinical AD may represent an opportunity for early intervention to slow the disease course.

Keywords: Alzheimer's disease; circadian system; clock; neurodegeneration; sleep.

Objectives: Nonpharmacologic delirium management is recommended by current guidelines, but studies on the impact of ICU design are still limited. The study's primary purpose was to determine if a multicomponent change in room design prevents ICU delirium. Second, the influence of lighting conditions on serum melatonin was assessed.

Design: Prospective observational cohort pilot study.

Setting: The new design concept was established in two two-bed ICU rooms of a university hospital. Besides modifications aimed at stress relief, it includes a new dynamic lighting system.

Patients: Seventy-four adult critically ill patients on mechanical ventilation with an expected ICU length of stay of at least 48 hours, treated in modified or standard rooms.

Interventions: None.

Measurements and main results: The clinical examination included a prospective assessment for depth of sedation, delirium, and pain every 8 hours using validated scores. Blood samples for serum melatonin profiles were collected every 4 hours for a maximum of three 24-hour periods. Seventy-four patients were included in the analysis. Seventy-six percent ( n = 28) of patients in the standard rooms developed delirium compared with 46% of patients ( n = 17) in the modified rooms ( p = 0.017). Patients in standard rooms (vs. modified rooms) had a 2.3-fold higher delirium severity (odds ratio = 2.292; 95% CI, 1.582-3.321; p < 0.0001). Light intensity, calculated using the measure of circadian effective irradiance, significantly influenced the course of serum melatonin ( p < 0.0001). Significant interactions ( p < 0.001) revealed that differences in serum melatonin between patients in standard and modified rooms were not the same over time but varied in specific periods of time.

Conclusions: Modifications in ICU room design may influence the incidence and severity of delirium. Dedicated light therapy could potentially influence delirium outcomes by modulating circadian melatonin levels.

Background: Critical illness myopathy (CIM) increases mortality and causes long-term disabilities. CIM is characterized by reduced muscle excitability, muscle atrophy, weakness, and impaired glucose metabolism. Functional circadian rhythms are important for skeletal muscle homeostasis. Circadian rhythms are often disrupted during critical illness in the Intensive Care Unit (ICU). This analysis investigates whether diurnal temperature rhythms differ in critically ill CIM compared to no-CIM patients.

Methods: This is a secondary analysis of two prospective trials including critically ill patients with CIM (n = 32) or no-CIM (n = 30) based on electrophysiological tests. Diurnal body temperature rhythms were compared between CIM and no-CIM groups in reference to n = 16 participants included in a bed rest study. Cosinor analysis was performed to determine the rhythm parameters and classify into rhythm classes. Aggregated and longitudinal data were compared between groups using non-parametric tests. Rhythm parameters were correlated with muscle atrophy, weakness and insulin sensitivity.

Results: CIM and no-CIM patients had severe multiorgan failure (median SOFA score 12 in both groups, p = 0.39). The temperature rhythm nadir timepoint was shifted in CIM patients (10:43 [09:21, 12:22]) and no-CIM (11:12 [09:43, 13:30]) compared to the healthy bed rest group (5:03 [3:22, 6:36]) p < 0.001. CIM patients showed lower temperature rhythm mesors than no-CIM patients (p = 0.041). The temperature rhythm amplitude was lower in both CIM and no-CIM patients compared to the healthy bed rest group (CIM: 0.3 °C [0.2, 0.4]; no-CIM: 0.2 °C [0.2, 0.3]; healthy bed rest: 0.5 °C [0.2, 0.6]; p < 0.01). Compared to no-CIM patients, CIM patients had higher temperature rhythm amplitudes (p = 0.021) and showed a less pronounced reduction in temperature rhythm amplitudes during ICU stay (p = 0.017). A higher temperature rhythm amplitude correlated negatively with M. vastus lateralis myocyte cross-sectional area.

Conclusions: Heterogeneous phase shifts of diurnal temperature rhythms in CIM and no-CIM groups compared to healthy bed rest volunteers may indicate ICU-related circadian disruption. Suppression of temperature rhythm amplitude during ICU stay could represent an adaptive response to this disruption. Blunted amplitude suppression observed in CIM compared to no-CIM patients might reflect reduced adaptation, potentially contributing to muscle catabolism. This hypothesis-generating analysis underlines the need for mechanistic studies exploring circadian regulation in skeletal muscle during critical illness.

Keywords: Body temperature; Circadian rhythm disruption; Circadian rhythms; Critical illness; Critical illness myopathy; Diurnal rhythms; Muscle weakness; Skeletal muscle atrophy; Temperature rhythm.

Background: Circadian rhythms are often severely disrupted in critically ill patients in the ICU. The ICU environment, characterized by irregular light-dark signals, continuous nutrition, and round-the-clock interventions, contributes to this disruption by providing weak and conflicting timing cues to the circadian system. Extensive scientific research has demonstrated that circadian rhythms play a vital role in regulating physiology and maintaining overall health. Therefore, integrating circadian principles into critical care may represent a promising strategy to improve patient outcomes in the ICU.

Research question: What are the key challenges of integrating circadian medicine into critical care, what steps can address these challenges, and which recommendations can guide future study designs and clinical implementation?

Study design and methods: We convened a 5-day workshop in September 2024 that brought together 24 international experts with backgrounds in circadian biology, critical care, and implementation science. Each day was organized around a predefined theme, with morning presentations and plenary discussions, and afternoons dedicated to drafting a list of Propositions and Recommendations in breakout groups. Propositions and Recommendations were finalized via a post-workshop survey requiring ≥ 75% agreement.

Results: This roadmap summarizes the discussions and outcomes of the workshop, structured around a set of Propositions and Recommendations, and provides a framework for building a robust evidence base for integrating circadian principles into ICU practice. Key recommendations include the development of circadian outcome measures tailored for use in the ICU and using standardized frameworks for evaluating the effect of circadian interventions in clinical trials.

Interpretation: Altogether, this roadmap provides an interdisciplinary framework resulting from a collaborative effort of ICU clinicians, circadian biologists, and implementation specialists, for building a robust evidence base for integrating circadian principles into ICU research and practice.

Keywords: ICU; circadian rhythms; critical care; critical illness; meeting report.

The circadian clock comprises a cellular endogenous timing system coordinating the alignment of physiological processes with geophysical time. Disruption of circadian rhythms has been associated with several metabolic diseases. In this review, we focus on liver as a major metabolic tissue and one of the most well-studied organs with regard to circadian regulation. We summarize current knowledge about the role of local and systemic clocks and rhythms in regulating biological functions of the liver. We discuss how the disruption of circadian rhythms influences the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We also critically evaluate whether NAFLD/NASH may in turn result in chronodisruption. The last chapter focuses on potential roles of the clock system in prevention and treatment of NAFLD/NASH and the interaction of current NASH drug candidates with liver circadian rhythms and clocks. It becomes increasingly clear that paying attention to circadian timing may open new avenues for the optimization of NAFLD/NASH therapies and provide interesting targets for prevention and treatment of these increasingly prevalent disorders.

Keywords: NAFLD; NASH; chronotherapy; circadian rhythms; clock genes; liver; metabolic-associated fatty liver disease (MAFLD).

Background & aims: The liver ensures organismal homeostasis through modulation of physiological functions over the course of the day. How liver diseases such as nonalcoholic steatohepatitis (NASH) affect daily transcriptome rhythms in the liver remains elusive.

Methods: To start closing this gap, we evaluated the impact of NASH on the diurnal regulation of the liver transcriptome in mice. In addition, we investigated how stringent consideration of circadian rhythmicity affects the outcomes of NASH transcriptome analyses.

Results: Comparative rhythm analysis of the liver transcriptome from diet-induced NASH and control mice showed an almost 3-hour phase advance in global gene expression rhythms. Rhythmically expressed genes associated with DNA repair and cell-cycle regulation showed increased overall expression and circadian amplitude. In contrast, lipid and glucose metabolism-associated genes showed loss of circadian amplitude, reduced overall expression, and phase advances in NASH livers. Comparison of NASH-induced liver transcriptome responses between published studies showed little overlap (12%) in differentially expressed genes (DEGs). However, by controlling for sampling time and using circadian analytical tools, a 7-fold increase in DEG detection was achieved compared with methods without time control.

Conclusions: NASH had a strong effect on circadian liver transcriptome rhythms with phase- and amplitude-specific effects for key metabolic and cell repair pathways, respectively. Accounting for circadian rhythms in NASH transcriptome studies markedly improves DEG detection and enhances reproducibility.

Keywords: Circadian Bioinformatics; Circadian Clock; Circadian RNAseq; Energy Metabolism; Nonalcoholic Fatty Liver Disease (NAFLD).