Gen Shinozaki

Epigenetic studies of psychiatric and neurological disorders rely largely on peripheral tissues, yet where peripheral DNA methylation (DNAm) reflects the brain remains unclear. We generated a paired brain and peripheral DNAm dataset from 148 donors in three cohorts and combined it with five published cohorts for consensus brain–peripheral correlations. By cross-validation across cohorts, we defined brain epigenome shared sites (BrESS), more than 100,000 CpGs per tissue at which peripheral DNAm reproducibly predicts brain DNAm. BrESS lay at promoters active in both brain and periphery and in housekeeping genes, and most were not explained by genetic effects. BrESS did not contribute to the heritability of seven disorders, and CpGs from epigenome-wide association studies of these disorders were not enriched at BrESS. Peripheral DNAm reflects the brain mainly in a regulatory compartment shared across tissues, outside which disease signals largely lie, and BrESS separate peripheral signals attributable to the brain from others.

Delirium is an acute, fluctuating brain dysfunction that commonly follows surgery and systemic inflammation, disproportionately affects older adults, and remains difficult to quantify continuously over time and treat pharmacologically. Here, we tested whether the neuroactive steroid zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABA_A receptors, mitigates delirium-like abnormalities across two complementary murine delirium models, a lipopolysaccharide-induced systemic inflammation (LPS) model and a postoperative delirium (POD) model, primarily in young and aged mice, with selected analyses in super-aged mice. Using continuous EEG with a validated bispectral EEG (BSEEG) metric, we found that zuranolone attenuated delirium-like EEG slowing in the LPS model in young mice in a dose-dependent manner and retained efficacy in aged mice. In the POD model, prophylactic dosing provided limited benefit in young mice, whereas post-surgery treatment reduced postoperative BSEEG elevations. In aged mice, prophylactic dosing suppressed POD-associated BSEEG abnormalities, and in super-aged mice, prophylactic zuranolone improved survival after POD induction. In parallel, zuranolone reduced microglial density and activation markers (IBA1 and CD68 immunoreactivity) at 24 h after POD surgery and after LPS challenge, with effects that were particularly evident in peri-screw site tissue in young POD mice and more broadly distributed across regions in aged mice. Finally, in young mice, zuranolone improved a composite behavioral severity score in the LPS model, whereas behavioral effects in the POD model were modest and domain-specific. Together, these findings support zuranolone as a candidate strategy to reduce delirium-like electrophysiological and neuroimmune abnormalities, with the strongest effects in inflammation-driven and age-vulnerable contexts.

Delirium is a common yet underdiagnosed condition in elderly hospitalized patients. The lack of effective diagnostic and therapeutic methods can be attributed to the limited understanding of its pathophysiology. Delirium has recently been reported to be linked to neuroinflammation and epigenetic changes. The aim of this study was to validate the pathways in a larger cohort with a uniform type of surgery, while rigorously adjusting for potential covariates. This study primarily investigated DNA methylation (DNAm) changes before and after surgery in postoperative delirium (POD) among older adults having undergone femoral fracture surgery. After propensity analysis, 65 subjects were divided into 2 subgroups; one consisted of subjects who had blood samples collected preoperatively and on postoperative day 0, and the other consisted of those who had samples collected preoperatively and on postoperative day 3. We performed differential methylation analysis and enrichment analysis on each subgroup. Enrichment analysis using CpGs that exhibited substantial DNAm changes between pre- and postoperative day 0 samples in POD cases showed inflammation- and immunity-related pathways such as “leukocyte mediated immunity” and “NF-kappa B signaling pathway.” Inflammation- and immunity-related pathways became less noticeable between pre- and postoperative day 3 samples. Inflammation- and immunity-related pathways showed in this study align with previous studies across diverse populations, reinforcing the role of inflammation- and immunity-related epigenetic mechanisms in delirium including POD. Notably, these DNAm changes were potentially transient, corresponding to the typical onset of delirium, suggesting their potential as biomarkers for early diagnosis.

Delirium is an acute cognitive failure characterized by an acute onset and psychomotor disturbances. It is associated with poor outcomes in hospitalized patients, resulting in prolonged hospital stays, elevated rates of mortality, and cognitive dysfunctions after hospital discharge. The pathophysiology of delirium remains poorly understood, making the development of animal models a promising avenue for researchers to elucidate the mechanisms underlying human delirium. These models not only aid in understanding the pathophysiology and etiology of the disease but also enhance the efficacy of nonpharmacological interventions and identify pharmacological therapies. This review aims to present the most relevant and translational animal models of delirium available in the literature and to provide a critical appraisal of these models using contemporary translational benchmarks. In preclinical models, delirium-like behavior is induced in various methods to reproduce the fundamentals of human delirium, including anesthesia, surgery, sepsis, and drug interventions. However, researchers must select a model encompassing face, construct, predictive, and target validity. Delirium currently lacks pharmacological therapies, and this review is to encourage more researchers to delve deeper and shed light on this medical condition, which is highly prevalent in vulnerable and hospitalized patients.

Background: Human DNA is known to exhibit an overall tendency toward demethylation with aging. However, assuming a simple linear relationship between DNA methylation and age does not align with the phenotype of human development and the aging process. This study aimed to investigate the existence of DNA methylation patterns with peaks or troughs at specific ages in addition to simple linear changes. Methods: A large-scale dataset of genome-wide DNA methylation data from 10,420 individuals was analyzed. Hierarchical multiple regression models were applied to detect patterns of the association between age and DNA methylation: linear increase, linear decrease, U-shaped curve, and inverse U-shaped curve. Results: Among the 864,627 CpG sites analyzed, 8.4% exhibited an increase in DNA methylation with age, 23.9% showed a decrease, and 5.5% were better explained by a quadratic model (P < 5.7815×10 ). Within the non-linear subset, inverse U-shaped CpG sites peaking in methylation during middle age were predominant. Genes exhibiting quadratic association patterns between DNA methylation and age, and those linked to diseases with common onset during middle age, were also detected. Conclusions: Non-linear age-related DNA methylation patterns, with peaks or troughs occurring at specific ages, were detected. This suggests that humans do not simply age linearly, but that programmed mechanisms or cascade-like processes may exist to promote or suppress the expression of specific genes at certain ages, contributing onset of certain diseases at specific timings.

Aims: Postoperative delirium (POD) is a severe neuropsychiatric state characterized by acute fluctuating various mental symptoms. Despite its prevalence, the underlying mechanisms of POD remain largely unknown, and effective biomarkers for its detection are lacking. We have successfully developed a novel delirium detection method, the bispectral electroencephalography (BSEEG) method, which has shown excellent performance in delirium detection and outcome prediction. From there, like the clinical situation, we hypothesize that BSEEG scores can serve as indicators of POD‐like states in mice. This study investigated the correlation between POD‐like behavior and BSEEG score in a mouse model following EEG head‐mount implantation surgery.Methods: First, 2–3‐ and 22–23‐month‐old male C57BL/6J mice underwent EEG head‐mount implantation surgery, followed by EEG monitoring and a battery of behavioral tests, including the buried food test, the open field test, and the Y‐maze, to assess POD‐like behavior. We measured BSEEG scores and analyzed the correlation between these scores and the behavior measurements.Results: The results showed BSEEG scores correlated with attention deficit and decreases in locomotor activity in young mice, whilst BSEEG scores only correlated with a decrease in locomotor activity in aged mice. Notably, composite Z scores representing delirium severity also showed a correlation with BSEEG scores in young mice.Conclusion: Our findings indicate that the BSEEG method can be an indicator of POD‐like states consistent with those measured by behavior tests. This study provides a novel preclinical framework for understanding the pathophysiology of POD and underscores the potential of BSEEG as a valuable tool for delirium detection and severity assessment.