A prospective investigation of impacts of comorbid attention deficit hyperactivity disorder (ADHD) on clinical features and long-term treatment response in adult patients with obsessive-compulsive disorder (OCD).

BACKGROUND: A close association between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been investigated in previous studies. However, few studies examined the relationship between lifetime comorbidity of ADHD and OCD in adults. Therefore, we sought to investigate the clinical and psychopathological features related to comorbid ADHD in Japanese adult patients with OCD. METHODS: We assessed lifetime comorbidity of ADHD in 93 adult Japanese patients with OCD. Additionally, we used the Japanese version of Conners' Adult ADHD Rating Scales to assess the characteristics and severity of ADHD in each participant. According to the results, we excluded OCD patients that did not have ADHD but who exhibited elevated levels of ADHD traits. We compared OCD patients with ADHD (ADHD+ group) and those without ADHD or its trait (ADHD- group) in terms of background profiles and clinical features, such as OCD symptomatology and psychometric test results. Additionally, the 6-month treatment outcome was compared prospectively between groups. RESULTS: Of the 93 OCD participants, the prevalence of lifetime comorbidity of ADHD was estimated as 16.1%. Compared with the ADHD- group, participants in the ADHD+ group had an earlier age of onset of OCD, higher frequencies of hoarding symptoms, higher levels of depressive and anxiety symptoms and lower quality of life, more elevated levels of impulsivity, and higher rates of substance or behavioral addiction and major depression. Finally, the mean improvement rate on the Yale-Brown Obsessive Compulsive Scale after 6 months of standardized OCD treatment in the ADHD+ group (16.1%) was significantly lower than that in the ADHD- group (44.6%). CONCLUSION: The lifetime comorbidity of ADHD is likely to exert a significant effect on clinical features and treatment outcome in adult patients with OCD. It is important to consider that underlying ADHD pathology may function as a facilitator for increased severity of global clinical features and treatment refractory conditions in OCD patients. Further studies are required to examine treatment strategies for such patients.

Molecular Mechanisms of IL18 in Disease.

Interleukin 18 (IL18) was originally identified as an inflammation-induced cytokine that is secreted by immune cells. An increasing number of studies have focused on its non-immunological functions, with demonstrated functions for IL18 in energy homeostasis and neural stability. IL18 is reportedly required for lipid metabolism in the liver and brown adipose tissue. Furthermore, IL18 (Il18) deficiency in mice leads to mitochondrial dysfunction in hippocampal cells, resulting in depressive-like symptoms and cognitive impairment. Microarray analyses of Il18-/- mice have revealed a set of genes with differential expression in liver, brown adipose tissue, and brain; however, the impact of IL18 deficiency in these tissues remains uncertain. In this review article, we discuss these genes, with a focus on their relationships with the phenotypic disease traits of Il18-/- mice.

Evaluation of hemodynamic changes using near-infrared spectroscopy in patients with tic-related obsessive-compulsive disorder.

AIM: A tic-related specifier is included in the DSM-5 diagnostic criteria to identify a clinically specific obsessive-compulsive disorder (OCD) subtype. The current study sought to evaluate hemodynamic changes during executive function tasks among OCD patients with and without a lifetime history of tic disorder (TD) and healthy controls, and to investigate the relation between brain activation and clinical variables in each group using structured equation modeling. METHODS: Twenty-nine OCD patients diagnosed according to the DSM-IV-TR and 15 healthy controls were recruited. Patients were divided into two groups according to the presence or absence of a lifetime history of TD (TD+, n = 11; TD-, n = 18). Prefrontal hemodynamic changes were measured using multi-channel near-infrared spectroscopy during the Verbal Fluency Task, Trail-Making Task, and Tower of London (ToL) Task. RESULTS: There were significant brain activation differences in the frontopolar cortex between OCD patients with and without TD during Verbal Fluency Task and ToL performance. Brain activation in the dorsolateral prefrontal cortex (DLPFC) during the ToL Task in OCD patients with TD exerted a direct causal effect on the severity of compulsions. In addition, we detected a direct causal effect of the severity of obsessions in OCD patients without TD on brain activation in the DLPFC during the ToL Task. CONCLUSION: Brain activation in the frontopolar cortex exhibits different hemodynamics depending on the task, and DLPFC function may play a different role in the neural basis of developing OCD symptoms between OCD patients with and without TD.

Impaired function of aorta and perivascular adipose tissue in IL-18-deficient mice.

IL-18 is ubiquitously produced by both hematopoietic and non-hematopoietic cells. The present study examined the thoracic aorta, including the surrounding perivascular adipose tissue (PVAT), of IL-18KO mice from functional and histological perspectives. IL-18KO mice exhibited raised blood pressure compared with wild-type mice. Echocardiographic examination showed a thickened vascular wall and narrowed vascular diameter of the aorta. Examination by the Magnus test demonstrated dysfunction of endothelial cells (ECs) in the IL-18KO thoracic aorta and impairment of the anticontractile function of IL-18KO PVAT. Histological examination showed no inflammatory lesions in the aorta but indicated progressive fibrosis in the vessel and conversion of PVAT from brown adipose tissue-like features to white adipose tissue-like features. Electron microscopic observation suggested several deformed mitochondria in the aorta and vacuole-like structures in ECs from IL-18KO mice. In addition, activity of complex IV was lower and production of reactive oxygen species was augmented in the mitochondria of IL-18KO aorta. Although expression of LC3 B was higher, rapamycin-induced autophagy flux was impaired in the IL-18KO PVAT. Moreover, Western blot analysis revealed that LAMP 1/2 was increased in IL-18KO PVAT, and measurement of cathepsin-D activity indicated decreased levels in IL-18KO PVAT. The IL-18KO thoracic aorta thus showed defects in physiological functions related to histological alterations, and the inflammasome/IL-18 system was suggested to play a protective role in cardiovascular cells, probably through quality control of mitochondria via promotion of autophagosome/autophagolysosome formation.NEW & NOTEWORTHY IL-18 deficiency caused aortic abnormalities in terms of morphology and functions in parallel with an accumulation of damaged mitochondria and anomalous turnover of protein complexes, such as PGC-1 and LAMP1 and -2 in PVAT. These findings suggested that IL-18 plays roles in maintaining the homeostasis of vessels and PVAT around the aorta, possibly by promoting autophagy.

Low-intensity walking as mild medication for pressure control in prehypertensive and hypertensive subjects: how far shall we wander?

Successful prevention and treatment of hypertension depend on the appropriate combination of antihypertensive drug therapy and nondrug lifestyle modification. While most hypertension guidelines recommend moderate- to high-intensity exercise, we decided to explore a mild yet effective type of exercise to add to hypertension management, especially in populations with complications or frailty. After comparing the short-term cardiovascular effects of low-speed walking versus high-speed walking for 3 kilometers (km) (3 km/h versus 6 km/h) in young, healthy volunteers, we delivered low-speed walking (low-intensity walking, 2.5 metabolic equivalents of task, METs) as exercise therapy in 42 prehypertensive and 43 hypertensive subjects. We found that one session of 3 km low-intensity walking exerted a transient pressure-lowering effect as well as a mild negative chronotropic effect on heart rate in both the prehypertensive and hypertensive subjects; these short-term benefits on blood pressure and heart rate were accompanied by a brief increase in urine ß-endorphin output. Then we prescribed regular low-intensity walking with a target exercise dose (exercise volume) of 500-1000 METs·min/week (50-60 min/day and 5-7 times/week) in hypertensive subjects in addition to their daily activities. Regular low-intensity walking also showed mild but significant blood pressure-lowering and heart rate-reducing effects in 7 hypertensive subjects within two months. It is hypothesized that regular low-intensity exercise of the necessary dose could be taken as a pragmatic and supplementary medication for hypertension management.

Physiological and molecular effects of interleukin-18 administration on the mouse kidney.

BACKGROUND: The cytokine interleukin-18 was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence to suggest that it has non-immunological effects on physiological functions. We previously investigated the potential pathophysiological relationship between interleukin-18 and dyslipidemia, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, and suggested interleukin-18 as a possible novel treatment for not only these diseases but also for cancer immunotherapy. Before clinical application, the effects of interleukin-18 on the kidney need to be determined. In the current study, we examined the kidney of interleukin-18 knockout (Il18-/-) mice and the effects of interleukin-18 on the kidney following intravenous administration of recombinant interleukin-18. METHODS: Il18-/- male mice were generated on the C57Bl/6 background and littermate C57Bl/6 Il18+/+ male mice were used as controls. To assess kidney damage, serum creatinine and blood urea nitrogen levels were measured and histopathological analysis was performed. For molecular analysis, microarray and quantitative reverse transcription PCR was performed using mice 6 and 12 weeks old. To evaluate the short- and long-term effects of interleukin-18 on the kidney, recombinant interleukin-18 was administered for 2 and 12 weeks, respectively. RESULTS: Compared with Il18+/+ mice, Il18-/- mice developed kidney failure in their youth-6 weeks of age, but the condition was observed to improve as the mice aged, even though dyslipidemia, arteriosclerosis, and higher insulin resistance occurred. Analyses of potential molecular mechanisms involved in the onset of early kidney failure in Il18-/- mice identified a number of associated genes, such as Itgam, Nov, and Ppard. Intravenous administration of recombinant interleukin-18 over both the short and long term showed no effects on the kidney despite significant improvement in metabolic diseases. CONCLUSIONS: Short- and long-term administration of interleukin-18 appeared to have no adverse effects on the kidney in these mice, suggesting that administration may be a safe and novel treatment for metabolic diseases and cancer.

Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia.

BACKGROUND: The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis. METHODS: Il18-/- male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18+/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively. RESULTS: Compared with Il18+/+ mice, BAT of Il18-/- mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18+/+ and Il18-/- mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18-/- BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18+/+ and Il18-/- mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the 'Quantity of adipocytes' identified three associated genes, apolipoprotein C3 (Apoc3), insulin-induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes' size. CONCLUSIONS: This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.

Ten-year follow-up study of Japanese patients with obsessive-compulsive disorder.

AIM: Obsessive-compulsive disorder (OCD) is a well-known chronic illness. This study retrospectively investigated 10-year outcomes and associated clinical factors in Japanese OCD patients. We focused on the impact of several sociocultural factors, including medical expenses and insurance systems specific to each country, on the differences or biases in follow-up procedures of OCD. METHODS: Seventy-nine patients diagnosed with OCD who received a standardized combination of treatments for 10 continuous years were divided into three groups according to their improvement rates on the Yale-Brown Obsessive-Compulsive Scale after 10 years of treatment. RESULTS: A survival analysis revealed that the rate of patients achieving full remission increased every year. Following 10 years of treatment, 56% of OCD patients experienced 'full remission' for at least 1 year. Consequently, 48% exhibited full remission, and 37% exhibited partial remission at the end-point of this study. We identified several factors that were predictive of poorer outcomes, including lower Global Assessment of Functioning Scale scores and the presence of hoarding symptoms or involvement behaviors. In addition, improvement rates after 1 year significantly predicted better 10-year outcomes. CONCLUSION: Our findings highlight the transcultural nature of long-term outcomes of OCD treatment, which appear to be independent of sociocultural differences.

Dysfunction of mitochondria and deformed gap junctions in the heart of IL-18-deficient mice.

Interleukin-18 (IL-18) was discovered as an interferon-γ-inducing factor and has been regarded as a proinflammatory cytokine. However, IL-18 is ubiquitously expressed both in immune/inflammatory cells and in nonimmune cells, and its biological roles have not been sufficiently elucidated. Here, we demonstrate that IL-18-deficient [IL-18 knockout (KO)] mice have heart abnormalities that may be related to impaired autophagy. In endurance running tests, IL-18KO mice ran significantly shorter distances compared with wild-type (WT) mice. Echocardiographs indicated disability in the systolic and diastolic functions of the IL-18KO mouse heart. Immunostaining of connexin 43 showed heterogeneous localization of gap junctions in the lateral membranes of the IL-18KO cardiac myocytes. Western blotting analysis revealed decreased phosphorylated connexin 43 in the IL-18KO heart. Electron microscopy revealed unusual localization of intercalated disks, swollen or damaged mitochondria, and broad, indistinct Z-lines in the IL-18KO heart. In accordance with the morphological observation, mitochondrial respiratory function, including that of complexes I and IV, was impaired, and production of reactive oxygen species was augmented in IL-18KO hearts. Notably, levels of LC3-II were markedly lower in the IL-18KO hearts than in WT hearts. In the culture of cardiac myocytes of IL-18KO neonates, exogenous IL-18 upregulated LC3-II and increased the number of intact mitochondria with high mitochondrial membrane potential. These results indicated that IL-18 has roles apart from those as a proinflammatory cytokine in cardiac myocytes and suggested that IL-18 contributes to the homeostatic maintenance of mitochondrial function and gap-junction turnover in cardiac myocytes, possibly by upregulating autophagy.

Clinically related or predictive factors and impacts on long-term treatment outcomes of involvement behaviors in patients with obsessive-compulsive disorder.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) frequently exhibit involvement behaviors (IBs) in which they accommodate their caregivers to their OCD symptoms by 1) asking them for reassurance, 2) forcing them to participate in their rituals, or 3) forcing them to assist in avoidance according to the patients' rules or demands. Such behaviors correspond to those of their caregivers, and are referred to as family accommodation (FA). METHODS: We performed multifactorial comparisons between 256 OCD patients with and without IBs in order to examine the clinical characteristics and long-term treatment outcomes of OCD patients with IBs. A multiple logistic regression analysis was also performed to identify the related and predictive factors of IBs. RESULTS: A total of 108 out of the 256 OCD patients examined (42%) were determined to exhibit IBs. OCD patients with IBs were differentially characterized by demographic and phenomenological characteristics (e.g. female predominance and poorer insight), more severe psychopathological features (e.g. lower GAFS, higher anxiety, or a depressive status), and poorer treatment outcomes. Furthermore, the predictive factors of IBs such as being female, having a higher compulsive score, and lower GAFS were identified by logistic analyses and structural equation modeling. CONCLUSION: The presence of IBs correlated with the severe clinical features, treatment refractoriness, and poorer long-term outcome of OCD. The severity of compulsions, being female, and lower GAFS were identified as predictive factors for the presence of IBs. Similar to FA, these findings appear to support the effectiveness of early identification and family-focused intervention in the treatment of OCD patients with IBs.

[A Case with Multiple Comorbidities of Obsessive-Compulsive and Related Disorders].

Obsessive-compulsive and related disorders (OCRDs) have been introduced in a revision to DSM-5 as a novel category that is distinct from other anxiety disorders in DSM-IV. OCRDs consist of 5 primary disorders: obsessive-compulsive disorder (OCD), body dysmorphic disorder (BDD), hoarding disorder (HD), skin picking disorder (SPD), and hair pulling disorder (HPD), which share core clinical features such as preoccupation or recurrent thoughts and/or repetitive behaviors. Repetitive behaviors in BDD and HD can be differentially characterized by the presence of cognitive components associated with preceding anxiety from those in SPD or HPD, which are only observed as motoric components that regulate emotions or alleviate tension. Thus, the validity of the OCRD category and specific interrelationships between each OCRD remain uncertain. In the present study, therefore, we presented a case of multiple comorbidities of OCRDs in order to discuss the nature of the OCRD category. Our patient was a 20-year-old female university student. At the age of 11 years old, she started picking at acne on her face. The psychopathological, and treatment features observed in this case indicated possible interrelationships among OCRDs, especially between cognitive and motoric OCRDs, which supported the clinical utility and continuous nature of this category.

The impacts of elevated autism spectrum disorder traits on clinical and psychosocial features and long-term treatment outcome in adult patients with obsessive-compulsive disorder.

BACKGROUND: While a close relation between obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) has been pointed out, there are few studies that have investigated whether highly elevated ASD traits may have significant impacts on clinical and psychosocial features as well as long-term treatment outcome in adult OCD patients. METHODS: We assessed ASD traits using the Autism Spectrum Quotient (AQ) in 81 Japanese patients with OCD. The relation between degree of ASD traits and clinical and psychosocial variables and the 48-week treatment outcomes was analyzed in the subjects. RESULTS: A substantial proportion of the subjects showed higher ASD traits (35%) with more severe depressive or pervasive anxiety status, and social impairments and lower QOL compared to other OCD individuals. However, elevated ASD traits may exert rather smaller impact on the OCD phenomenology along with on the long-term treatment outcome than expected. CONCLUSIONS: Elevated ASD traits may further emphasize the general psychopathological and socio-dysfunctional features rather than clinical aspects associated with OCD. Co-existing depressive or anxious symptom severity may further exacerbate the core-deficits related to ASD pathology. Thus the assessment of ASD traits should be important for understanding the clinical and psychosocial features and treatment responses in OCD patients.

Meteorin-like Protein and Zonulin in Polycystic Ovary Syndrome: Exploring Associations with Obesity, Metabolic Parameters, and Inflammation.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a prevalent hormonal and metabolic disorder, wherein the adipose tissue and gut microbiome have been demonstrated to contribute to its pathogenesis. This study aims to assess the concentrations of the adipokine, meteorin-like protein (Metrnl) and the protein, zonulin, related to intestine permeability, in individuals with PCOS with a particular emphasis on their relationship with obesity, clinical manifestations, hormonal profiles, and metabolic parameters. METHODS: A cohort comprising 58 women with PCOS, classified according to the Rotterdam criteria, was enrolled. The study also considered age, body mass index (BMI), and ethnicity-matched controls (n = 30). Comprehensive anthropometric and clinical evaluations, hormonal assays, and biochemical analyses were conducted during the follicular phase. Subsequent subgroup analyses were executed within the PCOS cohort based on waist-to-height ratio (WHtR), insulin resistance (IR), and free androgen index (FAI). Serum concentrations of Metrnl and zonulin were quantified via the enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: The Metrnl and zonulin levels exhibited no significant disparity between PCOS patients and controls. Nevertheless, within the entire participant cohort and the PCOS group exclusively, overweight/obese participants demonstrated higher Metrnl concentrations relative to their normal-weight counterparts (p < 0.001, p = 0.001, respectively). Furthermore, higher Metrnl concentrations were identified in subgroups characterized by high WHtR and IR in comparison to those with low WHtR (p = 0.001) and without IR (p = 0.001), respectively. A correlation emerged between Metrnl levels and various anthropometric and metabolic parameters, as well as sex-hormone-binding globulin (SHBG) and interleukin-18 (IL-18) within the PCOS group. Multiple linear regression analysis identified HOMA-IR as the sole independent predictor of Metrnl levels. CONCLUSION: While Metrnl and zonulin levels do not serve as diagnostic indicators of PCOS, elevated Metrnl concentrations exhibited robust associations with proinflammatory and metabolic irregularities within the PCOS population.

Genome-wide DNA methylation analysis in female veterans with military sexual trauma and comorbid PTSD/MDD.

BACKGROUND: Military sexual trauma (MST) is a prevalent issue within the U.S. military. Victims are more likely to develop comorbid diseases such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Nonetheless, not everyone who suffers from MST develops PTSD and/or MDD. DNA methylation, which can regulate gene expression, might give us insight into the molecular mechanisms behind this discrepancy. Therefore, we sought to identify genomic loci and enriched biological pathways that differ between patients with and without MST, PTSD, and MDD. METHODS: Saliva samples were collected from 113 female veterans. Following DNA extraction and processing, DNA methylation levels were measured through the Infinium HumanMethylationEPIC BeadChip array. We used limma and bump hunting methods to generate the differentially methylated positions and differentially methylated regions (DMRs), respectively. Concurrently, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome to find enriched pathways. RESULTS: A DMR close to the transcription start site of ZFP57 was differentially methylated between subjects with and without PTSD, replicating previous findings and emphasizing the potential role of ZFP57 in PTSD susceptibility. In the pathway analyses, none survived multiple correction, although top GO terms included some potentially relevant to MST, PTSD, and MDD etiology. CONCLUSION: We conducted one of the first DNA methylation analyses investigating MST along with PTSD and MDD. In addition, we found one DMR near ZFP57 to be associated with PTSD. The replication of this finding indicates further investigation of ZFP57 in PTSD may be warranted.

The Bispectral Electroencephalography Method Quantifies Postoperative Delirium-Like States in Young and Aged Male Mice After Head-Mount Implantation Surgery.

Delirium, a syndrome characterized by an acute change in attention, awareness, and cognition, is commonly observed in older adults, although there are few quantitative monitoring methods in the clinical setting. We developed a bispectral electroencephalography (BSEEG) method capable of detecting delirium and can quantify the severity of delirium using a novel algorithm. Preclinical application of this novel BSEEG method can capture a delirium-like state in mice following lipopolysaccharide administration. However, its application to postoperative delirium (POD) has not yet been validated in animal experiments. This study aimed to create a POD model in mice with the BSEEG method by monitoring BSEEG scores following EEG head-mount implantation surgery and throughout the recovery. We compared the BSEEG scores of C57BL/6J young (2-3 months old) with aged (18-19 months old) male mice for quantitative evaluation of POD-like states. Postoperatively, both groups displayed increased BSEEG scores and a loss of regular diurnal changes in BSEEG scores. In young mice, BSEEG scores and regular diurnal changes recovered relatively quickly to baseline by postoperative day (PO-Day) 3. Conversely, aged mice exhibited prolonged increases in postoperative BSEEG scores and it reached steady states only after PO-Day 8. This study suggests that the BSEEG method can be utilized as a quantitative measure of POD and assess the effect of aging on recovery from POD in the preclinical model.

The Genome-wide DNA methylation changes in gastrointestinal surgery patients with and without postoperative delirium: Evidence of immune process in its pathophysiology.

AIM: The pathophysiological mechanisms of postoperative delirium (POD) are still unclear, and there is no reliable biomarker to distinguish between those with and without POD. Our aim was to discover DNAm markers associated with POD in blood collected from patients before and after gastrointestinal surgery. METHOD: We collected blood samples from 16 patients including 7 POD patients at three timepoints; before surgery (pre), the first and third postoperative days (day1 and day3). We measured differences in DNA methylation between POD and control groups between pre and day1 as well as between pre and day3 using the Illumina EPIC array method. Besides, enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also performed after excluding influence of common factors related to surgery and anesthesia. RESULT: The results showed that pre and day1 comparisons showed that immune and inflammatory signals such as 'T-cell activation' were significantly different, consistent with our previous studies with non-Hispanic White subjects. In contrast, we found that these signals were not significant any more when pre was compared with day3. CONCLUSION: These results provide strong evidence for the involvement of inflammatory and immune-related epigenetic signals in the pathogenesis of delirium, including POD, regardless of ethnic background. These findings also suggest that DNAm, which is involved in inflammation and immunity, is dynamically altered in patients with POD. In summary, the present results indicate that these signals may serve as a new diagnostic tool for POD.

Epigenetic signals associated with delirium replicated across four independent cohorts.

Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic pathophysiology of delirium remains largely unknown. We aimed to discover reliable and replicable epigenetic (DNA methylation: DNAm) markers that are associated with delirium including post-operative delirium (POD) in blood obtained from patients among four independent cohorts. Blood DNA from four independent cohorts (two inpatient cohorts and two surgery cohorts; 16 to 88 patients each) were analyzed using the Illumina EPIC array platform for genome-wide DNAm analysis. We examined DNAm differences in blood between patients with and without delirium including POD. When we compared top CpG sites previously identified from the initial inpatient cohort with three additional cohorts (one inpatient and two surgery cohorts), 11 of the top 13 CpG sites showed statistically significant differences in DNAm values between the delirium group and non-delirium group in the same directions as found in the initial cohort. This study demonstrated the potential value of epigenetic biomarkers as future diagnostic tools. Furthermore, our findings provide additional evidence of the potential role of epigenetics in the pathophysiology of delirium including POD.

Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.