Tsuyoshi Nishiguchi

All Publications

• The Genome-wide DNA methylation changes in gastrointestinal surgery patients with and without postoperative delirium: Evidence of immune process in its pathophysiology. Journal of psychiatric research Nishizawa, Y., Yamanashi, T., Nishiguchi, T., Kajitani, N., Miura, A., Matsuo, R., Tanio, A., Yamamoto, M., Sakamoto, T., Fujiwara, Y., Thompson, K., Malicoat, J., Yamanishi, K., Seki, T., Kanazawa, T., Iwata, M., Shinozaki, G. 2024; 177: 249-255

  Abstract

  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.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.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.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.

  View details for DOI 10.1016/j.jpsychires.2024.07.013

  View details for PubMedID 39043004

• Epigenetic signals associated with delirium replicated across four independent cohorts. Translational psychiatry Nishizawa, Y., Thompson, K. C., Yamanashi, T., Wahba, N. E., Saito, T., Marra, P. S., Nagao, T., Nishiguchi, T., Shibata, K., Yamanishi, K., Hughes, C. G., Pandharipande, P., Cho, H., Howard, M. A., Kawasaki, H., Toda, H., Kanazawa, T., Iwata, M., Shinozaki, G. 2024; 14 (1): 275

  Abstract

  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.

  View details for DOI 10.1038/s41398-024-02986-w

  View details for PubMedID 38965205

  View details for PubMedCentralID 2698979

• The bispectral electroencephalography (BSEEG) method quantifies post-operative delirium-like states in young and aged male mice after head mount implantation surgery. The journals of gerontology. Series A, Biological sciences and medical sciences Nishiguchi, T., Shibata, K., Yamanishi, K., Dittrich, M. N., Islam, N. Y., Patel, S., Phuong, N. J., Marra, P. S., Malicoat, J. R., Seki, T., Nishizawa, Y., Yamanashi, T., Iwata, M., Shinozaki, G. 2024

  Abstract

  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. Pre-clinical application of this novel BSEEG method can capture a delirium-like state in mice following LPS 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 3. Conversely, aged mice exhibited prolonged increases in postoperative BSEEG scores and it reached steady states only after postoperative 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 pre-clinical model.

  View details for DOI 10.1093/gerona/glae158

  View details for PubMedID 38877811

• Genome-wide DNA methylation analysis in female veterans with military sexual trauma and comorbid PTSD/MDD. Journal of affective disorders Marra, P., Seki, T., Nishizawa, Y., Chang, G., Yamanishi, K., Nishiguchi, T., Shibata, K., Braun, P., Shinozaki, G. 2024

  Abstract

  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.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.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.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.

  View details for DOI 10.1016/j.jad.2024.01.241

  View details for PubMedID 38309478

• A Prospective Randomized Study of the Herbal Medicine Yokukansan for Preventing Delirium After Gastrointestinal Cancer Surgery YONAGO ACTA MEDICA Tanio, A., Yamamoto, M., Uejima, C., Tada, Y., Yamanashi, T., Matsuo, R., Miura, A., Kajitani, N., Nishiguchi, T., Iwata, M., Fujiwara, Y. 2023; 66 (4): 432-439

  Abstract

  Yokukansan, the Chinese Herbal Medicine, may be effective for treating postoperative delirium. However, there is no sufficient evidence supporting this notion. This study aimed to investigate whether yokukansan was effective for preventing delirium after gastrointestinal cancer surgery by the prospective randomized study.This was a double-blind, randomized, controlled trial. Patients aged 75 years or older who underwent surgery between May 2017 and December 2019 were randomized to the yokukansan or anchusan (another Herbal Medicine) group. They received treatments with oral intake of assigned medicine from the day before surgery until postoperative day 3. Then, the incidence of postoperative delirium was compared. A psychiatrist diagnosed patients with postoperative delirium.Seventy-seven patients were enrolled in this study, and the full analysis set comprised 68 patients. In total, 25 of 68 (36.8%) patients presented with postoperative delirium. Specifically, 13 (37.1%) patients in the control group and 12 (36.4%) in the yokukansan group were diagnosed with postoperative delirium. However, the results did not differ significantly in both groups. Moreover, there was no remarkable difference in terms of delirium severity, and adverse events correlated with the medications were not observed.Yokukansan was ineffective in preventing delirium after gastrointestinal cancer surgery.

  View details for DOI 10.33160/yam.2023.11.008

  View details for Web of Science ID 001113280600007

  View details for PubMedID 38028268

  View details for PubMedCentralID PMC10674061

• NSAIDs use history: impact on the genome-wide DNA methylation profile and possible mechanisms of action. Clinical and experimental medicine Marra, P. S., Nishizawa, Y., Yamanashi, T., Sullivan, E. J., Comp, K. R., Crutchley, K. J., Wahba, N. E., Shibata, K., Nishiguchi, T., Yamanishi, K., Noiseux, N. O., Karam, M. D., Shinozaki, G. 2023

  Abstract

  NSAIDs inhibit cyclooxygenase, but their role in aging and other diseases is not well understood. Our group previously showed the potential benefit of NSAIDs in decreasing the risk of delirium and mortality. Concurrently, epigenetics signals have also been associated with delirium. Therefore, we sought to find differentially methylated genes and biological pathways related to exposure with NSAIDs by comparing the genome-wide DNA methylation profiles of patients with and without a history of NSAIDs use.Whole blood samples were collected from 171 patients at the University of Iowa Hospital and Clinics from November 2017 to March 2020. History of NSAIDs use was assessed through a word-search function in the subjects' electronic medical records. DNA was extracted from the blood samples, processed with bisulfite conversion, and analyzed using Illumina's EPIC array. The analysis of top differentially methylated CpG sites and subsequent enrichment analysis were conducted using an established pipeline using R statistical software.Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) showed several biological pathways relevant to NSAIDs' function. The identified GO terms included "arachidonic acid metabolic process," while KEGG results included "linoleic acid metabolism," "cellular senescence," and "circadian rhythm." Nonetheless, none of the top GO and KEGG pathways and the top differentially methylated CpG sites reached statistical significance.Our results suggest a potential role of epigenetics in the mechanisms of the action of NSAIDs. However, the results should be viewed with caution as exploratory and hypothesis-generating given the lack of statistically significant findings.

  View details for DOI 10.1007/s10238-023-01119-9

  View details for PubMedID 37341931

  View details for PubMedCentralID 7486988

• Bispectral EEG (BSEEG) Algorithm Captures High Mortality Risk Among 1,077 Patients: Its Relationship to Delirium Motor Subtype. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry Nishizawa, Y., Yamanashi, T., Saito, T., Marra, P., Crutchley, K. J., Wahba, N. E., Malicoat, J., Shibata, K., Nishiguchi, T., Lee, S., Cho, H. R., Kanazawa, T., Shinozaki, G. 2023

  Abstract

  Delirium is dangerous and a predictor of poor patient outcomes. We have previously reported the utility of the bispectral EEG (BSEEG) with a novel algorithm for the detection of delirium and prediction of patient outcomes including mortality. The present study employed a normalized BSEEG (nBSEEG) score to integrate the previous cohorts to combine their data to investigate the prediction of patient outcomes. We also aimed to test if the BSEEG method can be applicable regardless of age, and independent of delirium motor subtypes.We calculated nBSEEG score from raw BSEEG data in each cohort and classified patients into BSEEG-positive and BSEEG-negative groups. We used log-rank test and Cox proportional hazards models to predict 90-day and 1-year outcomes for the BSEEG-positive and -negative groups in all subjects and motor subgroups.A total of 1,077 subjects, the BSEEG-positive group showed significantly higher 90-day (hazard ratio 1.33 [95% CI 1.16-1.52] and 1-year (hazard ratio 1.22 [95% CI 1.06-1.40] mortality rates than the negative group after adjustment for covariates such as age, sex, CCI, and delirium status. Among patients with different motor subtypes of delirium, the hypoactive group showed significantly higher 90-day (hazard ratio 1.41 [95% CI 1.12-1.76] and 1-year mortality rates (hazard ratio 1.32 [95% CI 1.05-1.67], which remained significant after adjustment for the same covariates.We found that the BSEEG method is capable of capturing patients at high mortality risk.

  View details for DOI 10.1016/j.jagp.2023.03.002

  View details for PubMedID 37003894

• Genome-wide DNA methylation analysis of post-operative delirium with brain, blood, saliva, and buccal samples from neurosurgery patients. Journal of psychiatric research Wahba, N. E., Nishizawa, Y., Marra, P. S., Yamanashi, T., Crutchley, K. J., Nagao, T., Shibata, K., Nishiguchi, T., Cho, H., Howard, M. A., Kawasaki, H., Hefti, M., Kanazawa, T., Shinozaki, G. 2022; 156: 245-251

  Abstract

  OBJECTIVE: No previous study demonstrates the difference in the genome-wide DNA methylation status of post-operative delirium (POD) using human brain tissue obtained from neurosurgery and multiple peripheral tissues such as blood, saliva, and buccal samples from the same individuals. We aimed to identify epigenetic marks of DNA methylation in the brain and peripheral tissues to elucidate the potential pathophysiological mechanism of POD.METHODS: The four tissue types (brain, blood, saliva, buccal) of DNA samples from up to 40 patients, including 11 POD cases, were analyzed using Illumina EPIC array. DNAm differences between patients with and without POD were examined. We also conducted enrichment analysis based on the top DNAm signals.RESULTS: The most different CpG site between control and POD was found at cg16526133 near the ADAMTS9 gene from the brain tissue(p=8.66E-08). However, there are no CpG sites to reach the genome-wide significant level. The enrichment analysis based on the 1000 top hit CpG site (p<0.05) on the four tissues showed several intriguing pathways. In the brain, there are pathways including "positive regulation of glial cell differentiation". Blood samples showed also pathways related to immune function. Besides, both saliva and the buccal sample showed pathways related to circadian rhythm, although these findings were not FDR significant.CONCLUSION: Enrichment analysis found several intriguing pathways related to potential delirium pathophysiology. Present data may further support the role of epigenetics, especially DNA methylation, in the molecular mechanisms of delirium pathogenesis.

  View details for DOI 10.1016/j.jpsychires.2022.10.023

  View details for PubMedID 36270064

• Stress increases blood beta-hydroxybutyrate levels and prefrontal cortex NLRP3 activity jointly in a rodent model. Neuropsychopharmacology reports Nishiguchi, T., Iwata, M., Kajitani, N., Miura, A., Matsuo, R., Murakami, S., Nakada, Y., Pu, S., Shimizu, Y., Tsubakino, T., Yamanashi, T., Shinozaki, G., Tsubota, J., Shirayama, Y., Watanabe, K., Kaneko, K. 2021; 41 (2): 159-167

  Abstract

  This study aimed to assess the response of endogenous beta-hydroxybutyrate to psychological stress, and its association with nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome, and stress-induced behavior.Male C57BL/6J mice were subjected to 1-hour restraint stress to examine changes in the endogenous beta-hydroxybutyrate and active NLRP3 levels in the prefrontal cortex. Subsequently, we created a depression model applying 10-day social defeat stress to the male C57BL/6J mice.One-hour restraint stress rapidly increased beta-hydroxybutyrate levels in the blood. The active NLRP3 levels in the prefrontal cortex also increased significantly. A correlation was found between the increased beta-hydroxybutyrate levels in the blood and the active NLRP3 levels in the prefrontal cortex. The mice exposed to social defeat stress exhibited depression- and anxiety-like behavioral changes in the open field, social interaction, and forced swim tests. There was a correlation between these behavioral changes and endogenous beta-hydroxybutyrate levels. Among the social defeat model mice, those with high beta-hydroxybutyrate levels tended to have more depression- and anxiety-like behavior.The increased blood beta-hydroxybutyrate levels due to psychological stress correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that the increased beta-hydroxybutyrate levels due to stress may reflect a reaction to brain inflammation. In addition, mice with higher blood beta-hydroxybutyrate levels tend to exhibit increased depression- and anxiety-like behaviors; thus, an increase in blood beta-hydroxybutyrate levels due to stress may indicate stress vulnerability.

  View details for DOI 10.1002/npr2.12164

  View details for PubMedID 33609086