Gen Shinozaki, MD

All Publications

• Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography. Translational psychiatry Nishiguchi, T., Yamanishi, K., Patel, S., Malicoat, J. R., Phuong, N. J., Seki, T., Ishii, T., Aoyama, B., Shimura, A., Gorantla, N., Yamanashi, T., Iwata, M., Pieper, A. A., Shinozaki, G. 2024; 14 (1): 413

  Abstract

  Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

  View details for DOI 10.1038/s41398-024-03130-4

  View details for PubMedID 39358319

• 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

• 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

• Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity AGING-US Marra, P. S., Yamanashi, T., Crutchley, K. J., Wahba, N. E., Anderson, Z. M., Modukuri, M., Chang, G., Tran, T., Iwata, M., Cho, H., Shinozaki, G. 2023; 15 (3): 601-616

  View details for Web of Science ID 000935831100003

• The potential benefit of metformin to reduce delirium risk and mortality: a retrospective cohort study AGING-US Yamanashi, T., Anderson, Z. M., Modukuri, M., Chang, G., Tran, T., Marra, P. S., Wahba, N. E., Crutchley, K. J., Sullivan, E. J., Jellison, S. S., Comp, K. R., Akers, C. C., Meyer, A. A., Lee, S., Iwata, M., Cho, H. R., Shinozaki, E., Shinozaki, G. 2022; 14 (22): 8927-8943

  View details for Web of Science ID 000892356700006

• The genome-wide DNA methylation profiles among neurosurgery patients with and without post-operative delirium. Psychiatry and clinical neurosciences Yamanashi, T., Crutchley, K. J., Wahba, N. E., Nagao, T., Marra, P. S., Akers, C. C., Sullivan, E. J., Iwata, M., Howard, M. A., Cho, H. R., Kawasaki, H., Hughes, C. G., Pandharipande, P. P., Hefti, M. M., Shinozaki, G. 2022

  Abstract

  AIMS: There is no previous study demonstrating the differences of genome-wide DNA methylation (DNAm) profiles between patients with and without postoperative delirium (POD). We aimed to discover epigenetic (DNAm) markers that are associated with POD in blood obtained from patients before and after neurosurgery.METHODS: Pre- and post-surgical blood DNA samples from 37 patients, including 10 POD cases, were analyzed using the Illumina EPIC array genome-wide platform. We examined DNAm differences in blood from patients with and without POD. Enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also conducted.RESULTS: When POD cases were tested for DNAm change before and after surgery, enrichment analyses showed many relevant signals with statistical significance in immune response related-pathways and inflammatory cytokine related-pathways such as "cellular response to cytokine stimulus", "regulation of immune system process", "regulation of cell activation", and "regulation of cytokine production". Furthermore, after excluding the potential effect of common factors related to surgery and anesthesia between POD cases and non-POD controls, the enrichment analyses showed significant signals such as "immune response" and "T cell activation", which are same pathways previously identified from an independent non-surgical inpatient cohort.CONCLUSIONS: Our first genome-wide DNAm investigation of POD showed promising signals related to immune response, inflammatory response and other relevant signals considered to be associated with delirium pathophysiology. Our data supports the hypothesis that epigenetics are playing an important role in pathophysiological mechanism of delirium and suggest the potential usefulness of epigenetics based biomarker of POD. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/pcn.13495

  View details for PubMedID 36266784

• DNA methylation in the inflammatory genes after neurosurgery and diagnostic ability of post-operative delirium. Translational psychiatry Yamanashi, T., Nagao, T., Wahba, N. E., Marra, P. S., Crutchley, K. J., Meyer, A. A., Andreasen, A. J., Hellman, M. M., Jellison, S. S., Hughes, C. G., Pandharipande, P. P., Howard Iii, M. A., Kawasaki, H., Iwata, M., Hefti, M. M., Shinozaki, G. 2021; 11 (1): 627

  Abstract

  The pathophysiological mechanisms of postoperative delirium (POD) are still not clear, and no reliable biomarker is available to differentiate those with and without POD. Pre- and post-surgery blood from epilepsy subjects undergoing neurosurgery were collected. DNA methylation (DNAm) levels of the TNF gene, IL1B gene, and IL6 gene by the Illumina EPIC array method, and DNAm levels of the TNF gene by pyrosequencing, were analyzed. Blood from 37 subjects were analyzed by the EPIC array method, and blood from 27 subjects were analyzed by pyrosequencing. Several CpGs in the TNF gene in preoperative blood showed a negative correlation between their DNAm and age both in the POD group and in the non-POD group. However, these negative correlations were observed only in the POD group after neurosurgery. Neurosurgery significantly altered DNAm levels at 17 out of 24 CpG sites on the TNF gene, 8 out of 14 CpG sites on the IL1B gene, and 4 out of 14 CpG sites on the IL6 gene. Furthermore, it was found that the Inflammatory Methylation Index (IMI), which was based on the post-surgery DNAm levels at the selected five CpG sites, can be a potential detection tool for delirium with moderate accuracy; area under the curve (AUC) value was 0.84. The moderate accuracy of this IMI was replicated using another cohort from our previous study, in which the AUC was 0.79. Our findings provide further evidence of the potential role of epigenetics and inflammation in the pathophysiology of delirium.

  View details for DOI 10.1038/s41398-021-01752-6

  View details for PubMedID 34887385

• Evaluation of point-of-care thumb-size bispectral electroencephalography device to quantify delirium severity and predict mortality. The British journal of psychiatry : the journal of mental science Yamanashi, T., Crutchley, K. J., Wahba, N. E., Sullivan, E. J., Comp, K. R., Kajitani, M., Tran, T., Modukuri, M. V., Marra, P. S., Herrmann, F. M., Chang, G., Anderson, Z. M., Iwata, M., Kobayashi, K., Kaneko, K., Umeda, Y., Kadooka, Y., Lee, S., Shinozaki, E., Karam, M. D., Noiseux, N. O., Shinozaki, G. 1800: 1-8

  Abstract

  BACKGROUND: We have developed the bispectral electroencephalography (BSEEG) method for detection of delirium and prediction of poor outcomes.AIMS: To improve the BSEEG method by introducing a new EEG device.METHOD: In a prospective cohort study, EEG data were obtained and BSEEG scores were calculated. BSEEG scores were filtered on the basis of standard deviation (s.d.) values to exclude signals with high noise. Both non-filtered and s.d.-filtered BSEEG scores were analysed. BSEEG scores were compared with the results of three delirium screening scales: the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), the Delirium Rating Scale-Revised-98 (DRS) and the Delirium Observation Screening Scale (DOSS). Additionally, the 365-day mortalities and the length of stay (LOS) in the hospital were analysed.RESULTS: We enrolled 279 elderly participants and obtained 620 BSEEG recordings; 142 participants were categorised as BSEEG-positive, reflecting slower EEG activity. BSEEG scores were higher in the CAM-ICU-positive group than in the CAM-ICU-negative group. There were significant correlations between BSEEG scores and scores on the DRS and the DOSS. The mortality rate of the BSEEG-positive group was significantly higher than that of the BSEEG-negative group. The LOS of the BSEEG-positive group was longer compared with that of the BSEEG-negative group. BSEEG scores after s.d. filtering showed stronger correlations with delirium screening scores and more significant prediction of mortality.CONCLUSIONS: We confirmed the usefulness of the BSEEG method for detection of delirium and of delirium severity, and prediction of patient outcomes with a new EEG device.

  View details for DOI 10.1192/bjp.2021.101

  View details for PubMedID 35049468

• Mortality prediction by bispectral electroencephalography among 502 patients: its role in dementia. Brain communications Saito, T., Malicoat, J. R., Leyden, L. R., Williams, J. C., Jellison, S. S., Long, H., Hellman, M. M., Crutchley, K. J., Anderson, Z. E., Lo, D., Modukuri, M. V., Schacher, C. J., Yoshino, A., Toda, H., Shinozaki, E., Cho, H. R., Lee, S., Shinozaki, G. 2021; 3 (2): fcab037

  Abstract

  Complications of delirium and dementia increase mortality; however, it is difficult to diagnose delirium accurately, especially among dementia patients. The bispectral electroencephalography score can detect delirium and predict mortality in elderly patients. We aimed to develop an efficient and reliable bispectral electroencephalography device for high-throughput screening. We also hypothesized that bispectral electroencephalography score can predict mortality among dementia patients. A prospective cohort study was conducted between January 2016 and December 2018 to measure bispectral electroencephalography from elderly patients and correlate with outcomes. A total of 502 elderly (55 years old or older) patients with and without dementia were enrolled. For a replication of the utility of bispectral electroencephalography, mortalities between bispectral electroencephalography-positive and bispectral electroencephalography-negative group were compared. In addition, patients with and without dementia status were added to examine the utility of bispectral electroencephalography among dementia patients. The mortality within 180 days in the bispectral electroencephalography-positive group was higher than that of the bispectral electroencephalography-negative group in both the replication and the total cohorts. Mortality of those in the bispectral electroencephalography-positive group showed a dose-dependent increase in both cohorts. When the dementia patients showed bispectral electroencephalography positive, their mortality was significantly higher than those with dementia but who were bispectral electroencephalography-negative. Mortality within 30 days in the bispectral electroencephalography-positive group was significantly higher than that of the bispectral electroencephalography-negative group. The utility of the bispectral electroencephalography to predict mortality among large sample of 502 elderly patients was shown. The bispectral electroencephalography score can predict mortality among elderly patients in general, and even among dementia patients, as soon as 30 days.

  View details for DOI 10.1093/braincomms/fcab037

  View details for PubMedID 34136808

  View details for PubMedCentralID PMC8204260

• Topological data analysis (TDA) enhances bispectral EEG (BSEEG) algorithm for detection of delirium. Scientific reports Yamanashi, T., Kajitani, M., Iwata, M., Crutchley, K. J., Marra, P., Malicoat, J. R., Williams, J. C., Leyden, L. R., Long, H., Lo, D., Schacher, C. J., Hiraoka, K., Tsunoda, T., Kobayashi, K., Ikai, Y., Kaneko, K., Umeda, Y., Kadooka, Y., Shinozaki, G. 2021; 11 (1): 304

  Abstract

  Current methods for screening and detecting delirium are not practical in clinical settings. We previously showed that a simplified EEG with bispectral electroencephalography (BSEEG) algorithm can detect delirium in elderly inpatients. In this study, we performed a post-hoc BSEEG data analysis using larger sample size and performed topological data analysis to improve the BSEEG method. Data from 274 subjects included in the previous study were analyzed as a 1st cohort. Subjects were enrolled at the University of Iowa Hospitals and Clinics (UIHC) between January 30, 2016, and October 30, 2017. A second cohort with 265 subjects was recruited between January 16, 2019, and August 19, 2019. The BSEEG score was calculated as a power ratio between low frequency to high frequency using our newly developed algorithm. Additionally, Topological data analysis (TDA) score was calculated by applying TDA to our EEG data. The BSEEG score and TDA score were compared between those patients with delirium and without delirium. Among the 274 subjects from the first cohort, 102 were categorized as delirious. Among the 206 subjects from the second cohort, 42 were categorized as delirious. The areas under the curve (AUCs) based on BSEEG score were 0.72 (1st cohort, Fp1-A1), 0.76 (1st cohort, Fp2-A2), and 0.67 (2nd cohort). AUCs from TDA were much higher at 0.82 (1st cohort, Fp1-A1), 0.84 (1st cohort, Fp2-A2), and 0.78 (2nd cohort). When sensitivity was set to be 0.80, the TDA drastically improved specificity to 0.66 (1st cohort, Fp1-A1), 0.72 (1st cohort, Fp2-A2), and 0.62 (2nd cohort), compared to 0.48 (1st cohort, Fp1-A1), 0.54 (1st cohort, Fp2-A2), and 0.46 (2nd cohort) with BSEEG. BSEEG has the potential to detect delirium, and TDA is helpful to improve the performance.

  View details for DOI 10.1038/s41598-020-79391-y

  View details for PubMedID 33431928

  View details for PubMedCentralID PMC7801387

• Bispectral EEG (BSEEG) quantifying neuro-inflammation in mice induced by systemic inflammation: A potential mouse model of delirium. Journal of psychiatric research Yamanashi, T., Malicoat, J. R., Steffen, K. T., Zarei, K., Li, R., Purnell, B. S., Najafi, A., Saito, K., Singh, U., Toth, B. A., Lee, S., Dailey, M. E., Cui, H., Kaneko, K., Cho, H. R., Iwata, M., Buchanan, G. F., Shinozaki, G. 2021; 133: 205-211

  Abstract

  Most of the animal studies using inflammation-induced cognitive change have relied on behavioral testing without objective and biologically solid methods to quantify the severity of cognitive disturbances. We have developed a bispectral EEG (BSEEG) method using a novel algorithm in clinical study. This method effectively differentiates between patients with and without delirium, and predict long-term mortality. In the present study, we aimed to apply our bispectral EEG (BSEEG) method, which can detect patients with delirium, to a mouse model of delirium with systemic inflammation induced by lipopolysaccharides (LPS) injection. We recorded EEG after LPS injection using wildtype early adulthood mice (2~3-month-old) and aged mice (18-19-month-old). Animal EEG recordings were converted for power spectral density to calculate BSEEG score using the similar BSEEG algorithm previously developed for our human study. The BSEEG score was relatively stable and slightly high during the day. Alternatively, the BSEEG score was erratic and low in average during the night. LPS injection increased the BSEEG score dose-dependently and diminished the diurnal changes. The mean BSEEG score increased much more in the aged mice group as dosage increased. Our results suggest that BSEEG method can objectively "quantify" level of neuro-Inflammation induced by systemic inflammation (LPS), and that this BSEEG method can be useful as a model of delirium in mice.

  View details for DOI 10.1016/j.jpsychires.2020.12.036

  View details for PubMedID 33360427

• New Cutoff Scores for Delirium Screening Tools to Predict Patient Mortality. Journal of the American Geriatrics Society Yamanashi, T., Iwata, M., Crutchley, K. J., Sullivan, E. J., Malicoat, J. R., Anderson, Z. M., Marra, P. S., Chang, G., Kaneko, K., Shinozaki, E., Lee, S., Shinozaki, G. 2021; 69 (1): 140-147

  Abstract

  Detecting delirium is important to identify patients with a high risk of poor outcomes. Although many different kinds of screening instruments for delirium exist, there is no solid consensus about which methods are the most effective. In addition, it is important to find the most useful tools in predicting outcomes such as mortality.Retrospective cohort study.University of Iowa Hospitals and Clinics.A total of 1,125 adult inpatients (mean age = 67.7; median age = 69).Post hoc analyses were performed based on existing data from the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), Delirium Rating Scale-Revised-98 (DRS), and the Delirium Observation Screening Scale (DOSS). Correlation among these scales and relationships between 365-day mortality and each scale were evaluated.A positive result on the CAM-ICU ("CAM-ICU positive") was associated with higher DRS and DOSS scores. A DRS score = 9/10 was the best cutoff to detect CAM-ICU positive, and DOSS = 2/3 was the best cutoff to detect CAM-ICU positive. CAM-ICU positive was associated with high 365-day mortality. DRS score = 9/10 and DOSS score = 0/1 were found to differentiate mortality risk the most significantly. Higher DRS and DOSS scores significantly coincided with a decrease in a patient's survival rate at 365 days.The best DRS and DOSS cutoff scores to differentiate 365-day mortality risk were lower than those commonly used to detect delirium in the literature. New cutoff scores for the DRS and DOSS might be useful in differentiating risk of mortality among hospital patients.

  View details for DOI 10.1111/jgs.16815

  View details for PubMedID 32905636

• Epigenetics of neuroinflammation: Immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients. Journal of psychiatric research Saito, T., Toda, H., Duncan, G. N., Jellison, S. S., Yu, T., Klisares, M. J., Daniel, S., Andreasen, A. J., Leyden, L. R., Hellman, M. M., Shinozaki, E., Lee, S., Yoshino, A., Cho, H. R., Shinozaki, G. 2020; 129: 61-65

  Abstract

  Previously our study has shown that the DNA methylation (DNAm) levels at CpG sites in the pro-inflammatory cytokine gene, TNF-alpha, decrease along with aging, suggesting the potential role of DNAm in aging and heightened inflammatory process leading to increased risk for delirium. However, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, we examined genome-wide DNAm differences in blood between patients with delirium and controls to identify useful epigenetic biomarkers for delirium. Data from a total of 87 subjects (43 delirium cases) were analyzed by a genome-wide DNAm case-control association study. A genome-wide significant CpG site near the gene of LDLRAD4 was identified (p = 5.07E-8). In addition, over-representation analysis showed several significant pathways with a false discovery rate adjusted p-value < 0.05. The top pathway with a Gene Ontology term was immune response, and the second top pathway with a Kyoto Encyclopedia of Genes and Genomes term was cholinergic synapse. Significant DNAm differences related to immune/inflammatory response were shown both at gene and pathway levels between patients with delirium and non-delirium controls. This finding indicates that DNAm status in blood has the potential to be used as epigenetic biomarkers for delirium.

  View details for DOI 10.1016/j.jpsychires.2020.06.005

  View details for PubMedID 32590150

  View details for PubMedCentralID PMC7486988

• Identification of Patients With High Mortality Risk and Prediction of Outcomes in Delirium by Bispectral EEG. The Journal of clinical psychiatry Shinozaki, G., Bormann, N. L., Chan, A. C., Zarei, K., Sparr, N. A., Klisares, M. J., Jellison, S. S., Heinzman, J. T., Dahlstrom, E. B., Duncan, G. N., Gaul, L. N., Wanzek, R. J., Cramer, E. M., Wimmel, C. G., Sabbagh, S., Yuki, K., Weckmann, M. T., Yamada, T., Karam, M. D., Noiseux, N. O., Shinozaki, E., Cho, H. R., Lee, S., Cromwell, J. W. 2019; 80 (5)

  Abstract

  Delirium is common and dangerous, yet underdetected and undertreated. Current screening questionnaires are subjective and ineffectively implemented in busy hospital workflows. Electroencephalography (EEG) can objectively detect the diffuse slowing characteristic of delirium, but it is not suitable for high-throughput screening due to size, cost, and the expertise required for lead placement and interpretation. This study hypothesized that an efficient and reliable point-of-care EEG device for high-throughput screening could be developed.This prospective study, which measured bispectral EEG (BSEEG) from elderly inpatients to assess their outcomes, was conducted at the University of Iowa Hospitals and Clinics from January 2016 to October 2017. A BSEEG score was defined based on the distribution of 2,938 EEG recordings from the 428 subjects who were assessed for delirium; primary outcomes measured were hospital length of stay, discharge disposition, and mortality.A total of 274 patients had BSEEG score data available for analysis. Delirium and BSEEG score had a significant association (P < .001). Higher BSEEG scores were significantly correlated with length of stay (P < .001 unadjusted, P = .001 adjusted for age, sex, and Charlson Comorbidity Index [CCI] score) as well as with discharge not to home (P < .01). Hazard ratio for survival controlling for age, sex, CCI score, and delirium status was 1.35 (95% CI,1.04 to 1.76; P = .025).In BSEEG, an efficient and reliable device that provides an objective measurement of delirium status was developed. The BSEEG score is significantly associated with pertinent clinical outcomes of mortality, hospital length of stay, and discharge disposition. The BSEEG score better predicts mortality than does clinical delirium status. This study identified a previously unrecognized subpopulation of patients without clinical features of delirium who are at increased mortality risk.

  View details for DOI 10.4088/JCP.19m12749

  View details for PubMedID 31483958

  View details for PubMedCentralID PMC7181374

• Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Translational psychiatry Braun, P. R., Han, S., Hing, B., Nagahama, Y., Gaul, L. N., Heinzman, J. T., Grossbach, A. J., Close, L., Dlouhy, B. J., Howard, M. A., Kawasaki, H., Potash, J. B., Shinozaki, G. 2019; 9 (1): 47

  Abstract

  Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5-61 years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n = 12) and HumanMethylationEPIC BeadChip arrays (n = 21). For the EPIC methylation data averaged for each CpG across subjects, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.86) and buccal-brain (r = 0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.

  View details for DOI 10.1038/s41398-019-0376-y

  View details for PubMedID 30705257

  View details for PubMedCentralID PMC6355837

• Delirium detection by a novel bispectral electroencephalography device in general hospital PSYCHIATRY AND CLINICAL NEUROSCIENCES Shinozaki, G., Chan, A. C., Sparr, N. A., Zarei, K., Gaul, L. N., Heinzman, J. T., Robles, J., Yuki, K., Chronis, T. J., Ando, T., Wong, T., Sabbagh, S., Weckmann, M. T., Lee, S., Yamada, T., Karam, M. D., Noiseux, N. O., Shinozaki, E., Cromwell, J. W. 2018; 72 (12): 856–63

  Abstract

  Delirium is common and dangerous among elderly inpatients; yet, it is underdiagnosed and thus undertreated. This study aimed to test the diagnostic characteristics of a noninvasive point-of-care device with two-channel (bispectral) electroencephalography (EEG) for the screening of delirium in the hospital.Patients admitted to the University of Iowa Hospitals and Clinics were assessed for the presence of delirium with a clinical assessment, the Confusion Assessment Method for Intensive Care Unit and Delirium Rating Scale. Subsequently, we obtained a 10-min bispectral EEG (BSEEG) recording from a hand-held electroencephalogram device during hospitalization. We performed power spectral density analysis to differentiate between those patients with and without delirium.Initially 45 subjects were used as a test dataset to establish a cut-off. The BSEEG index was determined to be a significant indicator of delirium, with sensitivity 80% and specificity 87.7%. An additional independent validation dataset with 24 patients confirmed the validity of the approach, with a sensitivity of 83.3% and specificity of 83.3%.In this pilot study, the BSEEG method was able to distinguish delirious patients from non-delirious patients. Our data showed the feasibility of this technology for mass screening of delirium in the hospital.

  View details for PubMedID 30246448

• Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging. Frontiers in aging neuroscience Shinozaki, G., Braun, P. R., Hing, B. W., Ratanatharathorn, A., Klisares, M. J., Duncan, G. N., Jellison, S. S., Heinzman, J. T., Nagahama, Y., Close, L., Sabbagh, S., Dlouhy, B. J., Howard, M. A., Kawasaki, H., Cho, H. R. 2018; 10: 311

  Abstract

  Background: Delirium in elderly patients is common and dangerous. Major risk factors include aging and exogenous insults, such as infection or surgery. In animal models, aging enhances pro-inflammatory cytokine release from microglia in response to exogenous insults. The epigenetic mechanism DNA methylation (DNAm) regulates gene expression and changes with age. Older individuals may have methylation changes that influence the increased cytokine upon insult, but the degree to which aging affects DNAm of cytokine genes is not fully understood. Methods: The relationship between DNAm and aging of pro-inflammatory cytokine genes (TNF-alpha, IL1-beta, IL-6) was investigated using methylation array data in two cohorts. Brain and blood samples were collected from a neurosurgery cohort (NSG) of 21 subjects who underwent brain resection. A second cohort, the Grady Trauma Project (GTP), included blood samples from 265 subjects. Results: In the NSG cohort, a significant negative correlation between age and DNAm in brain was found at a CpG in IL-6. With the GTP dataset, significant negative correlations between age and DNAm were seen at most of the CpGs in TNF-alpha. Also, TNF-Alpha expression increases with age. These GTP DNAm correlations were also nominally significant in NSG blood samples. In neuronal negative NSG brain tissue, a similar negative trend was observed. Conclusions: With aging, a decrease in DNAm of cytokines gene CpGs in glia and blood was seen. As this can affect their expression, additional research is needed to fully elucidate the role of DNAm in aging and how it may influence the pathogenesis of delirium.

  View details for DOI 10.3389/fnagi.2018.00311

  View details for PubMedID 30405391

  View details for PubMedCentralID PMC6206747

• Relationship between FKBP5 polymorphisms and depression symptoms among kidney transplant recipients. Depression and anxiety Shinozaki, G., Jowsey, S., Amer, H., Biernacka, J., Colby, C., Walker, D., Black, J., Rundell, J., Stegall, M., Mrazek, D. A. 2011; 28 (12): 1111-8

  Abstract

  Several polymorphisms in FK506 Binding Protein gene (FKBP5) and a history of child abuse have been shown to be associated with an increased risk for posttraumatic stress disorder (PTSD). It has also been demonstrated that the same polymorphisms of FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. However, there are only limited numbers of studies replicating the polymorphisms as vulnerability factors for the development of mental illnesses, such as PTSD and depression after stressful life event, especially with a specific incidence, such as kidney transplant surgery.A retrospective analysis was conducted using the electronic medical records of 131 adult kidney transplant recipients. Depression severity after kidney transplantation was measured by PHQ-9, and stored blood was genotyped for variants in the Serotonin Transporter (SLC6A4), Brain-Derived Neurotrophic Factor, Catecholamine-O-Methyltransferase, Corticotropin-Releasing Hormone Receptor, and FKBP5 genes. Spearman correlations were used to test for association between genetic variants and depression severity.The rare alleles at three out of four SNPs in FKBP5 (rs1360780, rs9296158, and rs9470080) were associated with increased PHQ-9 scores (P<.05), whereas the last FKBP5 SNP (rs3800373) showed a trend of association (P<.10). All four FKBP5 SNPs are in strong linkage disequilibrium. Although in a subgroup of Caucasian non-Hispanic subjects the association was not statistically significant, the direction of association was consistent with that observed in the entire sample as well as in previous studies. Polymorphisms in genes other than FKBP5 were not associated with PHQ-9 scores.Polymorphisms in FKBP5 may be associated with higher depression scores in kidney transplant recipients.

  View details for DOI 10.1002/da.20879

  View details for PubMedID 22134958

• A new interaction between SLC6A4 variation and child abuse is associated with resting heart rate. Depression and anxiety Shinozaki, G., Romanowicz, M., Kung, S., Mrazek, D. A. 2011; 28 (3): 227-33

  Abstract

  The short form of the indel promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) and a history of child abuse have been reported to be associated with an increased risk for the development of depression. A child abuse history has also been associated with more rapid heart rate reactions.A retrospective chart review identified 282 patients with major depression who had been hospitalized and genotyped for the 5HTTLPR polymorphism. A subgroup of 185 females of European ancestry was also identified and analyzed. While hospitalized, heart rate was measured. Child abuse history was documented during the diagnostic evaluation. Analyses of the relationship between 5HTTLPR genotype, history of child abuse, and admission heart rate were conducted.No main effect on heart rate from the 5HTTLPR genotype or a child abuse history was demonstrated for the entire sample or the subgroup of female patients. However, a genotype-by-abuse interaction was associated with resting heart rate on admission to the hospital (P<.05). Depressed patients, who were homozygous for the long allele and who had been abused, had a heart rate on hospital admission, which was statistically higher than patients with the same genotype but who had not been abused. These findings were consistent both for the 282 patients (7.2 bpm higher) as well as for the subgroup of 185 female patients of European ancestry (9.6 bpm higher).A 5HTTLPR genotype interaction of elevated heart rate with a history of child abuse was demonstrated in depressed psychiatric inpatients.

  View details for DOI 10.1002/da.20779

  View details for PubMedID 21394855

• 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

• A web-based delirium detection application using bispectral electroencephalography (BSEEG). General hospital psychiatry Shimura, A., Seki, T., Nishiguchi, T., Yamanishi, K., Ishii, T., Aoyama, B., Nguyen, H. D., Gorantla, N., Inoue, T., Shinozaki, G. 2024

  View details for DOI 10.1016/j.genhosppsych.2024.07.005

  View details for PubMedID 39060191

• 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

• Correlation of telomere length in brain tissue with peripheral tissues in living human subjects. Frontiers in molecular neuroscience Carver, A. J., Hing, B., Elser, B. A., Lussier, S. J., Yamanashi, T., Howard, M. A., Kawasaki, H., Shinozaki, G., Stevens, H. E. 2024; 17: 1303974

  Abstract

  Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.

  View details for DOI 10.3389/fnmol.2024.1303974

  View details for PubMedID 38516039

• 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

• Anti-inflammatory medication use associated with reduced delirium risk and all-cause mortality: A retrospective cohort study. Journal of psychosomatic research Yamanashi, T., Sullivan, E. J., Comp, K. R., Nishizawa, Y., Akers, C. C., Chang, G., Modukuri, M., Tran, T., Anderson, Z. E., Marra, P. S., Crutchley, K. J., Wahba, N. E., Iwata, M., Karam, M. D., Noiseux, N. O., Cho, H. R., Shinozaki, G. 2023; 168: 111212

  Abstract

  To investigate the relationship between history of anti-inflammatory medication use and delirium risk, as well as long-term mortality.In this retrospective cohort study, subjects recruited between January 2016 and March 2020 were analyzed. Information about anti-inflammatory medication use history including aspirin, NSAIDs, glucosamine, and other anti-inflammatory drugs, was collected. Logistic regression analysis investigated the relationship between anti-inflammatory medications and delirium. Log-rank analysis and cox proportional hazards model investigated the relationship between anti-inflammatory medications and one-year mortality.The data from 1274 subjects were analyzed. The prevalence of delirium was significantly lower in subjects with NSAIDs usage (23.0%) than in those without NSAIDs usage (35.0%) (p < 0.001). Logistic regression analysis controlling for age, sex, dementia status, and hospitalization department showed that the risk of delirium tended to be reduced by a history of NSAIDs use (OR, 0.76 [95% CI, 0.55 to 1.03]). The one-year mortality in the subjects with NSAIDs (survival rate, 0.879 [95% CI, 0.845 to 0.906]) was significantly higher than in the subjects without NSAIDs (survival rate, 0.776 [95% CI, 0.746 to 0.803]) (p < 0.001). A history of NSAIDs use associated with the decreased risk of one-year mortality even after adjustment for age, sex, Charlson Comorbidity Index, delirium status, and hospitalization department (HR, 0.70 [95% CI, 0.51 to 0.96]).This study suggested that NSAIDs usage was associated with decreased delirium prevalence and lower one-year mortality. The potential benefit of NSAIDs on delirium risk and mortality were shown.

  View details for DOI 10.1016/j.jpsychores.2023.111212

  View details for PubMedID 36963165

• Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues. Translational psychiatry Nishitani, S., Isozaki, M., Yao, A., Higashino, Y., Yamauchi, T., Kidoguchi, M., Kawajiri, S., Tsunetoshi, K., Neish, H., Imoto, H., Arishima, H., Kodera, T., Fujisawa, T. X., Nomura, S., Kikuta, K., Shinozaki, G., Tomoda, A. 2023; 13 (1): 72

  Abstract

  Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13-73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva-brain correlation (r=0.90) was higher than that for blood-brain (r=0.87) and buccal-brain (r=0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, cross-database correlations of the correlation coefficients revealed a relatively low (brain vs. blood: r=0.27, saliva: r=0.18, and buccal: r=0.24). To the best of our knowledge, this is the fifth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.

  View details for DOI 10.1038/s41398-023-02370-0

  View details for PubMedID 36843037

• Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity. Aging Marra, P. S., Yamanashi, T., Crutchley, K. J., Wahba, N. E., Anderson, Z. M., Modukuri, M., Chang, G., Tran, T., Iwata, M., Cho, H. R., Shinozaki, G. 2023; 15

  Abstract

  BACKGROUND: Metformin, a commonly prescribed anti-diabetic medication, has repeatedly been shown to hinder aging in pre-clinical models and to be associated with lower mortality for humans. It is, however, not well understood how metformin can potentially prolong lifespan from a biological standpoint. We hypothesized that metformin's potential mechanism of action for longevity is through its epigenetic modifications.METHODS: To test our hypothesis, we conducted a post-hoc analysis of available genome-wide DNA methylation (DNAm) data obtained from whole blood collected from inpatients with and without a history of metformin use. We assessed the methylation profile of 171 patients (first run) and only among 63 diabetic patients (second run) and compared the DNAm rates between metformin users and nonusers.RESULTS: Enrichment analysis from the Kyoto Encyclopedia of Genes and Genome (KEGG) showed pathways relevant to metformin's mechanism of action, such as longevity, AMPK, and inflammatory pathways. We also identified several pathways related to delirium whose risk factor is aging. Moreover, top hits from the Gene Ontology (GO) included HIF-1alpha pathways. However, no individual CpG site showed genome-wide statistical significance (p < 5E-08).CONCLUSION: This study may elucidate metformin's potential role in longevity through epigenetic modifications and other possible mechanisms of action.

  View details for DOI 10.18632/aging.204498

  View details for PubMedID 36734879

• The potential benefit of metformin to reduce delirium risk and mortality: a retrospective cohort study. Aging Yamanashi, T., Anderson, Z. E., Modukuri, M., Chang, G., Tran, T., Marra, P. S., Wahba, N. E., Crutchley, K. J., Sullivan, E. J., Jellison, S. S., Comp, K. R., Akers, C. C., Meyer, A. A., Lee, S., Iwata, M., Cho, H. R., Shinozaki, E., Shinozaki, G. 2022; 14

  Abstract

  PURPOSE: Metformin has been reported to improve age-related disorders, including dementia, and to lower mortality. This study was conducted to investigate whether metformin use lower delirium risk, as well as long-term mortality.METHODS: In this retrospective cohort study, previously recruited 1,404 subjects were analyzed. The relationship between metformin use and delirium, and the relationship between metformin use and 3-year mortality were investigated.MAIN FINDINGS: 242 subjects were categorized into a type 2 diabetes mellitus (DM)-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for confounding factors. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for confounding factors (HR, 0.69 [95% CI, 0.48 to 0.98]).CONCLUSIONS: Metformin use may lower the risk of delirium and mortality in DM patients.

  View details for DOI 10.18632/aging.204393

  View details for PubMedID 36399107

• 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

• Clinical Markers Associated with Risk of Suicide or Drug Overdose Among Heavy Smokers - A Longitudinal Follow-Up Study of the COPDGene Cohort. Chest Adviento, B. A., Regan, E. A., Make, B. J., Han, M. K., Foreman, M. G., Iyer, A. S., Bhatt, S. P., Kim, V., Bon, J., Soler, X., Kinney, G. L., Hanania, N. A., Lowe, K. E., Holm, K. E., Yohannes, A. M., Shinozaki, G., Hoth, K. F., Fiedorowicz, J. G. 2022

  Abstract

  Studies have shown that chronic obstructive pulmonary disease (COPD) and smoking are associated with increased suicide risk. To date there are no prospective studies examining suicide risk among smokers along a spectrum of pulmonary disease ranging from completely normal spirometry to severe COPD.Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of heavy smokers within the COPDGene study?We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of current and former smokers. Primary cause of adjudicated deaths was identified using death certificates, family reports, and medical records. We examined time to death by suicide/overdose as the primary outcome in Cox regression adjusted for age, sex, race, BMI, pack-years, current smoking status, airflow limitation (%predicted FEV1), dyspnea (mMRC≥2), 6-minute walk distance, supplemental oxygen use, and severe exacerbations in the prior year with time varying covariates and other causes of death as a competing risk.The cohort was 47% female, 33% Black (67% White), had a mean (SD) age of 59.6 (9.0) years, and mean FEV1 %predicted of 76.1 (25.5). 63 individuals died by suicide/overdose. Factors associated with risk of suicide/overdose were current smoking (HR=6.44, 95% CI 2.64-15.67), use of sedative/hypnotics (HR=2.33, 95% CI 1.24-4.38), and dyspnea (HR=2.23, 95% CI 1.34-3.70). Lower risk of was associated with older age (per decade HR=0.45, 95% CI 0.31-0.67), higher BMI (HR=0.95, 95% CI 0.91-0.99), and African American race (HR=0.41, 95% CI 0.23-0.74). Severity of airflow limitation (FEV %predicted) was not associated with suicide risk.In this well-characterized cohort of current and former smokers with and without COPD, we identified risk factors for suicide/overdose that emphasize the subjective experience of illness over objective assessments of lung function.

  View details for DOI 10.1016/j.chest.2022.09.022

  View details for PubMedID 36167120

• Deep learning predicts DNA methylation regulatory variants in the human brain and elucidates the genetics of psychiatric disorders. Proceedings of the National Academy of Sciences of the United States of America Zhou, J., Chen, Q., Braun, P. R., Perzel Mandell, K. A., Jaffe, A. E., Tan, H. Y., Hyde, T. M., Kleinman, J. E., Potash, J. B., Shinozaki, G., Weinberger, D. R., Han, S. 2022; 119 (34): e2206069119

  Abstract

  There is growing evidence for the role of DNA methylation (DNAm) quantitative trait loci (mQTLs) in the genetics of complex traits, including psychiatric disorders. However, due to extensive linkage disequilibrium (LD) of the genome, it is challenging to identify causal genetic variations that drive DNAm levels by population-based genetic association studies. This limits the utility of mQTLs for fine-mapping risk loci underlying psychiatric disorders identified by genome-wide association studies (GWAS). Here we present INTERACT, a deep learning model that integrates convolutional neural networks with transformer, to predict effects of genetic variations on DNAm levels at CpG sites in the human brain. We show that INTERACT-derived DNAm regulatory variants are not confounded by LD, are concentrated in regulatory genomic regions in the human brain, and are convergent with mQTL evidence from genetic association analysis. We further demonstrate that predicted DNAm regulatory variants are enriched for heritability of brain-related traits and improve polygenic risk prediction for schizophrenia across diverse ancestry samples. Finally, we applied predicted DNAm regulatory variants for fine-mapping schizophrenia GWAS risk loci to identify potential novel risk genes. Our study shows the power of a deep learning approach to identify functional regulatory variants that may elucidate the genetic basis of complex traits.

  View details for DOI 10.1073/pnas.2206069119

  View details for PubMedID 35969790

• Mortality among patients with sepsis associated with a bispectral electroencephalography (BSEEG) score. Scientific reports Yamanashi, T., Marra, P. S., Crutchley, K. J., Wahba, N. E., Malicoat, J. R., Sullivan, E. J., Akers, C. C., Nicholson, C. A., Herrmann, F. M., Karam, M. D., Noiseux, N. O., Kaneko, K., Shinozaki, E., Iwata, M., Cho, H. R., Lee, S., Shinozaki, G. 2021; 11 (1): 14211

  Abstract

  We have previously developed a bispectral electroencephalography (BSEEG) device, which was shown to be effective in detecting delirium and predicting patient outcomes. In this study we aimed to apply the BSEEG approach for a sepsis. This was a retrospective cohort study conducted at a single center. Sepsis-positive cases were identified based on retrospective chart review. EEG raw data and calculated BSEEG scores were obtained in the previous studies. The relationship between BSEEG scores and sepsis was analyzed, as well as the relationship among sepsis, BSEEG score, and mortality. Data were analyzed from 628 patients. The BSEEG score from the first encounter (1st BSEEG) showed a significant difference between patients with and without sepsis (p=0.0062), although AUC was very small indicating that it isnot suitable for detection purpose. Sepsis patients with high BSEEG scores showed the highest mortality, and non-sepsis patients with low BSEEG scores showed the lowest mortality. Mortality of non-sepsis patients with high BSEEG scores was as bad as that of sepsis patients with low BSEEG scores. Even adjusting for age, gender, comorbidity, and sepsis status, BSEEG remained a significant predictor of mortality (p=0.008). These data are demonstrating its usefulness as a potential tool for identification of patients at high risk and management of sepsis.

  View details for DOI 10.1038/s41598-021-93588-9

  View details for PubMedID 34244577

• 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

• Increased mortality in patients with standard EEG findings of 'diffuse slowing'. Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists Wanzek, R., Bormann, N., Shabbir, Y., Saito, T., Yamada, T., Shinozaki, G. 2021; 33 (2): 93-100

  Abstract

  We aimed to confirm the association between slow brain wave activity typically described as "diffuse slowing" on standard electroencephalogram (EEG) and patient outcomes, including mortality.This retrospective study was conducted with patient chart data from March 2015 to March 2017 at a tertiary care academic hospital in the midwestern United States. In total, 1,069 participants age ≥55 years on an inpatient floor or ICU received a standard 24-hour EEG. The primary outcome was all-cause mortality at 30, 90, 180, and 365 days. Secondary outcomes were time to discharge, and discharge to home.Having diffuse slowing on standard EEG was significantly associated with 30-, 90-, 180-, and 365-day mortality compared with patients who had normal EEG findings, after controlling for age, sex, and Charlson Comorbidity Index score. When controlling for these factors, patients with diffuse slowing had a significantly longer time to discharge and were significantly less likely to discharge to home. Our findings showed that a standard EEG finding of diffuse slowing for inpatients age ≥55 years is associated with poor outcomes, including greater mortality.This study suggested that the finding of diffuse slowing on EEG may be an important clinical marker for predicting mortality in geriatric inpatients.

  View details for DOI 10.12788/acp.0018

  View details for PubMedID 33878283

• DNA methylation in the TNF-alpha gene decreases along with aging among delirium inpatients. Neurobiology of aging Yamanashi, T., Saito, T., Yu, T., Alario, A., Comp, K., Crutchley, K. J., Sullivan, E. J., Anderson, Z. M., Marra, P. S., Chang, G., Wahba, N. E., Jellison, S. S., Meyer, A. A., Mathur, S., Pandharipande, P., Yoshino, A., Kaneko, K., Lee, S., Toda, H., Iwata, M., Shinozaki, G. 2021; 105: 310-317

  Abstract

  It has been suggested that aging and inflammation play key roles in the development of delirium. In the present study, we investigated the differences of the DNAm patterns in the TNF gene between patients with delirium and without. The data and samples derived from previous and ongoing cohort studies were analyzed. DNAm levels of the TNF gene were analyzed using the Illumina EPIC array genome-wide method and pyrosequencing method. Correlations between age and DNAm levels of each CpG were calculated. Several CpG in the TNF gene in blood showed negative correlation between their DNAm and age in delirium cases both with the EPIC array and by the pyrosequencing method. However, there was no CpG that had significant correlation between their DNAm and age regardless of delirium status among buccal samples. On the other hand, among peripheral blood mononuclear cells samples, it was found that several CpG showed negative correlation between their DNAm and age in delirium cases. The evidence of DNAm change in the TNF gene among delirious subjects was demonstrated.

  View details for DOI 10.1016/j.neurobiolaging.2021.05.005

  View details for PubMedID 34192631

• Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model. Scientific reports Yamanashi, T., Iwata, M., Shibushita, M., Tsunetomi, K., Nagata, M., Kajitani, N., Miura, A., Matsuo, R., Nishiguchi, T., Kato, T. A., Setoyama, D., Shirayama, Y., Watanabe, K., Shinozaki, G., Kaneko, K. 2020; 10 (1): 21629

  Abstract

  Accumulating evidence suggests that elevated inflammation contributes to the pathophysiology of post-traumatic stress disorder (PTSD) and that anti-inflammatory drugs might be a new treatment strategy for PTSD. It has been reported that beta-hydroxybutyrate (BHB), one of the main ketone bodies produced, can have an anti-inflammatory and antidepressant effect. Here, we investigated the potential anti-anxiety and anti-inflammatory effects of BHB using a rodent PTSD model, induced by single prolonged stress (SPS). Male, Sprague-Dawley rats were employed in this study. Repeated administration of BHB attenuated SPS-induced anxiety-related behaviors evaluated by the elevated plus maze test. SPS increased the serum levels of TNF-α and IL-1β. In contrast, BHB administration partially attenuated the increase of serum TNF-α. These findings demonstrate that BHB exerts its anxiolytic effects, possibly by inhibiting systemic TNF-α. Hence, BHB may be a novel therapeutic candidate for the treatment of PTSD.

  View details for DOI 10.1038/s41598-020-78410-2

  View details for PubMedID 33303808

  View details for PubMedCentralID PMC7728809

• Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR. Nature communications Smith, A. K., Ratanatharathorn, A., Maihofer, A. X., Naviaux, R. K., Aiello, A. E., Amstadter, A. B., Ashley-Koch, A. E., Baker, D. G., Beckham, J. C., Boks, M. P., Bromet, E., Dennis, M., Galea, S., Garrett, M. E., Geuze, E., Guffanti, G., Hauser, M. A., Katrinli, S., Kilaru, V., Kessler, R. C., Kimbrel, N. A., Koenen, K. C., Kuan, P. F., Li, K., Logue, M. W., Lori, A., Luft, B. J., Miller, M. W., Naviaux, J. C., Nugent, N. R., Qin, X., Ressler, K. J., Risbrough, V. B., Rutten, B. P., Stein, M. B., Ursano, R. J., Vermetten, E., Vinkers, C. H., Wang, L., Youssef, N. A., Uddin, M., Nievergelt, C. M. 2020; 11 (1): 5965

  Abstract

  Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

  View details for DOI 10.1038/s41467-020-19615-x

  View details for PubMedID 33235198

  View details for PubMedCentralID PMC7686485

• The relationship between DNA methylation in neurotrophic genes and age as evidenced from three independent cohorts: differences by delirium status. Neurobiology of aging Saito, T., Braun, P. R., Daniel, S., Jellison, S. S., Hellman, M., Shinozaki, E., Lee, S., Cho, H. R., Yoshino, A., Toda, H., Shinozaki, G. 2020; 94: 227-235

  Abstract

  We previously reported the association between DNA methylation (DNAm) of pro-inflammatory cytokine genes and age. In addition, neurotrophic factors are known to be associated with age and neurocognitive disorders. Therefore, we hypothesized that DNAm of neurotrophic genes change with age, especially in delirium patients. DNAm was analyzed using the Illumina HumanMethylation450 or HumanMethylationEPIC BeadChip Kit in 3 independent cohorts: blood from 383 Grady Trauma Project subjects, brain from 21 neurosurgery patients, and blood from 87 inpatients with and without delirium. Both blood and brain samples showed that most of the DNAm of neurotrophic genes were positively correlated with age. Furthermore, DNAm of neurotrophic genes was more positively correlated with age in delirium cases than in non-delirium controls. These findings support our hypothesis that the neurotrophic genes may be epigenetically modulated with age, and this process may be contributing to the pathophysiology of delirium.

  View details for DOI 10.1016/j.neurobiolaging.2020.06.003

  View details for PubMedID 32650186

  View details for PubMedCentralID PMC7444651

• Effect of interaction between a specific subtype of child abuse and the FKBP5 rs1360780 SNP on DNA methylation among patients with bipolar disorder. Journal of affective disorders Saito, T., Shinozaki, G., Koga, M., Tanichi, M., Takeshita, S., Nakagawa, R., Nagamine, M., Cho, H. R., Morimoto, Y., Kobayashi, Y., Yoshino, A., Toda, H. 2020; 272: 417-422

  Abstract

  Child abuse is a risk factor for mood disorders, and linked to decreased DNA methylation (DNAm) of FKBP5 intron 7 through interactions with the single nucleotide polymorphism (SNP) rs1360780. However, no study has investigated which specific subtypes of child abuse are related to decreased DNAm of FKBP5 intron 7 in mood disorders. We therefore aimed to examine the relationship among various subtypes of child abuse, rs1360780, and the DNAm level of FKBP5 intron 7.A total of 190 subjects (87 patients with major depressive disorder [MDD], 61 patients with bipolar disorder [BD], and 42 healthy controls) participated. The Child Abuse and Trauma Scale (CATS) was used to evaluate child abuse. Whole blood was processed for genotyping, and pyrosequencing was conducted to assess the DNAm level of FKBP5 intron 7. A multiple regression analysis was used to analyze the DNAm level as a dependent variable, and the CATS subtypes and rs1360780 were used as independent variables.Emotional abuse/neglect, one of the specific subtypes of child abuse, was related to lower DNAm of FKBP5 intron 7 interacting with rs1360780 in the BD patients. There were no significant results in the MDD patients or the controls.Since the study was limited to Japanese individuals, particularly those with MDD and BD, the findings are not generalizable. Furthermore, as child abuse was measured retrospectively, there may be recall bias.This finding indicates that a specific subtype of child abuse may play an important role in the development of BD.

  View details for DOI 10.1016/j.jad.2020.03.120

  View details for PubMedID 32553385

• Bispectral EEG (BSEEG) to assess arousal after electro-convulsive therapy (ECT). Psychiatry research Zarei, K., Sparr, N. A., Trapp, N. T., Neuhaus, E. D., Cromwell, J. W., Boes, A. D., Shinozaki, G. 2020; 285: 112811

  Abstract

  Postictal confusion is encountered among most patients following electro-convulsive therapy (ECT). This study aimed to test the capabilities of a point-of-care electroencephalography (EEG) method to quantitatively measure and monitor postictal confusion immediately following ECT. We evaluated whether a two-channel frontal EEG device may provide a purely quantitative measure of the postictal state that could aid in the continuous, clinical monitoring of patients following ECT.50 patients receiving ECT at the University of Iowa Hospitals and Clinics were recruited for this study. Subsequently, we obtained 5 min of frontal bispectral EEG (BSEEG) recording from a hand-held EEG device at baseline and 10-20 min following ECT. We performed power spectral density analysis to yield a "BSEEG" score and to capture the difference between patients at baseline and after ECT.The BSEEG score was demonstrated to be a significant indicator of postictal confusion compared to baseline. For 5 patients, we also obtained continuous EEG recordings following ECT to determine the time course required for a patient's BSEEG score to return to baseline. In this subset of patients, it took between 2 and 3 h in duration for the BSEEG score to return to the baseline range.In this pilot study, we showed that BSEEG score was able to distinguish between baseline condition and postictal confusion in patients treated with ECT, and assess the duration for recovery from postictal confusion following ECT. BSEEG may provide a more sensitive measure of arousal in patients following ECT compared to traditional survey-based methods.

  View details for DOI 10.1016/j.psychres.2020.112811

  View details for PubMedID 32032823

  View details for PubMedCentralID PMC7605101

• Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples. Psychiatry and clinical neurosciences Braun, P. R., Tanaka-Sahker, M., Chan, A. C., Jellison, S. S., Klisares, M. J., Hing, B. W., Shabbir, Y., Gaul, L. N., Nagahama, Y., Robles, J., Heinzman, J. T., Sabbagh, S., Cramer, E. M., Duncan, G. N., Yuki, K., Close, L. N., Dlouhy, B. J., Howard, M. A., Kawasaki, H., Stein, K. M., Potash, J. B., Shinozaki, G. 2019; 73 (6): 323-330

  Abstract

  Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed.Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array.Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways.High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.

  View details for DOI 10.1111/pcn.12835

  View details for PubMedID 30821055

  View details for PubMedCentralID PMC6561812

• The point-of-care EEG for delirium detection in the emergency department. The American journal of emergency medicine Lee, S., Yuki, K., Chan, A., Cromwell, J., Shinozaki, G. 2019; 37 (5): 995-996

  View details for DOI 10.1016/j.ajem.2018.10.004

  View details for PubMedID 30340987

• Symptoms of anxiety and depression and use of anxiolytic-hypnotics and antidepressants in current and former smokers with and without COPD - A cross sectional analysis of the COPDGene cohort. Journal of psychosomatic research Iyer, A. S., Holm, K. E., Bhatt, S. P., Kim, V., Kinney, G. L., Wamboldt, F. S., Jacobs, M. R., Regan, E. A., Armstrong, H. F., Lowe, K. E., Martinez, C. H., Dransfield, M. T., Foreman, M. G., Shinozaki, G., Hanania, N. A., Wise, R. A., Make, B. J., Hoth, K. F. 2019; 118: 18-26

  Abstract

  To compare the frequency of anxiety/depressive symptoms and use of anxiolytic-hypnotics/antidepressants in smokers with and without COPD and to identify characteristics associated with having unmedicated symptoms.Cross-sectional analysis of ambulatory, current/former smokers ≥10 pack years enrolled in the COPDGene study. We measured anxiety/depressive symptoms using the Hospital Anxiety and Depression Scale (subscales ≥8), recorded anxiolytic-hypnotic/antidepressant use, and defined unmedicated symptoms as elevated anxiety/depressive symptoms and not on medications. Regression analysis identified characteristics associated with having unmedicated symptoms.Of 5331 current/former smokers (45% with and 55% without COPD), 1332 (25.0%) had anxiety/depressive symptoms. Anxiety symptoms were similar in frequency in smokers with and without COPD (19.7% overall), while depressive symptoms were most frequent in severe-very severe COPD at 20.7% (13.1% overall). In the entire cohort, 1135 (21.2%) were on medications. Anxiolytic-hypnotic use was highest in severe-very severe COPD (range 7.6%-12.0%), while antidepressant use showed no significant variation in smokers with and without COPD (range 14.7%-17.1%). Overall, 881 (66% of those with symptoms) had unmedicated symptoms, which was associated with African American race (adjusted OR 2.95, 95% CI 2.25-3.87), male gender (adjusted OR 1.93, 95% CI 1.57-2.36), no health insurance (adjusted OR 2.38, 95% CI 1.30-4.35), severe-very severe COPD (adjusted OR 1.48, 95% CI 1.04-2.11), and higher respiratory symptoms/exacerbation history (adjusted OR 2.21, 95% CI 1.62-3.02).Significant unmet mental health care needs exist in current and former smokers with and without COPD. One in five have unmedicated symptoms, identified by key demographic and clinical characteristics.National Institutes of Health and The COPD Foundation.

  View details for DOI 10.1016/j.jpsychores.2019.01.002

  View details for PubMedID 30782350

  View details for PubMedCentralID PMC6383809

• Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure. Journal of affective disorders Ahmed, A. T., Biernacka, J. M., Jenkins, G., Rush, A. J., Shinozaki, G., Veldic, M., Kung, S., Bobo, W. V., Hall-Flavin, D. K., Weinshilboum, R. M., Wang, L., Frye, M. A. 2019; 246: 62-68

  Abstract

  The purpose of this study was to identify specific pharmacokinetic (PK) and pharmacodynamics (PD) factors that affect the likelihood of treatment remission with a serotonin norepinephrine reuptake inhibitor (SNRI) in depressed patients whose initial selective serotonin reuptake inhibitor (SSRI) failed.Multiple logistic regression modeling of PK and PD variation hypothesized to contribute to SNRI (i.e. duloxetine or venlafaxine) treatment remission in prior SSRI (i.e. citalopram or escitalopram) failure was conducted on 139 subjects from the Pharmacogenomics Research Network (PGRN) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies. Depressive symptoms were assessed with the Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C16).Venlafaxine-XR remission was associated with a significant interaction between CYP2D6 ultra-rapid metabolizer (URM) phenotype and SLC6A4 5-HTTLPR L/L genotype. A similar significant interaction effect was observed between CYP2D6 URM and SLC6A2 G1287A GA genotype. Stratifying by transporter genotypes, venlafaxine-XR remission was associated with CYP2D6 URM in patients with SLC6A4 L/L (p = 0.001) and SLC6A2 G1287A GA genotypes.The primary limitation of this post hoc study was small sample size.Our results suggest that CYP2D6 ultra-rapid metabolizer status contributes to venlafaxine-XR treatment remission in MDD patients; in particular, there is a PK-PD interaction with treatment remission associated with CYP2D6 URM phenotype and SLC6A4 5-HTTLPR L/L or SLC6A2 G1287A G/A genotype, respectively. These preliminary data are encouraging and support larger pharmacogenomics studies differentiating treatment response to mechanistically different antidepressants in addition to further PK-PD interactive analyses.

  View details for DOI 10.1016/j.jad.2018.12.021

  View details for PubMedID 30578947

  View details for PubMedCentralID PMC6501809

• GWAS and systems biology analysis of depressive symptoms among smokers from the COPDGene cohort. Journal of affective disorders Heinzman, J. T., Hoth, K. F., Cho, M. H., Sakornsakolpat, P., Regan, E. A., Make, B. J., Kinney, G. L., Wamboldt, F. S., Holm, K. E., Bormann, N., Robles, J., Kim, V., Iyer, A. S., Silverman, E. K., Crapo, J. D., Han, S., Potash, J. B., Shinozaki, G. 2019; 243: 16-22

  Abstract

  Large sample GWAS is needed to identify genetic factors associated with depression. This study used genome-wide genotypic and phenotypic data from the COPDGene study to identify genetic risk factors for depression.Data were from 9716 COPDGene subjects with ≥10 pack-year history. Depression was defined as antidepressant use and/or a HADS depression subscale score ≥8. Non-Hispanic White (6576) and African-American (3140) subsets were analyzed. A GWAS pipeline identified SNPs associated with depression in each group. Network analysis software analyzed gene interactions through common biological pathways, genetic interactions, and tissue-specific gene expression.The mean age was 59.4 years (SD 9.0) with 46.5% female subjects. Depression was in 24.7% of the NHW group (1622) and 12.5% of the AA group (391). No SNPs had genome-wide significance. One of the top SNPs, rs12036147 (p = 1.28 × 10-6), is near CHRM3. Another SNP was near MDGA2 (rs17118176, p = 3.52 × 10-6). Top genes formed networks for synaptic transmission with a statistically significant level of more co-expression in brain than other tissues, particularly in the basal ganglia (p = 1.00 × 10-4).Limitations included a depression definition based on antidepressant use and a limited HADS score subgroup, which could increase false negatives in depressed patients not on antidepressants. Antidepressants used for smoking cessation in non-depressed patients could lead to false positives.Systems biology analysis identified statistically significant pathways whereby multiple genes influence depression. The gene set pathway analysis and COPDGene data can help investigate depression in future studies.

  View details for DOI 10.1016/j.jad.2018.09.003

  View details for PubMedID 30219690

  View details for PubMedCentralID PMC6186181

• Integrated Inpatient Medical and Psychiatric Care: Experiences of 5 Institutions. Annals of internal medicine Chan, A. C., Burke, C. A., Coffey, E. M., Hilden, D. R., Coira, D. L., Warner-Cohen, J., Grady, M., Muskin, P. R., Shinozaki, G. 2018; 168 (11): 815-817

  View details for DOI 10.7326/M17-3186

  View details for PubMedID 29710091

• Relationship of genetic variation in the serotonin transporter gene (SLC6A4) and congenital and acquired cardiovascular diseases. Genetic testing and molecular biomarkers Moyer, A. M., Walker, D. L., Avula, R., Lapid, M. I., Kung, S., Bryant, S. C., Edwards, K. K., Black, J. L., Karpyak, V. M., Shinozaki, G., Jowsey-Gregoire, S. G., Ehlers, S. L., Romanowicz, M., Litzow, M. R., Hogan, W. J., Rundell, J. R., Hooten, W. M., Baudhuin, L. M. 2015; 19 (3): 115-23

  Abstract

  Recent reports have suggested an association between variation in the serotonin transporter and primary pulmonary hypertension and myocardial infarction. We set out to determine whether these associations were present in a population of patients who underwent SLC6A4 genotyping and to explore whether genetic variation in the serotonin transporter might be also associated with other cardiovascular functional and structural abnormalities. Included were 3473 patients who were genotyped for the SLC6A4 5HTTLPR polymorphism and a subset for rs25531 (n=816) and STin2 (n=819). An association was observed between 5HTTLPR and primary pulmonary hypertension (p=0.0130), anomalies of the cerebrovascular system (p<0.0001), and other anomalies of great veins (p=0.0359). The combined 5HTTLPR and rs25531 genotype was associated with tachycardia (p=0.0123). There was an association of the STin2 genotype with abnormal electrocardiogram (ECG) (p=0.0366) and abnormal cardiac study (0.0311). Overall, these results represent a step toward the understanding of the impact of SLC6A4 variation on cardiovascular pathology.

  View details for DOI 10.1089/gtmb.2014.0250

  View details for PubMedID 25671637

• CYP2C19 variation, not citalopram dose nor serum level, is associated with QTc prolongation. Journal of psychopharmacology (Oxford, England) Kumar, Y., Kung, S., Shinozaki, G. 2014; 28 (12): 1143-8

  Abstract

  Recently, a FDA Safety Communication warned of a dose-dependent risk for QTc prolongation with citalopram, which is metabolized by CYP2C19 of the cytochrome P450 system. We investigate associations between citalopram and escitalopram dose, serum concentration, CYP2C19 phenotype, and QTc. We undertook a retrospective chart review of citalopram or escitalopram patients with the inclusion criteria of consistent medication dose, CYP2C19 phenotype (extensive metabolizers [EM], intermediate metabolizers [IM], poor metabolizers [PM]), and QTc interval on ECG. We further identified 42 citalopram users with citalopram serum concentration measurements and ECG. Regression and one-way ANOVA were used to examine the relationship between citalopram dose, citalopram serum concentration, CYP2C19 phenotype, and QTc interval. Of 75 citalopram patients, the EM group had significantly shorter QTc intervals than a combined IM+PM group (427.1±23.6 ms vs. 440.1±26.6 ms, one-tailed t-test, p=0.029). In the 80 escitalopram cohort, there was no significant difference in QTc between phenotype groups. There was no statistical correlation between citalopram (p=0.62) or escitalopram (p=0.30) dose and QTc. QTc was not associated with citalopram serum level (p=0.45). In contrast to the FDA warning, this study found no association between citalopram/escitalopram dose and QTc. However, PM of the drug tended to have longer QTc intervals. Our findings suggest cytochrome P450 genotyping in select patients may be helpful to guide medication optimization while limiting harmful effects.

  View details for DOI 10.1177/0269881114543720

  View details for PubMedID 25122046

• New developments in the genetics of bipolar disorder. Current psychiatry reports Shinozaki, G., Potash, J. B. 2014; 16 (11): 493

  Abstract

  The last several years have been breakthrough ones in bipolar disorder (BPD) genetics, as the field has identified robust risk variants for the first time. Leading the way have been genome-wide association studies (GWAS) that have assessed common genetic markers across very large groups of patients and controls. These have resulted in findings in genes including ANK3, CACNA1C, SYNE1, ODZ4, and TRANK1. Additional studies have begun to examine the biology of these genes and how risk variants influence aspects of brain and behavior that underlie BPD. For example, carriers of the CACNA1C risk variant have been found to exhibit hippocampal and anterior cingulate dysfunction during episodic memory recall. This work has shed additional light on the relationship of bipolar susceptibility variants to other disorders, particularly schizophrenia. Even larger BPD GWAS are expected with samples now amassed of 21,035 cases and 28,758 controls. Studies have examined the pharmacogenomics of BPD with studies of lithium response, yielding high profile results that remain to be confirmed. The next frontier in the field is the identification of rare bipolar susceptibility variants through large-scale DNA sequencing. While only a couple of papers have been published to date, many studies are underway. The Bipolar Sequencing Consortium has been formed to bring together all of the groups working in this area, and to perform meta-analyses of the data generated. The consortium, with 13 member groups, now has exome data on ~3,500 cases and ~5,000 controls, and on ~162 families. The focus will likely shift within several years from exome data to whole genome data as costs of obtaining such data continue to drop. Gene-mapping studies are now providing clear results that provide insights into the pathophysiology of the disorder. Sequencing studies should extend this process further. Findings could eventually set the stage for rational therapeutic development.

  View details for DOI 10.1007/s11920-014-0493-5

  View details for PubMedID 25194313

• Biological pathways, candidate genes, and molecular markers associated with quality-of-life domains: an update. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation Sprangers, M. A., Thong, M. S., Bartels, M., Barsevick, A., Ordoñana, J., Shi, Q., Wang, X. S., Klepstad, P., Wierenga, E. A., Singh, J. A., Sloan, J. A. 2014; 23 (7): 1997-2013

  Abstract

  There is compelling evidence of a genetic foundation of patient-reported quality of life (QOL). Given the rapid development of substantial scientific advances in this area of research, the current paper updates and extends reviews published in 2010.The objective was to provide an updated overview of the biological pathways, candidate genes, and molecular markers involved in fatigue, pain, negative (depressed mood) and positive (well-being/happiness) emotional functioning, social functioning, and overall QOL.We followed a purposeful search algorithm of existing literature to capture empirical papers investigating the relationship between biological pathways and molecular markers and the identified QOL domains.Multiple major pathways are involved in each QOL domain. The inflammatory pathway has the strongest evidence as a controlling mechanism underlying fatigue. Inflammation and neurotransmission are key processes involved in pain perception, and the catechol-O-methyltransferase (COMT) gene is associated with multiple sorts of pain. The neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depression. Oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways play a role in social functioning. Inflammatory pathways, via cytokines, also play an important role in overall QOL.Whereas the current findings need future experiments and replication efforts, they will provide researchers supportive background information when embarking on studies relating candidate genes and/or molecular markers to QOL domains. The ultimate goal of this area of research is to enhance patients' QOL.

  View details for DOI 10.1007/s11136-014-0656-1

  View details for PubMedID 24604075

  View details for PubMedCentralID PMC4199387

• Treatment outcomes of depression: the pharmacogenomic research network antidepressant medication pharmacogenomic study. Journal of clinical psychopharmacology Mrazek, D. A., Biernacka, J. M., McAlpine, D. E., Benitez, J., Karpyak, V. M., Williams, M. D., Hall-Flavin, D. K., Netzel, P. J., Passov, V., Rohland, B. M., Shinozaki, G., Hoberg, A. A., Snyder, K. A., Drews, M. S., Skime, M. K., Sagen, J. A., Schaid, D. J., Weinshilboum, R., Katzelnick, D. J. 2014; 34 (3): 313-7

  Abstract

  The effectiveness of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD) is controversial.The clinical outcomes of subjects with nonpsychotic MDD were reported and compared with the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study outcomes to provide guidance on the effectiveness of SSRIs.Subjects were treated with citalopram/escitalopram for up to 8 weeks. Depression was measured using the Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) and the 17-item Hamilton Depression Rating Scale.The group of subjects with at least 1 follow-up visit had a remission (QIDS-C16 ≤ 5) rate of 45.8% as well as a response (50% reduction in QIDS-C16) rate of 64.8%, and 79.9% achieved an improvement of 5 points or higher in QIDS-C16 score. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study subjects were more likely to achieve a response than STAR*D study subjects. After adjustment for demographic factors, the response rates were not significantly different. When reporting the adverse effect burden, 60.5% of the subjects reported no impairment, 31.7% reported a minimal-to-mild impairment, and 7.8% reported a moderate-to-severe burden at the 4-week visit.Patients contemplating initiating an SSRI to treat their MDD can anticipate a high probability of symptom improvement (79.9%) with a low probability that their symptoms will become worse. Patients with lower baseline severity have a higher probability of achieving remission. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study replicates many findings of the first phase of the STAR*D study after controlling for the differences between the studies.

  View details for DOI 10.1097/JCP.0000000000000099

  View details for PubMedID 24743713

  View details for PubMedCentralID PMC3992481

• Does 5HTTLPR long allele prevent hospitalization? Test of Hardy-Weinberg equilibrium. Psychiatric genetics Shinozaki, G., Kung, S., Mrazek, D. A. 2014; 24 (1): 34-6

  Abstract

  Many studies suggest an association of the serotonin transporter gene polymorphism (5HTTLPR) long allele with better antidepressant treatment response than the short allele. However, there is controversy over these findings. We hypothesized that if the long allele is associated with a better outcome, we would find fewer inpatients with the long allele compared with the short allele. Chart review identified 925 depressed inpatients and 201 outpatients genotyped for 5HTTLPR. The sample was primarily White (>90%). We tested potential departures from Hardy-Weinberg equilibrium for each sample. We analyzed three independent sets of inpatient samples separately and combined, a White subgroup of 791 patients of the total 925 inpatients, and 201 outpatients. There was no departure from Hardy-Weinberg equilibrium with any of these samples. We also compared 5HTTLPR genotype prevalence between 925 inpatients and 201 outpatients, which showed no statistically significant difference.

  View details for DOI 10.1097/YPG.0000000000000024

  View details for PubMedID 24300662

• "Diminished" association between the serotonin transporter linked polymorphism (5HTTLPR) and body mass index in a large psychiatric sample. Journal of affective disorders Shinozaki, G., Kumar, Y., Rosen, B. H., Rundell, J. R., Mrazek, D. A., Kung, S. 2013; 151 (1): 397-400

  Abstract

  The role of the promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) in psychiatric illnesses has been studied extensively. Serotonergic function also regulates many central nervous system, including appetite and feeding behaviors. The 5HTTLPR short allele was found to be associated with increased body mass index and obesity risk among the general population. No data is available to support generalizability of such association among psychiatric population.We examined the relationship between BMI and the 5HTTLPR genotype in a large sample of 1831 psychiatric patients at Mayo Clinic, Rochester, Minnesota, using a retrospective chart review.Average BMI among groups with the short/short (28.29 ± 7.27 kg/m(2)), the short/long (28.07 ± 6.45 kg/m(2)) and the long/long (28.15 ± 7.51 kg/m(2)) genotypes of 5HTTLPR were not statistically different. This negative association persisted even with the sub-analysis of the Caucasians. However, we observed an increased rate of obesity among our psychiatric patient sample compared to the general population of Minnesota (36.6% versus 27.6%, p=0.0001 for males, 30.3% versus 24.4%, p=0.0001 for females). Also, sub-analysis showed female inpatients to have a significantly higher average BMI than outpatients (28.64 ± 8.08 kg/m(2) versus 27.13 ± 6.92 kg/m(2), p=0.026). This confirmed a significant association between mental health disorder and BMI.Retrospective study design with limited control for potential confounders.In this large sample of psychiatric patients we found no significant association between 5HTTLPR genotype and BMI, which is different from the case with general population reported in the literature.

  View details for DOI 10.1016/j.jad.2013.06.021

  View details for PubMedID 23838390

• HTR2A gene-child abuse interaction and association with a history of suicide attempt among Caucasian depressed psychiatric inpatients JOURNAL OF AFFECTIVE DISORDERS Shinozaki, G., Romanowicz, M., Mrazek, D. A., Kung, S. 2013; 150 (3): 1200-1203

  Abstract

  The serotonin transporter gene polymorphism (5HTTLPR) has been associated with vulnerability for depression after exposure to stressful life event as well as with difference in treatment response to SSRI. Although the A/A genotype of the serotonin receptor SNP (rs7997012) was associated with better citalopram response than the G/G in the STAR⁎D sample, the effects of this SNP in the moderation of child abuse history on the characteristics of mental illnesses are not well understood. We examined if there are similar gene-environment interaction with the SNP.Retrospective chart review of 250 Caucasian depressed psychiatric inpatients, who had genotype for rs7997012. Subjects with each genotype were subcategorized into 2 groups with/without history of child abuse. The history of suicide attempts of each group was compared.A trend for an interaction was found between the HTR2A genotype and child abuse history influencing the prevalence of suicide attempts. Although each genotype did not show significant difference in the risk of suicide attempt when there was no abuse history, the A carriers (A/A+A/G) showed significantly higher rate of suicide attempt compared to the G/G when there is a history of child abuse (48.4% versus 22.7% respectively, p=0.0050). The likelihood ratio test from the logistic model showed a trend for an interaction between the A/A genotype and abuse history (Odds Ratio 2.10, χ(2)=2.49, p=0.11).Retrospective study design and small sample size with borderline significance.Our findings showed a potential interaction between the HTR2A gene and stressful life events.

  View details for DOI 10.1016/j.jad.2013.05.028

  View details for Web of Science ID 000324038000073

  View details for PubMedID 23759279

• Biological pathways and genetic mechanisms involved in social functioning. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation Ordoñana, J. R., Bartels, M., Boomsma, D. I., Cella, D., Mosing, M., Oliveira, J. R., Patrick, D. L., Veenhoven, R., Wagner, G. G., Sprangers, M. A. 2013; 22 (6): 1189-200

  Abstract

  To describe the major findings in the literature regarding associations between biological and genetic factors and social functioning, paying special attention to: (1) heritability studies on social functioning and related concepts; (2) hypothesized biological pathways and genetic variants that could be involved in social functioning, and (3) the implications of these results for quality-of-life research.A search of Web of Science and PubMed databases was conducted using combinations of the following keywords: genetics, twins, heritability, social functioning, social adjustment, social interaction, and social dysfunction.Variability in the definitions and measures of social functioning was extensive. Moderate to high heritability was reported for social functioning and related concepts, including prosocial behavior, loneliness, and extraversion. Disorders characterized by impairments in social functioning also show substantial heritability. Genetic variants hypothesized to be involved in social functioning are related to the network of brain structures and processes that are known to affect social cognition and behavior.Better knowledge and understanding about the impact of genetic factors on social functioning is needed to help us to attain a more comprehensive view of health-related quality-of-life (HRQOL) and will ultimately enhance our ability to identify those patients who are vulnerable to poor social functioning.

  View details for DOI 10.1007/s11136-012-0277-5

  View details for PubMedID 23054492

• State dependent gene-environment interaction: Serotonin transporter gene-child abuse interaction associated with suicide attempt history among depressed psychiatric inpatients JOURNAL OF AFFECTIVE DISORDERS Shinozaki, G., Romanowicz, M., Passov, V., Rundell, J., Mrazek, D., Kung, S. 2013; 147 (1-3): 373-378

  Abstract

  The serotonin transporter gene polymorphism (5HTTLPR) and child abuse history have been associated with an increased suicide risk for general population, but such association is not clear among psychiatric depressed inpatients.A chart review identified 422 depressed inpatients genotyped for 5HTTLPR. Child abuse and suicide attempt history were recorded. The relationship between 5HTTLPR, child abuse, and suicide attempts were analyzed.There was a significant relationship between 5HTTLPR and history of suicide attempt (the long/long versus the short carriers, 47.9% versus 31.8%, p=0.0015). There was also a significant main effect from child abuse history (abused versus not abused, 45.1% versus 28.6%, p=0.0001). The likelihood ratio test showed a significant result for the l/l genotype group with child abuse history (odds ratio 4.11, χ2 = 23.5, p<0.0001). No significant result was obtained from other groups.This is a retrospective study based on chart review. Replication with more standardized research setting for measurements of child abuse history and suicide attempt history is needed. The rs25531 variant among a long allele (long-A and long-G) of 5HTTLPR was not genotyped.In addition to the direct effect from 5HTTLPR and child abuse history, an interaction between the 5HTTLPR gene and child abuse history influenced psychiatric profiles of depressed inpatients. Contrary to the widely recognized "reactivity" associated with the short allele, our patients with the l/l genotype and child abuse history showed significantly severer psychiatric pathology than short carriers with child abuse history.

  View details for DOI 10.1016/j.jad.2012.11.043

  View details for Web of Science ID 000316790400053

  View details for PubMedID 23261136

• Testing a Diathesis-Stress Model: Potential Genetic Risk Factors for Development of Distress in Context of Acute Leukemia Diagnosis and Transplant PSYCHOSOMATICS Romanowicz, M., Ehlers, S., Walker, D., Decker, P., Rundell, J., Shinozaki, G., Litzow, M., Hogan, W., Mrazek, D., Black, J. L. 2012; 53 (5): 456-462

  Abstract

  Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes, specifically in the context of stressful life events. We hypothesized that this single-nucleotide polymorphism will predict the development of psychological distress among patients diagnosed with acute leukemia and preparing for hematopoietic stem cell transplant (HSCT). We also explored the relationship of other genetic factors to psychological distress, including 5HTTLPR and STin2, FKBP5, and the CRHR1 TAT haplotype.In a retrospective cohort design, 107 adult acute leukemia survivors preparing for HSCT at a major medical center completed a pre-HSCT psychological evaluation and volunteered to donate blood to the HSCT Cell and Serum Research Repository for future research studies.There was evidence of a potential association between BDNF (Val66Met) and psychological distress. More specifically, rs6265 was related to both personal mental health history (P = 0.09, 0.06 adjusted) and diagnosis of depression/adjustment disorder at time of pre-transplant evaluation (P = 0.11, 0.09 adjusted). Other genetic factors were unrelated to distress.The BDNF Val66Met polymorphism may contribute to development of depressive symptomatology in patients undergoing stressful life events, such as diagnosis of acute leukemia and preparation for HSCT. The SNPs in BDNF might be applicable in identifying patients at risk for developing psychological distress and depression in the context of coping with stressful medical conditions. Polymorphism in other genes (FKBP5, CRHR1, and 5HTT) did not show any significant relationships. Replication studies are needed with larger samples of people undergoing similar significant life stressors.

  View details for DOI 10.1016/j.psym.2012.01.004

  View details for Web of Science ID 000309030000007

  View details for PubMedID 22652301

• Investigation of serotonin transporter gene (SLC6A4) by child abuse history interaction with body mass index and diabetes mellitus of White female depressed psychiatric inpatients. Psychiatric genetics Shinozaki, G., Romanowicz, M., Kung, S., Rundell, J., Mrazek, D. 2012; 22 (3): 109-14

  Abstract

  The serotonin transporter gene promoter polymorphism (5HTTLPR) and child abuse have been associated with an increased risk for depression. We previously reported the long/long (l/l) genotype of 5HTTLPR being associated with higher heart rate among patients with a history of child abuse compared with those without a history of child abuse, whereas the short allele carriers did not have heart rate differences dependent on child abuse history. This time, we extended our investigation to other outcomes with body mass index (BMI), and diabetes mellitus (DM) diagnosis.A retrospective chart review identified 185 White female depressed inpatients who were genotyped for 5HTTLPR. Child abuse history, BMI, and DM diagnosis were recorded. The relationship between 5HTTLPR, child abuse, and BMI, as well as a prevalence of DM were analyzed.Among the l/l genotype group, patients with a history of child abuse had a higher prevalence of DM (14.3 vs. 0%, P=0.06), and higher BMI (32.3 vs. 27.3 kg/m, P=0.03) compared with those without. Patients with the short allele (s/s or s/l) had fewer differences on the basis of abuse history.A potential interaction between 5HTTLPR and child abuse influenced metabolic profiles of White female depressed inpatients. In contrast with the widely recognized 'reactivity' associated with the short allele of 5HTTLPR, our White female depressed psychiatric inpatients with the l/l genotype showed relatively greater clinical pathology in metabolic profiles if they have a history of child abuse than inpatients with at least one short allele who had a history of child abuse.

  View details for DOI 10.1097/YPG.0b013e32834f3542

  View details for PubMedID 22311265

• State Dependent Gene-Environment Interaction: Serotonin Transporter Gene-Child Abuse Interaction Associated with Suicide Attempt among Large Sample of Depressed Psychiatric Inpatients Shinozaki, G., Romanowicz, M., Rundell, J., Mrazek, D., Kung, S. ELSEVIER SCIENCE INC. 2012: 157S

  View details for Web of Science ID 000302466000494

• The integrated model of serotonin transporter gene variation (5HTTLPR) and the glial cell transporter in stress vulnerability and depression. Medical hypotheses Shinozaki, G. 2012; 78 (3): 410-4

  Abstract

  The serotonin transporter gene (SLC6A4) promoter polymorphism (5HTTLPR) has been associated with individual stress responses such that individuals with childhood abuse history have higher rates of depression in later life if they are homozygous short (s/s) of the gene. It is hypothesized that these findings could be explained by an integrated model of a role of the glial cell transporter and a functional difference of 5HTTLPR in the capacity of absorbing serotonin from the synapse. A hypothetical integrated model of the SLC6A4 function and the role of glial cells are put forward to explain accumulating results of recent investigations exploring the relationship between the gene and the diverse mental activities including depression and stress response. A model based on SLC6A4 variation is proposed to explain individual differences in stress vulnerability/resilience. The role of the glial cell transporter surrounding the synapse is integrated in the model to understand the modulation of the neurotransmission. It is hypothesized that a synapse with less serotonin transporter contributes to unstable processing in neurotransmission as compared to a synapse with more serotonin transporter. As such, based on functional differences of 5HTTLPR in the expression of the serotonin transporter, it is asserted that individuals with the s/s genotype process neurotransmission differently and in a reactive way. This integrated model of 5HTTLPR and glial cells suggests that the efficacy of serotonin reuptake in the synapse may play a crucial role in variability of neurotransmission, which can lead to differences in the stress response and the pathophysiology of depression.

  View details for DOI 10.1016/j.mehy.2011.10.043

  View details for PubMedID 22236459

• Continuous un-SERT-ainty of 5-HTTLPR. Pharmacogenomics Shinozaki, G. 2011; 12 (7): 935-8

  View details for DOI 10.2217/pgs.11.80

  View details for PubMedID 21787187

• Post-pump chorea--choreiform movements developing after pulmonary thromboendarterectomy for chronic pulmonary hypertension presenting as "functional" movement disorder. Psychosomatics Das, P., Shinozaki, G., McAlpine, D. 2011; 52 (5): 459-62

  View details for DOI 10.1016/j.psym.2011.01.022

  View details for PubMedID 21907066

• I'm so tired: biological and genetic mechanisms of cancer-related fatigue. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation Barsevick, A., Frost, M., Zwinderman, A., Hall, P., Halyard, M. 2010; 19 (10): 1419-27

  Abstract

  The goal of this paper is to discuss cancer-related fatigue (CRF) and address issues related to the investigation into potential biological and genetic causal mechanisms. The objectives are to: (1) describe CRF as a component of quality of life (QOL); (2) address measurement issues that have slowed progress toward an understanding of mechanisms underlying this symptom; (3) review biological pathways and genetic approaches that have promise for the exploration of causal mechanisms of CRF; and (4) offer directions for future research.Review, synthesis, and interpretation of the literature.Until recently, CRF and QOL have been understood primarily as subjective patient-reported experiences. With increased understanding of human genetics, theories and research are being expanded to incorporate biological and genetic understandings of these subjective experiences. Proposed biological and genetic mechanisms of CRF that have been examined include cytokine dysregulation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, five hydroxy tryptophan (5-HT) neurotransmitter dysregulation, circadian rhythm disruption, alterations in adenosine triphosphate (ATP) and muscle metabolism, and vagal afferent activation. Approaches to the study of genetic mechanisms have also been addressed including candidate genes, genome-wide scanning, and gene expression. Based on the review and synthesis of the literature, directions for future research are proposed.Understanding the biological and genetic basis of CRF has the potential to contribute to a more complete understanding of the genetic determinants of QOL.

  View details for DOI 10.1007/s11136-010-9757-7

  View details for PubMedID 20953908

  View details for PubMedCentralID PMC3031957

• Which patient will feel down, which will be happy? The need to study the genetic disposition of emotional states. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation Sprangers, M. A., Bartels, M., Veenhoven, R., Baas, F., Martin, N. G., Mosing, M., Movsas, B., Ropka, M. E., Shinozaki, G., Swaab, D. 2010; 19 (10): 1429-37

  Abstract

  In quality-of-life (QL) research, the genetic susceptibility of negative and positive emotions is frequently ignored, taken for granted, or treated as noise. The objectives are to describe: (1) the major findings of studies addressing the heritable and environmental causes of variation in negative and positive emotional states and (2) the major biological pathways of and genetic variants involved in these emotional states.Literature overview.The heritability estimates for anxiety and depression are 30-40%. Related traits as neuroticism and loneliness are also highly heritable. The hypothalamo-pituitary-adrenal axis is the 'final common pathway' for most depressive symptoms. The many findings of investigated genes are promising but not definitive. Heritability estimates of positive emotional states range between 40 and 50%. Life satisfaction and mental health share common genetic factors with optimism and self-esteem. The prefrontal cortex is a candidate brain area for positive emotional states. Biological and genetic research into positive emotional states is scarce.Genetically informative studies may provide insights into a wide variety of complex questions that traditional QL studies cannot deliver. This insight in turn will help us to design more effective supportive programs that could moderate the outcomes of genetically based predispositions.

  View details for DOI 10.1007/s11136-010-9652-2

  View details for PubMedID 20419396

  View details for PubMedCentralID PMC2977055

• Biological pathways and genetic variables involved in pain. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation Shi, Q., Cleeland, C. S., Klepstad, P., Miaskowski, C., Pedersen, N. L. 2010; 19 (10): 1407-17

  Abstract

  This paper summarizes current knowledge of pain-related and analgesic-related pathways as well as genetic variations involved in pain perception and management.The pain group of the GENEQOL Consortium was given the task of summarizing the current status of research on genetic variations in pain and analgesic efficacy. This review is neither exhaustive nor comprehensive; we focus primarily on single-nucleotide polymorphisms.Two categories of potential genetic pain-perception pathways were identified: neurotransmission modulators and mechanisms that affect inflammation. Four categories were identified for analgesic efficacy: genes related to receptor interaction, modulation of opioid effects, metabolism, and transport. Various genetic variations involved in these pathways are proposed as candidate genetic markers for pain perception and for individual sensitivity to analgesics.Candidate gene association studies have been used to provide evidence for the genetic modulation of pain perception and response to analgesics. However, the nature and range of genetic modulation of pain is not well addressed due to the limited number of patients and the limited number of genes and genetic variants investigated in studies to date. Moreover, personalized analgesic treatments will require a more complete understanding of the effects of genetic variants and gene-gene interactions in response to analgesics.

  View details for DOI 10.1007/s11136-010-9738-x

  View details for PubMedID 20842532

• Scientific imperatives, clinical implications, and theoretical underpinnings for the investigation of the relationship between genetic variables and patient-reported quality-of-life outcomes. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation Sprangers, M. A., Sloan, J. A., Barsevick, A., Chauhan, C., Dueck, A. C., Raat, H., Shi, Q., Van Noorden, C. J. 2010; 19 (10): 1395-403

  Abstract

  There is emerging evidence for a genetic basis of patient-reported quality-of-life (QOL) outcomes that can ultimately be incorporated into clinical research and practice. Objectives are (1) to provide arguments for the timeliness of investigating the genetic basis of QOL given the scientific advances in genetics and patient-reported QOL research; (2) to describe the clinical implications of such investigations; (3) to present a theoretical foundation for investigating the genetic underpinnings of QOL; and (4) to describe a series of papers resulting from the GENEQOL Consortium that was established to move this work forward.Discussion of scientific advances based on relevant literature.In genetics, technological advances allow for increases in speed and efficiency and decreases in costs in exploring the genetic underpinnings of disease processes, drug metabolism, treatment response, and survival. In patient-based research, advances yield empirically based and stringent approaches to measurement that are scientifically robust. Insights into the genetic basis of QOL will ultimately allow early identification of patients susceptible to QOL deficits and to target care. The Wilson and Cleary model for patient-reported outcomes was refined by incorporating the genetic underpinnings of QOL.This series of papers provides a path for QOL and genetics researchers to work together to move this field forward and to unravel the intricate interplay of the genetic underpinnings of patient-reported QOL outcomes. The ultimate result will be a greater understanding of the process relating disease, patient, and doctor that will have the potential to lead to improved survival, QOL, and health services delivery.

  View details for DOI 10.1007/s11136-010-9759-5

  View details for PubMedID 20945161

  View details for PubMedCentralID PMC2977054

• Sexual abuse and lifetime diagnosis of psychiatric disorders: systematic review and meta-analysis. Mayo Clinic proceedings Chen, L. P., Murad, M. H., Paras, M. L., Colbenson, K. M., Sattler, A. L., Goranson, E. N., Elamin, M. B., Seime, R. J., Shinozaki, G., Prokop, L. J., Zirakzadeh, A. 2010; 85 (7): 618-29

  Abstract

  To systematically assess the evidence for an association between sexual abuse and a lifetime diagnosis of psychiatric disorders.We performed a comprehensive search (from January 1980-December 2008, all age groups, any language, any population) of 9 databases: MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO, ACP Journal Club, CCTR, CDSR, and DARE. Controlled vocabulary supplemented with keywords was used to define the concept areas of sexual abuse and psychiatric disorders and was limited to epidemiological studies. Six independent reviewers extracted descriptive, quality, and outcome data from eligible longitudinal studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled across studies by using the random-effects model. The I(2) statistic was used to assess heterogeneity.The search yielded 37 eligible studies, 17 case-control and 20 cohort, with 3,162,318 participants. There was a statistically significant association between sexual abuse and a lifetime diagnosis of anxiety disorder (OR, 3.09; 95% CI, 2.43-3.94), depression (OR, 2.66; 95% CI, 2.14-3.30), eating disorders (OR, 2.72; 95% CI, 2.04-3.63), posttraumatic stress disorder (OR, 2.34; 95% CI, 1.59-3.43), sleep disorders (OR, 16.17; 95% CI, 2.06-126.76), and suicide attempts (OR, 4.14; 95% CI, 2.98-5.76). Associations persisted regardless of the victim's sex or the age at which abuse occurred. There was no statistically significant association between sexual abuse and a diagnosis of schizophrenia or somatoform disorders. No longitudinal studies that assessed bipolar disorder or obsessive-compulsive disorder were found. Associations between sexual abuse and depression, eating disorders, and posttraumatic stress disorder were strengthened by a history of rape.A history of sexual abuse is associated with an increased risk of a lifetime diagnosis of multiple psychiatric disorders.

  View details for DOI 10.4065/mcp.2009.0583

  View details for PubMedID 20458101

  View details for PubMedCentralID PMC2894717

• Serotonin transporter gene promotor polymorphism (5-HTTLPR) associations with number of psychotropic medication trials in a tertiary care outpatient psychiatric consultation practice. Psychosomatics Rundell, J. R., Staab, J. P., Shinozaki, G., McAlpine, D. 2010; 52 (2): 147-53

  Abstract

  The authors tested the hypothesis that the short allele of 5-HTTLPR is associated with number of psychotropic medication trials as a measure of treatment-resistance or intolerance in psychosomatic medicine (PM) outpatients.Review of Mayo Clinic PM outpatient 2008 records identified 44 (20.6%) who had 5-HTTLPR genotype tests. A univariate analysis screened for factors that could account for number of medication trials. Logistic regression then determined degree of association between 5-HTTLPR genotype category and number of pharmacological trials.Univariate analysis revealed significant differences across the ordinal genotype spectrum long/long, short/long, short/short in mean number of overall psychotropic medication trials (8.9, 14.8, 18.0, P = 0.002), mean number of antidepressant trials (4.3, 7.2, 8.1, P = 0.018), mean number of mood stabilizer trials (0.8, 1.9, 2.3, P = 0.008), percent living alone (7%, 25%, 50%, P = 0.020), reported family history of depression (93%, 65%, 40%, P = 0.006), and reported family history of chemical dependency treatment (50%, 35%, 10%, P = 0.050). There were trends for differences in consultation reason for unexplained symptoms (14%, 25%, 50%, P = 0.063), and diagnoses of somatoform disorder (7%, 30%, 40%, P = 0.060), and generalized anxiety disorder (43%, 65%, 80%, P = 0.064). After controlling for other differences, presence of the short allele remained associated with number of psychotropic medication trials (OR 4.779, 95% CI 2.263-6.771, P = 0.004), and number of antidepressant trials (OR 1.591, 95% CI 1.072-2.762, P = 0.019).5-HTTLPR testing may identify PM outpatients at higher relative risk for pharmacotherapy treatment non-response or intolerance who may benefit from alternative or augmentative medication recommendations or non-pharmacological interventions.

  View details for DOI 10.1016/j.psym.2010.12.013

  View details for PubMedID 21397107

• Pharmacogenomic testing in a tertiary care outpatient psychosomatic medicine practice. Psychosomatics Rundell, J. R., Staab, J. P., Shinozaki, G., Saad-Pendergrass, D., Moore, K., McAlpine, D., Mrazek, D. 2009; 52 (2): 141-6

  Abstract

  Pharmacogenomic testing (PGT) has applicability in psychosomatic medicine (PM) practice where medical comorbidity and polypharmacy present particularly difficult challenges of drug-drug and drug-disease interactions. No guidelines currently exist for cost-effective use of PGT in PM practice.The authors tested the hypothesis that naturalistically observed PGT ordering patterns and clinical data on test utility derived from a PM practice where PGT is readily available may inform the development of clinical guidelines for cost-effective use of PGT.Two sets of data were collected from an outpatient PM practice staffed by seven PM-certified psychiatrists. Psychiatrists were surveyed regarding their indications for ordering PGT. Medical records of patients seen in the PM practice during 2008 were reviewed. Patients who had PGT were compared with two sets of case controls who were not tested, one matched by demographics, the other by ordering psychiatrist. Psychiatrists' ordering indications were compared with clinical data derived from the case-control analyses.Psychiatrists listed treatment-resistance as the most common reason for PGT, ahead of intolerance to previous medications. Tested patients differed from controls on measures of both clinical severity and treatment-resistance, including higher self-reported anxiety and depression levels, greater likelihood of family history of mood or anxiety disorders, and larger numbers of prior antidepressant, mood stabilizer, and antipsychotic medication trials.Ordering guidelines that emphasize markers of clinical severity and early indicators of treatment-resistance may provide a useful rationale for PGT in outpatient PM practice. Prospective investigations of this proposition are warranted.

  View details for DOI 10.1016/j.psym.2010.12.023

  View details for PubMedID 21397106

• The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes. Twin research and human genetics : the official journal of the International Society for Twin Studies Sprangers, M. A., Sloan, J. A., Veenhoven, R., Cleeland, C. S., Halyard, M. Y., Abertnethy, A. P., Baas, F., Barsevick, A. M., Bartels, M., Boomsma, D. I., Chauhan, C., Dueck, A. C., Frost, M. H., Hall, P., Klepstad, P., Martin, N. G., Miaskowski, C., Mosing, M., Movsas, B., Van Noorden, C. J., Patrick, D. L., Pedersen, N. L., Ropka, M. E., Shi, Q., Shinozaki, G., Singh, J. A., Yang, P., Zwinderman, A. H. 2009; 12 (3): 301-11

  Abstract

  To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcomes.

  View details for DOI 10.1375/twin.12.3.301

  View details for PubMedID 19456223

  View details for PubMedCentralID PMC2824176