bluuebunny/crossref_metadata_2025 huggingface dataset:
CLINICAL BENEFIT AND UTILITY OF ARIPIPRAZOLE ONCE MONTHLY IN ROUTINE PRACTICE FOR KOREAN SCHIZOPHRENIA PATIENTS (CAMP)
Authors: Moon *Jiwan , Yang Hyeryun , Kim Eun Soo , Jeon Sang-Won , Shin Young-Chul , Cho Sung Joon
Published: February 2025

Background

Antipsychotic polypharmacy is prevalent in clinical settings, with an increasing adoption of long-acting injectables to alleviate side effects. Aripiprazole once monthly (AOM) offers enhanced compliance, functional recovery, and symptom relief, yet evidence is lacking within polypharmacy.

Aims & Objectives

The objectives of this observational study are to investigate the clinical benefits and effectiveness of AOM within a general clinical environment. This investigation entails assessing shifts in clinical functionality, alterations in psychotic symptoms, and modifications in medication dosages and quantities.

Method

Participants were recruited from six sites, and clinical as well as demographic data were extracted from electronic medical records (EMR) during the screening, baseline, 1-month, 3-month, 6-month, 9-month, and 12-month intervals, with the initiation of AOM treatment serving as the baseline point. Changes of various measures including in GAF (Global Assessment of Functioning), CGI-S (Clinical Global Impression-Severity), CGI-I (Clinical Global Impression-Improvement), PANSS-6 (The Positive and Negative Syndrome Scale-6) scores, as well as alterations in medication dosage and quantity over the 12- month period, were analyzed.

Results

Data of 85 patients were available and notable improvements were observed in key measures. The GAF score increased by 17.2%, the CGI-S score decreased by 17.5%, the CGI-I score decreased by 25%, and the PANSS-6 total score decreased by 22% at 12 months. Particularly noteworthy was the decrease of PANSS-6 score observed as early as month 1, compared to the baseline, with other scales exhibited significant improvement from month 3. At the 12-month juncture, a statistically significant reduction was evident in several medication-related aspects, including the total pill count, antipsychotic pill count, cumulative chlorpromazine-equivalent dosage of antipsychotics, benzodiazepine pill count, and cumulative lorazepam-equivalent dosage of benzodiazepines. Notably, the initial month saw a significant drop in both overall pill count and antipsychotic pill count and dosage.

Furthermore, a pronounced reduction in anticholinergic drug and beta-blocker pill counts was observed at the 12-month point compared to baseline, further suggesting AOM's contribution to reducing side effects. Although 31 subjects reported adverse events, no instances of serious adverse events were documented.

Discussion & Conclusion

The findings of this study strongly suggest that efficacy becomes apparent early on when transitioning to AOM in patients undergoing antipsychotic polypharmacy within the routine clinical practice for schizophrenia patients in Korea. The observed improvements encompass not only enhanced functionality and amelioration of clinical symptoms but also a significant reduction in medication quantity and dosage.
THE NITRIC OXIDE (NO) DONOR MOLSIDOMINE COUNTERACT BEHAVIOURAL DEFICITS RESEMBLING NEGATIVE SYMPTOMS AND COGNITIVE DEFCITS IN THE RAT
Authors: Pitsikas *Nikolaos , Katsanou Lamprini , Vartzoka Foteini
Published: February 2025

Background

The deficiency of the gaseous molecule nitric oxide (NO) seems to be critically involved in the pathogenesis of schizophrenia. Thus, molecules that can normalize NO levels as are the NO donors, might be of utility for the medication of this psychiatric disease.

Aims & Objectives

The aim of the present study was to detect the ability of the NO donor molsidomine to reduce schizophrenia-like impairments produced either by blockade of the N-methyl-D-aspartate (NMDA) receptor or by dysregulation of the brain dopaninergic system in the rat.

Method

Molsidomine's ability to attenuate social withdrawal and spatial recognition memory deficits induced by the NMDA receptor antagonist ketamine were assessed using the social interaction and the object location test, respectively. Further, the ability of molsidomine to attenuate spatial recognition and emotional memory deficits induced by the dopaminergic agonist apomorphine was evaluated among the object location and the step-through passive avoidance test, respectively. Finally the efficacy of the combination of sub-threshold doses of molsidomine with sub-effective doses of the atypical neuroleptics clozapine and risperidone to attenuate non-spatial recognition memory impairments caused by treatment either of ketamine or apomorphine was also assessed using the object recognition test.

Results

Molsidomine (2 and 4 mg/kg) attenuated ketamine-induced social withdrawal and counteracted spatial recognition and emotional memory deficits induced either by ketamine or apomorphine. Further, the joint administration of inactive doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) and risperidone (0.03 mg/kg) counteracted non-spatial recognition memory deficits caused either by ketamine or apomorphine.

Discussion & Conclusions

The present results indicate that molsidomine is sensitive to glutamate hypofunction since it attenuated behavioural deficits in animal models mimicking the negative symptoms and cognitive impairments of schizophrenia. Additionally, the current findings propose that molsidomine is sensitive to dopaminergic dysfunction since it reduced cognitive defcits induced by apomorphine.

Finally, the findings here reported support the potential of molsidomine as an adjunctive drug for the therapy of schizophrenia.
THE STATUS OF HOPELESSNESS AND RELATED FACTORS IN KOREAN FEMALE FULL-TIME HOMEMAKERS: A COMMUNITY-BASED CROSS- SECTIONAL SURVEY STUDY
Authors: Hwang *Tae-Young
Published: February 2025

Background

Although the labor of full-time homemakers contributes to the stable maintenance of society as much as that of working women, social attention and support to full-time homemakers is relatively insufficient. Accordingly, a psychiatric evaluation of the mental health status of full-time homemakers is required.

Aims & Objectives

This study aimed to investigate the status of hopelessness and related factors in community-dwelling female full-time homemakers, and to evaluate the necessity of policy approaches to the full-time homemakers as a high-risk group for mental health.

Method

This survey study were sequentially and randomly conducted targeting community-dwelling full-time female homemakers aged 19 to 50, using structured questionnaires composed of general items as well as the Korean version of Beck Hopelessness Scale (K-BHS), the Korean version of the Glasgow Sleep Effort Scale (K-GSES), and Resenberg Self-Esteem Scale (RSES). The monetary values of the labor of individual full- time homemakers were measured through the willingness-to-pay (WTP) approach.

Results

A total of 180 questionnaires were distributed, of which 154 were analyzed. In the frequency analysis, the total proportion of hopelessness group was 62.3%, of which 42.2% was for the mild level, 16.2% for moderate level, and 3.9% for the severe level. In between-group comparative analyses [Normal group (n = 58) vs. Hopelessness group (n = 96)], significant differences were manifested in the length of career (t = - 2.667, p = 0.008), level of social activity (t = 2.762, p = 0.008), degree of emotional bond with husband (t = 2.339, p = 0.021), K-GSES (t = -2.459, p = 0.015), and RSES(t = 5.380, p <0.001). Furthermore, in binary logistic regression analysis, significant negative factor for the transition to the hopelessness group was level of social activity (p = 0.021; odds ratio (OR), 0.694; 95% confidence interval (CI), 0.508 - 0.946), and significant positive factor was the score on K-GSES (p = 0.041; OR, 1.155; 95% CI, 1.006 – 1.328).

Discussion & Conclusion

The findings of this study showed that a substantial number of female full-time homemakers might be in a state of hopelessness, implicating that full-time homemakers are at high-risk for mental health and suicide. Therefore, policy and psychiatric intervention to promote and recover mental health of full-time homemakers is essential.
IN VIVO CLASSIFICATION OF TAU PATHOLOGIES BY POSITRON EMISSION TOMOGRAPHY IN PATIENTS WITH FRONTOTEMPORAL DEMENTIA
Authors: Kubota *Manabu , Endo Hironobu , Takahata Keisuke , Tagai Kenji , Suzuki Hisaomi , Onaya Mitsumoto , Sano Yasunori , Yamamoto Yasuharu , Kurose Shin , Matsuoka Kiwamu , Seki Chie , Shinotoh Hitoshi , Kawamura Kazunori , Zhang Ming-Rong , Takado Yuhei , Shimada Hitoshi , Higuchi Makoto
Published: February 2025

Background

Frontotemporal dementia (FTD) is a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of FTD at an individual level have not hitherto been successful.

Aims & Objectives

In this study, we aimed to classify patients with FTD based on topologies of tau protein aggregates captured by positron emission tomography (PET) with 18F-florzolotau (aka 18F-APN-1607, 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer’ s disease (AD) and non-AD tauopathies.

Method

Twenty-six patients with FTD, consisting of 15 patients with behavioral variant FTD (bvFTD) and 11 patients with other FTD phenotypes, and 20 age- and gender-matched healthy controls were studied. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively.

Results

By combining visual and semiquantitative analyses of PET images, the bvFTD patients were classified into the following subgroups: 1) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = 3); 2) predominant tau accumulations in subcortical structures accompanied by various degrees of neocortical accumulations resembling four-repeat tauopathies (n = 4); 3) amyloid and tau accumulations consistent with AD (n = 4); and 4) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localization of brain atrophy were not significantly different among the identified bvFTD subgroups. Patients with other FTD phenotypes were also classified into similar subgroups.

Discussion And Conclusion

PET with 18F-florzolotau potentially enables the characterization of each individual with FTD on a biological basis, thereby possibly contributing to diagnostic and therapeutic approaches to this illness.
RISK OF DEMENTIA IN CANCER SURVIVORS: A NATIONWIDE COHORT STUDY
Authors: Chu *Che-Sheng , Cheng Shu-Li , Bai Ya-Mei , Su Tung-Ping , Tsai Shih-Jen , Chen Tzeng-Ji , Yang Fu-Chi , Chen Mu-Hong , Liang Chih-Sung
Published: February 2025

Background

Several observational studies have identified a positive association between cancer survivors and subsequent dementia whereas others have negative or no association.

Aims & Objectives

This study aimed to determine the association in Taiwanese patients using a large, community-based national claim data.

Method

Using the Taiwan National Health Insurance Research Database, we recruited 32,250 patients surviving malignancies and 322,500 controls between 1998 and 2011 and followed them up until the end of 2013. A diagnosis of dementia, Alzheimer’ s disease (AD), vascular dementia (VaD), and unspecified dementia were identified during the follow-up period. Cox regression analyses were performed with adjustments for confounders. Sensitivity analysis was conducted to exclude patients with prodromal dementia.

Results

Cancer survivors were more likely to develop AD (hazard ratio [HR]: 1.68, 95% confidence interval [CI]: 1.38–2.06), unspecified dementia (HR: 1.19, 95% CI: 1.07–1.32), and any dementia (HR: 1.26, 95% CI: 1.16–1.37) compared with controls after adjusting for potential confounders. Specifically, cancers of digestive and genitourinary organs seemed to be associated with such risks, while only malignant neoplasm of the brain was more likely to develop VaD. Sensitivity analyses after exclusion of the first three years or first five years of observation and after exclusion case enrollment before 2009 or 2007 showed consistent findings.

Discussion & Conclusion

Cancer survivors were associated with higher risk of subsequent dementia. Further studies are necessary to investigate the underlying mechanisms of cancer survivors and dementia.
THE ROLE OF SERUM NFL AND INFLAMMATORY CYTOKINES IN THE EARLY RECOGNITION OF ALZHEIMER'S DISEASE
Authors: Jing Xinyang , Wang *Lan , An Cuixia
Published: February 2025

Background

Previous studies have found that blood neuroflament light chain protein(NfL) is associated with the assessment of cognitive function, and decreased cognitive function is associated with higher levels of circulating inflammation. However, the intrinsic association between blood NfL levels and inflammatory cytokines and cognitive function is not clear.

Aims & Objectives

The purpose of this study is to explore the role of serum NfL and inflammatory cytokines in the early recognition of Alzheimer's disease(AD), and explore the relationship between serum NfL and inflammatory cytokines.

Method

A total of 157 subjects aged 55 years above were recruited from the community and divided by cognitive function into three groups. Cognitive assessment and serum samples were collected by trained psychiatrists, and concentrations of neurofilament light chains, inflammatory factors and other pathological markers of AD were measured by enzyme linked immunosorbent assay(ELISA). The correlation between cognitive function, NfL, inflammatory factors and other pathological markers of AD was analyzed, and the ability to recognize MCI was explored. Counting data were compared by Chi-square test. The receiver operating characteristic (ROC) was analyzed for the concentration of various cognitive scales and blood indicators of the subjects, and the area under the curve (AUC) was calculated to evaluate the diagnostic performance with sensitivity and specificity.

Results

1. The level of serum NfL in MCI population and probably AD population was higher than that in healthy control group(F=7.582,P=0.023); 2. Serum NfL content was positively correlated with inflammatory cytokines IL-1β and IL-6 and Aβ40, and the correlation coefficients were 0.471,0.269 and 0.386, respectively;3. The combination of serum NfL with p-tau217 and Boston naming test significantly improved the accuracy of MCI prediction, the areas under the curve were 0.687 and 0.742, respectively. But the combination of serum NfL with inflammatory factors did not improve the accuracy of MCI prediction.

Discussion & Conclusion

This study found that serum NfL content is related to cognition and inflammatory factors, which can help early identification of MCI population, indicating that NfL can be an early identification of Alzheimer's disease peripheral blood biomarker, and hopefully provide a new concept for the treatment of Alzheimer's disease.
THE EFFECT OF DEPRESSION ON COGNITION IN ALZHEIMER’S DISEASE
Authors: Kim *Do Hoon , Moon Yoosun , Yoon Kyung Hee
Published: February 2025

Background

It is uncertain whether depression might affect cognitive function in Alzheimer’ s disease (AD). Most of studies on the effect of depression treatment on cognitive function in AD were briefly evaluated by Mini-Mental State Examination (MMSE). MMSE is poor sensitive to detect cognitive change.

Aims & Objectives

This study examined the cognitive response to depression treatment in AD via multi-domain assessment. Additionally, we explored whether effect of depression treatment in AD is different those of late-life depression (LLD).

Methods

This study include AD patients with depression (AD + D) and without depression (AD - D), LLD patients (LLD), and healthy controls (HC). The patients were treated according to their diagnosis for 16 weeks: Acetylcholinesterase inhibitors (AChEIs) and selective serotonin reuptake inhibitors (SSRIs) for AD + D, AChEIs for AD - D, and SSRIs for LLD. The cognitive changes from pre- to post-treatment were compared between AD + D and AD - D or LLD and HC. An independent sample t-test was performed to compare the degree of change between the groups. Paired t-tests were used to determine cognitive function changes in each depression treatment responder group.

Results

At baseline, AD + D had more impairment in language function compared to AD – D, and LLD had greater deficit in executive function than HC. After depression treatment, more impaired cognitive domains at baseline were improved in AD + D and LLD, respectively. Moreover, AD + D showed an improvement in the global cognitive function (MMSE).

Discussion & Conclusion

Results indicated that language function was influenced by depression in AD, which is first evidence for specific cognitive domain related to depression in AD. Our finding indicates that depression could negatively impact cognitive function, and depression treatment may have beneficial cognitive effect in both AD and LLD. This study suggests the importance of early detection and treatment of depression in AD and LLD.
REPURPOSING DISULFIRAM AS A TREATMENT OPTION OF "CHRONIC LYME DISEASE": A REVIEW
Authors: Saio *Takeo
Published: February 2025

Background

Chronic Lyme disease(CLD) is one of the most controversial-contested illness with non- specific medically unexplained symptoms(MUS) like fatigue, impairment of memory, arthralgia as well as myalgia which allegedly caused by tick-borne persistent infection of bacterial species of borrelia. Though this disease entity has been unalterably negated by the mainstream medical establishment, its advocators refute the negative verification of medical authorities passionately and sometimes vitriolic. Disulfiram(often abbreviated as DSM) is a medication used for the treatment of alcohol use disorder by producing a nauseating acute sensitivity to ethanol. The CLD patients and Lyme-literate physicians seeks cures for the disease which include disulfiram therapy.

Aims & Objectives

To clarify CLD concept and evaluate disulfiram therapy on CLD.

Method

narrative non-systematic review of literature on disulfiram therapy to CLD.

Results

CLD is mainly divided into four categories[i] but the difference between late tertiary phase (stage 3) of Lyme disease and CLD is obscure which indicates the existence of CLD as a disease albeit trifle. Though disulfiram is repurposed to treat CLD for anticipated antimicrobial activity based on the findings of preclinical-basic research, its clinical evidence is insufficient yet(only one small RCT and two case series) and severe adverse reactions are reported[ii].

Discussion & Conclusion

CLD is a poorly defined disease entity with a lot of differential diagnoses including fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, and functional somatic syndrome[iii] as well as major depressive disorder, rheumatoid arthritis, osteoarthritis, myasthenia gravis and amyotrophic lateral sclerosis. And besides, CLD is often overdiagnosed. Our current understanding of CLD indicates disulfiram therapy for the treatment option of CLD is not advised even though the suffers eagerly requested.

References

[i]Feder, H. M., Jr, Johnson, B. J., O'Connell, S., et al. (2007). A critical appraisal of "chronic Lyme disease". The New England journal of medicine, 357(14), 1422–1430.

[ii]Custodio, M. M., Sparks, J., &Long, T. E. (2022). Disulfiram: A Repurposed Drug in Preclinical and Clinical Development for the Treatment of Infectious Diseases. Anti-infective agents, 20(3), e040122199856.

[iii]Reid, M. C., Schoen, R. T., Evans, J., Rosenberg, J. C., &Horwitz, R. I. (1998). The consequences of overdiagnosis and overtreatment of Lyme disease: an observational study. Annals of internal medicine, 128(5), 354–362.
INVESTIGATION OF THE LONG-TERM EFFECTS OF LEMBOREXANT ON OBJECTIVE SLEEP MEASURES USING A MINIATURE ELECTROENCEPHALOGRAM
Authors: Miyata *Seiko , Okada Ippei , Iwamoto Kunihiro , Fujimoto Akihiro , Kogo Yuki , Amano Manabu , Matsuyama Nao , Ozaki Norio , Ikeda Masashi
Published: February 2025

Background

Lemborexant (LEM), a competitive dual orexin receptor antagonist, has improved both sleep onset and sleep maintenance in subjects with insomnia disorder in two phase 3 studies using polysomnography and/or sleep diaries. Older adults are more susceptible than younger adults to adverse events (somnolence, daytime cognitive and psychomotor impairment, falls, and fractures) commonly associated with prescribed sleep medications. Until now, the long-term efficacy of LEM has only been measured via subjective assessment for 6 months versus placebo and there have been no long-term objective measures in natural sleeping conditions.

Aims & Objectives

Sleep at home was assessed after 4 and 12 weeks of LEM administration using a small and light sleep electroencephalogram.

Methods

Subjects with insomnia disorder (DSM-5) were enrolled to receive LEM (5 mg or 10 mg) open- label at bedtime for 12 weeks. At baseline, after 4 weeks, and after 12 weeks, sleep indices (latency to persistent sleep [LPS], wake after sleep onset [WASO], total sleep time [TST], sleep efficiency [SE]) were evaluated. Sleep diaries were also completed throughout the study. The Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Beck Depression Inventory (BDI) were also assessed at baseline, 4 weeks, and 12 weeks. Written and oral consent was obtained from all subjects in accordance with the approval items of the Nagoya University Clinical Research Review Board.

Results

A total of 31 subjects (15 male, 16 female, mean age 58.5 years) enrolled in the study, all completed 4-week assessments and 29 completed 12-week assessments. Objective SE (both P<0.05) and all subjective sleeping measures (all P<0.001) were significantly improved at Weeks 4 and 12 of LEM treatment compared with baseline, and objective TST tended to increase at 12 weeks (P=0.05). When baseline values were considered (MANOVA), at 4 weeks objective WASO (P=0.003) and objective TST (P<0.001) significantly improved, and at 12 weeks all objective sleep measures (LPS [P=0.002], WASO [P=0.006], TST [P=0.009], SE [P<0.001]) significantly improved. ESS scores significantly improved (P<0.001) at 4 weeks compared with baseline and PSQI (P=0.012), ESS (P<0.001), and BDI (P=0.003) scores significantly improved at 12 weeks. Somnolence (29.0%, 9 of 31 subjects) was the most commonly reported adverse event (AE). AEs were mostly mild, and no serious AEs were reported.

Discussion & Conclusion

The findings of this study demonstrated improvement in objective SE with LEM treatment over 12 weeks, supporting the previously reported utility of short-term efficacy of LEM using polysomnography. LEM was well tolerated, and also associated with improvements in subjective sleep parameters, ESS, PSQI and BDI.

Support

Eisai Co., Ltd.
GENETIC CORRELATIONS BETWEEN SUICIDE ATTEMPTS AND PSYCHIATRIC AND INTERMEDIATE PHENOTYPES ADJUSTING FOR MENTAL DISORDERS
Authors: Fujikane *Daisuke , Ohi Kazutaka , Kuramitsu Ayumi , Takai Kentaro , Muto Yukimasa , Sugiyama Shunsuke , Shioiri Toshiki
Published: February 2025

Background

Suicide attempts are a moderately heritable trait, and genetic correlations with psychiatric and related intermediate phenotypes have been reported. However, as several mental disorders as well as major depressive disorder (MDD) are strongly associated with suicide attempts, these genetic correlations could be mediated by psychiatric disorders. Here, we investigated genetic correlations of suicide attempts with psychiatric and related intermediate phenotypes, with and without adjusting for mental disorders.

Methods

To investigate the genetic correlations, we utilized large-scale genome-wide association study summary statistics for suicide attempts (with and without adjusting for mental disorders), nine psychiatric disorders, and 15 intermediate phenotypes.

Results

Without adjusting for mental disorders, suicide attempts had significant positive genetic correlations with risks of attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, MDD, anxiety disorders and posttraumatic stress disorder; higher risk tolerance; earlier age at first sexual intercourse, at first birth and at menopause; higher parity; lower childhood IQ, educational attainment and cognitive ability; and lower smoking cessation. After adjusting for mental disorders, suicide attempts had significant positive genetic correlations with the risk of MDD; earlier age at first sexual intercourse, at first birth and at menopause; and lower educational attainment. After adjusting for mental disorders, most of the genetic correlations with psychiatric disorders were decreased, while several genetic correlations with intermediate phenotypes were increased.

Conclusions

These findings highlight the importance of considering mental disorders in the analysis of genetic correlations related to suicide attempts and suggest that susceptibility to MDD, reproductive behaviors, and lower educational levels share a genetic basis with suicide attempts after adjusting for mental disorders.
A PRELIMINARY INVESTIGATION OF RESTING STATE FUNCTIONAL CONNECTIVITY NETWORKS IN PATIENTS WITH TREATMENT-RESISTANT DEPRESSION AND A HISTORY OF SUICIDE ATTEMPT
Authors: Burhunduli *Patricia , Fang Zhuo , Vandeloo Katie L , Blier Pierre , Phillips Jennifer L
Published: February 2025

Background

Suicidal ideation (SI) and history of previous suicide attempt (SA) remain the most prominent prognostic factors for completed suicides. Understanding suicide is a nuanced multifaceted issue, and a mounting body of literature has used neuroimaging to enhance our understanding of suicide. Resting state functional magnetic resonance imaging (fMRI) strategies may reveal unique neuroimaging phenotypes related to suicide.

Aims & Objectives

This study examined resting-state functional connectivity (FC) differences between SI and SA in patients with treatment-resistant major depressive disorder (MDD).

Method

Resting-state FC data was obtained from N=40 patients with treatment-resistant MDD (n=21 with lifetime history of suicidal ideation and no attempts [SI-group]; n=19 with lifetime history of suicide ideation and attempts [SA-group]. Functional MRI data were acquired at 3T and pre-processed using the default CONN Functional Connectivity pipeline. A region of interest (ROI)-to-ROI approach was used to evaluate FC with the Harvard-Oxford and the resting-state network atlases. SI and SA history were examined using the Columbia Suicide Severity Rating Scale (C-SSRS). Findings were thresholded to p <0.005, false-discovery rate corrected.

Results

Resting-state FC analyses revealed that compared to the SA-group, the SI-group had higher FC between the right hippocampus and the DMN (lateral-parietal lobe) bilaterally (right hemisphere, t(38) = 3.8, pFDR = 0.02; left hemisphere, t(38) = 3.6, pFDR = 0.02) and decreased FC between the right DMN and regions of the salience network (bilateral supramarginal gyrus: t(38) = - 3.3, pFDR = 0.03 and bilateral anterior cingulate gyrus (t(38) = -3.2, pFDR = 0.03). A within group analysis revealed a negative correlation between current SI severity and FC between the caudate and the hippocampus/posterior para-hippocampus in the full sample (N = 40; pFDR = 0.05) and in the attempter grouper group specifically (n = 19; pFDR=0.008).

Discussion & Conclusion

Conceptualizing suicide is complex, and neuroimaging can identify neurobiological markers that reflect the underlying pathophysiology of depression and suicide. Our preliminary resting state functional MRI analyses shows significant differences in DMN FC in patients with SI and a lifetime history of SA compared to those with SI only. There were significant associations between limbic network FC and current SI severity. Our work contributes to a growing field highlighting the complex biosignatures involved in SI and SA in patients with treatment-resistant MDD.
AUTISTIC-LIKE BEHAVIORS MEDIATED BY THE DYSREGULATION OF ENDOCRINE SYSTEMS VIA OXYTOCIN AND CORTICOSTERONE IN CANNABINOID CB1 RECEPTOR KNOCKOUT MICE
Authors: Nawata *Yoko , Nishioku Tsuyoshi , Yamaguchi Taku
Published: February 2025

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, social communication deficits, and restrictive/repetitive behaviors. Children with ASD in some cases have comorbid disorders such as anxiety and/or learning disabilities. Recent evidences have reported that children with ASD and some animal models of ASD show abnormalities of endocannabinoid (eCB) system. To determine the causal role of the eCB systems in the ASD, we investigated the relationship between the eCB system and ASD-like symptoms, using the cannabinoid CB1 receptor knockout (CB1KO) mice. Social behaviors and repetitive grooming behaviors which reflect for core symptoms of ASD were evaluated with 3-chambered social approach task and hole-board test.

Learning and memory was also evaluated with Y-maze test and reversal learning task using T-maze. We found that CB1KO mice demonstrated reduced sociability and elevated repetitive grooming behaviors compared to wild-type mice. CB1KO mice also showed decline of alteration in Y-maze test and resistance to change a learned pattern of behavior in T-maze reversal task. We next measured serum corticosterone and serum/brain oxytocin, expected as biomarkers for ASD. As a result, serum corticosterone significantly increased in CB1KO mice. In contrast, both serum and brain (hippocampus and hypothalamus) oxytocin were decreased in CB1KO mice. Based on these results, we next attempted to recover the autistic-like behaviors in CB1KO mice. Then, single administration of LIT-001 (10 mg/kg, i.p.), an oxytocin receptor agonist, or SSR125543A (10 mg/kg, i.p.), a type 1 corticotropin-releasing factor (CRF1) receptor antagonist, significantly ameliorated the decrease of sociability and elevated repetitive behaviors in CB1KO mice. These results suggest that the endocrine abnormalities are involved in the expression of autistic-like behaviors observed in CB1KO mice. Therefore, CB1KO mice could have potential as a novel ASD model mouse and provide possibilities of drug development for ASD using the oxytocin receptor agonist and CRF1 receptor antagonist.
THE POSSIBLE ROLE OF RECEPTOR CHAPERONE MOLECULE/INTERFERON- STIMULATED GENE RTP4 IN THE DEVELOPMENT OF ANTINOCICEPTIVE TOLERANCE TO MORPHINE
Authors: Fujita *Wakako
Published: February 2025

Background

Although opioid analgesics exhibit potent antinociceptive effects, various side effects including antinociceptive tolerance limit their effective clinical use. Our previous studies show that neuronal receptor transporter protein 4 (RTP4), one of the receptor chaperone proteins that is also known as interferon (IFN)-stimulated gene, contributes to the mechanism of development of morphine tolerance. That is, the brain region (hypothalamus)-specific knock-down of RTP4 using AAV Cre recombinase in RTP4flox mice partially but significantly suppresses/delays the development of morphine tolerance (Fujita et al., 2022). Since chronic morphine treatment has been shown to increase Rtp4 in hypothalamus, this indicates a role for this chaperone in the mechanism of morphine tolerance.

Aims & Objectives

Although, studies suggest that glial as well as neuronal cells contribute to antinociceptive tolerance, the role of RTP4 in the specific cell types on opiate induced tolerance has not yet been elucidated. Here, we examined the changes in RTP4 levels in both neuronal and microglial cells after morphine exposure.

Methods

A neuronal cell line, Neuro2AMOPr cells, that express mu opioid recepor (MOPr) and a microglial cell line, SIM-A9 cells, were treated with DAMGO or morphine (10 µM to 1 mM), both are the MOPr agonist, for 24 hrs. The cells were collected and the RTP4 mRNA levels were evaluated by using RT-qPCR. Inhibitors were pretreated 30 to 60 min before the morphine treatment.

Results

We find that DAMGO treatment (10 µM, 24 hr) significantly up-regulates RTP4 mRNA levels in Neuro2AMOPr cell. This up-regulation was completely reversed by naltrexone, a MOPr antagonist and by U0126, a mitogen-activated protein kinase (MAPK) inhibitor. On the other hand, in SIM-A9 cells, only higher concentration of morphine (1 mM, 24-hr) significantly up-regulates RTP4 mRNA levels. This up- regulation was not reversed by naltrexone while it was significantly inhibited by a neutralizing antibody targeting toll-like receptor 4 (TLR4), antibody targeting IFN receptor, and by a janus kinase (JAK) inhibitor. Furthermore, interferon (IFN)-β mRNA levels were increased by morphine treatment in microglial cell.

Discussion & Conclusion

These findings suggest that in neuronal cells Rtp4 induction involves MOPr, Gi-mediated signaling and MAPK activation. Alternatively, Rtp4 induction in glial cells occurs via Toll-like receptor 4 and not MOPr. Together, these studies highlight a distinctive role for morphine activity in regulating RTP4 in neuronal and glial cells, which, in turn, may play an important role in modulating morphine effects in vivo.

References

Fujita, W. et al. (2022) 'Receptor transporter protein 4 (RTP4) in the hypothalamus is involved in the development of antinociceptive tolerance to morphine,' Biomolecules, 12(10), p. 1471. https://doi.org/10.3390/biom12101471.
EXAMINING THE EFFECTS OF SIGMA-1 RECEPTOR AGONISTS ON THE INTRACELLULAR LOCALIZATION OF THE ENDOGENOUS RECEPTOR IN NEURO2A CELLS
Authors: Yasui *Yuko , Couly Simon , Su Tsung-Ping
Published: February 2025

Background

Sigma-1 receptor (SIGMAR1) is a ligand-operated transmembrane protein highly expressed in the central nervous system, implicated in various psychiatric diseases such as addiction, depression and schizophrenia. Several psychostimulants and drugs for psychiatric diseases have affinity to SIGMAR1.

Pharmacological studies using animal models show that SIGMAR1 ligands have treatment effects on the disease conditions suggesting that SIGMAR1 can be a promising target for therapeutic approaches.

However, how SIGMAR1 ligands influence the molecular function of SIGMAR1 remains ambiguous. One potential aspect of SIGMAR1 ligand-mediated regulation lies on the localization of SIGMAR1. SIGMAR1 is enriched in the endoplasmic reticulum (ER), mostly at the membrane contact sites between ER and mitochondria, where SIGMAR1 associates with GRP78. Currently, there are contradicting reports on whether SIGMAR1 dissociates from GRP78 at the ER and translocates to other cellular compartments, such as the plasma membrane (PM), upon agonist stimulation. Also, many studies were conducted using overexpression of SIGMAR1 to examine the localization in cells, which may not represent the behavior of the endogenous protein.

Aims & Objectives

The aim of this study is to investigate the effects of agonist stimulation on SIGMAR1 intracellular localization at the endogenous level in the neuroblastoma cell line Neuro2a.

Methods

We utilized a novel immunocytochemistry protocol which can effectively label endogenous SIGMAR1 in cells. We fixed the cells and labeled SIGMAR1 and organelle marker proteins by using specific antibodies. Images were captured using confocal microscopy and analyzed to obtain Pearson’ s correlation co- efficiency. To test the agonist effect, we treated the cells with 10 mM of (+)-Pentazocine or PRE-084 for 30 min and performed the immunocytochemistry as described above.

Results

In untreated conditions, most of SIGMAR1 co-localizes with ER marker proteins followed by mitochondria markers, as expected. On the other hand, co-localization with other organelle markers, such as PM and ER-PM contact sites, was insignificant. The presence of SIGMAR1 in the nuclear envelope (NE) was negligible as well. With agonist stimulation, we found that SIGMAR1 co-staining with marker proteins for PM, ER-PM contact sites and NE did not increase. Nor was there any effect on the co-localization of SIGMAR1 with GRP78.

Discussion & Conclusion

In summary, our results confirm that SIGMAR1 localizes primarily in the ER in Neruo2a cells. When SIGMAR1 is stimulated with an agonist, it does not apparently translocate to PM, PM-ER contact site or NE. Nevertheless, it is possible that SIGMAR1 shows cell-type dependent dynamics. We speculate that SIGMAR1 stays in the ER and moves along within the peripheral ER structure after agonist stimulation and currently plan to study the dynamics of SIGMAR1 within the ER structures.
GLIA RESPONSES ARE ASSOCIATED WITH ABNORMAL BEHAVIORS IN AN ANIMAL MODEL OF TAU PATHOLOGIES
Authors: Liu *Yue , Mizoguchi Hiroyuki , Sobue Akira , Sahara Naruhiko , Yamanaka Koji , Yamada Kiyofumi
Published: February 2025

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’ s disease and related tauopathies and has gained prominence in the development of therapies for Alzheimer’ s disease. Glia responses are key feature of AD and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical Alzheimer’ s disease-like pathology have been developed to examine the pathogenic mechanisms underlying Alzheimer’ s disease and evaluate therapeutic approaches targeting tau and glial reactivity, but the relevant mechanisms remain unknown. In this study, we investigated changes in gene expression related to neuroinflammation in glial cells of rTg4510 mice, an animal model of non-Alzheimer’ s disease tauopathy. We first analyzed the behaviors of rTg4510 mice at 4- and 6-month-old that mimic behavioral and psychological problems of dementia. By using a magnetic-activated cell sorting technique, we then analyzed the gene expression related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nesting behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a greater amount of time in the open arm of the plus-maze test than control mice. In rTg4510 mice, Axl, Cd11c, and CD68 expression levels were increased in the microglial cells, and H2-D1, Psmb8, and H2-T23 expression levels in astrocyte cells were also increased when mice reached 6 months compared with control mice. These results raise a possibility that glia responses in rTg4510 mice may be related to their abnormal behavior.
DIFFERENTIAL EXPRESSION AND DISTINCT ROLES OF PROTEINASE- ACTIVATED RECEPTOR 2 IN MICROGLIA AND NEURONS IN NEONATAL MOUSE BRAIN AFTER HYPOXIA-ISCHEMIC INJURY
Authors: Liu *Yicong , Ni Junjun
Published: February 2025

Regulation of microglial activation and neuroinflammation are critical factors in the pathogenesis of ischemic brain injury. Interest in protease-activated receptor 2 (PAR2) as a pharmaceutical target for various diseases is creasing. However, it is unclear the expression and functions of PAR2 in hypoxia- ischemic (HI) brain injury. Mice with HI and cells with oxygen– glucose deprivation and reoxygenation (OGD/R) were studied. Immunoblot and qRT-PCR were used to study the differential gene expression in cultured microglia and neurons. Immunofluorescent staining was used to study the expression pattern of PAR2 in the HI brain and phagocytotic activity of microglia after OGD/R. In neonatal mice brain after HI, we found PAR2 expression was abundant in neurons, but barely in microglia from the contralateral side of cortex and hippocampus. Conversely, PAR2 expression was barely in neurons while significantly increased in activated microglia from the ipsilateral side of cortex and hippocampus. The activations of PAR2 were increased in both microglia and neuron in a cell model of OGD/R. PAR2 activation mediated the cross-talk between microglia and neurons including the following: microglial PAR2 mediated inflammatory responses that induced neuronal damage; neuronal PAR2 regulated chemokines that recruited activated microglia to damage area; microglia PAR2 controlled the phagocytosis of degenerating neurons. These data suggested differential expression and distinct roles of PAR2 in microglia and neurons after HI injury; thereby, interventions targeting PAR2 may provide insights into the inflammatory-related diseases.
INTRA-HIPPOCAMPAL INJECTION OF ALPHA-SYNUCLEIN PRE-FORMED FIBRILS TRIGGERS COGNITIVE DEFECT AND CHANGES TRANSCRIPTOME PROFILES
Authors: Huang *Yu Ting , Chen Jin Chung , Li Yu Ying
Published: February 2025

Parkinson's disease (PD) constitutes a significant aspect of motor and non-motor symptoms, the latter includes cognitive defect and mood disorders. Clinically, abnormal aggregation of α-synuclein (α-Syn) was found in patient’ s brain, but the pathogenesis mechanism of synucleinopathy remains to be defined. In this study, we aimed to determine whether hippocampal synucleinopathy contributes to cognitive dysfunction and to investigate the molecular changes connecting hippocampal synucleinopathy to dementia. To understand synucleinopathy-induced dementia, mice were injected α-Syn preformed fibrils (PFFs) into the hippocampus bilaterally. After 8 months of PFF injection, there was a significant increase in amount of α-Syn/pSer129. In the behavioral test, mice displayed cognitive deficits in recognition memory, social memory, working memory, and long-term memory. In addition, RNA-sequencing analysis identified 2,585 differentially expressed genes (DEGs, p-value <0.05) in the PFF-treated mice compared to the PBS control, In particular, pathway of transforming growth factor beta (TGFβ) was enriched in the PFF-injected mice. The TGFβ-related genes were increased in the hippocampus during the progress of synucleinopathy, i.e. BMPR2, BMP2, BMP5, TGFβ1 and the downstream signals of Smad1/5/8 and Smad2. Furthermore, there is a time-dependent change in the expression of GFAP, Iba1, inflammasome and the complement system, with those gene expression decreased at 8 months, while increased at 12-13 months after PFF injection. Moreover, amount of AMPA1/pSer845 of glutamate receptor increased after post- PFF injection across both time intervals. Collectively, our findings demonstrate that hippocampal synucleinopathy effectively induces cognitive impairments associated with dementia. These effects parallel with the altered BMP/TGFβ pathways, immune responses, the complement system, and glutamate systems. These molecular changes may serve as valuable biomarkers and potential therapeutic targets that bridge the link between hippocampal synucleinopathy and dementia.
ASSOCIATION BETWEEN GUT MICROBIOME AND DRINKING TYPES OF ALCOHOL USE DISORDER
Authors: Wu *Lawrence Shih Hsin , Huang Ming Chyi , Meng Shi Chun
Published: February 2025

Background

Alcohol use disorder (AUD) presents as a diverse condition, with clinical characteristics linked to treatment effectiveness varying among individuals. For example, distinct patterns of drinking exhibit distinct reactions to Naltrexone therapy. Individuals classified as reward drinkers tend to display a higher likelihood of positive response to Naltrexone treatment. Utilizing the gut-brain axis mechanism as a foundation, we explore disparities in gut microbiome profiles across various drinking patterns.

Methods

So far, a total of 36 patients diagnosed with AUD were included in the study, and their drinking patterns were evaluated following the guideline. DNA was extracted from the patients' stool samples, and high-throughput sequencing was employed for 16S rRNA data analysis, which was subsequently analyzed through bioinformatics methods. The AUD patients were categorized into four groups based on their reward and relief levels: low reward/low relief (4 subjects), high reward/low relief (2 subjects), low reward/high relief (9 subjects), and high reward/high relief (21 subjects).

Results

Analysis of alpha diversity in the stool samples from these groups revealed no significant differences in the microbial community richness. However, beta diversity analysis using NMDS, PCA, and PCoA indicated statistically significant distinctions in the stool microbiome patterns among the four groups.

Additionally, we conducted pairwise comparisons between low and high reward as well as relief groups using LDA. The analysis revealed a higher frequency of Bacillales and a decreased occurrence of Bacteroides species, including uniformis and fragilis, in the high relief group. Studies have linked Bacteroides uniformis and Bacteroides fragilis to depression in both human and mouse models. Moreover, Parabacteroides distasonis was more prevalent in low reward subjects compared to the high reward group and has been associated with inducing depression-like behavior in mouse models.

Conclusion

Various patterns in the gut microbiome are expected among different types of alcohol use disorder (AUD). Certain bacteria linked to specific drinking patterns have been associated with depression.

Subsequent research should explore the clinical aspects related to these drinking patterns, considering the alterations in gut bacterial composition in individuals with AUD.
DOES A DEPRESSIVE EPISODE PRECEDE PROBLEMATIC SMARTPHONE USE? : A NATIONWIDE STUDY IN KOREA
Authors: Seong *Su Jeong , Hong Jin Pyo , Hahm Bong-Jin , Chang Sung Man , Kim Byung-Soo , Lee Dong-Woo , Cho Seong-Jin , Park Jong-Ik , Park Jee Eun , Jeon Hong Jin
Published: February 2025

Background

Although many studies have consistently demonstrated the association between depression and problematic smartphone use (PSU), the temporal precedence and causality of this relationship remain controversial.

Aims & Objectives

This study aimed to investigate the relationship between major depressive disorder (MDD) and PSU in a sample of the general adult population by analyzing the association between present PSU and both past and current MDD.

Method

The study utilized data from the Korean Epidemiologic Catchment Area study, a nationwide epidemiologic survey that employed a multistage cluster sampling method. Participants were assessed using the Korean version of the Composite International Diagnostic Interview to diagnose MDD and the Smartphone Overuse Screening Questionnaire to identify PSU.

Results

Of the 916 subjects, 139 (15.2%) belonged to the PSU group. The prevalence of PSU in older adults was substantial, with 9.3% for the 36-50 age group and 5.4% for the over 50 age group. We found a significant association between MDD and PSU. Both current (OR 6.366, 95% CI 1.253-32.353) and previous (OR 2.826, 95% CI 1.528-5.227) MDD episodes were associated with increased risk of PSU.

Discussion & Conclusion

This study confirmed the association between PSU and MDD among the general adult population. Specifically, previously resolved depression was found to affect the current PSU. This study also contributes to the literature by utilizing standardized tools for diagnosing MDD, providing more robust evidence on the association between depression and PSU. Additionally, the study also highlighted that PSU is not limited to young populations.