bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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&lt;0.05) and all subjective sleeping measures (all P&lt;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&lt;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&lt;0.001]) significantly improved. ESS scores significantly improved (P&lt;0.001) at 4 weeks compared with baseline and PSQI (P=0.012), ESS (P&lt;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

Abstract

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

Abstract

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 &lt;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

Abstract
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

Abstract

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 &micro;M 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 &micro;M, 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.