牧之段 学

AIM: This study aimed to explore the relationship between self-esteem and tumor necrotic factor-alpha (TNF-α) expression in individuals with autism spectrum disorder (ASD). Self-esteem was assessed using the Contingencies of Self-Worth (CSW) scale, with a focus on external and internal contingencies, and TNF-α expression was measured, given its association with both ASD pathophysiology and self-esteem in prior studies. METHODS: We enrolled 51 high-functioning individuals with ASD and 34 typically developed (TD) individuals. Self-esteem was assessed using the Japanese version of the CSW scale, which evaluates seven domains, and the Personal Sense of Power. TNF-α expression in plasma was quantified via ELISA. Correlations of CSW scores and the Personal Sense of Power with TNF-α levels were analyzed using multiple regression models adjusted for confounding factors such as age, sex, education level, and autistic symptoms. RESULTS: In ASD individuals, TNF-α expression was significantly negatively correlated with the external CSW domain of others' approval and showed a trend toward negative correlations with appearance and relationship harmony. These correlations were not observed in the TD individuals. Likewise, the Personal Sense of Power within family settings showed a trend toward positive correlations with TNF-α expression in ASD individuals, but not in TD individuals. DISCUSSION: This study highlights the implication of TNF-α levels in the self-esteem of ASD individuals, particularly in interpersonal relationships. Lower TNF-α expression was associated with higher self-esteem in social contexts, independent of the severity of autistic symptoms. These findings suggest a biological link between inflammatory pathways and self-esteem in ASD, contributing to a deeper understanding of the interplay between immune function and psychological well-being in this population.

Sensory issues are common in autism spectrum disorders (ASD) and can significantly affect daily living. The phenomena of gating and habituation of event-related potentials (ERPs) to repetitive stimuli have been suggested as potential biomarkers reflecting atypical sensory processing in ASD. Sensory hypersensitivity and anxiety are closely related in ASD, and habituation to emotionally evocative stimuli may serve as a more sensitive biomarker for sensory hypersensitivity symptoms. However, previous studies have primarily used tonal stimuli, and there has been little investigation into whether habituation to emotionally evocative sounds is impaired in ASD patients. In this study, we compared the degree of habituation of the P1-N1 peak-to-peak amplitude in response to repeated tones and fearful vocalizations between control and ASD groups. Contrary to expectations, no significant difference was observed for fearful vocalizations between the groups, while ASD patients showed significantly reduced habituation to tonal sounds in the left parieto-occipital region. Furthermore, we found a significant correlation between the degree of habituation to tonal sounds in the left parieto-occipital region and sensory hypersensitivity symptoms in ASD patients, and similar abnormalities in BTBR mice, an animal model of ASD. These results suggest that habituation to tonal sounds, rather than emotionally evocative stimuli, may serve as a translational biomarker reflecting sensory hypersensitivity symptoms.

Dendritic spine abnormalities are believed to be one of the critical etiologies of autism spectrum disorder (ASD). Over the past decade, the importance of microglia in brain development, particularly in synaptic elimination, has become evident. Thus, microglial abnormalities may lead to synaptic dysfunction, which may underlie the pathogenesis of ASD. Several human studies have demonstrated aberrant microglial activation in the brains of individuals with ASD, and studies in animal models of ASD have also shown a relationship between microglial dysfunction and synaptic abnormalities. However, there are very few methods available to directly assess whether phagocytosis by human microglia is abnormal. Microglia are tissue-resident macrophages with phenotypic similarities to monocyte-derived macrophages, both of which consistently exhibit pathological phenotypes in individuals with ASD. Therefore, in this study, we examined the phagocytosis capacity of human macrophages derived from peripheral blood monocytes. These macrophages were polarized into two types: those induced by granulocyte-macrophage colony-stimulating factor (GM-CSF MΦ, traditionally referred to as "M1 MΦ") and those induced by macrophage colony-stimulating factor (M-CSF MΦ, traditionally referred to as "M2 MΦ"). Synaptosomes purified from human induced pluripotent stem cell-derived neuron were used to assess phagocytosis capacity. Our results revealed that M-CSF MΦ exhibited higher phagocytosis capacity compared to GM-CSF MΦ, whereas ASD-M-CSF MΦ showed a marked impairment in phagocytosis. Additionally, we found a positive correlation between phagocytosis capacity and cluster of differentiation 209 expression. This research contributes to a deeper understanding of the pathobiology of ASD and offers new insights into potential therapeutic targets for the disorder.

AIM: Autism spectrum disorder (ASD) is a neurodevelopmental condition that markedly impairs the physical, emotional, and social domains of health-related quality of life (HRQOL). Children with ASD typically report lower HRQOL than their neurotypical peers. This study investigated the impact of self-esteem and depressive symptoms on HRQOL in children with ASD and explored the discrepancies between parent-reported and self-reported HRQOL. METHODS: This study involved 94 participants, comprising 50 children with ASD and 44 typically developed. HRQOL was measured using the J-KIDSCREEN-52 (self-reported and parent-reported). Self-esteem, depressive symptoms, and social support were assessed using the Rosenberg Self-Esteem Scale, the Depression Self-Rating Scale for Children, and the Multidimensional Scale of Perceived Social Support, respectively. Discrepancies between parent-reported and self-reported HRQOL were examined. Multiple regression analyses were performed to determine the influence of depressive symptoms and self-esteem on HRQOL. RESULTS: Children with ASD showed markedly lower HRQOL than their neurotypical peers. Discrepancies between parent-reported and self-reported HRQOL revealed differing perspectives. Higher depressive symptoms were strongly correlated with poorer HRQOL. Conversely, higher self-esteem was linked to better HRQOL, notably in terms of self-perception. Social support also markedly influenced HRQOL. CONCLUSION: This study underscores the necessity of addressing depressive symptoms, self-esteem, and social support as interventions to enhance HRQOL in children with ASD. The differences between parent-reported and self-reported HRQOL highlight the need to incorporate both views into clinical assessments for comprehensive and effective interventions. Future research should explore these dynamics longitudinally and across diverse populations to refine the intervention strategies.

Objective: To provide proof-of-concept (PoC), dose-range finding, and safety data for BI 1358894, a TRPC4/5 ion channel inhibitor, in patients with borderline personality disorder (BPD). Methods: This was a phase 2, multinational, randomized, double-blind, placebo controlled trial. Patients were randomized to oral placebo or BI 1358894 (5 mg, 25 mg, 75 mg, or 125 mg) once daily in a 2.5:1:1:1:2 ratio for 12 weeks. The primary end point was change from baseline in the Zanarini Rating Scale for BPD (ZAN BPD) total score at Week 10. Secondary end points included ≥30% ZAN-BPD reduction response from baseline at Week 10, change from baseline at Week 10 in the Difficulties in Emotion Regulation Scale-16 item total, State-Trait Anxiety Inventory-State Anxiety total, Patient Health Questionnaire-9 total, Clinical Global Impressions-Severity, and Patient Global Impression-Severity scores. Results: Of 655 enrolled patients, 390 were randomized and 323 (82.8%) completed the trial. For primary and secondary end points, no differences were observed between treatment and placebo; therefore, PoC was not established. The proportion of patients with adverse events (AEs, BI 1358894 overall vs placebo: 77.9% vs 75.0%) and serious AEs (SAEs; 10.3% vs 8.6%) was comparable between treatments. The proportion of patients with an SAE of suicidal ideation was 4.2% (BI 1358894 overall) and 6.3% (placebo). Conclusions: Although the primary end point was not met, BI 1358894 was well tolerated with no increase in self harm or suicidality. More targeted populations, alternative outcome assessments, and additional measures to minimize placebo effects should be considered for future trials. Trial Registration: ClinicalTrials.gov identifier: NCT04566601.