鳥塚 通弘

BACKGROUND: Alzheimer's disease (AD) is associated with memory impairment and social cognitive dysfunction, including facial emotion recognition (FER) deficits. Our previous diffusion tensor imaging (DTI) study linked poor recognition of negative facial emotions in patients with AD to increased mean diffusivity (MD) in the left uncinate fasciculus (UF). Whether FER deficits in AD reflect microstructural alterations in related grey matter regions remains unclear. METHODS: In this cross-sectional study, 74 patients with AD and 28 cognitively normal (CN) subjects underwent behavioural assessments using the Facial Emotion Selection Test (FEST). A subset of 67 AD patients and 23 CN patients underwent magnetic resonance imaging. DTI was used to assess the fractional anisotropy (FA) and MD of the bilateral UF, and neurite orientation dispersion and density imaging (NODDI) was used to evaluate the neurite density index (NDI) and orientation dispersion index (ODI) of the insula, amygdala and temporal lobe. RESULTS: Patients with AD showed significantly lower FEST total, negative emotion, positive emotion and neutral expression scores. DTI revealed significantly lower FA and higher MD in the bilateral UF. In the AD group, higher bilateral UF MD was significantly associated with lower total FEST and negative emotional scores. NODDI analyses demonstrated significantly lower ODI in the insula, amygdala and temporal lobe in the AD group, whereas no significant between-group differences were observed in the NDI. In the uncorrected analyses, ODI showed trend-level positive associations with FEST performance; however, these associations did not remain significant after false discovery rate correction. Bilateral UF MD was negatively correlated with ODI in the insula and temporal lobes. CONCLUSIONS: FER is broadly impaired in AD and is associated with bilateral UF abnormalities and reduced ODI in the frontotemporal-limbic regions. These findings suggest that social cognitive dysfunction in AD involves broader frontotemporal-limbic network disruption than isolated white matter abnormalities.

BACKGROUND: This study examined whether the timing of adverse childhood experiences (ACEs) is associated with differences in intellectual ability in adults with autism spectrum disorder (ASD) without intellectual disability. METHODS: A total of 161 adults with ASD were categorized into three groups based on ACE onset: no ACEs (Group 0), early childhood ACEs (≤ 10 years; Group 1), and adolescent ACEs (11-18 years; Group 2). Intellectual ability was assessed using the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV). RESULTS: Findings revealed that Group 1 outperformed Group 2 on the picture completion and figure weights subtests, suggesting that early ACE exposure may be linked to distinct cognitive profiles in ASD. To account for the higher severity of post-traumatic stress disorder (PTSD) symptoms, including hypervigilance, in Group 1 compared to Group 2, we conducted multivariate analyses of covariance and logistic regression to control for potential confounders such as years of education and PTSD symptom severity, given that hypervigilance may influence cognitive task performance. However, the observed differences remained significant. CONCLUSION: These results suggest a potential association between the timing of ACE exposure and specific cognitive subdomains in adults with ASD. Furthermore, WAIS-IV subtests, particularly picture completion and figure weights, may serve as potential markers for identifying cognitive adaptations associated with early adversity in ASD individuals. CLINICAL TRIAL REGISTRATION: Since this study was not a clinical trial, this section does not apply.

AIM: Given that alterations in oxytocinergic and immune systems have been implicated in the social and emotional difficulties of autism spectrum disorder (ASD), yet the associations between these biological factors and internal psychological constructs remain unclear, we examined the relationship between salivary oxytocin (OT) levels, inflammatory markers (interleukin-1β [IL-1β], IL-6, IL-8), self-esteem, and perceived social support in children and adolescents with and without ASD. METHODS: 26 children and adolescents with ASD and 23 typically developing (TD) controls were included. Salivary OT and inflammatory cytokine levels were measured using enzyme-linked immunosorbent and multiplex immunoassays. RESULTS: Salivary oxytocin levels were significantly lower in the ASD group than in the TD group after adjusting for age. In contrast, no significant group differences were observed in inflammatory markers (IL-1β, IL-6, or IL-8). However, across participants, including those with ASD, higher OT levels were associated with greater self-esteem and perceived social support. These findings suggest that oxytocin-related socio-emotional processes may be associated with socio-emotional functioning across children and adolescents, including those with ASD. Participants with higher OT levels were associated with greater self-esteem and perceived social support. Among the inflammatory markers, none of the cytokines (IL-1β, IL-6, or IL-8) showed significant associations with the psychological measures, including AQ-J total scores. CONCLUSION: OT levels may be associated with socio-emotional functioning and psychological well-being across children and adolescents with and without ASD, regardless of diagnostic status. In contrast, no significant associations were observed between inflammatory markers and psychological measures in the present sample.

Sex differences in autism spectrum disorder (ASD) are increasingly recognized, not only in symptom presentation but also in underlying neurobiology and response to environmental factors. However, current diagnostic practices and animal models are male-centric, overlooking female-specific phenotypes and mechanisms. We conducted a multimodal, cross-species study to assess sex-dependent ASD phenotypes. In high-functioning adults with ASD and typically developing (TD) controls, we evaluated self-reported autistic traits, self-reported sensory sensitivity, and clinician-observed behaviors using standardized tools: Autism-Spectrum Quotient, Adolescent/Adult Sensory Profile, and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). In parallel, we assessed behavioral phenotypes in a paternal 15q11-q13 duplication mouse model (15q dup/+) using open-field, light-dark transition, and augmented reality-based behavioral assays. Among humans, individuals with ASD showed greater self-reported sensory sensitivity and autistic traits than TD individuals. Within the ASD group, female participants reported greater self-reported sensory sensitivity and exhibited lower clinician-rated impairments (ADOS-2) than male participants, despite comparable self-reported autistic traits. No sex differences were found among TD individuals. In contrast, female 15q dup/+ mice exhibited heightened light-related sensory reactivity and reduced exploratory behavior under bright light. These findings suggest that sex differences in light-related sensory reactivity may be more readily detected through behavioral measures in animal models. Our findings underscore the importance of considering sex as a biological and behavioral variable in ASD research. Cross-species, phenotype-oriented approaches that integrate human and animal data may uncover subtle phenotypic variations and enhance sex-informed diagnostics and interventions.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and restricted repetitive behaviors, yet the contribution of trace elements remains poorly defined. We profiled 21 trace elements in individuals with ASD and identified significantly reduced copper levels, which negatively correlated with social symptom severity. Magnetic resonance imaging revealed decreased white matter volume in ASD, which also correlated with social impairment. To explore the mechanisms, we generated a copper-deficient mouse model that displayed ASD-like behaviors and impaired oligodendrocyte (OL) development. Copper deficiency disrupted hypoxia-inducible factor 1α (HIF1α)–dependent angiogenesis and metabolic regulation in the embryonic brain, leading to oxidative stress, mitochondrial dysfunction, and BCL2 interacting protein 3 (BNIP3)-mediated mitophagy in oligodendrocyte progenitor cells. These processes suppressed mechanistic target of rapamycin kinase (mTOR) signaling, reduced OL-lineage cells, and caused hypomyelination. Restoring mTOR activity rescued OL maturation and improved social behavior in copper-deficient mice. These findings identify a copper-HIF1α-BNIP3-mTOR signaling axis that links trace element imbalance to glial dysfunction and ASD-relevant behavioral phenotypes, providing mechanistic insight into neurodevelopment.