The etiology of autism spectrum disorder (ASD) is complex, and its pathobiology is characterized by enhanced inflammatory activities; however, the precise pathobiology and underlying causes of ASD remain unclear. This study was performed to identify inflammatory indicators useful for diagnosing ASD. The mRNA expression of cytokines, including tumor necrosis factor‐α (TNF‐α), was measured in cultured M1 and M2 macrophages from patients with ASD (n = 29) and typically developed (TD) individuals (n = 30). Additionally, TNF‐α expression in the monocytes of patients with ASD (n = 7), showing aberrations in TNF‐α expression in M1/M2 macrophages and TD individuals (n = 6), was measured. TNF‐α expression in M1 macrophages and the TNF‐α expression ratio in M1/M2 macrophages were markedly higher in patients with ASD than in TD individuals; however, this increase was not observed in M2 macrophages (M1: sensitivity = 34.5%, specificity = 96.7%, area under the curve = 0.74, positive likelihood ratio = 10.34; ratio of M1/M2: sensitivity = 55.2%, specificity = 96.7%, area under the curve = 0.79, positive likelihood ratio = 16.55). Additionally, TNF‐α expression in monocytes did not significantly differ between patients with ASD and TD individuals. In conclusion, further studies on TNF‐α expression in cultured macrophages may improve the understanding of ASD pathobiology. Lay Summary TNF‐α expression in differentiated M1 macrophages and TNF‐α expression ratio in differentiated M1/M2 macrophages were markedly higher in patients with ASD than in TD individuals, while no difference in TNF‐α expression was found in pre‐differentiation cells such as monocytes. These measurements allow elucidation of the novel pathobiology of ASD and can contribute to biomarker implementation for the diagnosis of adult high‐functioning ASD.
The gut hormone ghrelin has been implicated in a variety of functional roles in the central nervous system through the brain-gut axis, one of which is an anti-inflammatory effect. An aberrant brain-gut axis producing immune dysfunction has been implicated in the pathobiology of autism spectrum disorder (ASD), and elevated expression of inflammatory markers has been shown in blood and brain tissue from subjects with ASD. We hypothesized that ghrelin may mitigate this effect. Lymphoblastoid cell lines from typically developed children (TD-C) ( N = 20) and children with ASD (ASD-C) ( N = 20) were cultured with PBS or human ghrelin (0.01 μM) for 24 h, and mRNA expression levels of the inflammation-related molecules interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B (NF-κB) were measured to examine the effects of ghrelin as an anti-inflammatory agent. Expression levels of TNF-α and NF-κB mRNA, but not IL-1β or IL-6, were significantly elevated in ASD-C compared to TD-C. Ghrelin showed a tendency to reduce the expression of TNF-α and NF-κB, but this was not statistically significant. Considering the heterogenous pathobiology of ASD, we examined the effects of ghrelin on TD-C and ASD-C with expression levels of TNF-α and NF-κB in the highest and lowest quartiles. We found that ghrelin markedly reduced mRNA expression of TNF-α and NF-κB s in ASD-C with highest-quartile expression, but there were no effects in ASD-C with lowest-quartile expression, TD-C with highest quartile expression, or TD-C with lowest quartile expression. Together, these findings suggest that ghrelin has potential as a novel therapeutic agent for ASD with inflammation and/or immune dysfunction.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Recent studies have indicated that early rehabilitative intervention can alleviate the symptoms of individuals with ASD. However, it remains unknown whether rehabilitative intervention can restore brain structures such as myelin, which generally shows abnormalities in individuals with ASD. Therefore, in the present study, we used a mouse model of ASD (BTBR mice) that demonstrated asocial behaviors and hypomyelination in the medial prefrontal cortex (mPFC) to investigate whether interaction with social peers (C57BL/6J mice) has an effect on myelination. We found that housing with C57BL/6J mice after weaning through adulthood increased the myelin thickness in mPFC, but not in the motor cortex, of BTBR mice. There was no effect of cross-rearing with C57BL/6J mice on axon diameter in mPFC of BTBR mice. This finding suggests that early rehabilitative intervention may alleviate myelin abnormalities in mPFC as well as clinical symptoms in individuals with ASD.
Abstract:A number of studies have indicated that relaxing and pleasant melodies are useful for the treatment of patients with psychiatric disorders, including schizophrenia, depression, and dementia. However, few studies have investigated what constitutive elements of the music had an effect on brain activity. As Canon chord progression is one of critical elements for pleasant melodies, we sought to examine the effects of Canon chord progression and pitch-shifted Canon chord progression on brain activity using performance on the auditory oddball task during event-related potentials (ERPs) in 30 healthy subjects. Unexpectedly, we found no differences in ERP components between subjects listening to Canon chord progression (n=15) or pitchshifted Canon chord progression (n=15). Next, we divided participants into two groups: those who found the melody pleasant (n=17) and those who did not (n=13), for both Canon chord progression and pitch-shifted Canon chord progression. The average of P300 amplitude was higher at Fz in subjects found the music pleasant versus those finding it unpleasant. Moreover, subjects who found it pleasant exhibited higher motivation scores than those who felt it was unpleasant, whereas listening to Canon chord progression did not matter. These findings suggest that the effects of Canon chord progression on brain activity and motivation depend on subjective feelings, not the chord progression per se.
Background The etiology of autism spectrum disorder (ASD) is complex. Its pathobiology is characterized by enhanced inflammatory activities; however, the exact ASD pathobiology remains unclear. Some cases of ASD are difficult to diagnose using existing psychological assessments because the careful exclusion of other psychiatric disorders is challenging. To distinguish between the appropriate targets for interventions and research, the demand for identifying efficient diagnostic biomarkers is increasing. This study aimed to find an inflammatory indicator beneficial for the diagnosis of ASD.Methods Cytokine mRNA expression, including tumor necrosis factor-α (TNF-α), was measured in the differentiated M1 and M2 macrophages of ASD patients (n = 29) and typically developed (TD) individuals (n = 30). TNF-α expression was also measured in the monocytes of ASD patients (n = 7) and TD individuals (n = 6).Results TNF-α expression in M1 macrophages and TNF-α expression ratio of M1/M2 macrophages were markedly higher in ASD patients than in TD subjects; however, this difference was not observed in M2 macrophages (M1: p < 0.01; ratio of M1/M2: p < 0.0001; M2: p > 0.05), suggesting that this indicator could be a useful tool for diagnosing ASD (M1: sensitivity = 34.5%, specificity = 96.7%, area under the curve (AUC) = 0.74, positive likelihood ratio (PLR) = 10.34; ratio of M1/M2: sensitivity = 55.2%, specificity = 96.7%, AUC = 0.79, PLR = 16.55). However, there was no significant difference in the TNF-α expression in monocytes between ASD and TD individuals (p > 0.05).Conclusion These findings suggest that TNF-α expression in differentiated macrophages represents a novel adjunctive tool for the diagnosis of ASD.
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