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This study aimed to determine the prevalence of lumbar ligamentum flavum lesions and identify correlations between radiological and pathological findings. We conducted an observational cross-sectional study of 349 patients (lumbar: n = 296, thoracic: n = 39, lumbar and thoracic: n = 14, mean age: 69 ± 12 years, male: 74%) who underwent posterior surgery for thoracolumbar spinal canal stenosis between January 2008 and April 2023 at our hospital. Computed tomography (CT) revealed that the prevalence of ligamentum flavum lesions defined as a high-density area with a CT value of 200 Hounsfield Unit or higher in the lumbar and thoracic spine was 47% (147/310) and 85% (45/53), respectively. CT showed that most patients had radiologically suspected ossification in the lumbar (90%) and thoracic spine (98%) than radiologically suspected calcification. Lumbar lesions were thinner than the thoracic lesions (2.5 vs 3.7 mm, p < 0.01). Pathological examinations were performed in specimens collected from 34 cases (lumbar: n = 13, thoracic: n = 21), and ossification was found in 62% (8/13) and 95% (20/21) of lumbar and thoracic lesions (p = 0.02), respectively. Lastly, ossification was confirmed pathologically in 72% (8/11) and 95% (19/20) of lumbar and thoracic lesions that showed ossification on imaging (p = 0.13), respectively. The literature review revealed that the prevalence of the lumbar ligamentum flavum lesions varied from 1.5 to 35% and the patient population was mostly asymptomatic. Collectively, we found that the prevalence of lumbar ligamentum flavum lesions in symptomatic patients was greater than previously reported. Histologically confirmed ossification was less common in lumbar lesions than in thoracic lesions.

Abstract DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global “hypomethylator phenotype”, are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.

Abstract Background A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte–macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. Methods To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. Results Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. Limitations The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. Conclusions Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.

BackgroundSocial isolation during critical periods of development is associated with alterations in behavior and neuronal circuitry. This study aimed to investigate the immediate and developmental effects of social isolation on firing properties, neuronal activity-regulated pentraxin (NARP) and parvalbumin (PV) expression in the prefrontal cortex (PFC), social behavior in juvenile socially isolated mice, and the biological relevance of NARP expression in autism spectrum disorder (ASD).MethodsMice were subjected to social isolation during postnatal days 21–35 (P21–P35) and were compared with group-housed control mice. Firing properties in the PFC pyramidal neurons were altered in P35 socially isolated mice, which might be associated with alterations in NARP and PV expression.ResultsIn adulthood, mice that underwent juvenile social isolation exhibited difficulty distinguishing between novel and familiar mice during a social memory task, while maintaining similar levels of social interaction as the control mice. Furthermore, a marked decrease in NARP expression in lymphoblastoid cell lines derived from adolescent humans with ASD as compared to typically developing (TD) humans was found.ConclusionOur study highlights the role of electrophysiological properties, as well as NARP and PV expression in the PFC in mediating the developmental consequences of social isolation on behavior.

Abstract In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2 R172K and TP53 R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2 R172K and TP53 R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

Acute disseminated encephalomyelitis (ADEM), which is a disease that causes multifocal inflammatory demyelination of the central nervous system, occurs predominantly in children and young adults. We report an autopsy case of an elderly man with brainstem ADEM that progressed over a period of about 3 months. An 82-year-old man developed disturbance of consciousness, dysphagia, and ataxic gait over a period of about 3 months. He was admitted to another hospital for aspiration pneumonia and recovered but was transferred to our hospital due to prolonged disturbance of consciousness. The patient was able to follow simple commands but had a tendency to somnolence. In addition to meningeal stimulation signs, the patient had left-dominant upper and lower limb ataxia and right-dominant limb spasticity. Brain FLAIR/T2-weighted imaging showed high-intensity lesions from the brainstem to the middle cerebellar peduncle bilaterally, medulla oblongata and upper cervical spinal cord, and T1-weighted imaging revealed contrast-enhanced lesions in the left middle cerebellar peduncle and cervical spinal cord. Although spinal fluid examination revealed elevated proteins, other laboratory tests indicated no evidence of infection, vasculitis, collagen diseases or tumors, and anti-ganglioside, anti-AQP4 and anti-MOG antibodies were negative. After admission, the patient again developed aspiration pneumonia, which progressed to acute respiratory distress syndrome, and he died on the 15th day of hospitalization. Autopsy findings indicated acute and subacute demyelination mainly in the brainstem and cerebellum, and perivascular lymphocyte and macrophage infiltration in the areas of demyelination. A postmortem diagnosis of ADEM was made based on the generally monophasic course of the disease and the absence of regenerating myelinated sheaths. There are very few reports of elderly patients with brainstem ADEM. ADEM should be considered as a differential diagnosis in patients with brainstem encephalitis.

Glioneuronal and neuronal tumors (GNTs) are slow-growing lower-grade neuroepithelial tumors with mature neuronal and, less consistently, glial differentiation. Their identification has relied solely on histological proof of neuronal differentiation, which was considered to represent the well-differentiated nature of GNTs. However, after discovering the genetic alterations in GNTs, particularly those in the MAP-kinase pathway, it became evident that histological diagnoses are not always concurrent with genetic alterations and vice versa. Furthermore, since several inhibitors mediating the MAP-kinase pathway are available, at least for clinical trials, molecular-based classification is now warranted. Thus, the upcoming WHO Classification of Central Nervous System Tumors, 5th edition (WHO5CNS) applied DNA methylation profiling to segregate low-grade neuroepithelial tumors. This review gives an overview of the pathological features of GNTs with particular reference to the newly listed tumor types in WHO5CNS. The knowledge and awareness of each tumor type are essential to make a correct diagnosis and avoid unnecessary radical resection and chemoradiotherapy, as GNTs are relatively indolent and have a prolonged clinical course. In addition, being distinctive in location, age group, and histology, the integration of clinicopathological information will help identify relevant tumor types of GNTs without genetic testing, even in resource-limited settings.

The transmantle sign is considered to be a magnetic resonance imaging feature specific to patients with type II focal cortical dysplasia; however, this sign can be difficult to distinguish from other pathologies, such as a radial-oriented white matter band in tuberous sclerosis. Here, we report a case showing a high-intensity area on T2-weighted and fluid-attenuated inversion recovery images extending from the ventricle to the cortex associated with atypical histopathological findings containing corpora amylacea. This case demonstrates that some instances of transmantle signs may be due to corpora amylacea accumulation.

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans histiocyte disorder of unknown origin. Recently, biomarkers for the confirmation of HS diagnosis have been reported. This report describes a case of primary HS of the central nervous system with description of the pathological anatomy. The patient was older than those in other such cases reported in the literature and presented with unspecific symptoms. This case highlights the difficulty in diagnosis and importance of suspicion of HS.

Abstract Adverse experience in early life can affect the formation of neuronal circuits during postnatal development and exert long-lasting influences on neural functions that can lead to the development of a variety of psychiatric disorders including depression, anxiety disorders, and post-traumatic stress disorder. Many studies have demonstrated that daily repeated maternal separation, an animal model of early-life stress, can induce impairments in emotional behaviours and cognitive function during adolescence and adulthood. However, the behavioural phenotypes of maternally separated mice under long-term group-housing conditions are largely unknown. In this study, we applied our newly developed assay system to investigate the effects of maternal separation on behaviours under group-housing conditions during four days of continuous observations. Using our system, we found that repeated maternal separation resulted in inappropriate social distance from cagemates, altered approach preferences to others, and induced a lower rank in the time spent on the running wheel under group-housing conditions in adult male mice. Focussing on these behavioural abnormalities that appear in an environment with a social context will be important insights to understand the pathogenesis of psychiatric disorders.

Abstract Aim We assessed the efficacy of buprenorphine replacement taper therapy in a psychiatric hospital in Japan. Methods Based on the medical records, a retrospective analysis was performed to evaluate the outcomes of buprenorphine replacement taper therapy in 106 subjects with heroin dependence. Results We found that replacement and taper therapy with buprenorphine could significantly reduce withdrawal symptoms during detoxification. In addition, the completion rate of detoxification was significantly improved and the length of hospital stay was significantly reduced relative to those who received conventional treatment without buprenorphine. However, the readmission rate increased after the introduction of detoxication therapy with buprenorphine. Conclusion The present findings suggest not only the efficacy and safety of buprenorphine replacement and taper therapy, but also the requirement for maintenance therapy for individuals with heroin dependence.

Abstract Background Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies. Methods Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined. Results Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively. Conclusions In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.

Recurrent glioblastoma (GBM) remains one of the most challenging clinical issues, with no standard treatment and effective treatment options. To evaluate the efficacy of talaporfin sodium (TS) mediated photodynamic therapy (PDT) as a new treatment for this condition, we retrospectively analyzed 70 patients who underwent surgery with PDT (PDT group) for recurrent GBM and 38 patients who underwent surgery alone (control group). The median progression-free survival (PFS) in the PDT and control groups after second surgery was 5.7 and 2.2 months, respectively (p = 0.0043). The median overall survival (OS) after the second surgery was 16.0 and 12.8 months, respectively (p = 0.031). Both univariate and multivariate analyses indicated that surgery with PDT and a preoperative Karnofsky Performance Scale were significant independent prognostic factors for PFS and OS. In the PDT group, there was no significant difference regarding PFS and OS between patients whose previous pathology before recurrence was already GBM and those who had malignant transformation to GBM from lower grade glioma. There was also no significant difference in TS accumulation in the tumor between these two groups. According to these results, additional PDT treatment for recurrent GBM could have potential survival benefits and its efficacy is independent of the pre-recurrence pathology.

Abstract Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

Abstract Background Because soluble (or secreted) amyloid precursor protein-β (sAPPβ) and -α (sAPPα) possibly reflect pathological features of Alzheimer’s disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPβ in CSF as diagnostic biomarkers of dementia disorders. Methods We used a modified and sensitive detection method to analyze sAPPs levels in CSF in four groups of patients: AD (N = 33), MCI-AD (N = 17), non-AD dementia (N = 27), and disease controls (N = 19). Phosphorylated tau (p-tau), total tau, and Aβ42 were also analyzed using standard methods. Results A strong correlation was observed between sAPPα and sAPPβ, consistent with previous reports. Both sAPPα and sAPPβ were highly correlated with p-tau and total tau, suggesting that sAPPs possibly reflect neuropathological changes in the brain. Levels of sAPPα were significantly higher in MCI-AD cases compared with non-AD and disease control cases, and those of sAPPβ were also significantly higher in MCI-AD and AD cases relative to other cases. A logistic regression analysis indicated that sAPPα and sAPPβ have good discriminative power for the diagnosis of MCI-AD. Conclusions Our findings collectively suggest that both sAPPs are pathologically relevant and potentially useful biomarkers for early and accurate diagnosis of dementia disorders. We also suggest that careful measurement is important in assessing the diagnostic utility of CSF sAPPs.

Abstract Social isolation is an important factor in the development of psychiatric disorders. It is necessary to develop an effective psychological treatment, such as cognitive rehabilitation, for children who have already suffered from social isolation, such as neglect and social rejection. We used socially isolated mice to validate whether elaborate re-socialization after juvenile social isolation can restore hypomyelination in the medial prefrontal cortex (mPFC) and the attendant functions manifested in socially isolated mice. While mice who underwent re-socialization with socially isolated mice after juvenile social isolation (Re-IS mice) demonstrated less mPFC activity during exposure to a strange mouse, as well as thinner myelin in the mPFC than controls, mice who underwent re-socialization with socially housed mice after juvenile social isolation (Re-SH mice) caught up with the controls in terms of most mPFC functions, as well as myelination. Moreover, social interaction of Re-IS mice was reduced as compared to controls, but Re-SH mice showed an amount of social interaction comparable to that of controls. These results suggest that the mode of re-socialization after juvenile social isolation has significant effects on myelination in the mPFC and the attendant functions in mice, indicating the importance of appropriate psychosocial intervention after social isolation.

Abstract Backgrounds Social hierarchy is one of the most influential social structures employed by social species. While dominants in such hierarchies can preferentially access rich resources, subordinates are forced into lower social statuses and lifestyles with inferior resources. Previous studies have indicated that the social rank regulates social behaviors and emotion in a variety of species, whereby individual organisms live within the framework of their ranks. However, in human societies, people, particularly young men, who cannot accept their own social status may show social withdrawal behaviors such as hikikomori to avoid confronting their circumstances. Methods This article reviews the neural mechanisms underlying social status identified in animal studies with rodents and primates, and assesses how social rank affects animal's social behaviors and emotion which may be relevant to modern type depression. Results Several brain regions such as medial prefrontal cortex are implicated in the formation of animal's social status, which leads to the differences in vulnerability and resilience to social stress. Conclusion On the basis of these findings, we propose that physical interventions such as voluntary exercise, diet, transcranial direct current stimulation, and psychotherapy, rather than psychotropic drugs, may be useful therapeutic approaches for modern type depression, which is a typical example of social status conflict and a phenotype of adjustment disorder to the traditional hierarchical social order.

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.

ObjectiveThe goal of this study was to demonstrate the feasibility of intraoperative photodynamic diagnosis (PDD) of malignant glioma using the fluorescence from talaporfin sodium (TS), which is used simultaneously for photodynamic therapy (PDT).MethodsPatients with suspected primary malignant glioma who were eligible for surgical removal of the tumor and PDT with TS were enrolled in this prospective study. Tissue samples were obtained from the contrast-enhanced (CE) region and from the surrounding non-contrast-enhanced (NCE) marginal tissue at the boundary between the tumor and normal tissue. The excised samples were set into a fluorescence measurement system, which consisted of a semiconductor laser with a 400-nm wavelength for excitation, and a compact spectrometer for detection, which were applied and received through a custom-made probe consisting of coaxial optical fibers. The fluorescence spectrum was obtained, and peak intensity was calculated. Tumor cellularity was histopathologically analyzed and semi-quantitatively classified into four (0–3) categories.Results86 samples from 17 surgical cases were available for fluorescence measurement and analysis. The fluorescence from TS had a single peak at 664 nm that was easily distinguished from the 400-nm excitation light. Samples from the CE regions showed higher fluorescence intensity than those from the NCE regions (P

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.