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We herein report a case of multiple myeloma and polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes (POEMS) syndrome. The patient experienced exacerbated gait disturbance due to weakness and numbness in the lower limbs. Thoracic magnetic resonance imaging revealed an extramedullary tumor with spinal compression that required surgical resection. Plasmacytoma was diagnosed based on a biopsy. Radiation, betamethasone, and chemotherapy were therefore administered. Surgical removal of extramedullary tumors improved his symptoms, motor conduction velocity, and amplitude of the muscle action potential in the peroneal and tibial nerves, as shown by the nerve conduction study. Surgery also decreased the serum vascular endothelial growth factor levels. The patient required additional chemotherapy due to multiple myeloma and showed better outcomes nine months after discharge. The benefits of some treatments remain controversial due to the small number of patients. However, our findings reveal that an early diagnosis and comprehensive treatment may result in better outcomes in such patients.

Multiple sclerosis and neuromyelitis optica spectrum disorders are both neuroinflammatory diseases and have overlapping clinical manifestations. We developed a convolutional neural network model that differentiates between the two based on magnetic resonance imaging data. Thirty-five patients with relapsing-remitting multiple sclerosis and eighteen age-, sex-, disease duration-, and Expanded Disease Status Scale-matched patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders were included in this study. All patients were scanned on a 3-T scanner using a multi-dynamic multi-echo sequence that simultaneously measures R1 and R2 relaxation rates and proton density. R1, R2, and proton density maps were analyzed using our convolutional neural network model. To avoid overfitting on a small dataset, we aimed to separate features of images into those specific to an image and those common to the group, based on SqueezeNet. We used only common features for classification. Leave-one-out cross validation was performed to evaluate the performance of the model. The area under the receiver operating characteristic curve of the developed convolutional neural network model for differentiating between the two disorders was 0.859. The sensitivity to multiple sclerosis and neuromyelitis optica spectrum disorders, and accuracy were 80.0%, 83.3%, and 81.1%, respectively. In conclusion, we developed a convolutional neural network model that differentiates between multiple sclerosis and neuromyelitis optica spectrum disorders, and which is designed to avoid overfitting on small training datasets. Our proposed algorithm may facilitate a differential diagnosis of these diseases in clinical practice.

To identify factors associated with burnout among Japanese physician and to use them in future measures, the Japanese Society of Neurology conducted a survey of neurologists on burnout using a web-based questionnaire in October 2019. A total of 1,261 respondents, 15.0% of the 8,402 members, responded to the survey. The mean of the subscales of the Japanese Burnout Scale was 2.86/5 points for emotional exhaustion, 2.21/5 points for depersonalization, and 3.17/5 points for lack of personal accomplishment. In addition, the burnout of our country's neurologists is not related to workloads such as working hours and the number of patients in charge, but also to a decreased meaningfulness and professional accomplishment. Therefore, it is necessary to take comprehensive measures to improve these issues at the individual, hospital, academic and national levels.

A questionnaire survey was conducted on 8,402 members of the Japanese Neurological Society to examine the current status and countermeasures for physician burnout, and 1,261 respondents (15.0%) responded. In this paper, we report the results of a comparison between male and female physicians. There was a significant difference in working and living conditions only for married people. It was confirmed that men work under stricter conditions in terms of working hours, and that the burden on women is heavier in the division of housework. Analysis using the Japanese Burnout Scale revealed no gender differences in overall scores, but as for factors related to burnout, in addition to factors common to both men and women, factors specific to men or women were clarified.

Purpose: A current algorithm to obtain a synthetic myelin volume fraction map (SyMVF) from rapid simultaneous relaxometry imaging (RSRI) has a potential problem, that it does not incorporate information from surrounding pixels. The purpose of this study was to develop a method that utilizes a convolutional neural network (CNN) to overcome this problem. Methods: RSRI and magnetization transfer images from 20 healthy volunteers were included. A CNN was trained to reconstruct RSRI-related metric maps into a myelin volume-related index (generated myelin volume index: GenMVI) map using the MVI map calculated from magnetization transfer images (MTMVI) as reference. The SyMVF and GenMVI maps were statistically compared by testing how well they correlated with the MTMVI map. The correlations were evaluated based on: (i) averaged values obtained from 164 atlas-based ROIs, and (ii) pixel-based comparison for ROIs defined in four different tissue types (cortical and subcortical gray matter, white matter, and whole brain). Results: For atlas-based ROIs, the overall correlation with the MTMVI map was higher for the GenMVI map than for the SyMVF map. In the pixel-based comparison, correlation with the MTMVI map was stronger for the GenMVI map than for the SyMVF map, and the difference in the distribution for the volunteers was significant (Wilcoxon sign-rank test, P < 0.001) in all tissue types. Conclusion: The proposed method is useful, as it can incorporate more specific information about local tissue properties than the existing method. However, clinical validation is necessary.

Herein, we combined neurite orientation dispersion and density imaging (NODDI) and synthetic magnetic resonance imaging (SyMRI) to evaluate the spatial distribution and extent of gray matter (GM) microstructural alterations in patients with relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica spectrum disorder (NMOSD). The NODDI (neurite density index [NDI], orientation dispersion index [ODI], and isotropic volume fraction [ISOVF]) and SyMRI (myelin volume fraction [MVF]) measures were compared between age- and sex-matched groups of 30 patients with RRMS (6 males and 24 females; mean age, 51.43 ± 8.02 years), 18 patients with anti-aquaporin-4 antibody-positive NMOSD (2 males and 16 females; mean age, 52.67 ± 16.07 years), and 19 healthy controls (6 males and 13 females; mean age, 51.47 ± 9.25 years) using GM-based spatial statistical analysis. Patients with RRMS showed reduced NDI and MVF and increased ODI and ISOVF, predominantly in the limbic and paralimbic regions, when compared with healthy controls, while only increases in ODI and ISOVF were observed when compared with NMOSD. Compared to NDI and MVF, the changes in ODI and ISOVF were observed more widely, including in the cerebellar cortex. These abnormalities were associated with disease progression and disability. In contrast, patients with NMOSD only showed reduced NDI mainly in the cerebellar, limbic, and paralimbic cortices when compared with healthy controls and patients with RRMS. Taken together, our study supports the notion that GM pathologies in RRMS are distinct from those of NMOSD. However, owing to the limitations of the study, the results should be cautiously interpreted.

Background Anti-aquaporin 4 (AQP4) antibody (AQP4-Ab) is involved in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism involved in AQP4-Ab production remains unclear. Methods We analyzed the immunophenotypes of patients with NMOSD and other neuroinflammatory diseases as well as healthy controls (HC) using flow cytometry. Transcriptome analysis of B cell subsets obtained from NMOSD patients and HCs was performed. The differentiation capacity of B cell subsets into antibody-secreting cells was analyzed. Results The frequencies of switched memory B (SMB) cells and plasmablasts were increased and that of naïve B cells was decreased in NMOSD patients compared with relapsing–remitting multiple sclerosis patients and HC. SMB cells from NMOSD patients had an enhanced potential to differentiate into antibody-secreting cells when cocultured with T peripheral helper cells. Transcriptome analysis revealed that the profiles of B cell lineage transcription factors in NMOSD were skewed towards antibody-secreting cells and that IL-2 signaling was upregulated, particularly in naïve B cells. Naïve B cells expressing CD25, a receptor of IL-2, were increased in NMOSD patients and had a higher potential to differentiate into antibody-secreting cells, suggesting CD25+ naïve B cells are committed to differentiate into antibody-secreting cells. Conclusions To the best of our knowledge, this is the first study to demonstrate that B cells in NMOSD patients are abnormally skewed towards antibody-secreting cells at the transcriptome level during the early differentiation phase, and that IL-2 might participate in this pathogenic process. Our study indicates that CD25+ naïve B cells are a novel candidate precursor of antibody-secreting cells in autoimmune diseases.

BackgroundMitochondrial dysfunction has been suggested to play an important role in all stages of multiple sclerosis (MS).ObjectiveTo determine the expression of two mitophagy-related proteins, PTEN-induced kinase 1 (PINK1) and PARKIN, in a cohort of Japanese patients with different neuroinflammatory disorders.MethodsProtein concentrations were measured using commercial ELISA in paired cerebrospinal fluid (CSF) and serum samples from patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), and from age- and sex-matched controls.ResultsCSF and serum concentrations of PINK1 were higher in patients with MS than in patients with NMOSD (p = 0.004 and p < 0.001, respectively), MOGAD (p = 0.008 and p = 0.011, respectively), and controls (p = 0.021 and p = 0.002, respectively). CSF and concentrations of PARKIN were elevated in patients with MS in comparison with those in controls (p = 0.016 and p = 0.05, respectively).ConclusionsOur study highlighted the importance of mitophagy in MS and suggested the potential application of PINK1 and PARKIN as biomarkers to predict disease activity.

Objective Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. Materials and Methods Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). Results LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. Conclusion Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy.

Background Pembrolizumab is an immune-checkpoints inhibitor that enhances the immune response against cancer cells and therefore is useful for the treatment of several carcinomas. However, pembrolizumab sometimes perturbs the immune system resulting in various autoimmune neurological complications. In this situation, autoimmune myositis due to pembrolizumab is a rare but not-negligible complication. Here, we report two cases of autoimmune myositis due to pembrolizumab, with systemic myositis involving levator palpebrae superioris, extraocular and hindneck muscles. Case presentation Case 1 was a 78-year-old man with advanced urinary cancer referred to the neurological ward presenting with bilateral ptosis, restriction of eye movements, dropped head and weakness in the lower extremities after pembrolizumab administration. His blood examination showed elevated serum levels of creatine kinase with positive anti-PM-Scl 75 and anti-signal recognition particle antibodies. Needle electromyography and MRI suggested systemic inflammatory myopathy. There were no findings to indicate myocardial involvement on electrocardiogram or echocardiogram. Administration of intravenous methylprednisolone following plasma exchange ameliorated creatine kinase levels and inhibited the progression of clinical symptoms. Case 2 was a 72-year-old female with lung cancer and multiple metastasis, including lymph nodes and brain. She presented with back pain, right-sided ptosis, weakness of her neck extensors and flexors and elevated serum creatine kinase after receiving pembrolizumab. Although myositis specific autoantibodies were negative, needle electromyography and MRI suggested systemic inflammatory myopathy and muscle biopsy indicated necrotizing myopathy. There were no signs indicating heart dysfunction and her electrocardiogram was normal. Clinical symptoms and serum creatine kinase levels were ameliorated after the administration of intravenous methylprednisolone. Conclusions Both cases showed atypical extensive inflammatory myositis including levator palpebrae superioris, extraocular and hindneck muscles, resembling myasthenia gravis (MG), but they did not have MG-related antibodies. Edrophonium test was negative and showed no daily fluctuation. Two previously reported cases also presented with systemic necrotizing systemic myositis involving extraocular and facial muscles caused by pembrolizumab. Idiopathic inflammatory myositis evolving levator palpebrae superioris and ocular muscles is quite rare; however, myositis due to immune-checkpoint inhibitors may preferentially involve these muscles. This case report will alert physicians to the possibility of systemic inflammatory myopathy evolving levator palpebrae superioris, extraocular and hindneck muscles mimicking MG due to pembrolizumab.

3q29 microdeletion, a rare recurrent copy number variant (CNV), greatly confers an increased risk of psychiatric disorders, such as schizophrenia and autism spectrum disorder (ASD), as well as intellectual disability. However, disease-relevant cellular phenotypes of 3q29 deletion syndrome remain to be identified. To reveal the molecular and cellular etiology of 3q29 deletion syndrome, we generated a mouse model of human 3q29 deletion syndrome by chromosome engineering, which achieved construct validity. 3q29 deletion (Df/+) mice showed reduced body weight and brain volume and, more importantly, impaired social interaction and prepulse inhibition. Importantly, the schizophrenia-related impaired prepulse inhibition was reversed by administration of antipsychotics. These findings are reminiscent of the growth defects and neuropsychiatric behavioral phenotypes in patients with 3q29 deletion syndrome and exemplify that the mouse model achieves some part of face validity and predictive validity. Unbiased whole-brain imaging revealed that neuronal hyperactivation after a behavioral task was strikingly exaggerated in a restricted region of the cortex of Df/+ mice. We further elucidated the cellular phenotypes of neuronal hyperactivation and the reduction of parvalbumin expression in the cortex of Df/+ mice. Thus, the 3q29 mouse model provides invaluable insight into the disease-causative molecular and cellular pathology of psychiatric disorders.

Synthetic MRI (SyMRI) enables automatic brain tissue and myelin volumetry based on the quantification of R1 and R2 relaxation rates and proton density. This study aimed to determine the validity of SyMRI brain tissue and myelin volumetry using various in-plane resolutions at 3T in patients with multiple sclerosis (MS). We scanned 19 MS patients and 10 healthy age- and gender-matched controls using a 3T MR scanner with in-plane resolutions of 0.8, 1.8, and 3.6 mm. The acquisition times were 5 min 8 s, 2 min 52 s, and 2 min 1 s, respectively. White matter (WM), gray matter (GM), cerebrospinal fluid (CSF), and myelin and non-WM/GM/CSF (NoN) volumes; brain parenchymal volume (BPV); and intracranial volume (ICV) were compared between different in-plane resolutions. These parameters were also compared between both groups, after ICV normalization. No significant differences in measured volumes were noted between the 0.8 and 1.8 mm in-plane resolutions, except in NoN and CSF for healthy controls and NoN for MS patients. Meanwhile, significant volumetric differences were noted in most brain tissues when compared between the 3.6 and 0.8 or 1.8 mm resolution for both healthy controls and MS patients. The normalized WM volume, myelin volume, and BPV showed significant differences between controls and MS patients at in-plane resolutions of 0.8 and 1.8 mm. SyMRI brain tissue and myelin volumetry with in-plane resolution as low as 1.8 mm can be useful in the evaluation of MS with a short acquisition time of

We hypothesize that myelin is more susceptible to damage over time than axons. We investigated the association between the estimated duration from the onset of multiple sclerosis (MS) plaques and myelin- and axon-related quantitative synthetic magnetic resonance imaging (SyMRI) and neurite orientation dispersion and density imaging (NODDI) metrics.We analyzed 31 patients with MS with 73 newly appeared plaques. Simple linear regression analysis was performed to assess the association between the estimated duration from the onset of plaques and quantitative MRI metrics. These metrics included the myelin volume fraction (MVF), axon volume fraction, and g-ratio in plaque and normal-appearing white matter.MS plaques with a longer estimated duration from onset were significantly correlated with a lower MVF (slope = - 0.0070, RThese results suggested that myelin in plaques undergoes continuous damage, more so than axons. Myelin imaging with SyMRI and NODDI may be useful for the quantitative assessment of temporal changes in MS plaques.

BACKGROUND AND PURPOSE: Synthetic MR imaging creates multiple contrast-weighted images based on a single time-efficient quantitative scan, which has been mostly performed for 2D acquisition. We assessed the utility of 3D synthetic MR imaging in patients with MS by comparing its diagnostic image quality and lesion volumetry with conventional MR imaging. MATERIALS AND METHODS: Twenty-four patients with MS prospectively underwent 3D quantitative synthetic MR imaging and conventional T1-weighted, T2-weighted, FLAIR, and double inversion recovery imaging, with acquisition times of 9 minutes 3 seconds and 18 minutes 27 seconds for the synthetic MR imaging and conventional MR imaging sequences, respectively. Synthetic phase-sensitive inversion recovery images and those corresponding to conventional MR imaging contrasts were created for synthetic MR imaging. Two neuroradiologists independently assessed the image quality on a 5-point Likert scale. The numbers of cortical lesions and lesion volumes were quantified using both synthetic and conventional image sets. RESULTS: The overall diagnostic image quality of synthetic T1WI and double inversion recovery images was noninferior to that of conventional images (P = .23 and .20, respectively), whereas that of synthetic T2WI and FLAIR was inferior to that of conventional images (both Ps

Despite differences in the pathogenesis and treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), it remains difficult to distinguish them. In this study, we aimed to discriminate between MS and NMOSD using diffusion tensor imaging (DTI), free water (FW) imaging, and neurite orientation dispersion and density imaging (NODDI).Thirty patients with relapsing-remitting (RR) MS, 18 NMOSD patients with positive anti-aquaporin-4 immunoglobulin G seroreactivity, and 20 age- and sex- matched currently healthy subjects underwent MRI. The differences in the DTI (fractional anisotropy [FA], axial diffusivity [AD], mean diffusivity [MD], and radial diffusivity [RD]), FW and FW-corrected DTI, and NODDI indices between the three groups were evaluated using tract-based spatial statistics (TBSS) and region-of-interest (ROI) analyses.The ROI analysis of lesions indicated that the RRMS group had significantly higher AD, MD, RD, ISO and FW-corrected AD, and MD; and lower intracellular volume fraction (ICVF) than the NMOSD group. TBSS analysis showed increased water content in RRMS patients compared to NMOSD patients. Compared with healthy controls (HCs) using TBSS and ROI analysis, the changes in FW imaging indices were more limited than those of in DTI in RRMS patients.FW imaging and NODDI were useful for identifying the etiology of neurodegeneration- and neuroinflammation-related microstructural changes in RRMS and NMOSD patients.

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Background Diverse mechanisms including infections, autoimmune inflammatory reactions, neoplasms, and degeneration are involved in the central nervous system in cases of acquired immune deficiency syndrome. In such cases, it is difficult to determine the precise pathogenesis by radiological examination and laboratory testing. Case presentation We report a 37-year-old Japanese woman who had untreated hypertension and gender identity disorder and had been taking testosterone injections since she was 19 years old. She developed a headache and visual field deficits together with elevated blood pressure. According to radiological findings, she was initially suspected as having posterior reversible encephalopathy syndrome in the right parieto-occipital lobe with reversible cerebral vasoconstriction syndrome. Human immunodeficiency virus antibody was positive and the CD4+ T-lymphocyte count was 140 cells/μl. Therefore, antiretroviral therapy was started. Antiretroviral therapy suppressed the activity of acquired immune deficiency syndrome but worsened her visual symptoms and expanding radiological lesions. Brain biopsy led to the diagnosis of CD8+ encephalitis, and she also fulfilled the diagnosis of paradoxical immune reconstitution inflammatory syndrome. Corticosteroid therapy alleviated her symptoms. Conclusions This is a rare case of CD8+ encephalitis, with an exacerbation owing to paradoxical immune reconstitution inflammatory syndrome after antiretroviral therapy, which radiologically mimicked posterior reversible encephalopathy syndrome. Corticosteroid therapy was effective; thus, it is important to provide a pathological diagnosis in such cases.

Mycobacterium avium subsp. paratuberculosis (MAP) and Mycobacterium bovis (BCG) have been associated to several human autoimmune diseases such as multiple sclerosis (MS), but there are conflicting evidence on the issue. The objective of this study is to evaluate their role in Japanese patients affected by inflammatory demyelinating disorders of the central nervous system (IDDs). A total of 97 IDDs subjects including 51 MS and 46 neuromyelitis optica spectrum disorder (NMOSD) patients, and 34 healthy controls (HCs) were tested for the detection of IgG, IgM and IgA against mycobacterial antigens by indirect ELISA. The levels of anti-MAP IgG were higher in MS patients compared to NMOSD patients (AUC = 0.59, p = 0.02) and HCs (AUC = 0.67, p = 0.01), and the anti-MAP antibodies were more prevalent in MS patients treated with interferon-beta (OR = 11.9; p = 0.004). Anti-BCG IgG antibodies were detected in 8% of MS, 32% of NMOSD and 18% of HCs, the difference between MS and NMOSD groups was statistically significant (AUC = 0.66, p = 0.005). Competition experiments showed that nonspecific IgM were elicited by common mycobacterial antigens. Our study provided further evidence for a possible association between MAP and MS, while BCG vaccination seemed to be inversely related to the risk of developing MS.

To investigate whether antibody production against mycobacterium avium subsp. paratuberculosis (MAP) is related to clinical characteristics of multiple sclerosis (MS) and human leukocyte antigen (HLA) alleles, IgG antibody against three MAP peptides and two human peptides homologous to MAP were measured in sera from 103 MS patients and 50 healthy controls (HCs). MS patients had higher IgG levels against MAP2694295-303 (MAP2694-IgG) than HCs, while the other antibodies were comparable. Multivariate analysis demonstrated that higher MAP2694-IgG titers were associated with higher EDSS scores, but not with HLA alleles or dairy product consumption. Immune response against MAP may worsen MS disability.

Objectives We investigated changes in the optic tract and optic radiation in patients with multiple sclerosis (MS) by comparing unilateral and bilateral optic nerve damage assessed based on visual evoked potentials (VEPs) using advanced diffusion MR metrics. Methods In 21 MS patients, diffusion MRI was performed. Maps of fractional anisotropy, apparent diffusion coefficient (ADC), and mean kurtosis (MK) were computed. On the basis of the P100 latency in VEPs, the MS patients were divided into three groups: bilateral (n=7), unilateral (n=7), and no abnormality (n=7). Their optic tracts and optic radiations were analyzed with diffusion MRI-based fiber tracking. We also investigated the correlations between diffusion parameters and VEPs (n=21). Results In the optic tract, the diffusion changes in each of the three groups showed step-like changes. The diffusion changes in the optic radiations of the unilateral group were similar to those in the normal VEP group. Only the bilateral group showed significantly higher ADC and lower MK relative to the other two groups (P Conclusions We first evaluated the relationship between VEPs and DKI and concluded that the lateral geniculate nucleus may compensate for unilateral damage in the pre-geniculate optic pathway via neural plasticity.

Objective: Alzheimer’ disease (AD) is characterized by increase of cortical amyloid deposition in prodromal stage and subsequent decrease of cerebral glucose metabolism as disease progresses. The present study introduces the voxel-wise metabolism to amyloid deposits ratio (MAR) image and to evaluate its reliability for the diagnosis of AD. Methods: Consecutive one-hundred and forty-three subjects with AD and 181 normal subjects who underwent both 18 F-FDG PET and 18 F-florbetapir (AV-45) PET at baseline were included to this study from the database of Alzheimer's disease neuroimaging initiative (ADNI). After normalizing to a standard stereotactic space, the MAR image was created by dividing each FDG-PET image by corresponding AV-45 PET image using with voxel-wise inter-image computation. We examined voxel wise comparison in the MAR images between AD subjects and normal subjects and compared the diagnostic performances between the MAR image and FDG-PET and AV-45 image. Results: In the voxel wise comparison, the MAR images of AD subjects exhibited severe and extensive decrease compared with normal subjects in the affected region in both FDG-PET and AV-45, especially in the precuneus /posterior cingulate. The highest t-value was equivalent to FDG-PET and the voxel extent was much greater than the other images. In the ROI analysis, the diagnostic accuracies were 82.6% (sensitivity: 86.7%, specificity: 79.5%), 80.7% (sensitivity: 77%, specificity: 83.4%), and 78.8% (sensitivity: 75.2%, specificity: 81.5%) for the MAR image, FDG-PET, and AV-45, respectively. AUC for the MAR image was 0.904 (95%CI: 0.867-0.942), and was larger than those for FDG-PET (AUC: 0.884, 95%CI: 0.843-0.926), and AV-45 (AUC: 0.847, 95%CI: 0.798-0.897). Conclusion: MAR image reflected not only amyloid deposition but the cerebral glucose metabolisms and successfully classified the subjects with AD. These data suggest that the MAR image might be a more proper appropriate diagnostic marker for AD reflecting cerebral metabolisms and amyloid deposition.

Renal cell carcinoma (RCC) patients who develop a paraneoplastic syndrome may present with neuromuscular disorders. We herein report the case of a 50-year-old man who suffered from progressive gait disturbance and muscle weakness. The results of a nerve conduction study fulfilled the criteria of chronic inflammatory demyelinating polyneuropathy. An abdominal CT scan detected RCC, the pathological diagnosis of which was clear cell type. After tumor resection and a single course of intravenous immunoglobulin therapy, the patient's symptoms drastically improved over the course of one year. The patient's neurological symptoms preceded the detection of cancer. A proper diagnosis and the initiation of suitable therapies resulted in a favorable outcome.

A 67-year-old woman with neuromyelitis optica spectrum disorder (NMOSD) developed severe somnolence. Ten days after admission, fluid-attenuated inversion-recovery magnetic resonance imaging (MRI) revealed hyperintense areas around the bilateral hypothalamus, which were not present on MRI at admission. The orexin level, which is decreased in idiopathic narcolepsy, was slightly decreased in her cerebrospinal fluid. Immunosuppressive treatment and methylphenidate markedly improved her somnolence. This case shows that NMOSD in the acute phase can cause somnolence in a patient without apparent lesions in the hypothalamus.

A healthy 28-year-old woman presented suddenly with intractable status epilepticus: a focal seizure evolved into a generalized seizure preceded by a high fever. Brain magnetic resonance imaging indicated bilateral hyperintensities in the hippocampus on T2-weighted imaging. Electroencephalograms continuously demonstrated diffuse sharp waves and poly-spikes. Comprehensive immunomodulation therapies and anti-epileptic drugs did not lead to any improvements. We therefore diagnosed her with cryptogenic limbic encephalitis and new-onset refractory status epilepticus (NORSE). We detected positive anti-ganglioside antibodies, IgG-GQ1b, GD1a, and GT1b, which were negative at six months after the onset. We emphasize the heterogeneous pathogenesis and intractable conditions of NORSE.

BACKGROUND AND PURPOSE: A number of MR-derived quantitative metrics have been suggested to assess the pathophysiology of MS, but the reports about combined analyses of these metrics are scarce. Our aim was to assess the spatial distribution of parameters for white matter myelin and axon integrity in patients with relapsing-remitting MS by multiparametric MR imaging. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting MS and 24 age- and sex-matched controls were prospectively scanned by quantitative synthetic and 2-shell diffusion MR imaging. Synthetic MR imaging data were used to retrieve relaxometry parameters (R1 and R2 relaxation rates and proton density) and myelin volume fraction. Diffusion tensor metrics (fractional anisotropy and mean, axial, and radial diffusivity) and neurite orientation and dispersion index metrics (intracellular volume fraction, isotropic volume fraction, and orientation dispersion index) were retrieved from diffusion MR imaging data. These data were analyzed using Tract-Based Spatial Statistics. RESULTS: Patients with MS showed significantly lower fractional anisotropy and myelin volume fraction and higher isotropic volume fraction in widespread white matter areas. Areas with different isotropic volume fractions were included within areas with lower fractional anisotropy. Myelin volume fraction showed no significant difference in some areas with significantly decreased fractional anisotropy in MS, including in the genu of the corpus callosum and bilateral anterior corona radiata, whereas myelin volume fraction was significantly decreased in some areas where fractional anisotropy showed no significant difference, including the bilateral posterior limb of the internal capsule, external capsule, sagittal striatum, fornix, and uncinate fasciculus. CONCLUSIONS: We found differences in spatial distribution of abnormality in fractional anisotropy, isotropic volume fraction, and myelin volume fraction distribution in MS, which might be useful for characterizing white matter in patients with MS.

Objectives: To compare the effects of inpatient enhanced multidisciplinary care (EMC) and multidisciplinary rehabilitation (MR) on the symptoms and quality of life (QOL) of patients with Parkinson disease (PD) and to clarify the relation between reduction in symptoms and the improved QOL. Methods: This study was a quasi-randomized controlled (alternate allocation), assessor-blinded, single-center study. We recruited 80 patients with idiopathic Parkinson disease, Hoehn and Yahr stage 2 to 4, on stable medication. Patients were included in an EMC or MR group. Both rehabilitation programs were performed for 8 weeks (17 h/wk). Main outcome measures were Parkinson’s Disease Questionnaire-39 and Unified Parkinson’s Disease Rating Scale. Results: The EMC induced significant improvements in QOL compared to MR. We found that body axis symptoms (rising from a chair, posture, postural stability, falling, and walking) as well as nonmotor symptoms (depression) in patients with PD were relieved by the inpatient EMC. Conclusions: Enhanced multidisciplinary care for patients with PD appears to be effective in improving the QOL. The improvement in motor and nonmotor symptoms, including depression, may contribute to the improved QOL.

BACKGROUND AND PURPOSE Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms

Multiple sclerosis (MS) is a brain network disconnection syndrome. Although the brain network topology in MS has been evaluated using diffusion MRI tractography, the mechanism underlying disconnection in the disorder remains unclear. In this study, we evaluated the brain network topology in MS using connectomes with connectivity strengths based on the ratio of the inner to outer myelinated axon diameter (i.e., g-ratio), thereby providing enhanced sensitivity to demyelination compared with the conventional measures of connectivity. We mapped g-ratio-based connectomes in 14 patients with MS and compared them with those of 14 age- and sex-matched healthy controls. For comparison, probabilistic tractography was also used to map connectomes based on the number of streamlines (NOS). We found that g-ratio- and NOS-based connectomes comprised significant connectivity reductions in patients with MS, predominantly in the motor, somatosensory, visual, and limbic regions. However, only the g-ratio-based connectome enabled detection of significant increases in nodal strength in patients with MS. Finally, we found that the g-ratio-weighted nodal strength in motor, visual, and limbic regions significantly correlated with inter-individual variation in measures of disease severity. The g-ratio-based connectome can serve as a sensitive biomarker for diagnosing and monitoring disease progression.

PATH study group., In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre‐randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow‐up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post‐study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., Editorial support was provided by Meridian HealthComms Ltd, funded by CSL Behring.

Purpose This study aimed to identify regional asymmetry in dopaminergic and serotoninergic dysfunction in degenerative parkinsonisms, using dopamine transporter single-photon emission computed tomography images. Material and methods This study included 213 consecutive participants (Parkinson's disease [n = 111], dementia with Lewy bodies [n = 64], progressive supranuclear palsy with Richardson's syndrome [n = 18], and healthy participants [n = 20]) who underwent both magnetic resonance imaging and 123I-labelled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane single-photon emission computed tomography/computed tomography. Using normalized specific binding ratio images, we created voxel-wise regional asymmetry index images to identify the regional specific pattern of regional asymmetries in degenerative parkinsonisms. Results Compared with healthy controls, patients with Parkinson's disease showed a regional asymmetry index increase in the nigrostriatal dopaminergic pathway, and those with dementia with Lewy bodies showed a regional asymmetry index increase confined to the bilateral caudate. Individuals with progressive supranuclear palsy exhibited a distinct regional asymmetry index increase in the pallido-subthalamic pathway. Notably, the regional asymmetry index increase in the subthalamic nucleus was significantly greater in progressive supranuclear palsy than in Parkinson's disease. Conclusion The current study revealed distinctive regional asymmetry in dopaminergic and serotoninergic dysfunction in degenerative parkinsonisms. The present findings highlight the potential application of visual diagnosis in degenerative parkinsonisms.

A 53-year-old right-handed woman had an extensive lesion in the left hemisphere due to an infarction caused by vasospasm secondary to subarachnoid bleeding. She exhibited persistent expressive-vocal amusia with no symptoms of aphasia. Evaluation of the patient's musical competence using the Montreal Battery for Evaluation of Amusia, rhythm reproduction tests, acoustic analysis of pitch upon singing familiar music, Japanese standard language tests, and other detailed clinical examinations revealed that her amusia was more dominantly related to pitch production. The intactness of her speech provided strong evidence that the right hemisphere played a major role in her linguistic processing. Data from functional magnetic resonance imaging while she was singing a familiar song, a scale, and reciting lyrics indicated that perilesional residual activation in the left hemisphere was associated with poor pitch production, while right hemispheric activation was involved in linguistic processing. The localization of infarction more anterior to the left Sylvian fissure might be related to the dominant deficits in expressive aspects of the singing of the patient. Compromised motor programming producing a single tone may have made a major contribution to her poor singing. Imperfect auditory feedback due to borderline perceptual ability or improper audio-motor associations might also have played a role.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder caused by antibody to aquaporin-4 (AQP4). NMOSD can infrequently present as a complication of posterior reversible encephalopathy syndrome (PRES). Moreover, few cases of NMOSD patients with brain hemorrhage have been reported. We report a rare case of PRES together with NMOSD recurrence, subsequent to pontine hemorrhage after intravenous methylprednisolone (IVMP) therapy. A 51-year-old Japanese woman, with a history of hypertension and dyslipidemia, and recurrent episodes of left visual acuity disorder related to AQP4-positive NMOSD, developed blindness in the left eye. Brain MRI showed a hyperintense lesion in pons. She was initially diagnosed with recurrence of NMOSD and 1000 mg of IVMP was administered for 3 days. After the 3rd course of IVMP, she developed left-sided sensory disturbance, and blood pressure was increased to 202/127 mmHg. Brain computed tomography (CT) showed pontine hemorrhage, and she was referred to our hospital again. We diagnosed PRES associated with NMOSD recurrence, along with development of pontine hemorrhage induced by the increase in blood pressure resulting from IVMP. The patient was treated with nicardipine to strictly control blood pressure, and tranexamic acid and glycerol for pontine hemorrhage and PRES. We also extended IVMP for 5 consecutive days in total, followed by plasmapheresis. After therapy, blindness in the left eye improved to light perception. Collectively, anti-AQP4 antibody could induce PRES together with recurrent NMOSD, and pontine hemorrhage could thus be induced by blood pressure increases resulting from IVMP.

Extensive gray matter (GM) involvement has been demonstrated in multiple sclerosis (MS) patients. This study was aimed to identify GM alterations in relapsing-remitting MS (RRMS) patients using synthetic quantitative MRI (qMRI). We assessed myelin volume fraction (MVF) in each voxel on the basis of R1 and R2 relaxation rates and proton density in 14 early and 28 late (disease duration ≤5 and >5 years, respectively) RRMS patients, and 15 healthy controls (HCs). The MVF and myelin volumes of GM (GM-MyVol) were compared between groups using GM-based spatial statistics (GBSS) and the Kruskal-Wallis test, respectively. Correlations between MVF or GM-MyVol and disease duration or expanded disability status scale were also evaluated. RRMS patients showed a lower MVF than HCs, predominantly in the limbic and para-limbic areas, with more extensive areas noted in late RRMS patients. Late-RRMS patients had the smallest GM-MyVol (20.44 mL; early RRMS, 22.77 mL; HCs, 23.36 mL). Furthermore, the GM-MyVol in the RRMS group was inversely correlated with disease duration (r = −0.43, p = 0.005). In conclusion, the MVF and MyVol obtained by synthetic qMRI can be used to evaluate GM differences in RRMS patients.

BACKGROUND AND PURPOSE: Synthetic FLAIR images are of lower quality than conventional FLAIR images. Here, we aimed to improve the synthetic FLAIR image quality using deep learning with pixel-by-pixel translation through conditional generative adversarial network training. MATERIALS AND METHODS: Forty patients with MS were prospectively included and scanned (3T) to acquire synthetic MR imaging and conventional FLAIR images. Synthetic FLAIR images were created with the SyMRI software. Acquired data were divided into 30 training and 10 test datasets. A conditional generative adversarial network was trained to generate improved FLAIR images from raw synthetic MR imaging data using conventional FLAIR images as targets. The peak signal-to-noise ratio, normalized root mean square error, and the Dice index of MS lesion maps were calculated for synthetic and deep learning FLAIR images against conventional FLAIR images, respectively. Lesion conspicuity and the existence of artifacts were visually assessed. RESULTS: The peak signal-to-noise ratio and normalized root mean square error were significantly higher and lower, respectively, in generated-versus-synthetic FLAIR images in aggregate intracranial tissues and all tissue segments (all P < .001). The Dice index of lesion maps and visual lesion conspicuity were comparable between generated and synthetic FLAIR images (P = 1 and .59, respectively). Generated FLAIR images showed fewer granular artifacts (P = .003) and swelling artifacts (in all cases) than synthetic FLAIR images. CONCLUSIONS: Using deep learning, we improved the synthetic FLAIR image quality by generating FLAIR images that have contrast closer to that of conventional FLAIR images and fewer granular and swelling artifacts, while preserving the lesion contrast.

Mika Saarela työryhmän jäsenenä. Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.

BACKGROUND AND PURPOSE: Myelin and axon volume fractions can now be estimated via MR imaging in vivo, as can the g-ratio, which equals the ratio of the inner to the outer diameter of a nerve fiber. The purpose of this study was to evaluate WM damage in patients with MS via this novel MR imaging technique. MATERIALS AND METHODS: Twenty patients with relapsing-remitting MS with a combined total of 149 chronic plaques were analyzed. Myelin volume fraction was calculated based on simultaneous tissue relaxometry. Intracellular and CSF compartment volume fractions were quantified via neurite orientation dispersion and density imaging. Axon volume fraction and g-ratio were calculated by combining these measurements. Myelin and axon volume fractions and g-ratio were measured in plaques, periplaque WM, and normal-appearing WM. RESULTS: All metrics differed significantly across the 3 groups (P < .001, except P = .027 for g-ratio between periplaque WM and normal-appearing WM). Those in plaques differed most from those in normal-appearing WM. The percentage changes in plaque and periplaque WM metrics relative to normal-appearing WM were significantly larger in absolute value for myelin volume fraction than for axon volume fraction and g-ratio (P < .001, except P = .033 in periplaque WM relative to normal-appearing WM for comparison between myelin and axon volume fraction). CONCLUSIONS: In this in vivo MR imaging study, the myelin of WM was more damaged than axons in plaques and periplaque WM of patients with MS. Myelin and axon volume fractions and g-ratio may potentially be useful for evaluating WM damage in patients with MS.

Myasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis.We studied 393 patients with MG who underwent thymectomy at 6 tertiary centers in Japan (275 patients for derivation and 118 for validation). Clinical characteristics, such as gender, age at onset and operation, body mass index, disease duration, MG subtype, severity, symptoms, preoperative therapy, operative data, and laboratory data, were reviewed retrospectively. A multivariate logistic regression with LASSO penalties was used to determine the factors associated with postoperative myasthenic crisis, and a score was assigned. Finally, the predictive score was evaluated using bootstrapping technique in the derivation and validation groups.Multivariate logistic regression identified 3 clinical factors for predicting postoperative myasthenic crisis risk: (1) vital capacity 80%, (2) disease duration 3 months, and (3) bulbar symptoms immediately before thymectomy. The postoperative myasthenic crisis predictive score, ranging from 0 to 6 points, had areas under the curve of 0.84 (0.66-0.96) in the derivation group and 0.80 (0.62-0.95) in the validation group.A simple scoring system based on 3 preoperative clinical characteristics can predict the possibility of postoperative myasthenic crisis. Ann Neurol 2017;82:841-849.

BACKGROUND AND PURPOSE: Synthetic MR imaging enables the creation of various contrast-weighted images including double inversion recovery and phase-sensitive inversion recovery from a single MR imaging quantification scan. Here, we assessed whether synthetic MR imaging is suitable for detecting MS plaques. MATERIALS AND METHODS: Quantitative and conventional MR imaging data on 12 patients with MS were retrospectively analyzed. Synthetic T2-weighted, FLAIR, double inversion recovery, and phase-sensitive inversion recovery images were produced after quantification of T1 and T2 values and proton density. Double inversion recovery images were optimized for each patient by adjusting the TI. The number of visible plaques was determined by a radiologist for a set of these 4 types of synthetic MR images and a set of conventional T1-weighted inversion recovery, T2-weighted, and FLAIR images. Conventional 3D double inversion recovery and other available images were used as the criterion standard. The total acquisition time of synthetic MR imaging was 7 minutes 12 seconds and that of conventional MR imaging was 6 minutes 29 seconds The lesion-to-WM contrast and lesion-to-WM contrast-to-noise ratio were calculated and compared between synthetic and conventional double inversion recovery images. RESULTS: The total plaques detected by synthetic and conventional MR images were 157 and 139, respectively (P = .014). The lesion-to-WM contrast and contrast-to-noise ratio on synthetic double inversion recovery images were superior to those on conventional double inversion recovery images (P = .001 and < 0.001, respectively). CONCLUSIONS: Synthetic MR imaging enabled detection of more MS plaques than conventional MR imaging in a comparable acquisition time. The contrast for MS plaques on synthetic double inversion recovery images was better than on conventional double inversion recovery images.

Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms and cognitive deficits. The exact cause of schizophrenia is still unknown, but substantial evidence indicates that it has a genetic component. Genome wide association studies demonstrate variants within miR-137 host gene are a risk factor for schizophrenia. However, the direct relationship between the pathophysiology of schizophrenia and the dosage of miR-137 remains unclear. Therefore, in this study, we generated transgenic mice overexpressing miR-137 (miR-137 Tg mice) with the neuron-specific Thy-1 promoter and examined schizophrenia-related phenotypes in these mice. Overexpression of miR-137 was observed in various brain regions of the miR-137 Tg mice, with down-regulation of putative miR-137 targets. MiR-137 Tg mice showed sensory gating deficits in a prepulse inhibition test, social deficits in a sociability and social novelty test, and cognitive deficits in a novel object recognition test. Interestingly, the predicted-altered pathways of the medial prefrontal cortex of miR-137 Tg mice were partially overlapped with those of the dorsolateral prefrontal cortex in postmortem brain of patients who died in equal to or less than 4 years after initial diagnosis of schizophrenia in published data. These results suggest that overexpression of miR-137 in the whole brain induces the several phenotypes that are relevant to aspects of psychiatric disorders, such as schizophrenia. Based on these findings, miR-137 Tg mice may have the potential to become a useful tool in researching the pathophysiology of psychiatric disorders.

Summary Highly topographic organization of neural circuits exists for the regulation of various brain functions in corticobasal ganglia circuits. Although neural circuit-specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered δ2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17 −/− mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors.

Several works have demonstrated the existence of a link between Mycobacterium avium subsp. paratuberculosis (MAP) and MS in Italy. In this study, we analyzed the serology of MAP in a Japanese population while looking at several markers of MAP. Fifty MS patients, 12 clinically isolated syndrome (CIS) patients, 30 other neurological disorders (OND) patients and 50 healthy controls (HCs) were tested using ELISA for the presence of IgG antibodies toward immunodominant epitopes MAP_0106c121-132, homologues MBP85-98, homologues IRF5424-432, MAP_402718-32, and MAP_2694295-303. MAP-positive patients were also analyzed in relation to their clinical/demographic characteristics. Amongst all peptides, only antibodies against MAP_2694295-303 were more prevalent in MS patients (30%), as compared to OND patients (3%) (p = 0.009; area under roc curve (AUC) = 0.61) and HCs (2%) (p = 0.0004; AUC = 0.65) and in CIS patients (25%) compared to HCs (p = 0.023; AUC = 0.55). Logistic regression analysis showed a higher frequency of anti-MAP_2694295-303 antibodies in the sera of oligoclonal bands positive MS patients (p = 0.2; OR = 2, 95%CI: 0.55–7.7). These findings support the view that MAP could act as a risk factor or a triggering agent of MS in some Japanese patients with a genetic susceptibility to the mycobacterium.

Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.

We evaluated diffusional changes in normal-appearing white matter (NAWM) regions remote from multiple sclerosis (MS) plaques by using diffusional kurtosis imaging (DKI) to investigate the non-Gaussian behavior of water diffusion.Participants were 11 MS patients and 6 age-matched healthy volunteers. DKI was performed on a 3-T MR imager. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), and diffusional kurtosis (DK) maps were computed. Regions of interest (ROIs) were compared in 24 cerebral regions, including the frontal, parietal, and temporal lobe white matter (WM) in controls and NAWM in MS patients.The mean FA of all ROIs was 0.468 ± 0.014 (SD) (controls) or 0.431 ± 0.029 (MS group) (P = 0.016). Mean ADC was 0.785 ± 0.034 × 10(-3) mm(2)/s (controls) or 0.805 ± 0.041 × 10(-3) mm(2)/s (MS group). The mean DK of all ROIs was 0.878 ± 0.020 (controls) or 0.823 ± 0.032 (MS group) (P = 0.002). Analysis of individual ROIs revealed significant differences in DK in 3 ROIs between normal WM and NAWM, but significant differences in ADC and FA in only one ROI each.DKI may be a new sensitive indicator for detecting tissue damage in MS patients in addition to conventional diffusional evaluations, for example diffusion tensor imaging.

Human infection with the dog and cat roundworm, Toxocara anis (T. canis) and Toxocara cati (T. cati), is a result of accidental ngestion of embryonated eggs [1–5]. These roundworms cannot evelop to adult worms in humans, but tissue-migrating larvae may nduce serious complications, such as the visceral larva migrans VLM) or ocular larva migrans (OLM) [1–5]. Although VLM has been ound in various organs, such as the liver, lung, heart, or skin [1–5], nvolvement of the central nervous system (CNS) is extremely rare. here have been several reports of myelitis caused by VLM due to T. anis [2,3]. Here, we report the first patient with myelitis evidently ssociated with VLM due to T. cati infection.

The aim of this study was to evaluate the gender and age differences in the normal adult human brain, using voxel‐based morphometry. In this study, 227 right‐handed normal adults (male:female = 111:116) were examined. Three‐dimensional magnetic resonance brain images of each subject were segmented into gray and white matter using statistical parametric mappings. All individual data were transformed to standard brain space and then divided into older and younger age groups before examining the effects of age and gender. There was a significant negative correlation between gray matter concentration and age in each gender group. The differences were more prominent in the older age groups compared with the younger age groups. Gray matter concentrations in the bilateral inferior frontal lobes, anterior cingulate gyrus, medial thalamus, and hypothalamus were more retained in females as they aged, whereas those in the occipital regions were more retained in aging males. Our findings are consistent with biologically and hormonally established gender differences. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.

The increase in the aging population, the drastic change to a new system for postgraduate clinical training, and the lack of medical doctors have all become objects of national concern. Medical divide and melt down of the medical system brought stress especially to rural areas. Other types of stress are also found in urban University hospitals where doctors are forced to accomplish tons of paper work, while struggling on research, education, and clinical work. In this symposium, I would like to show some background and reasons for the shortage of the doctors in Japan. I also present our daily clinical practice and approach for new residents. I will also discuss the future improvement of our medical system especially in the field of Neurology. We need to show strong leadership and appeal to our comrades with medical ethics, one's dignity or self-esteem as a doctor.

Major depressive and bipolar disorders are serious illnesses that affect millions of people. Growing evidence implicates glutamate signalling in depression, though the molecular mechanism by which glutamate signalling regulates depression-related behaviour remains unknown. In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to depression-related behaviour. The NR2A subunit of the NMDA receptor is tyrosine-phosphorylated, with Tyr 1325 as its one of the major phosphorylation site. We have generated mice expressing mutant NR2A with a Tyr-1325-Phe mutation to prevent the phosphorylation of this site in vivo. The homozygous knock-in mice show antidepressant-like behaviour in the tail suspension test and in the forced swim test. In the striatum of the knock-in mice, DARPP-32 phosphorylation at Thr 34, which is important for the regulation of depression-related behaviour, is increased. We also show that the Tyr 1325 phosphorylation site is required for Src-induced potentiation of the NMDA receptor channel in the striatum. These data argue that Tyr 1325 phosphorylation regulates NMDA receptor channel properties and the NMDA receptor-mediated downstream signalling to modulate depression-related behaviour.