Progressive conus medullaris lesions are suggestive of intravascular large B-cell lymphoma.

BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

[Herpes simplex encephalitis presenting as a stroke-like episode following a migraine attack: a case report].

A 23-year-old woman, who had been suffering from migraine since primary school age, presented with left arm paralysis three days after one such migraine attack. On admission, brain MRI diffusion-weighted imaging (DWI) demonstrated high-signal-intensity lesions in the white matter of the right fronto-parietal lobe, and no abnormal lesions were evident in the limbic system. Although the patient had a fever of 38.7°C, the CSF cell count was not elevated. On the 4|th day, the left arm paralysis worsened, with an increase in body temperature to 39.8°C. Brain MRI revealed that the white matter lesions had spread to the right postcentral gyrus and the bilateral insular cortex. Also, MR angiography demonstrated no spasms or dissection of the major vessels. On the 6|th day, the CSF cell count was elevated to 54/µl and herpes simplex virus DNA was detected. Acyclovir and steroid pulse therapy ameliorated the symptoms. Cervical artery dissection and reversible cerebral vasoconstriction are well known complications of migraine attack. However, herpes simplex encephalitis should also be considered as a differential diagnosis in patients with a high fever of unknown origin.

Bipolar disorder in megalencephalic leukoencephalopathy with subcortical cysts: a case report.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC), or Van der Knaap disease, is a rare spongiform leukodystrophy that is characterized by macrocephaly, progressive motor dysfunction, and mild mental retardation. It is very rare for mental illness such as psychotic disorders, affective disorders and anxiety disorders to occur in MLC. CASE PRESENTATION: A 17-year-old boy was admitted to our hospital after he developed symptoms of depressive state with catatonia after being diagnosed as having MLC with confirmed MLC1 mutation. His catatonic symptoms were improved with administration of olanzapine and sertraline and he was discharged after 4 months. Several months later, he became hypomanic. He was diagnosed with bipolar II disorder. Mood swings were controlled with the administration of carbamazepine. CONCLUSIONS: This case is the first report of bipolar disorder during the clinical course of MLC. This case indicate the possibility that MLC influences the development of bipolar disorder in MLC, however, further studies involving more patients are required to clarify this.

Angiogenesis in the ischemic core: A potential treatment target?

The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.

Brain structure differences among male schizophrenic patients with history of serious violent acts: an MRI voxel-based morphometric study.

BACKGROUND: The biological underpinnings of serious violent behaviors in patients with schizophrenia remain unclear. The aim of this study was to identify the characteristics of brain morphometry in patients with schizophrenia and a history of serious violent acts, who were being treated under relatively new legislation for offenders with mental illness in Japan where their relevant action should be strongly associated with their mental illness. We also investigated whether morphometric changes would depend on types of serious violent actions or not. METHODS: Thirty-four male patients with schizophrenia who were hospitalized after committing serious violent acts were compared with 23 male outpatients or inpatients with schizophrenia and no history of violent acts. T1-weighted magnetic resonance imaging (MRI) with voxel-based morphometry was used to assess gray matter volume. Additionally, patients with violent acts were divided based on whether their relevant actions were premeditated or not. The regional volumes of these two groups were compared to those of the control patient group. RESULTS: Patients with schizophrenia and a history of serious violent acts showed significantly smaller regional volumes of the right inferior temporal area expanded to the middle temporal gyrus and the temporal pole, and the right insular area compared to patients without a history of violence. Patients with premeditated violent acts showed significantly smaller regional volumes of the right inferior temporal area, the right insular area, the left planum polare area including the insula, and the bilateral precuneus area including the posterior cingulate gyrus than those without a history of violence, whereas patients with impulsive violent acts showed significantly smaller volumes of only the right inferior temporal area compared to those without a history of violence. CONCLUSIONS: Patients with schizophrenia and a history of serious violent acts showed structural differences in some brain regions compared to those with schizophrenia and no history of violence. Abnormalities in the right inferior temporal area were relatively common but did not depend on whether the violent actions were premeditated or not, and abnormalities in a wider range may be attributed to not only planning the violent action against others but also to maintaining that plan. TRIAL REGISTRATION: UMIN.ac.jp UMIN000008065 . Registered 2012/05/31.

Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats.

Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-ß polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.

A case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration successfully treated with antitumor and immunotherapy.

We report a case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) with breast cancer in a 54-year-old woman. The symptoms of limb and truncal ataxia, and dysarthria gradually progressed during the course of 1 year, and the modified Rankin scale (mRS) score was 2. A mastectomy with sentinel lymph node resection was performed for the breast cancer. No malignant cells were found on histopathological examination of the lymph node. Combination chemotherapy with adriamycin and cyclophosphamide (AC) prevented neurologic deterioration. However, subsequent treatment with trastuzumab and paclitaxel did not prevent progression of the symptoms (mRS score 3). Brain magnetic resonance imaging showed atrophy of the cerebellar hemispheres without brain stem atrophy. Anti-Yo antibody was detected in the serum, which led to a diagnosis of anti-Yo-associated PCD. We resected an enlarged axillary lymph node, which was found on computed tomography. The histopathological analysis of the lymph node revealed foreign body granuloma, which suggested an association with necrotic malignant tissue. Following additional tegafur-uracil therapy and two courses of intravenous immunoglobulin (IVIg), the cerebellar signs and symptoms gradually improved (mRS score 2). The clinical course shows that PCD can present as a slowly progressive cerebellar symptom. We propose an active treatment for anti-Yo-associated PCD consisting of tumor resection, combined chemotherapy, and IVIg.

Neurocognitive features in male patients with schizophrenia exhibiting serious violence: a case control study.

BACKGROUND: The relationship between violence and neurocognitive function in schizophrenia is unclear. We examined the backgrounds and neurocognitive functions of violent and nonviolent patients with schizophrenia to identify factors associated with serious violence. METHODS: Thirty male patients with schizophrenia who were hospitalized after committing serious violent acts were compared with 24 hospitalized male patients with schizophrenia and no history of violence. We evaluated psychiatric symptoms using the Positive and Negative Syndrome Scale (PANSS) and neurocognitive functions using the Brief Assessment of Cognition in Schizophrenia (BACS)-Japanese version. RESULTS: Repeated-measures analyses of variance on BACS subcomponents z-scores showed that the violent and control groups had different neuropsychological profiles at trend level (p = 0.095). Post hoc analyses of variance indicated that the violent group had significantly better working memory and executive function than the control group. In post hoc ANOVAs also controlling for the effect of the presence of substance abuse on cognitive function, violent or nonviolent group had a significant main effect on executive function but not on working memory. CONCLUSIONS: Patient with violent or non-violent schizophrenia have distinct neuropsychological profiles. These results may help develop improved psychosocial treatments.

[Effects of Mental Disorders on the Academic Outcomes of University Students--A Retrospective Study Using Medical Records from a Health Services Center].

OBJECTIVE: Falling behind in class is a serious problem for university students as it can lead to social problems and increase the risk of suicide. Although it is common for students suffering from mental disorders to fall behind academically, there have been few studies investigating the difficulties these students face in order to graduate from university. Therefore, we investigated factors associated with dropping out of school with the purpose of creating a strategy to improve the academic outcomes of students who regularly seek psychiatric consultation. SUBJECTS: We investigated undergraduate students who received consultation at Tsukuba University's Health Services Center Psychiatry Department and whose academic outcomes between the 2004 and 2013 academic years were known. METHODS: Academic outcomes were obtained from Tsukuba University's grade management system by permission of the authority. The students were divided into either a graduate or dropout group depending on their academic outcomes. The medical records for both groups were retrospectively investigated, and factors that were predicted to affect academic outcomes were assessed using statistical methods. RESULTS: The dropout group was younger in grade and had a greater severity of illness at initial consultation. Moreover, this group had a greater number of consultation visits, showed less cooperation with the instructor in charge, had a significantly longer duration of social with drawal and temporary leave of absence from school, and had a significantly greater number of students with grade retention. When a time factor was incorporated in the analysis, the presence of grade retention/temporary leave of absence from school and social withdrawal was significantly correlated with dropping out of school. CONCLUSION: It was revealed that not only the mental disorder itself, but also psychosocial severity and the maladjusted state that occur secondary to such mental disorder influence academic outcomes. These results indicated that in order to improve academic outcomes, it is necessary not only to appropriately treat the disorder, but to also provide university community support for social maladjusted states of the students in psychiatric treatments, such as social withdrawal, educational support for daily living, individual support for daily living, and academic support, through cooperation with the educational organization.

Pseudo-continuous arterial spin labeling MRI study of schizophrenic patients.

UNLABELLED: Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a novel noninvasive technique that can measure regional cerebral blood flow (rCBF). To our knowledge, few studies have examined rCBF in patients with schizophrenia by ASL-MRI. Here we used pseudo-continuous ASL (pCASL) to examine the structural and functional imaging data in schizophrenic patients, taking the regional cerebral gray matter volume into account. The subjects were 36 patients with schizophrenia and 42 healthy volunteers who underwent 3-tesla MRI, diffusion tensor imaging (DTI), and pCASL. We evaluated the gray matter volume imaging, DTI, and pCASL imaging data in a voxel-by-voxel statistical analysis. The schizophrenia patients showed reduced rCBF in the left prefrontal and bilateral occipital cortices compared to the healthy volunteers. There was a significant reduction of gray matter volume in the left inferior frontal cortex in the schizophrenia patients. With respect to the fractional anisotropy (FA) values in the DTI, there were significant FA reductions in the left superior temporal, left external capsule, and left inferior prefrontal regions in the patients compared to the controls. CONCLUSION: Our pCASL study with partial volume effect correction together with volumetry and DTI data demonstrated hypoactivity in the left prefrontal area beyond structural abnormalities in schizophrenia patients. There were also hypofunction areas in bilateral occipital cortices, although structural abnormalities were not apparent.

Immunohistochemical analysis of ubiquilin-1 in the human hippocampus: association with neurofibrillary tangle pathology.

This post mortem immunohistochemical study examined the localization and distribution of ubiquilin-1 (UBL), a shuttle protein which interacts with ubiquitin and the proteasome, in the hippocampus from Alzheimer's disease (AD) dementia cases, and age-matched cases without dementia. In Braak stages 0-I-II cases, UBL immunoreactivity was detected in a dense fiber network in the neuropil, and in the cell cytoplasm and nucleoplasm of neurons in Cornu Ammonis (CA) fields and dentate gyrus granular neurons. In Braak stages III-IV and V-VI cases, UBL immunoreactivity was reduced in the neuropil and in the cytoplasm of the majority of CA1 neurons; some CA1 pyramidal neurons and the majority of CA2/3 pyramidal, CA4 multipolar, and dentate granular neurons had markedly increased UBL immunoreactivity in the nucleoplasm. Dual immunofluorescence analysis of UBL and antibody clone AT8 revealed co-localization most frequently in CA1 pyramidal neurons in Braak stage III-IV and V-VI cases. Further processing using the pan-amyloid marker X-34 revealed prominent UBL/X-34 dual labeling of extracellular NFT confined to the CA1/subiculum in Braak stage V-VI cases. Our results demonstrate that in AD hippocampus, early NFT changes are associated with neuronal up-regulation of UBL in nucleoplasm, or its translocation from the cytoplasm to the nucleus. The perseverance of UBL changes in CA2/3, CA4 and dentate gyrus, generally considered as more resistant to NFT pathology, but not in the CA1, may mark a compensatory, potentially protective response to increased tau phosphorylation in hippocampal neurons; the failure of such a response may contribute to neuronal degeneration in end-stage AD.

Discrimination between schizophrenia and major depressive disorder by magnetic resonance imaging of the female brain.

BACKGROUND: Although schizophrenia and major depressive disorder (MDD) differ on a variety of neuroanatomical measures, a diagnostic tool to discriminate these disorders has not yet been established. We tried to identify structural changes of the brain that best discriminate between schizophrenia and MDD on the basis of gray matter volume, ventricle volume, and diffusion tensor imaging (DTI). METHOD: The first exploration sample consisted of 25 female patients with schizophrenia and 25 females with MDD. Regional brain volumes and fractional anisotropy (FA) values were entered into a discriminant analysis. The second validation sample consisted of 18 female schizophrenia and 16 female MDD patients. RESULTS: The stepwise discriminant analysis resulted in correct classification rates of 0.80 in the schizophrenic group and 0.76 in MDD. In the second validation sample, the obtained model yielded correct classification rates of 0.72 in the schizophrenia group and 0.88 in the MDD group. CONCLUSION: Our results suggest that schizophrenia and MDD have differential structural changes in the examined brain regions and that the obtained discriminant score may be useful to discriminate the two disorders.

Discrimination of female schizophrenia patients from healthy women using multiple structural brain measures obtained with voxel-based morphometry.

AIM: Although schizophrenia and control subjects differ on a variety of neuroanatomical measures, the specificity and sensitivity of any one measure for differentiating between the two groups are low. To identify the correlative pattern of brain changes that best discriminate schizophrenia patients from healthy subjects, discriminant analysis techniques using voxel-based morphometry were applied. METHODS: The first analysis was conducted to obtain a statistical model that classified 105 female healthy subjects and 38 female schizophrenia patients. First, the differences in gray matter and cerebrospinal fluid volume between the patients and healthy subjects were evaluated using optimized voxel-based morphometry. Then, a discriminant analysis reflecting the results of this evaluation was adopted. The second analysis was performed to prospectively validate the statistical model by successfully classifying a new group that consisted of 23 female healthy subjects and 23 female schizophrenia patients. RESULTS: The use of these variables resulted in correct classification rates of 0.72 in the control subjects and 0.76 in the schizophrenia patients. In the second validation analysis using these variables, correct classification rates of 0.70 in the control subjects and 0.74 in the schizophrenia patients were achieved. CONCLUSION: Schizophrenia patients have structural deviations in multiple brain areas, and a combination of structural brain measures can distinguish between patients and controls.

Criterion and construct validity of the CogState Schizophrenia Battery in Japanese patients with schizophrenia.

BACKGROUND: The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia. METHODOLOGY/PRINCIPAL FINDINGS: Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. CONCLUSIONS/SIGNIFICANCE: This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.

Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients.

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.

An immunohistochemical study of the serotonin 1A receptor in the hippocampus of subjects with Alzheimer's disease.

Alzheimer's disease (AD) is associated with neuronal degeneration, synaptic loss and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5-HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and Positron emission tomography (PET) imaging studies have demonstrated that 5-HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5-HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of NFT severity defined by Braaks' pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non-AD controls (NC) stratified into three Braaks' stages (Braak 0-II, NC; Braak III/IV and V/VI, AD). In the Braak 0-II group, 5-HT1A-immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5-HT1A-ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5-HT1A-ir intensity was markedly decreased in the CA1 region in 6/11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A-ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5-HT1A receptors are mainly preserved until the end-stage of NFT progression in AD. Thus, the utility of PET imaging using a 5-HT1A-specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases.

Possible association of the semaphorin 3D gene (SEMA3D) with schizophrenia.

Semaphorins are ligands of plexins, and the plexin-semaphorin signaling system is widely involved in many neuronal events including axon guidance, cell migration, axon pruning, and synaptic plasticity. The plexin A2 gene (PLXNA2) has been reported to be associated with schizophrenia. This finding prompted us to examine the possible association between the semaphorin 3D gene (SEMA3D) and schizophrenia in a Japanese population. We genotyped 9 tagging single nucleotide polymorphisms (SNPs) of SEMA3D including a non-synonymous variation, Lys701Gln (rs7800072), in a sample of 506 patients with schizophrenia and 941 healthy control subjects. The Gln701 allele showed a significant protective effect against the development of schizophrenia (p = 0.0069, odds ratio = 0.76, 95% confidence interval 0.63 to 0.93). Furthermore, the haplotype-based analyses revealed a significant association. The four-marker analysis (rs2190208-rs1029564-rs17159614-rs12176601), in particular, not including the Lys701Gln, revealed a highly significant association (p = 0.00001, global permutation), suggesting that there may be other functional polymorphisms within SEMA3D. Our findings provide strong evidence that SEMA3D confers susceptibility to schizophrenia, which could contribute to the neurodevelopmental impairments in the disorder.