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.

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.

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.

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.

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 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.

[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.

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.

An immunohistochemical study of GABA A receptor gamma subunits in Alzheimer's disease hippocampus: relationship to neurofibrillary tangle progression.

Immunohistochemical characterization of the distribution of GABA(A) receptor subunits gamma1/3 and 2 in the hippocampus relative to neurofibrillary tangle (NFT) pathology staging was performed in cognitively normal subjects (Braak stage I/II, n = 4) and two groups of Alzheimer's disease (AD) patients (Braak stage III/IV, n = 4; Braak stage V/VI, n = 8). In both Braak groups of AD patients, neuronal gamma1/3 and gamma2 immunoreactivity was preserved in all hippocampal subfields. However, compared to normal controls neuronal gamma1/3 immunoreactivity was more intense in several end-stage AD subjects. Despite increased NFT pathology in the Braak V/VI AD group, GABA(A)gamma1/3 and gamma2 immunoreactivity did not co-localize with markers of NFT. These results suggest that upregulating or preserving GABA(A)gamma1/3 and gamma2 receptors may protect neurons against neurofibrillary pathology in AD.

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.

Immunohistochemical and immunoblot analysis of Dopamine and cyclic AMP-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32) in the prefrontal cortex of subjects with schizophrenia and bipolar disorder.

Dopamine and cyclic adenosine 3':5'-monophosphate (AMP)-regulated phosphoprotein, relative molecular mass 32,000 (DARPP-32), plays an important role in modulating the functions of various neurotransmitter systems. To explore the alterations in DARPP-32 in subjects with schizophrenia and bipolar disorder, we employed immunohistochemical and Western blotting techniques and examined the distribution and expression of DARPP-32 in the postmortem dorsolateral prefrontal cortex (DLPFC) from 12 subjects with schizophrenia, 10 subjects with bipolar disorder, and 11 control subjects. Immunohistochemical study demonstrated that DARPP-32 immunolabeling in the neuronal soma from subjects with schizophrenia and bipolar disorder was lower than in that from the controls. The results of the immunoblot analysis were consistent with those of the immunohistochemistry, and the amount of DARPP-32 in subjects with schizophrenia and bipolar disorder was found to be lower than that in the control subjects. The present study suggests that DARPP-32 decreases in the DLPFC of patients with schizophrenia and bipolar disorder, and further suggests that this decrease is associated with dysfunction of dopaminoceptive neurons in the DLPFC of patients affected by these two mental disorders.

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.

GABA(A) receptor gamma subunits in the hippocampus of the rat after perforant pathway lesion.

Immunohistochemical and Western blotting techniques were employed to examine the alterations in immunostaining of the gamma-amino butyric acid (GABA) receptor subunits gamma 1/3 and 2 within the hippocampus of the rat brain at 1, 3, 7, 14, and 30 days after a unilateral perforant pathway lesion. At 1, 3, and 7 days post-lesion, we observed a remarkable decrease in gamma 1/3 neuropil staining in the deafferented zone (i.e., the outer molecular layer of the dentate gyrus ipsilateral to the lesion), although at 3 and 7 days post-lesion, staining intensity was considerably recovered. At 14 days post-lesion, the gamma 1/3 immunostaining was indistinguishable from that of controls and it appeared yet more robust at 30 days post-lesion. We also observed a slight decrease in gamma 2 neuropil staining until 7 days post-lesion, and an increase in gamma 2 staining at 30 days post-lesion. Western blot analysis demonstrated data that was relatively consistent with our immunohistochemical observations, although gamma 3 was hardly detectable. Our study suggests that gamma subunits of the GABA(A) receptor in the dentate gyrus display a plastic response to the deafferentation of the perforant pathway.

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.

Immunohistochemical and immunoblot analysis of gamma-aminobutyric acid B receptor in the prefrontal cortex of subjects with schizophrenia and bipolar disorder.

Immunohistochemical and immunoblot techniques were employed to examine the distribution and expression of GABA(B) receptors in the prefrontal cortex of postmortem subjects with schizophrenia and bipolar disorder. GABA(B)R1a/b immunoreactivity was observed in the neuronal soma and dendrites as well as in the neuropil in the control subjects. GABA(B)R1a/b immunolabeling in neurons from the subjects with schizophrenia and bipolar disorder was less intense than in those from the control subjects. In control subjects, the distribution of GABA(B)R2 immunoreactivity was found to be similar to that of GABA(B)R1a/b. GABA(B)R2 immunolabeling in neurons from the bipolar disorder group appeared less intense than that of the normal controls as well as that in schizophrenic groups. Immunoblot analysis demonstrated a significant decrease in GABA(B)R1a levels in schizophrenic subjects, while there was a significant decrease in GABA(B)R1a, GABA(B)R1b, and GABA(B)R2 levels in bipolar subjects compared with the controls. The present study suggests that the GABA(B) receptor is involved in the pathophysiology of schizophrenia and bipolar disorder, and further suggests that the patterns of changes in GABA(B) receptor subtypes are different between these two disorders.

Immunohistochemical study of the hnRNP A2 and B1 in the hippocampal formations of brains with Alzheimer's disease.

To elucidate the post-transcriptional regulation in the subjects with Alzheimer's disease (AD), we employed immunohistochemical techniques and examined the expression of the heterogeneous nuclear ribonucleoprotein (hnRNP) A2 and B1 in the hippocampus with neurofibrillary tangle (NFT) neuropathology. In the mildly affected subjects (Braak stages I and II), the most intense A2 immunoreactivity was observed in the CA3 to CA1 neurons. In the moderately (Braak stages III and IV) and severely affected subjects (Braak stages V and VI), the CA1 region demonstrated a decrease in the number of A2 immunoreactive neurons and in immunoreactivity in the remaining neurons, while within the CA4 to CA2 in the severely affected subjects, the majority of neurons showed increased A2 immunoreactivity. An intense B1 immunoreactivity was observed throughout the CA subfields. In the CA1 subfield of the moderately affected subjects and in the extensive hippocampal regions of the severely affected subjects, a decrease in B1 immunoreactivity was observed. Double-immunolabeling studies demonstrated that tangle-bearing neurons reduced A2 and B1 immunoreactivity. Our study suggests that hnRNP A2 and B1 display different responses in the AD hippocampus, and further suggests that the post-transcriptional regulation is disturbed in neurons of the AD hippocampus.