Language：English   Publishing type：Research paper (scientific journal)  

Brain biopsies are often considered for patients who cannot be diagnosed with various laboratory test results. However, physicians tend to be hesitant regarding their application in possibly non-neoplastic brain diseases, due to the invasiveness and risks. The aim was to determine the indications for brain biopsies in cases of neurological diseases of unknown etiology. We retrospectively evaluated diagnostic accuracy, laboratory findings (including a liquid biopsy for malignant lymphoma), magnetic resonance imaging (MRI) characteristics and the post-treatment outcomes of patients undergoing brain biopsies for neurological diseases of unknown etiology. The data of patients who had undergone a brain biopsy during their admission to Niigata University Hospital, between 2011 and 2024, were reviewed. Moreover, the laboratory data and MRI findings between patients with definitive and nonspecific biopsy diagnoses were compared. Twenty-six patients underwent a brain biopsy, and a definitive diagnosis was obtained in 14 patients (53.8%). Even in cases where a nonspecific diagnosis was made, biopsy findings helped rule out malignancy and guide clinical diagnosis and treatment decisions. The liquid biopsy for malignant lymphoma was performed in eight patients, with one yielding a positive result, consistent with primary central nervous system lymphoma. The sensitivity and specificity of liquid biopsy were 0.5 and 1, respectively. Diffusely contrasted cortical lesions and the presence of mass effects on MRI, were significantly associated with a definitive diagnosis, compared to a nonspecific diagnosis. In conclusion, brain MRI and liquid biopsies can assist in determining the appropriate indications for brain biopsies in neurological diseases of unknown etiology.

DOI： 10.1016/j.jns.2024.123150

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PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.

DOI： 10.1007/s00234-024-03432-w

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Abstract

Patients with neuronal intranuclear inclusion disease (NIID) can present with encephalitis‐like symptoms such as recurrent paroxysmal fever and unconsciousness. To date, no specific triggers for these symptoms have been reported. In our case, an 78‐year‐old woman became unconscious and developed fever after cerebral angiography. The patient had experienced four episodes of unconsciousness and fever in the past 7 years. Postangiography, she immediately became unconscious and developed fever. No vascular abnormalities were found and magnetic resonance imaging of the brain revealed expanding white matter lesions and hyperintense lesions along the corticomedullary junction. Genetic analysis revealed an abnormal GGC repeat expansion in NOTCH2NLC. Thus, we diagnosed the patient with NIID. We suggest that cerebral angiography is a possible trigger for encephalitis‐like symptoms in NIID.

DOI： 10.1111/ncn3.12839

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DOI： 10.1007/s00415-024-12276-6

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Language：Japanese   Publisher：(一社)日本神経学会  

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[This corrects the article DOI: 10.3389/fncel.2023.1225504.].

DOI： 10.3389/fncel.2024.1372045

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DOI： 10.1016/j.prdoa.2024.100279

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Progressive multifocal leukoencephalopathy (PML) is a rare central nervous system disease caused by JC virus (JCV) infection. Human immunodeficiency virus (HIV) infection is the greatest risk factor for PML. Other immunological diseases, including systemic sarcoidosis, have also been reported as risk factors for PML. Herein, we report a case of PML co-occurring with neurosarcoidosis. Early diagnosis using brain biopsy and appropriate therapeutic interventions achieved favorable outcomes. PML in patients with active intracranial neurosarcoidosis is extremely rare. We believe that it is important to perform brain biopsy at an early stage to allow diagnosis, even for central nervous system involvement with a progressive parenchymal lesion in patients with sarcoidosis, if PML is possible.

DOI： 10.3389/fimmu.2024.1447992

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BACKGROUND: Metformin (MET) treatment prior to stroke might have neuroprotective effects other than hypoglycemic effects. This study evaluated whether MET treatment prior to stroke is associated with neurological severity and functional outcome in patients with stroke who were not indicated for endovascular treatment and whether the effects of MET differ for each ischemic stroke subtype. METHODS: We investigated 160 type 2 diabetes mellitus patients with ischemic stroke without endovascular treatment who were taking some oral antidiabetic agents prior to stroke in two tertiary hospitals. Lower neurological severity was defined as a National Institutes of Health Stroke Scale score of 3 or lower on admission, and favorable functional outcome was defined as a modified Rankin Scale score = 0-2 at discharge. We analyzed the effects of MET on the neurological severity and functional outcome in each ischemic stroke subtype on logistic regression analysis with adjustments for multiple confounding factors. RESULTS: MET treatment prior to stroke was associated with lower stroke severity and favorable functional outcome. In the stroke subtypes, MET use affected both neurological severity (P = 0.037) and functional outcome (P = 0.041) in only patients with small-vessel disease (SVD). CONCLUSIONS: MET may be useful to improve the outcome of patients with SVD.

DOI： 10.1016/j.jns.2023.122812

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The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

DOI： 10.1093/braincomms/fcad296

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INTRODUCTION: A study is eagerly awaited that will reveal the unknown mechanisms of multiple system atrophy (MSA), in which the risk of sudden death is the greatest during sleep. The blunted pulse response to nocturnal respiratory events suggests an abnormal cardiac response to a sleep-related breathing disorder. Patients with MSA have a lower pulse event index (PEI), despite a greater hypoxic burden and a similar frequency of respiratory events. However, the evidence is speculative and not directly proven, and many limitations require further study. METHODS: We conducted a retrospective analysis of 26 patients with MSA who had undergone overnight oximetry between April 2016 and December 2022. RESULTS: The median 4% oxyhemoglobin desaturation index (ODI) was 11.6/h, the 6-bpm PEI was 8.9/h, and the PEI/ODI ratio was as low as 0.91. There were three patients with suspected sudden death; all had low PEI/ODI ratios. The PEI/ODI ratio was followed over time in seven patients, all of whom had a decrease in the ratio. However, the PEI was higher than the ODI in 12/26 (46%) of the patients. CONCLUSION: A low PEI/ODI ratio, reflecting a blunted pulse response to nocturnal respiratory events in patients with MSA, may indicate a worse prognosis. This finding and the significance of the longitudinal decrease in the PEI/ODI ratio will require a prospective study.

DOI： 10.1016/j.parkreldis.2023.105817

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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.

DOI： 10.1111/ene.15941

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media {SA}  

Theoretically, direct chemical reprogramming of somatic cells into neurons in the infarct area represents a promising regenerative therapy for ischemic stroke. Previous studies have reported that human fibroblasts and astrocytes transdifferentiate into neuronal cells in the presence of small molecules without introducing ectopic transgenes. However, the optimal combination of small molecules for the transdifferentiation of macrophages into neurons has not yet been determined. The authors hypothesized that a combination of small molecules could induce the transdifferentiation of monocyte-derived macrophages into neurons and that the administration of this combination may be a regenerative therapy for ischemic stroke because monocytes and macrophages are directly involved in the ischemic area. Transcriptomes and morphologies of the cells were compared before and after stimulation using RNA sequencing and immunofluorescence staining. Microscopic analyses were also performed to identify cell markers and evaluate functional recovery by blinded examination following the administration of small molecules after ischemic stroke in CB-17 mice. In this study, an essential combination of six small molecules [CHIR99021, Dorsomorphin, Forskolin, isoxazole-9 (ISX-9), Y27632, and DB2313] that transdifferentiated monocyte-derived macrophages into neurons in vitro was identified. Moreover, administration of six small molecules after cerebral ischemia in model animals generated a new neuronal layer in the infarct cortex by converting macrophages into neuronal cells, ultimately improving neurological function. These results suggest that altering the transdifferentiation of monocyte-derived macrophages by the small molecules to adjust their adaptive response will facilitate the development of regenerative therapies for ischemic stroke.

DOI： 10.3389/fncel.2023.1225504

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A 74-year-old woman who presented with a skin eruption involving the left lateral leg along the L5 dermatome and widespread eruptions on the buttocks and trunk was diagnosed with disseminated herpes zoster (HZ). She also had left lower extremity muscle weakness. The pattern of distribution of muscle weakness and gadolinium-enhanced magnetic resonance imaging findings indicated polyradiculoneuritis mainly affecting the L5 spinal root. Moreover, we observed severe weakness of the left tibialis anterior muscle. Weakness of the other L5 myotomes reduced after antiviral treatment; however, left tibialis anterior muscle weakness persisted. We concluded that lumbosacral polyradiculoneuritis was attributable to varicella-zoster virus (VZV) infection, which also caused fibular neuropathy in this case. Retrograde transport of the VZV may have infected the fibular nerve throughout the sites of skin eruption. It is important to be mindful of simultaneous nerve root and peripheral nerve involvement in cases of motor paralysis associated with HZ infection.

DOI： 10.5692/clinicalneurol.cn-001848

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

DOI： 10.3390/brainsci13060955

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Language：Japanese   Publisher：(一社)日本神経治療学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J02615&link_issn=&doc_id=20230825280022&doc_link_id=10.15082%2Fjsnt.40.3_259&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.40.3_259&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J02615&link_issn=&doc_id=20230825280022&doc_link_id=10.15082%2Fjsnt.40.3_259&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.40.3_259&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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DOI： 10.1212/WNL.0000000000202665

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Background

This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan.

Methods

This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or >55 years and with a positive family history (group 2). After conducting conventional genetic tests forNOTCH3andHTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups.

Results

Group 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadNOTCH3mutations, 11 patients hadHTRA1mutations, 6 patients hadABCC6mutations, 1 patient had aTREX1mutation, 1 patient had aCOL4A1mutation and 1 patient had aCOL4A2mutation. The total frequency of mutations inNOTCH3,HTRA1andABCC6was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134).

Conclusions

More than 90% of mgCSVDs were diagnosed by screening forNOTCH3,HTRA1andABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

DOI： 10.1136/jnnp-2022-329917

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DOI： 10.1016/J.CLINEURO.2022.107502

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jns.2022.120456

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02615&link_issn=&doc_id=20221114240031&doc_link_id=10.15082%2Fjsnt.39.6_S118&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.39.6_S118&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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Ferroptosis, a type of oxidative stress cell death, has been implicated in cell injury in several diseases, and treatments with specific inhibitors have been shown to protect cells and tissues. Here we demonstrated that a treatment with the nitroxide radical, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), prevented the ferroptotic cell death in an airborne manner. Other TEMPO derivatives and lipophilic antioxidants, such as Trolox and ferrostatin-1, also prevented cell death induced by erastin and RSL3; however, only TEMPO exhibited inhibitory activity from a physically distant location. TEMPO vaporized without decomposing, and then dissolved again into a nearby water solution. Volatilized TEMPO inhibited glutamate-induced cell death in mouse hippocampal cell lines, and also reduced neuronal cell death in a mouse ischemia model. These results suggest that TEMPO is a unique cell protective agent that acts in a volatility-mediated manner.

DOI： 10.1093/jb/mvac044

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/mdc3.13382

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Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

DOI： 10.1172/jci140555

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DOI： 10.1007/s10286-021-00826-1

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DOI： 10.1016/j.clineuro.2021.106496

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BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society.

DOI： 10.1002/mds.28521

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[This corrects the article DOI: 10.3389/fneur.2019.00693.].

DOI： 10.3389/fneur.2021.756038

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BACKGROUND: Reperfusion therapies by tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) have ushered in a new era in the treatment of acute ischemic stroke (AIS). However, reperfusion therapy-related HT remains an enigma. AIM: To provide a comprehensive review focused on emerging concepts of stroke and therapeutic strategies, including the use of protective agents to prevent HT after reperfusion therapies for AIS. METHODS: A literature review was performed using PubMed and the ClinicalTrials.gov database. RESULTS: Risk of HT increases with delayed initiation of tPA treatment, higher baseline glucose level, age, stroke severity, episode of transient ischemic attack within 7 days of stroke onset, and hypertension. At a molecular level, HT that develops after thrombolysis is thought to be caused by reactive oxygen species, inflammation, remodeling factor-mediated effects, and tPA toxicity. Modulation of these pathophysiological mechanisms could be a therapeutic strategy to prevent HT after tPA treatment. Clinical mechanisms underlying HT after MT are thought to involve smoking, a low Alberta Stroke Program Early CT Score, use of general anesthesia, unfavorable collaterals, and thromboembolic migration. However, the molecular mechanisms are yet to be fully investigated. Clinical trials with MT and protective agents have also been planned and good outcomes are expected. CONCLUSION: To fully utilize the easily accessible drug-tPA-and the high recanalization rate of MT, it is important to reduce bleeding complications after recanalization. A future study direction could be to investigate the recovery of neurological function by combining reperfusion therapies with cell therapies and/or use of pleiotropic protective agents.

DOI： 10.1016/j.jns.2020.117217

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Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞近年,脳梗塞に対する細胞療法の研究が盛んに行われているが,既存の細胞療法は,投与細胞の採取や調整に複雑な手技を要するため,一般臨床への普及が難しい。われわれは,末梢血単核球に,低酸素低糖刺激という簡便な刺激を加えることにより,脳梗塞に対して治療効果のある細胞を調整できることを証明した。本稿では,われわれの開発した技術と今後の展望について概説する。

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Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

DOI： 10.3390/ijms21176194

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Language：Japanese   Publisher：(一社)日本神経学会  

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BACKGROUND: Branch atheromatous disease (BAD) is one of the stroke subtypes caused by occlusion at the origin of a deep penetrating artery of the brain and is associated with a microatheroma or a junctional plaque. Patients with BAD often develop progressive worsening of neurologic deficits, although these patients often present minor stroke with clinical characteristics of lacunar syndrome at the onset. Pentraxin 3 (PTX3) is known to be a key molecule involved in the pathogenesis of atherosclerosis. Although a high level of serum PTX3 is observed in patients with acute coronary syndrome, there are no reports on PTX3 levels in patients with BAD. This study aimed to investigate whether serum PTX3 levels can distinguish BAD from other stroke subtypes. METHODS: We investigated 93 patients with ischemic stroke. Serum PTX3 levels on admission were measured using enzyme-linked immunosorbent assay in patients with BAD and those of other stroke subtypes (each n ≥ 20). RESULTS: The median PTX3 levels in patients with BAD (4840 pg/mL) were higher than those with other subtypes of stroke (3397 pg/mL in lacunar stroke, 1298 pg/mL in large artery atherosclerosis, 1470 pg/mL in cardioaortic embolism, and 1006 pg/mL in control) (all p < 0.01). CONCLUSION: Our results suggest that elevated serum pentraxin 3 levels might predict the diagnosis of BAD at a very early stage.

DOI： 10.1111/ene.14249

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Language：Japanese   Publisher：新潟医学会  

2018年4月から新たな内科専門医制度が開始となった。修了要件として56疾患以上の領域での160症例以上の症例登録や、29編の病歴要約などが必要である。56疾患以上の領域での症例登録のためには研修医症例をうまく活用することが大切となる。また、症例登録は500字以内の症例の概略と300字以内の自己省察に加え登録項目が複数あり、160症例を登録するには時間がかかる。病歴要約は指導医が承認した症例登録から作成するので、指導医による承認もまた重要である。新制度が開始されてから約1年半が経過した現時点で、専攻医の立場から、どのような点に注意すると円滑に修了要件を満たせるか考察した。(著者抄録)

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DOI： 10.1016/j.jns.2019.116577

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Progressive supranuclear palsy (PSP) is characterized by supranuclear gaze palsy, dystonic rigidity of the neck and upper trunk, frequent falls and mild cognitive impairment. Cerebellar ataxia is one of the exclusion criteria given by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. As a result, pathologically proven PSP patients exhibiting cerebellar ataxia have often been misdiagnosed with spinocerebellar degeneration, specifically multiple system atrophy with predominant cerebellar ataxia (MSA-C). However, more recently, it has been recognized that patients with PSP can present with truncal and limb ataxia as their initial symptom and/or main manifestation. These patients can be classified as having PSP with predominant cerebellar ataxia (PSP-C), a new subtype of PSP. Since the development of this classification, patients with PSP-C have been identified primarily in Asian countries, and it has been noted that this condition is very rare in Western communities. Furthermore, the clinical features of PSP-C have been identified, enabling it to be distinguished from other subtypes of PSP and MSA-C. In this review, we describe the clinical and neuropathological features of PSP-C. The hypothesized pathophysiology of cerebellar ataxia in PSP-C is also discussed.

DOI： 10.14802/jmd.19061

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Increased microvessel density in the peri-infarct region has been reported and has been correlated with longer survival times in ischemic stroke patients and has improved outcomes in ischemic animal models.This raises the possibility that enhancement of angiogenesis is one of the strategies to facilitate functional recovery after ischemic stroke. Blood vessels and neuronal cells communicate with each other using various mediators and contribute to the pathophysiology of cerebral ischemia as a unit. In this mini-review, we discuss how angiogenesis might couple with axonal outgrowth/neurogenesis and work for functional recovery after cerebral ischemia. Angiogenesis occurs within 4 to 7 days after cerebral ischemia in the border of the ischemic core and periphery. Post-ischemic angiogenesis may contribute to neuronal remodeling in at least two ways and is thought to contribute to functional recovery. First, new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by vascular endothelial growth factor and laminin/β1-integrin signaling. Second, blood vessels are thought to enhance neurogenesis in three stages: 1) Blood vessels enhance proliferation of neural stem/progenitor cells by expression of several extracellular signals, 2) microvessels support the migration of neural stem/progenitor cells toward the peri-infarct region by supplying oxygen, nutrients, and soluble factors as well as serving as a scaffold for migration, and 3) oxygenation induced by angiogenesis in the ischemic core is thought to facilitate the differentiation of migrated neural stem/progenitor cells into mature neurons. Thus, the regions of angiogenesis and surrounding tissue may be coupled, representing novel treatment targets.

DOI： 10.4103/1673-5374.264442

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Language：Japanese   Publisher：(一社)日本神経学会  

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Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

DOI： 10.3389/fneur.2020.00545

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

DOI： 10.1038/s41598-019-55308-2

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Language：English   Publisher：新潟医学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00990&link_issn=&doc_id=20201223020014&doc_link_id=%2Fdg3nigta%2F2019%2Fs13311%2F007%2F0391-0391%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2019%2Fs13311%2F007%2F0391-0391%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.

DOI： 10.1038/s41598-019-53418-5

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Tissue plasminogen activator (t-PA) treatment is beneficial for patients with ischemic stroke within 4.5 h of stroke onset, because the risk of intracerebral hemorrhagic transformation (HT) increases with delayed t-PA treatment. The benefits of t-PA thrombolysis are heavily dependent on time to treatment. Development of vasoprotective drugs that attenuate HT after delayed t-PA treatment might improve the prognosis of stroke patients and extend the therapeutic time window of t-PA and endovascular thrombolysis. An angiogenic factor, vascular endothelial growth factor (VEGF), might be associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia. By using a rat thromboembolic model, delayed t-PA treatment at 4 h after ischemia promoted expression of VEGF in BBB, matrix metalloproteinase-9 (MMP-9) activation, degradation of BBB components, and HT. We demonstrated that HT was inhibited by intravenous administration of an anti-VEGF neutralizing antibody/VEGF receptor antagonist. In addition, for clinical application, reverse translation studies, a path from bedside to bench, are necessary.

DOI： 10.5692/clinicalneurol.cn-001346

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：Movement Disorder Society of Japan (MDSJ)  

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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.

DOI： 10.1177/0271678X19834158

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Language：Japanese   Publisher：(株)中外医学社  

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Publishing type：Research paper (scientific journal)   Publisher：Progranulin and Central Nervous System Disorders  

DOI： 10.1007/978-981-13-6186-9_10

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Background: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Most carriers for HTRA1 mutations are asymptomatic, but more than 10 mutations have been reported in symptomatic carriers. The molecular differences between the mutations identified in symptomatic carriers and mutations identified only in CARASIL patients are unclear. HTRA1 is a serine protease that forms homotrimers, with each HTRA1 subunit activating the adjacent HTRA1 via the sensor domain of loop 3 (L3) and the activation domain of loop D (LD). Previously, we analyzed four HTRA1 mutant proteins identified in symptomatic carriers and found that they were unable to form trimers or had mutations in the LD or L3 domain. The mutant HTRA1s with these properties are presumed to inhibit trimer-dependent activation cascade. Indeed, these mutant HTRA1s inhibited wild-type (WT) protease activity. In this study, we further analyzed 15 missense HTRA1s to clarify the molecular character of mutant HTRA1s identified in symptomatic carriers. Methods: We analyzed 12 missense HTRA1s identified in symptomatic carriers (hetero-HTRA1) and three missense HTRA1s found only in CARASIL (CARASIL-HTRA1). The protease activity of the purified recombinant mutant HTRA1s was measured using fluorescein isothiocyanate-labeled casein as substrate. Oligomeric structure was evaluated by size-exclusion chromatography. The protease activities of mixtures of WT with each mutant HTRA1 were also measured. Results: Five hetero-HTRA1s had normal protease activity and were excluded from further analysis. Four of the seven hetero-HTRA1s and one of the three CARASIL-HTRA1s were unable to form trimers. The other three hetero-HTRA1s had mutations in the LD domain. Together with our previous work, 10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization or had mutations in the LD or L3 domain (P = 0.006). By contrast, eight of 11 hetero-HTRA1s and two of six CARASIL-HTRA1 inhibited WT protease activity (P = 0.162). Conclusions: HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade of HTRA1.

DOI： 10.3389/fneur.2019.00693

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Language：English   Publisher：Elsevier {BV}  

OBJECTIVE: To determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). METHODS: We recruited 59 patients with MSA and determined the predictors of a decline in the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. RESULTS: The MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. CONCLUSIONS: Impairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter.

DOI： 10.1016/j.jns.2018.03.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications Ltd  

Acutely following focal cerebral ischemia disruption of the microvessel blood–brain barrier allows transit of plasma proteins into the neuropil as edema formation that coincides with loss of microvessel endothelial β1-integrins. We extend previous findings to show that interference with endothelial β1-integrin–matrix adhesion by the monoclonal IgM Ha2/5 increases the permeability of primary cerebral microvascular endothelial cell monolayers through reorganization of claudin-5, occludin, and zonula occludens-1 (ZO-1) from inter-endothelial borders. Interference with β1-integrin–matrix adhesion initiates F-actin conformational changes that coincide with claudin-5 redistribution. β1-integrin–matrix interference simultaneously increases phosphorylation of myosin light chain (MLC), while inhibition of MLC kinase (MLCK) and Rho kinase (ROCK) abolishes the Ha2/5-dependent increased endothelial permeability by 6 h after β1-integrin–matrix interference. These observations are supported by concordant observations in the cortex of a high-quality murine conditional β1-integrin deletion construct. Together they support the hypothesis that detachment of β1-integrins from abluminal matrix ligands increases vascular endothelial permeability through reorganization of tight junction (TJ) proteins via altered F-actin conformation, and indicate that the β1-integrin–MLC signaling pathway is engaged when β1-integrin detachment occurs. These findings provide a novel approach to the research and treatment of cerebral disorders where the breakdown of the blood–brain barrier accounts for their progression and complication.

DOI： 10.1177/0271678X17722108

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Language：Japanese   Publisher：(株)中外医学社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

It is thought that posterior reversible encephalopathy syndrome (PRES) is both clinically and radiologically reversible. However, its reversible nature has been challenged based on reports of permanent neurological impairments. The factors that predict the development of irreversible neurological impairment are still unclear. In the present study, we investigated clinical manifestations, laboratory findings, and neuroradiological images to identify predictors of functional outcomes in PRES. We investigated 23 PRES patients. Apparent diffusion coefficient (ADC) reduction was observed in 4 patients in the poor outcome group, whereas no patients presented ADC reduction in the favourable outcome group (p &lt; 0.01). Further studies are warranted to evaluate the association between ADC reduction and functional outcome after PRES. (C). 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2017.08.002

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Other Link： http://orcid.org/0000-0001-6337-8156

Language：English   Publisher：MDPI AG  

Stroke is a leading cause of morbidity and mortality worldwide, and consists of two types, ischemic and hemorrhagic. Currently, there is no effective treatment to increase the survival rate or improve the quality of life after ischemic and hemorrhagic stroke in the subacute to chronic phases. Therefore, it is necessary to establish therapeutic strategies to facilitate functional recovery in patients with stroke during both phases. Cell-based therapies, using microglia and monocytes/macrophages preconditioned by optimal stimuli and/or any therapies targeting these cells, might be an ideal therapeutic strategy for managing stroke. Microglia and monocytes/macrophages polarize to the classic pro-inflammatory type (M1-like) or alternative protective type (M2-like) by optimal condition. Cell-based therapies using M2-like microglia and monocytes/macrophages might be protective therapeutic strategies against stroke for three reasons. First, M2-like microglia and monocytes/monocytes secrete protective remodeling factors, thus prompting neuronal network recovery via tissue (including neuronal) and vascular remodeling. Second, these cells could migrate to the injured hemisphere through the blood-brain barrier or choroid-plexus. Third, these cells could mitigate the extent of inflammation-induced injuries by suitable timing of therapeutic intervention. Although future translational studies are required, M2-like microglia and monocytes/macrophages therapies are attractive for managing stroke based on their protective functions.

DOI： 10.3390/ijms18102135

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

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-beta 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.

DOI： 10.1038/srep42582

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Other Link： http://orcid.org/0000-0001-6337-8156

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.

DOI： 10.1371/journal.pone.0170623

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DOI： 10.5551/jat.RV16006

DOI： 10.1111/NCN3.63

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DOI： 10.1016/J.JNS.2017.08.3694

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Language：English   Publisher：JAPAN ATHEROSCLEROSIS SOC  

This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still &lt; 5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuro-inflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile.

DOI： 10.5551/jat.RV16006

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Other Link： http://orcid.org/0000-0001-6337-8156

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Vibratory and joint position sensations are usually impaired simultaneously and afferents for both sensations ascend the dorsal columns. There are a few evidences that the central pathways in the spinal cord for position and vibratory sensations are not identical. In this study, we examined the clinical features of patients with sensory impairments of vibratory and joint position sensations. According to 43 evaluated patients’ results, the dissociation between an intact vibratory sensation and impaired joint position sensation may be important for the diagnosis of spinal disorders. We also report three cases of patients with spinal ataxia caused by sensory impairments and who show the dissociation between an impaired joint position sensation and an intact vibratory sensation. The combination of intact vibration sensation and impaired joint position sensation may suggest a dorsal column lesion in the spinal cord.

DOI： 10.1016/j.inat.2016.09.003

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1002/mds.26618

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Other Link： http://orcid.org/0000-0001-6337-8156

Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：Igaku-Shoin Ltd  

DOI： 10.11477/mf.1416200372

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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DOI： 10.1111/NCN3.12065

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.

DOI： 10.1038/jcbfm.2015.170

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Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jns.2015.06.057

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which progranulin exerts protective effects on ischaemic brain injury remains unknown. Furthermore, the therapeutic potential of progranulin against acute focal cerebral ischaemia, including combination treatment with tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of progranulin after ischaemia as well as the therapeutic effects of progranulin on ischaemic brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in progranulin expression in ischaemic Sprague-Dawley rats, including increased levels of progranulin expression in microglia within the ischaemic core, and increased levels of progranulin expression in viable neurons as well as induction of progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory isoform of progranulin (similar to 88 kDa) decreased, whereas the glycosylated immature isoform of progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature isoform was secreted only from the microglia. Second, we demonstrated that progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. We found that progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischaemia via anti-inflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43 as demonstrated in progranulin knockout mice (C57BL/6 background). Finally, we demonstrated the therapeutic potential of progranulin against acute focal cerebral ischaemia using a rat autologous thrombo-embolic model with delayed tissue plasminogen activator treatment. Intravenously administered recombinant progranulin reduced cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes (P = 0.007, 0.038, 0.007 and 0.004, respectively). In conclusion, progranulin may be a novel therapeutic target that provides vascular protection, antineuroinflammation, and neuroprotection related in part to vascular endothelial growth factor, interleukin 10, and TAR DNA-binding protein-43, respectively.

DOI： 10.1093/brain/awv079

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Hypoglycemic encephalopathy (HE) is caused by a lack of glucose availability to neuronal cells, and no neuroprotective drugs have been developed as yet. Studies on the pathogenesis of HE and the development of new neuroprotective drugs have been conducted using animal models such as the hypoglycemic coma model and non-coma hypoglycemia model. However, both models have inherent problems, and establishment of animal models that mimic clinical situations is desirable. In this study, we first developed a short-term hypoglycemic coma model in which rats could be maintained in an isoelectric electroencephalogram (EEG) state for 2 min and subsequent hyperglycemia without requiring anti-seizure drugs and an artificial ventilation. This condition caused the production of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic aldehyde, in neurons of the hippocampus and cerebral cortex, and a marked increase in neuronal death as evaluated by Fluoro-Jade B (FJB) staining. We also investigated whether N-(1,3-benzodioxole-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1), a small-molecule agonist of aldehyde dehydrogenase-2, could attenuate 4-HNE levels and reduce hypoglycemic neuronal death. After confirming that EEG recordings remained isoelectric for 2 min, Alda-1 (8.5 mg/kg) or vehicle (dimethyl sulfoxide; DMSO) was administered intravenously with glucose to maintain a blood glucose level of 250 to 270 mg/dL. Fewer 4-HNE and FJB-positive cells were observed in the cerebral cortex of Alda-1-treated rats than in DMSO-treated rats 24 h after glucose administration (P = 0.002 and P = 0.020). Thus, activation of the ALDH2 pathway could be a molecular target for HE treatment, and Alda-1 is a potentially neuroprotective agent that exerts a beneficial effect on neurons when intravenously administered simultaneously with glucose.

DOI： 10.1371/journal.pone.0128844

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objective: Fifty percent of patients with amyotrophic lateral sclerosis (ALS) have cervical spondylotic myelopathy (CSM) as a complication. Because patients with ALS do not develop bulbar signs and symptoms at onset, differentiating them from patients with CSM is sometimes difficult. We aimed to determine whether the apparent diffusion coefficients (ADCs) of intracranial corticospinal tracts can be used to distinguish between patients with ALS and those with CSM.
Methods: We evaluated 19 consecutive patients with ALS who did not have CSM by cervical MRI, 16 patients with CSM, and 11 healthy controls. We examined the mean ADCs in the precentral gyrus, the corona radiata, the posterior limbs of the internal capsule (PLIC), and the cerebral peduncle by 3T magnetic resonance imaging (MRI). The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM.
Results: The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM (p&lt;0.05). Additionally, the mean ADCs in the precentral gyrus, the PLIC, and the cerebral peduncle in the patients with ALS, including the patients who were initially diagnosed as having clinically possible ALS on the basis of the revised El Escorial criteria and did not develop bulbar symptoms at onset, were also higher than those in patients with CSM (p&lt;0.05).
Conclusions: Elevated ADCs in the intracranial corticospinal tracts might be useful for distinguishing ALS from CSM in the early stage of the disease. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.clineuro.2015.02.009

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Authorship：Lead author   Language：English   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/brain/awx141

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1212/NXI.0000000000000108

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DOI： 10.1007/S10719-015-9585-7

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An angiogenesis factor, angiopoietin-1 (Ang1), is associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia. However, whether hemorrhagic transformation and cerebral edema after tissue plasminogen activator (tPA) treatment are related to the decrease in Ang1 expression in the BBB remains unknown. We hypothesized that administering Ang1 might attenuate hemorrhagic transformation and cerebral edema after tPA treatment by stabilizing blood vessels and inhibiting hyperpermeability. Sprague-Dawley rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group (permanent middle cerebral artery occlusion; PMCAO) and groups treated with tPA at 1 h or 4 h after ischemia. Endogenous Ang1 expression was observed in pericytes, astrocytes, and neuronal cells. Western blot analyses revealed that Ang1 expression levels on the ischemic side of the cerebral cortex were decreased in the tPA-1h, tPA-4h, and PMCAO groups as compared to those in the control group (P = 0.014, 0.003, and 0.014, respectively). Ang1-positive vessel densities in the tPA-4h and PMCAO groups were less than that in the control group (p = 0.002 and &lt;0.001, respectively) as well as that in the tPA-1h group (p = 0.047 and 0.005, respectively). These results suggest that Ang1-positive vessel density was maintained when tPA was administered within the therapeutic time window (1 h), while it was decreased when tPA treatment was given after the therapeutic time window (4 h). Administering Ang1 fused with cartilage oligomeric protein (COMP) to supplement this decrease has the potential to suppress hemorrhagic transformation as measured by hemoglobin content in a whole cerebral homogenate (p = 0.007) and cerebral edema due to BBB damage (p = 0.038), as compared to administering COMP protein alone. In conclusion, Ang1 might be a promising target molecule for developing vasoprotective therapies for controlling hemorrhagic transformation and cerebral edema after tPA treatment.

DOI： 10.1371/journal.pone.0098639

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

Pyogenic ventriculitis is an uncommon and potentially fatal central nervous system infection. Delayed treatment due to non specific clinical symptoms may lead to an unfavorable outcome. Brain magnetic resonance imaging (MRI) plays an important role in the diagnosis of pyogenic ventriculitis. We describe two patients with pyogenic ventriculitis presenting with a pathognomonic MRI finding. The first patient, a 77-year-old female, developed high fever and consciousness disturbance. MR images revealed hyperintense lesions with a fluid-fluid level in the bilateral lateral ventricles on diffusion-weighted images (DWIs) and hypointense lesions on T2-weighted images (T2WIs). MR images also revealed findings of left otitis media. The second patient, a 63-year-old male, who had a past history of multiple myeloma and had received chemotherapy, developed high fever and left hemiparesis. MR images revealed a hyperintense lesion with a fluid-fluid level in the right lateral ventricle on DWIs and a hypointense lesion on T2WIs, multiple ring-enhancing lesions on gadolinium enhanced T1-weighted images, and pontine infarction on DWIs. Chest computed tomography revealed an infiltrative shadow in the lower lobe of the left lung. On the basis of MRI findings, both patients were diagnosed as having pyogenic ventriculitis and were administered high-dose meropenem intravenously. The second patient was also administered sulfamethoxazole-trimethoprim orally. Intraventricular abnormalities disappeared and the patients achieved complete remission after the antibacterial treatment. Intraventricular hyperintense lesions on DWIs and hypointense ones on T2WIs with a fluid-fluid level is a pathognomonic finding of pyogenic ventriculitis and has not been previously reported in other diseases. Recognition of the characteristic MRI features and initiation of high-dose and appropriate antibiotics in an early stage may lead to a favorable outcome of the disease.

DOI： 10.5692/clinicalneurol.54.732

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background: Patients who develop progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) develop cerebellar ataxia as the initial and principal symptom, may be misdiagnosed as having multiple system atrophy with predominant cerebellar features (MSA-C). Therefore, we investigated the clinical signs and symptoms between PSP-C and MSA-C early in their disease course.
Methods: We reviewed the medical records of 15 consecutive patients with pathologically proven PSP-C (4) and MSA-C (11). We recorded the presence or absence of clinical features that developed within 2 years of disease onset.
Results: The age at onset of PSP-C patients was older than that of MSA-C patients (p = 0.009). The frequencies of falls were higher in PSP-C patients than in MSA-C patients (p = 0.026). Additionally, the development of supranuclear vertical gaze palsy was higher in PSP-C patients than in MSA-C patients (p = 0.011), whereas the frequency of dysautonomia was lower in PSP-C patients than in MSA-C patients (p = 0.035).
Conclusions: Older onset, early falls, and supranuclear vertical gaze palsy without dysautonomia may predict the diagnosis of PSP-C in patients with late-onset sporadic cerebellar ataxia. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.parkreldis.2013.07.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Aims: The aim of this study was to investigate factors predicting poor prognosis in patients with hypoglycemic encephalopathy.
Methods: We retrospectively analyzed data on 165 consecutive patients with hypoglycemic encephalopathy. We evaluated their outcome 1 week after hypoglycemia onset using the Glasgow outcome scale (GOS) and compared the clinical features of patients with good outcomes (GOS = 5) and poor outcomes (GOS &lt;= 4).
Results: The poor-outcome group included 38 patients (23%). The initial blood glucose level in the poor-outcome group was lower than that in the good-outcome group (p = 0.002). The duration of hypoglycemia in the poor-outcome group was longer than that in the good-outcome group (p &lt; 0.001). Body temperature during hypoglycemia in the poor-outcome group was higher than that in the good-outcome group (p &lt; 0.001). Furthermore, lactic acid level in the poor-outcome group was lower than in the good-outcome group (p = 0.032). There was no significant difference in the frequency of posttreatment hyperglycemia between the good-outcome and poor-outcome groups (p = 0.984).
Conclusion: Profound and prolonged hypoglycemia, normal or higher body temperature, and a low lactic acid level during hypoglycemia may be predictors of a poor outcome in patients with hypoglycemic encephalopathy. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2013.05.007

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1016/j.parkreldis.2013.07.019

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DOI： 10.1111/NCN3.63

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DOI： 10.1111/ncn3.63

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DOI： 10.1016/j.parkreldis.2011.11.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Hemorrhage and edema accompany evolving brain tissue injury after ischemic stroke. In patients, these events have been associated with metalloproteinase (MMP)-9 in plasma. Both the causes and cellular sources of MMP-9 generation in this setting have not been defined. MMP-2 and MMP-9 in nonhuman primate tissue in regions of plasma leakage, and primary murine microglia and astrocytes, were assayed by immunocytochemistry, zymography, and real-time RT-PCR. Ischemia-related hemorrhage was associated with microglial activation in vivo, and with the leakage of plasma fibronectin and vitronectin into the surrounding tissue. In strict serum-depleted primary cultures, by zymography, pro-MMP-9 was generated by primary murine microglia when exposed to vitronectin and fibronectin. Protease secretion was enhanced by experimental ischemia (oxygen-glucose deprivation, OGD). Primary astrocytes, on each matrix, generated only pro-MMP-2, which decreased during OGD. Microglia astrocyte contact enhanced pro-MMP-9 generation in a cell density-dependent manner under normoxia and OGD. Compatible with observations in a high quality model of focal cerebral ischemia, microglia, but not astrocytes, respond to vitronectin and fibronectin, found when plasma extravasates into the injured region. Astrocytes alone do not generate pro-MMP-9. These events explain the appearance of MMP-9 antigen in association with ischemia-induced cerebral hemorrhage and edema. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 919--932; doi:10.1038/jcbfm.2012.11; published online 22 February 2012

DOI： 10.1038/jcbfm.2012.11

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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The hypothesis tested by these studies states that in addition to interendothelial cell tight junction proteins, matrix adhesion by beta(1)-integrin receptors expressed by endothelial cells have an important role in maintaining the cerebral microvessel permeability barrier. Primary brain endothelial cells from C57 BL/6 mice were incubated with beta(1)-integrin function-blocking antibody (Ha2/5) or isotype control and the impacts on claudin-5 expression and microvessel permeability were quantified. Both flow cytometry and immunofluorescence studies demonstrated that the interendothelial claudin-5 expression by confluent endothelial cells was significantly decreased in a time-dependent manner by Ha2/5 exposure relative to isotype. Furthermore, to assess the barrier properties, transendothelial electrical resistance and permeability measurements of the monolayer, and stereotaxic injection into the striatum of mice were performed. Ha2/5 incubation reduced the resistance of endothelial cell monolayers significantly, and significantly increased permeability to 40 and 150 kDa dextrans. Ha2/5 injection into mouse striatum produced significantly greater IgG extravasation than the isotype or the control injections. This study demonstrates that blockade of beta(1)-integrin function changes interendothelial claudin-5 expression and increases microvessel permeability. Hence, endothelial cell-matrix interactions via beta(1)-integrin directly affect interendothelial cell tight junction claudin-5 expression and brain microvascular permeability. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1972-1985; doi:10.1038/jcbfm.2011.99; published online 20 July 2011

DOI： 10.1038/jcbfm.2011.99

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An angiogenic factor, vascular endothelial growth factor (VEGF), might be associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia; however, it remains unknown whether hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment is related to the activation of VEGF signaling pathway in BBB. Here, we hypothesized that inhibition of VEGF signaling pathway can attenuate HT after tPA treatment. Rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group and groups treated with tPA at 1 or 4 hours after ischemia. Anti-VEGF neutralizing antibody or control antibody was administered simultaneously with tPA. At 24 hours after ischemia, we evaluated the effects of the antibody on the VEGF expression, matrix metalloproteinase-9 (MMP-9) activation, degradation of BBB components, and HT. Delayed tPA treatment at 4 hours after ischemia promoted expression of VEGF in BBB, MMP-9 activation, degradation of BBB components, and HT. Compared with tPA and control antibody, combination treatment with tPA and the anti-VEGF neutralizing antibody significantly attenuated VEGF expression in BBB, MMP-9 activation, degradation of BBB components, and HT. It also improved motor outcome and mortality. Inhibition of VEGF signaling pathway may be a promising therapeutic strategy for attenuating HT after tPA treatment. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1461-1474; doi:10.1038/jcbfm.2011.9; published online 9 February 2011

DOI： 10.1038/jcbfm.2011.9

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

P&gt;Nuclear factor TAR DNA-binding protein-43 (TDP-43) is considered to play roles in pathogenesis of human neurodegenerative diseases, so-called TDP-43 proteinopathy, via its proteolytic cleavage, abnormal phosphorylation, subcellular redistribution, and insolubilization generating TDP-43-positive neuronal intracellular inclusions. The purpose of this study was to elucidate biochemical and histopathological alternations in TDP-43 specific to acute ischemic stroke. Adult male rats were subjected to a 90-min middle cerebral artery occlusion. We examined the proteolytic cleavage, phosphorylation, subcellular localization, and solubility of TDP-43 by immunoblottings and histopathological examinations using the ischemic and sham-operated cortex. The level of full-length TDP-43 (43 kDa) decreased and that of the 25-kDa C-terminal fragment increased after acute ischemic stroke, which can be explained by proteolytic cleavage of TDP-43. Cytoplasmic redistribution and altered nuclear distribution of TDP-43 was observed after acute ischemic stroke, whereas abnormal phosphorylation and insolubilization of TDP-43 as well as formation of intracellular inclusions were not observed. Ischemic neurons with the cytoplasmic redistribution of TDP-43 expressed ubiquitin and activated caspase 3 and were terminal deoxynucleotidyl transferase-mediated uridine 5&apos;-triphosphate-biotin nick end labeling-positive. In conclusion, biochemical and histopathological alterations in TDP-43 were identified in rats after acute ischemic stroke, although there was very less similarity between TDP-43 alterations observed in acute ischemic stroke and those observed in TDP-43 proteinopathy.

DOI： 10.1111/j.1471-4159.2010.06860.x

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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The clinical heterogeneity of progressive supranuclear palsy (PSP), which is classified as classic Richardson&apos;s syndrome (RS) and PSP-Parkinsonism (PSP-P), has been previously discussed. We retrospectively analyzed 22 consecutive Japanese patients with pathologically proven PSP to investigate the clinicopathological heterogeneity. We investigated the clinical features both early in and at any time during the disease course. The pathological severities of neuronal loss with gliosis and tau pathology were also evaluated. On the basis of the clinical features, 10 patients were categorized as having RS, and 8 were categorized as having PSP-P. Four patients presenting with cerebellar ataxia or cerebral cortical signs were categorized as having unclassifiable PSP. Among them, 3 developed cerebellar ataxia as the initial and principal symptom. Notably, tau-positive inclusion bodies in Purkinje cells were significantly more frequently observed in the patients with cerebellar ataxia than in those without cerebellar ataxia. All the patients with cerebellar ataxia exhibited more neuronal loss with gliosis and higher densities of coiled bodies in the cerebellar dentate nucleus than those without cerebellar ataxia. This study confirms the wide spectrum of clinicopathological manifestations associated with PSP regardless of different ethnic origin, and demonstrates that PSP patients manifest cerebellar ataxia. (C) 2009 Movement Disorder Society

DOI： 10.1002/mds.22583

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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DOI： 10.1002/mds.21823

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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We investigated the incidence and clinical features of patients with myasthenia gravis (MG) associated with autoimmune diseases. Associated autoimmune diseases were found in 28 of 142 consecutive Japanese MG patients (19.7%), amongst which Graves' disease (7.7%) and Hashimoto's thyroiditis (4.2%) were predominant. The clinical features of MG patients with Graves' disease were different from those of MG patients without autoimmune diseases in terms of age at onset of MG symptoms (35.5 +/- 4.0 years and 49.0 +/- 1.7 years; P &lt; 0.05), positivity for the anti-acetylcholine receptor antibody (44.4% and 89.8%; P &lt; 0.05), and association with thymic hyperplasia (72.7 and 17.9%; P &lt; 0.05). The therapeutic outcome of MG patients with Graves' disease and that of those without autoimmune diseases were not significantly different. Further studies should be performed to investigate whether MG associated with Graves' disease is a distinct subtype of MG.

DOI： 10.1111/j.1468-1331.2007.01978.x

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We report the four patients with chronic myositis characterized by a very slow progression with cardiomyopathy and frequently with marked respiratory muscle weakness associated with other organ-specific autoimmune diseases such as primary biliary cirrhosis. The histopathology of the muscle showed many degenerative and regenerative fibers, but inflammatory-cell infiltration were minimal. The patients showed favorable response to high-dose corticosteroid treatment. Because of these clinical features, these patients are sometimes misdiagnosed as muscular dystrophy and not treated properly. It is important to distinguish this type of treatable myositis.

DOI： 10.1007/s10067-007-0698-7

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Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

DOI： 10.1093/brain/awm036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy ( DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 ( average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5Mb interval flanked by M9267 and D8S1139. We named this adult- onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

DOI： 10.1093/brain/awm036

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Language：English   Publisher：WILEY-LISS  

DOI： 10.1002/mds.21523

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DOI： 10.1002/mds.21367

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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DOI： 10.1212/01.WNL.0000267665.44477.85

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A 50-year-old woman lost about 10 kg of body weight within two months. Thereafter, she developed dysphagia and dysphonia. She visited our hospital and presented with a weak elevation of the soft palate, fasciculation of the tongue, hoarseness of voice, muscle weakness of the neck and extremities, and a decrement in vital capacity. She was admitted with a provisional diagnosis of motor neuron disease. The results of laboratory examinations showed an elevation in serum lysozyme and liquor protein levels, and pleocytosis in the liquor. Needle electromyography showed neurogenic changes, and bilateral hilar lymphadenopathy was revealed by computerized tomography. A biopsy specimen was excised from lymph nodes near the right anterior scalene muscle, which showed noncaseating granulomas consistent with sarcoidosis. All her symptoms improved after steroid administration. Such patients can be treatable with steroids. Moreover, the differential diagnosis from motor neuron disease is important.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 50-year-old woman lost about 10 kg of body weight within two months. Thereafter, she developed dysphagia and dysphonia. She visited our hospital and presented with a weak elevation of the soft palate, fasciculation of the tongue, hoarseness of voice, muscle weakness of the neck and extremities, and a decrement in vital capacity. She was admitted with a provisional diagnosis of motor neuron disease. The results of laboratory examinations showed an elevation in serum lysozyme and liquor protein levels, and pleocytosis in the liquor. Needle electromyography showed neurogenic changes, and bilateral hilar lymphadenopathy was revealed by computerized tomography. A biopsy specimen was excised from lymph nodes near the right anterior scalene muscle, which showed noncaseating granulomas consistent with sarcoidosis. All her symptoms improved after steroid administration. Such patients can be treatable with steroids. Moreover, the differential diagnosis from motor neuron disease is important.

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Language：English   Publisher：B M J PUBLISHING GROUP  

DOI： 10.1136/jnnp.2004.059543

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

A 47-year-old woman presented with facial spasm, swollen fingers and Raynaud's phenomenon due to cerebrovascular disorder and mixed connective tissue disease (MCTD). Although she was positive for both antineutrophil cytoplasmic antibodies against proteinase-3 (PR3-ANCA) and anti-U1 RNP antibodies, she did not meet the American College of Rheumatology classification criteria for Wegener's granulomatosis (WG). Physical and histopathological examinations revealed severe systemic atherosclerosis without any of the traditional risk factors. Elevated levels of malondialdehyde-modified LDL and antioxidized LDL autoantibodies, which are considered to be key factors in the pathogenesis of atherosclerosis, were also detected in the serum of this patient. In this case, systemic atherosclerosis might have been linked to these autoimmune reactions.

DOI： 10.1007/s10067-004-0911-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DR DIETRICH STEINKOPFF VERLAG  

In multiple system atrophy (MSA), symptoms associated with dysfunctions of the brainstem and autonomic nervous system are important prognostic factors. We investigated brainstem involvement in 12 patients with MSA with predominant cerebellar symptoms (MSA-C) (mean age, 56.3 +/- 9.9 years, median disease duration, 3 years), and 11 controls (57.6 +/- 12.0 years) matched for age using diffusion-weighted MR imaging (DWI). We demonstrated that apparent diffusion coefficients (ADCs) in the pons and middle cerebellar peduncle of MSA-C patients are significantly higher than those of normal controls even though the patients are in the early stage of the disease. Furthermore, we demonstrated that increased ADC values correlated well with the disease duration. The current study demonstrated that DWI is a useful noninvasive method for the quantitative evaluation of the brainstem involvement in MSA-C patients.

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We describe the case of a patient with cavernous angioma(CA). A 44-year-old woman complained of numbness on the left side of the body as an initial symptom of the disease. The initial magnetic resonance (MR) imaging revealed a cystic mass with a fluid-fluid level without perifocal edema in the right thalamus on the T2-weighted image (T 2WI) and T 2*-weighted image (T2*WI). Her symptoms were self-controllable
therefore we decided to observe her natural course only with serial MR imaging. The cystic mass was not enhanced by gadolinium on T 1-weighted images, although, we suspected the tumor was complicated by vascular malformation. Therefore, we performed cranial angiography to eliminate the possibility of bleeding from the vascular malformation. Angiography did not demonstrate tumor staining nor vascular malformation. Longitudinally, the tumor demonstrated mosaic signal intensities on each sequence with perifocal edema. Moreover, the tumor exhibited hypointensities on T 2* WIs without perifocal edema. The natural history of the tumor on MR imaging exhibited a typical case of CA. Some previous reports described cystic CA with perifocal edema and vascular malformation. In our present case, we clinically diagnosed CA on the basis of the final MR imaging together with previous reports. An intra-axial fluid-fluid level is a very rare finding of MR imaging. Here, we report the case of a patient with cystic CA accompanied by a fluid-fluid level. This finding is not a pathognomonic sign of CA
although, we consider that it is very important to follow up carefully the natural history of such cases.

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We describe the case of a patient with cavernous angioma(CA). A 44-year-old woman complained of numbness on the left side of the body as an initial symptom of the disease. The initial magnetic resonance (MR) imaging revealed a cystic mass with a fluid-fluid level without perifocal edema in the right thalamus on the T2-weighted image (T 2WI) and T 2*-weighted image (T2*WI). Her symptoms were self-controllable
therefore we decided to observe her natural course only with serial MR imaging. The cystic mass was not enhanced by gadolinium on T 1-weighted images, although, we suspected the tumor was complicated by vascular malformation. Therefore, we performed cranial angiography to eliminate the possibility of bleeding from the vascular malformation. Angiography did not demonstrate tumor staining nor vascular malformation. Longitudinally, the tumor demonstrated mosaic signal intensities on each sequence with perifocal edema. Moreover, the tumor exhibited hypointensities on T 2* WIs without perifocal edema. The natural history of the tumor on MR imaging exhibited a typical case of CA. Some previous reports described cystic CA with perifocal edema and vascular malformation. In our present case, we clinically diagnosed CA on the basis of the final MR imaging together with previous reports. An intra-axial fluid-fluid level is a very rare finding of MR imaging. Here, we report the case of a patient with cystic CA accompanied by a fluid-fluid level. This finding is not a pathognomonic sign of CA
although, we consider that it is very important to follow up carefully the natural history of such cases.

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We report a 37-year-old woman with slowly developing muscular weakness for 2 years following insidious stiffness of calf muscle. Serum CK was elevated up to 4,207 IU/l. She presented sleepiness, weakness of proximal and truncal muscles and systemic muscular atrophy. While she had not experienced dyspnea, her arterial blood gas analysis revealed extreme hypoxia and hypercapnea due to weakness of respiratory muscles. Echocardiogram showed thinness and hypokinesis of left ventricular wall, and arrhythmia was pointed out by holter ECG. Needle elctromyogram of the proximal muscles exhibited polyphasic units with low amplitude. Muscle biopsy showed degeneration and necrosis of muscle fibers as well as regeneration. Mild infiltration of inflammatory cells was shown. Serological examination showed positive antimitochondrial M2 antibody, especially specific for primary biliary chirrhosis (PBC). She was diagnosed as chronic myositis associated with PBC. Four cases of idiopathic myositis with severe weakness of respiratory muscle, associated with PBC had been reported. These cases and our present case share the similar feature in respect of insidious or chronic course and resistance to therapy. In our present patient, respiration had been supported by BiPAP and she has been successfully improving slowly by oral steroid following 4 courses of methylprednisolone pulse therapy.

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We report a 37-year-old woman with slowly developing muscular weakness for 2 years following insidious stiffness of calf muscle. Serum CK was elevated up to 4,207 IU/l. She presented sleepiness, weakness of proximal and truncal muscles and systemic muscular atrophy. While she had not experienced dyspnea, her arterial blood gas analysis revealed extreme hypoxia and hypercapnea due to weakness of respiratory muscles. Echocardiogram showed thinness and hypokinesis of left ventricular wall, and arrhythmia was pointed out by holter ECG. Needle elctromyogram of the proximal muscles exhibited polyphasic units with low amplitude. Muscle biopsy showed degeneration and necrosis of muscle fibers as well as regeneration. Mild infiltration of inflammatory cells was shown. Serological examination showed positive antimitochondrial M2 antibody, especially specific for primary biliary chirrhosis (PBC). She was diagnosed as chronic myositis associated with PBC. Four cases of idiopathic myositis with severe weakness of respiratory muscle, associated with PBC had been reported. These cases and our present case share the similar feature in respect of insidious or chronic course and resistance to therapy. In our present patient, respiration had been supported by BiPAP and she has been successfully improving slowly by oral steroid following 4 courses of methylprednisolone pulse therapy.

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We describe two patients with generalized tetanus, a 60-year-old man and a 76-year-old woman, presenting with dysphagia as an initial symptom of the disease. Eighty percent of patients with generalized tetanus manifest dysphagia on admission to a hospital. However, dysphagia is rare as an initial symptom. Both our patients had dysphagia as their initial symptom, followed by neck stiffness and trismus. We made a diagnosis of generalized tetanus based on these neurological findings in the absence of an apparent episode of trauma. After the administration of tetanus immunoglobulin on admission, they recovered without exhibiting generalized convulsion, autonomic storm, or any other serious complications. The vaccination of tetanus toxoid cannot maintain sufficient antibody titers more than ten years. Therefore, elderly people are considered susceptible to tetanus. We suggest that tetanus should be considered in the differential diagnosis of dysphagia particularly in elderly patients. We also suggest that treatment of tetanus should be initiated immediately, because tetanus still has a high mortality rate at present.

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We describe two patients with generalized tetanus, a 60-year-old man and a 76-year-old woman, presenting with dysphagia as an initial symptom of the disease. Eighty percent of patients with generalized tetanus manifest dysphagia on admission to a hospital. However, dysphagia is rare as an initial symptom. Both our patients had dysphagia as their initial symptom, followed by neck stiffness and trismus. We made a diagnosis of generalized tetanus based on these neurological findings in the absence of an apparent episode of trauma. After the administration of tetanus immunoglobulin on admission, they recovered without exhibiting generalized convulsion, autonomic storm, or any other serious complications. The vaccination of tetanus toxoid cannot maintain sufficient antibody titers more than ten years. Therefore, elderly people are considered susceptible to tetanus. We suggest that tetanus should be considered in the differential diagnosis of dysphagia particularly in elderly patients. We also suggest that treatment of tetanus should be initiated immediately, because tetanus still has a high mortality rate at present.

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Lipohyalinosis is an important concept in the independence of lacunar stroke; however, its role has been overemphasized and has led to much confusion in the understanding of lacunar stroke. Classical lipohyalinosis has declined following the widespread availability of antihypertensive therapy, and lacunar stroke secondary to age-related hyaline atherosclerosis is more commonly observed in clinical practice. Clinically diagnosed lacunar stroke is associated with several etiopathogenetic contributors. Excluding cardiogenic embolism, lacunar stroke can be categorized based on the detection of an atheroma. Atheroma imaging is possible in recent years, and strokes that are not associated with an atheroma are shown to present with deep white matter hyperintensity on MRI. Additionally, risk gene analysis has confirmed a group of risk genes associated with the extracellular matrix in lacunar stroke with white matter hyperintensity on MRI. These findings suggest the role of a variety of etiopathogenetic mechanisms underlying lacunar stroke and that lacunar stroke with deep white matter hyperintensity on MRI may be attributable to unique pathogenetic contributors. This group is known to be strongly associated with genetic contributors. Hopefully, lacunar stroke will be diagnosed from this perspective with the development of interventional strategies tailored to the pathogenesis of this condition.

DOI： 10.11477/mf.1416201876

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Many studies in recent years have reported cell therapies using embryonic stem cells, induced pluripotent stem cells, and bone marrow-derived mononuclear cells for cerebral ischemia. However, obtaining these cells is challenging, and these cell therapies require complicated procedures to prepare cells for administration. Notably, peripheral blood mononuclear cells (PBMCs) are a useful cell source for clinical applications because cell collection is easier. In this review, we report the therapeutic effects of PBMCs preconditioned by oxygen-glucose deprivation (OGD-PBMCs) on cerebral ischemia. Cell therapies using tissue-protective OGD-PBMCs might be a simple and ideal therapeutic strategy against ischemic stroke.

DOI： 10.11477/mf.1416201655

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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脳梗塞後遺症の機能を回復させる治療法の確立が望まれている.ミクログリアを保護的ミクログリア(M2)に変化させる低酸素低糖刺激(OGD)の条件を決定し,M2-likeミクログリアを亜急性期に投与することで,脳虚血後の機能予後を改善させることが可能かを検証した.初代ミクログリアの培養上清を試料として,血管内皮増殖因子(VEGF),トランスフォーミング増殖因子(TGF-β),およびマトリックス・メタロプロテナーゼ(MMP)-9活性を測定したところ,18時間のOGD後,M2極性となっていることがわかった.さらに,ラット一過性局所脳虚血モデルに対し,虚血7日後,M2-likeミクログリアを投与したところ,虚血中心の辺縁部におけるVEGF,TGF-β,MMP-9の発現は増加し,さらに同部位の血管新生,ペナンブラにおける軸索伸展は,非投与群と比べて促進され,虚血4週間後の機能を回復させた.OGDによりM2化したミクログリアを用いた細胞療法は,従来にない治療戦略になるものと考えられる.(著者抄録)

DOI： 10.16977/cbfm.28.2_315

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J02631&link_issn=&doc_id=20170911390011&doc_link_id=10.16977%2Fcbfm.28.2_315&url=https%3A%2F%2Fdoi.org%2F10.16977%2Fcbfm.28.2_315&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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ラットとマウス再灌流一過性局所脳虚血モデルにおいてプログラニュリン(PGRN)の虚血後の発現を確認した。初代培養細胞(神経細胞、ミクログリア、アストロサイト)に低酸素低グルコース刺激(OGD)を行い、PGRNや各種サイトカイン、血管破綻に関与する血管内皮増殖因子(VEGF)の産生について検討した。ラット脳塞栓モデルに組換えPGRNをtPAと同時投与し、予後を改善できるか検証した。PGRNは非虚血時、大脳皮質の神経細胞にのみに発現しているが、虚血再灌流後、虚血中心の辺縁部で経時的にPGRN陽性ミクログリアが増加し、虚血ペナンブラで神経細胞、ミクログリア、血管内皮細胞のPGRNの発現が増加した。虚血後に完全糖鎖修飾型PGRN(〜88kDa)の発現が減少するが、虚血中心、虚血ペナンブラ共に、不完全糖鎖修飾型PGRN(58〜68kDa)の発現が再灌流72時間後に著しく増加した。神経細胞を用いたOGD実験では、組換えPGRNを添加することで神経細胞死が有意に抑制された。

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我々は,脳梗塞に対する組織プラスミノゲン・アクチベーター(t-PA)療法に併用し,予後を改善する薬剤の開発を目指している.成長因子プログラニュリン(PGRN)に注目し検討を行ったところ,脳虚血後の著明な発現増加が確認され,虚血中心ではミクログリア,ペナンブラでは神経細胞がその産生を担っていた.脳虚血におけるPGRNの役割を確認するため,PGRN KOマウスとt-PA投与脳塞栓モデルを用いた検証を行ったところ,PGRNの欠乏は脳梗塞の増悪,逆にPGRN投与は脳保護的に作用した.PGRNの効果は多彩で,TAR DNA-binding protein 43 kDaを介する神経保護作用,血管内皮増殖因子の抑制を介する血管保護作用,インターロイキン10を介する抗炎症作用を認めた.PGRNは多面的な脳保護作用を持つ可能性があることから,脳梗塞の新規治療薬として有望である.(著者抄録)

DOI： 10.16977/cbfm.27.2_265

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Other Link： http://search.jamas.or.jp/link/ui/2016172925

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脳梗塞に対するtPAを用いた血栓溶解療法は,発症から4.5時間を超えて行った場合,脳出血を合併するリスクが高くなる.脳出血合併症を防止する治療の開発は,予後の改善と,tPA療法の治療可能時間域の延長をもたらす可能性がある.我々は,血管リモデリングに関与する血管内皮増殖因子(VEGF)やアンギオポイエチン1(Ang1)を標的とした血管保護療法の可能性について検討し,ラット脳塞栓モデルにおいて,(1)VEGF抑制薬,および(2)組み換えAng1の投与が脳出血合併症を防止し,予後を改善することを明らかにした.その後,知的財産権の確保,および米国ベンチャー企業との産学連携を行い,現在,臨床試験の実現を目指している.これまでの経験から,アカデミア研究者が,創薬研究の「死の谷」を乗り越えるためには,(1)動物実験の質の改善,(2)知的財産権の確保,(3)産学連携の推進が重要であると考えられた.(著者抄録)

DOI： 10.16977/cbfm.26.2_93

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Language：Japanese   Publisher：新潟医学会  

低血糖症のなかで、グルコース投与によっても神経症状が改善しない重篤なケースは「低血糖脳症」と区別して呼ばれている。我々は、低血糖脳症の治療薬の開発を目的として、治療標的の同定につながる予後を増悪する因子の検討、および治療薬の評価を行う簡便な動物モデルの開発を行った。前者に関して、臨床像の解析では、血糖値、低血糖状態の持続時間、体温、血中乳酸値、治療後高血糖が予後に影響を及ぼす可能性を見出した。また頭部MRIの解析では、異常信号病変の出現に、体温が影響する可能性が示唆された。後者に関しては、平坦脳波を短時間にし、人工呼吸器を使用しない、より生理的な低血糖脳症動物モデル(短時間昏睡モデル)を確立した。今後、これらの知見をもとに、低血糖脳症に対する神経保護療法の開発を目指したい。(著者抄録)

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Other Link： http://hdl.handle.net/10191/44112

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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血栓溶解療法後の脳出血合併症の機序として、血管リモデリングに伴う血管の不安定化が関与する可能性について検討した。ラット塞栓性中大脳動脈閉塞モデルを用いて、代表的な血管リモデリング因子である血管内皮増殖因子(vascular endothelial growth factor;VEGF)およびアンギオポイエチン1(Angiopoietin-1;Ang1)の、脳虚血後の変化について検討を行ったところ、虚血周辺部における(1)VEGF-VEGF受容体シグナル活性化、(2)Ang1陽性血管の減少が、脳虚血後24時間という早期から確認された。治療介入として、(1)抗VEGF中和抗体、VEGF受容体阻害薬、および(2)組み換えAng1の投与を行なったところ、脳出血は軽減した。以上より、血栓溶解療法後の脳出血合併症を抑制する治療として、血管リモデリング因子を標的とした治療介入が有効である可能性が示唆された。(著者抄録)

DOI： 10.3995/jstroke.37.188

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「パーキンソニズム」はパーキンソン症状、すなわち静止時振戦、筋強剛、動作緩慢、姿勢反射障害、歩行障害のうち、1つまたは複数が認められる疾患群の総称である。その基礎疾患はさまざまで、(1)パーキンソン病、(2)症候性(二次性)パーキンソニズム(パーキンソン症候群)に大別される。これらの疾患には、特異的な診断マーカーは存在しないため、診断において徴候と症状が重要であるが、症候性パーキンソニズムに含まれる進行性核上性麻痺(progressive supranuclear palsy:PSP)、大脳皮質基底核変性症(corticobasal degeneration:CBD)、多系統萎縮症(multiple system atrophy:MSA)、前頭側頭葉型認知症(frontotemporal dementia:FTD)、特発性正常圧水頭症(idiopathic normal pressure hydrocephalus:iNPH)、脳血管障害性パーキンソニズムの鑑別には、頭部MRI(magnetic resonance imaging)や脳血流シンチグラフィーが補助診断として有用である。(著者抄録)

DOI： 10.20837/12014092097

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(公財)先進医薬研究振興財団  

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Language：Japanese   Publisher：新潟医学会  

脳梗塞急性期の内科治療薬「組織プラスミノゲン・アクチベーター(tPA)」に伴う脳出血合併症防止を目指した血管保護の治療戦略について概説する。tPAは、脳出血を合併するリスクが高くなるため、発症から4.5時間までの適応である。我々は血管保護を目的としたtPAに併用薬剤の開発を行っている。治療標的分子として血管内皮増殖因子(VEGF)に注目し、ラット脳塞栓モデルにおいてその抑制が脳出血合併症を緩和することを明らかにした。臨床応用を目指した産学連携およびトランスレーショナルリサーチが進行中である。(著者抄録)

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Other Link： http://hdl.handle.net/10191/43594

Language：Japanese   Publisher：Societas Neurologica Japonica  

Pyogenic ventriculitis is an uncommon and potentially fatal central nervous system infection. Delayed treatment due to non specific clinical symptoms may lead to an unfavorable outcome. Brain magnetic resonance imaging (MRI) plays an important role in the diagnosis of pyogenic ventriculitis. We describe two patients with pyogenic ventriculitis presenting with a pathognomonic MRI finding. The first patient, a 77-year-old female, developed high fever and consciousness disturbance. MR images revealed hyperintense lesions with a fluid-fluid level in the bilateral lateral ventricles on diffusion-weighted images (DWIs) and hypointense lesions on T2-weighted images (T2WIs). MR images also revealed findings of left otitis media. The second patient, a 63-year-old male, who had a past history of multiple myeloma and had received chemotherapy, developed high fever and left hemiparesis. MR images revealed a hyperintense lesion with a fluid-fluid level in the right lateral ventricle on DWIs and a hypointense lesion on T2WIs, multiple ring-enhancing lesions on gadolinium enhanced T1-weighted images, and pontine infarction on DWIs. Chest computed tomography revealed an infiltrative shadow in the lower lobe of the left lung. On the basis of MRI findings, both patients were diagnosed as having pyogenic ventriculitis and were administered high-dose meropenem intravenously. The second patient was also administered sulfamethoxazole-trimethoprim orally. Intraventricular abnormalities disappeared and the patients achieved complete remission after the antibacterial treatment. Intraventricular hyperintense lesions on DWIs and hypointense ones on T2WIs with a fluid-fluid level is a pathognomonic finding of pyogenic ventriculitis and has not been previously reported in other diseases. Recognition of the characteristic MRI features and initiation of high-dose and appropriate antibiotics in an early stage may lead to a favorable outcome of the disease.

DOI： 10.5692/clinicalneurol.54.732

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：(株)中外医学社  

われわれは病理学的に診断が確定した進行性核上性麻痺progressive supranuclear palsy(PSP)症例の臨床像を検討し,病初期から小脳症状を認め,かつ主徴とする一群が少なからず存在することを報告した.この小脳症状を呈するPSP亜型は,欧米においてはきわめてまれと考えられる一方,日本においては自験例を含め,少なくとも21例が症例報告されている.臨床的な特徴として,(1)男性に多いこと,(2)罹病期間はさまざまであること,(3)失調歩行を呈する症例が多いが,四肢失調を呈する症例も存在すること,(4)四肢失調に左右差を認める症例が存在すること,(5)ミオクローヌスを合併する症例が存在することがあげられる.病理学的には小脳皮質のプルキンエ細胞のタウ陽性顆粒状封入体のほか,歯状核や上小脳脚の変性などが報告されており,これらの変性が小脳症状の出現に関与するものと推測される.(著者抄録)

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

脳虚血による神経細胞障害における核蛋白TAR DNA結合蛋白-43(TDP-43)の関与を明らかにすることを目的として、TDP-43の細胞内局在変化、限定分解、ユビキチン化、封入体形成、不溶化、異常リン酸化の有無を、ラット中大脳動脈閉塞モデルを用いて検討した。この結果、脳虚血後、TDP-43の核から細胞質への局在変化が生じること、限定分解により25kDaC末端断片が生成されること、TDP-43が細胞質に移行した神経細胞は、高率にユビキチン陽性、TUNEL反応陽性となるものの、封入体形成や不溶化、異常リン酸化は生じないことを明らかにした。以上より、虚血性神経細胞障害に、細胞内局在変化や限定分解に伴うTDP-43の生理的機能の喪失(loss of function)が関与する可能性が示唆された。(著者抄録)

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：日本脳循環代謝学会  

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Language：Japanese   Publisher：新潟医学会  

TAR DNA結合蛋白-43(TDP-43)は、ユビキチン陽性封入体を伴う前頭側頭葉変性症(FTLD-U)や筋萎縮性側索硬化症(ALS)における神経細胞やグリア細胞の細胞質内・核内封入体の主要な構成成分として同定されている。またFTLD-UやALSの患者剖検脳・脊髄におけるTDP-43蛋白は、高度にリン酸化されることや、核局在シグナルを欠くC末端断片(25kDa)に切断され、さらに不溶化されていることも示されている。これらの結果から、TDP-43は神経の機能維持や生存に重要な役割を果たすものと考えられる。本研究では局所脳虚血におけるTDP-43の役割を明らかにするため、虚血後のラット脳を用いてTDP-43の発現を経時的に解析した。動物モデルとして塞栓系による90分間の一過性中大脳動脈閉塞を行った。再灌流24時間後、全長型TDP-43(43kDa)は、虚血皮質においてsham手術群と比べ減少していたが(P&lt;0.01)、不溶化やリン酸化は認めなかった。また虚血皮質では、可溶性C末端断片(25kDa)はsham手術群と比べて、著増していた(P&lt;0.01)。25kDa C末端断片は細胞質分画にのみ認めた。免疫組織学的解析にて、sham手術群ではTDP-43は神経細胞の核に局在していたのに対し、虚血再灌流の24時間後には、TDP-43は細胞質にも局在が見られるようになった。caspase-3選択的阻害剤は、虚血再灌流の24時間後におけるTDP-43の限定分解を抑制した(P&lt;0.01)。さらに、虚血中の低体温療法(30℃)は、虚血後のTDP-43の限定分解を抑制し(P&lt;0.01)、細胞質における発現を抑制した。以上より、TDP-43は虚血後にcaspase-3依存性に限定分解を受け、細胞内局在も変化することが判明した。しかし、変性疾患で見られるようなリン酸化や不溶化は見られなかった。虚血に伴いTDP-43の限定分解や局在変化による機能喪失が生じた可能性が示唆されるが、TDP-43の神経細胞における機能の解明が今後重要である。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2010145093

Language：Japanese   Publisher：新潟医学会  

脳梗塞に対する血栓溶解薬「組織型プラスミノゲン・アクチベーター(t-PA)」は、1996年、米国において「初の本格的脳卒中治療薬」として認められ、以後、世界各国でその使用が承認された。しかしながらtherapeutic time window(治療可能時間)が発症後3時間以内ときわめて短く、その3時間を超えて使用した場合、有意な改善を認めないだけでなく、血管破綻に伴う出血性脳梗塞を合併し、予後増悪の原因となる。これらのt-PAの問題点を克服するためには、「虚血性ペナンブラ」を可能な限り維持し救出すること、そして「虚血性血管内皮障害」を緩和し、出血性梗塞への進展を防止する治療的介入が必要である。すなわちt-PAと併用することでneuro-vascular protectionを可能とする薬剤を開発することがきわめて重要である。(著者抄録)

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Language：Japanese   Publisher：日本脳低温療法・体温管理学会  

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Language：Japanese   Publisher：新潟県医師会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：日本神経感染症学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：新潟医学会  

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Other Link： http://search.jamas.or.jp/link/ui/2007258165

Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

50歳女.著明な体重減少,嚥下障害,嗄声を主訴とした.軟口蓋挙上不良,咽頭反射消失,舌辺縁に線維束攣縮があり,肺活量も低下していた.左胸鎖乳突筋の著明な萎縮があり,筋力はMedical Research Council法にて頸前屈2,大臀臀・大腿四頭筋3,腓腹筋・前脛骨筋2レベルに低下しており,握力は右11kg,左13kgであった.運動ニューロン疾患の疑いで入院となり,その際の検査所見にて針筋電図で舌・大腿直筋に明らかな神経原性変化を認め,頸髄,脳MRIでは両側メッケル腔がT2強調画像にて低信号を示した.髄液蛋白高値で,その後細胞数の上昇,血清リゾチームの高値を認め,CTでは両側肺門部リンパ節腫脹を,67Gaシンチグラフィーでは両側肺門部,涙腺,耳下腺に集積を認めた.右斜角筋生検にてサルコイドーシスと診断,プレドニゾロン内服を開始し,その後すべての症状に著明な改善を認めた

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本脳卒中学会  

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Language：Japanese   Publisher：(有)科学評論社  

通院加療中のパーキンソン(PD)病患者38例(平均年齢69.2±7.5歳,罹病期間5.9±4.1年)を対象に,睡眠障害に関するアンケート調査を行った.アンケート結果は,Epworth睡眠スケール(ESS)とPDスケール(PDSS)を用い,睡眠スケールと罹病期間,Hoehn-Yahr重症度,ドパミンアゴニストとの相関について検討した.なお,対照群は20例(平均年齢65.3±6.3歳)である.その結果,PD症例のESS,PDSSは対照群より有意に高く,睡眠スケールとHoehn-Yahr重症度はPDSSと有意な相関を認めた.ドパミンアゴニスト単独内服例ではESS高値で,日中の傾眠傾向を認めた

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Language：Japanese   Publisher：(有)科学評論社  

39歳女.統合失調症で入院中に拒食となり,尿糖が検出され耐糖能障害として経過観察していたところ,呼吸不全と意識レベルの低下が出現した.酸素投与及び果糖含有輸液により症状は改善したが,翌日に眼球が上転し,痛覚刺激への反応なく当科転院した.症状と検査及び画像所見よりWernicke脳症と診断し,サイアミン,マルチビタミン製剤投与及び高カロリー輸液を行った.しかし2型呼吸不全が持続し,気管切開術,末梢神経生検を施行した.入院時に認めたMRIの異常信号は消失し,全身状態も改善した

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)医学書院  

44歳女.初期のMRIにおいて,右側視床にfluid-fluid levelを伴う嚢胞性病変がみられた.その後,腫瘤内部はヘモジデリン沈着と考えられる不均一な信号となり,嚢胞性病変周囲は浮腫と考えられる高信号病変を示した.嚢胞性病変や浮腫は徐々に消失し,最終的に典型的な海綿状血管腫(CA)の所見を示した.CAにはfluid-fluid levelを伴い,嚢胞性病変を呈する症例も存在し,同様の所見を呈する症例ではMRIでの慎重な経過観察が重要だと思われた

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Language：Japanese  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：日本神経治療学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

37歳女.5年前から歩行困難,全身に力が入らないことを自覚し,それが増悪したことを契機に精査を行った.傾眠傾向,四肢体幹筋の萎縮と筋力低下を認め,呼吸苦はなかった.しかし,呼吸筋障害があり,著明な低酸素・高炭酸ガス血症を呈し,心筋障害と不整脈を認めた.CKは4207IU/lと著高であり,筋生検にて変性・壊死・再生線維を認めたが,炎症性細胞浸潤は軽度であった.原発性胆汁性肝硬変に特徴的な抗ミトコンドリアM2抗体が陽性であり,原発性胆汁性肝硬変を合併した慢性の筋炎と考えられた.ステロイド内服と4回のパルス療法およびBiPAPにより,改善傾向にある

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(株)医学書院  

嚥下障害を初発症状とし,全身痙攣を伴わなかった軽症破傷風2例を経験した.症例1:60歳男.著明な開口制限,嚥下障害を認め,破傷風を疑われた.外傷は認めなかったが,開口制限,舌の運動障害,頸部痛を認め,全身型破傷風と診断された.絶飲食,室内暗室とし,破傷風免疫グロブリンを投与し,ペニシリンGの連日投与を開始した.第7病日より症状改善し,第13病日より食事を開始した.筋逸脱酵素が低下し,開口制限,嚥下障害が消失したため,破傷風トキソイドを投与し,退院した.症例2:76歳女.嚥下時に違和感を自覚した.開口制限,舌の運動障害,後頸部痛を認めるため,全身型破傷風を疑い,入院当日に破傷風免疫グロブリンを投与した.投与後症状は改善傾向となり,入院第7病日には飲水可能となった.徐々に食事も摂取でき,開口制限もなくなり,退院した

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Language：Japanese   Publisher：日本自律神経学会  

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Language：Japanese   Publisher：日本赤十字社医学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：克誠堂出版(株)  

39歳男.2年前の職場検診の胸部X線像にて両側上肺野の気腫性変化を指摘されていた.今回,多関節痛,朝の手のこわばりと労作時呼吸困難を自覚して来院,胸部CTにて両側肺下葉の間質性病変が認められ,関節症状から慢性関節リウマチ(RA)と診断された.胸腔鏡下生検では間質性肺炎(IP)と気腫性変化が認められ,気道病変は認めなかったが,細気管支領域から肺胞腔内に泡沫細胞の集簇を認めた.これ迄に気道病変を伴わない気腫性変化とRAに伴うIPとの関連についての報告はないが,泡沫細胞の出現がみられたことから,び漫性汎細気管支炎類似の細気管支病変の潜在的な合併の可能性が考えられた.明らかな呼吸器症状を呈さないRA症例においても,早期から呼吸機能検査や胸部CTを含む肺病変の精査を行うことが重要であると考えられた

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Other Link： http://search.jamas.or.jp/link/ui/2002279145

Language：Japanese   Publisher：新潟医学会  

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