記述言語：英語   掲載種別：研究論文（学術雑誌）  

The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.

DOI： 10.1093/stcltm/szae018

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A strong relationship between Alzheimer's disease (AD) and vascular dysfunction has been the focus of increasing attention in aging societies. In the present study, we examined the long-term effect of scallop-derived plasmalogen (sPlas) on vascular remodeling-related proteins in the brain of an AD with cerebral hypoperfusion (HP) mouse model. We demonstrated, for the first time, that cerebral HP activated the axis of the receptor for advanced glycation endproducts (RAGE)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/provirus integration site for Moloney murine leukemia virus 1 (PIM1)/nuclear factor of activated T cells 1 (NFATc1), accounting for such cerebral vascular remodeling. Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD.

DOI： 10.1016/j.brainres.2024.148790

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A flavonoid, sudachitin, has been reported to show some beneficial health effects, including as an anti-inflammatory in LPS-stimulated macrophages, as well as improving glucose and lipid metabolism in mice fed a high-fat diet. In this study, we investigated the neuroprotective effect of sudachitin in the transient middle cerebral artery occlusion (tMCAO) mouse model. After daily pre-treatment of vehicle or sudachitin (5 or 50 mg/kg) for 14 days, mice (n = 76) were subjected to a sham operation or tMCAO for 45 min, and on the following days, they were treated daily with vehicle or sudachitin. The administration of sudachitin significantly reduced (p < 0.05) cerebral infarct volume and attenuated apoptosis, 5 days after tMCAO. Neurological impairment improved, the expression of an oxidative stress marker, 4-HNE, decreased, and the Sirt1/PGC-1α pathway was activated 5 days after tMCAO in the sudachitin-treated group. This is the first report to demonstrate the neuroprotective effect of sudachitin in cerebral ischemia/reperfusion injury mice model, probably by activating the Sirt1/PGC-1α axis. Sudachitin may be a promising supplement or therapeutic agent for reducing injury caused by ischemic strokes.

DOI： 10.1016/j.brainres.2023.148745

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.

DOI： 10.3390/ijms25052945

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: With the aging of populations worldwide, Alzheimer's disease (AD) has become a concern due to its high prevalence and the continued lack of established treatments. Early diagnosis is required as a preventive intervention to modify the disease's progression. In our previous study, we performed peptidomic analysis of serum samples obtained from AD patients and age-matched healthy subjects to seek peptide biomarker candidates for AD by using BLOTCHIP-MS analysis, and identified four peptides as AD biomarker candidates. OBJECTIVE: The objective was to validate the serum biomarker peptides to distinguish mild cognitive impairment (MCI) and AD in comparison to cognitively healthy controls using a new peptidome technology, the Dementia Risk Test. METHODS: We enrolled 195 subjects with normal cognitive function (NC; n = 70), MCI (n = 55), and AD (n = 70), The concentrations of cognitive impairment marker peptides (Fibrinogen α chain (FAC), Fibrinogen β chain (FBC), Plasma protease C1 inhibitor (PPC1I), α2-HS-glycoprotein (AHSG)) were quantified by using a selected reaction monitoring assay based on liquid chromatography-MS/MS. RESULTS: The present study confirmed that three peptides, FAC, FBC, and PPC1I, were significantly upregulated during the onset of AD. This three-peptide set was both highly sensitive in determining AD (sensitivity: 85.7%, specificity: 95.7%, AUC: 0.900) and useful in distinguishing MCI (sensitivity: 61.8%, specificity: 98.6%, AUC: 0.824) from NC. CONCLUSIONS: In this validation study, we confirmed the high diagnostic potential of the three peptides identified in our previous study as candidate serum biomarkers for AD. The Dementia Risk Test may be a powerful tool for detecting AD-related pathological changes.

DOI： 10.3233/JAD-230915

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The differential diagnosis of myelopathy in patients with malignancies may be challenging, as a spinal biopsy is not always applicable. A 66-year-old woman who had shown transient double vision and nausea developed spasticity and impaired deep sensation in both feet. Magnetic resonance imaging showed abnormal gadolinium enhancement of the brainstem, spinal meninges, and nerve root. Cerebrospinal fluid (CSF) revealed mild pleocytosis and elevated protein and decreased glucose levels, although CSF cytology was normal. Lung carcinoma was simultaneously detected, and noncaseating granuloma was detected from the hilar and axillary lymph nodes, so she was diagnosed with sarcoid-associated myelopathy. Her symptoms were kept stable by intravenous methylprednisolone, oral prednisolone, and methotrexate. This is the first case of sarcoid-associated myelopathy accompanied by lung cancer, suggesting the importance of clinical course, repetitive CSF cytology, and a biopsy of the lymph nodes to distinguish sarcoid-associated myelopathy from meningeal metastasis in patients with malignancies.

DOI： 10.2169/internalmedicine.0943-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tick-borne encephalitis (TBE) is an infection of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is endemic in parts of Europe and Asia. TBEV is transmitted to humans primarily by Ixodes ticks. There have been 5 TBE cases identified in Japan, all on the northern island of Hokkaido. Rodents with TBEV antibodies and Ixodes ticks have been identified throughout Japan, indicating that TBEV infection might be undiagnosed in Japan. Residual serum and cerebrospinal fluid (CSF) collected in 2010-2021 from 520 patients ≥1 year-of-age previously hospitalized with encephalitis or meningitis of unknown etiology at 15 hospitals (including 13 hospitals outside of Hokkaido) were screened by ELISA for TBEV IgG and IgM antibodies; TBEV infection was confirmed by the gold standard neutralization test. Residual serum was available from 331 (63.6%) patients and CSF from 430 (82.6%) patients; both serum and CSF were available from 189 (36.3%). Two patients were TBE cases: a female aged 61 years hospitalized for 104 days in Oita (2000 km south of Hokkaido) and a male aged 24 years hospitalized for 11 days in Tokyo (1200 km south of Hokkaido). Retrospective testing also identified a previous TBEV infection in a female aged 45 years hospitalized for 12 days in Okayama (1700 km south of Hokkaido). TBEV infection should be considered as a potential cause of encephalitis or meningitis in Japan. TBE cases are likely undiagnosed in Japan, including outside of Hokkaido, due to limited clinical awareness and lack of availability of TBE diagnostic tests.

DOI： 10.1080/22221751.2023.2278898

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掲載種別：研究論文（学術雑誌）  

Background and objectives: Oculopharyngodistal myopathy (OPDM) is an autosomal dominant myopathy clinically characterized by distal muscle weakness. Even though the identification of four causative genes, LRP12, GIPC1, NOTCH2NLC and RILPL1, it is unclear whether the myopathy progressed similarly among OPDM subtypes. We aimed to establish diagnostic clues in muscle imaging of OPDM in comparison with clinicopathologically similar oculopharyngeal muscular dystrophy (OPMD). Methods: Axial muscle CT and/or T1-weighted MRI data from 54 genetically confirmed patients with OPDM (OPDM_LRP12; n = 43, OPDM_GIPC1; n = 6, OPDM_NOTCH2NLC; n = 5) and 57 with OPMD were evaluated. We scored the degree of fat infiltration in each muscle by modified Mercuri score and performed hierarchical clustering analyses to classify the patients and infer the pattern of involvement on progression. Results: All OPDM subtypes showed a similar pattern of distribution in the affected muscles; soleus and medial gastrocnemius involved in the early stage, followed by tibialis anterior and extensor digitorum longus. For differentiating OPDM and OPMD, severely affected gluteus medius/minimus and adductor magnus was indicative of OPMD. Discussion: We identified a diagnostic muscle involvement pattern in OPDM reflecting its natural history. The results of this study will help in the appropriate intervention based on the diagnosis of OPDM, including its stage.

DOI： 10.1007/s00415-023-11906-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger with neuroprotective, antioxidant and anti-inflammatory effects against different models of cerebral ischemia. Therefore, we aimed to elucidate the different potential mechanisms through which PE affects fetal brain development using our previously established RUPP-placental ischemia mouse model. In addition, we investigated the neuroprotective effect of edaravone against the RUPP-induced fetal brain development alterations. On gestation day (GD) 13, pregnant mice were divided into four groups; sham (SV), edaravone (SE), RUPP (RV), and RUPP+edaravone (RE). SV and SE groups underwent sham surgeries, however, RV and RE groups were subjected to RUPP surgery via bilateral uterine ligation. Edaravone (3mg/kg) was injected via tail i.v. injection from GD 14-18. The fetal brains from different groups were collected on GD 18 and subjected to further investigations. The results showed that RUPP altered the structure of fetal brain cortex, induced neurodegeneration, increased the expression of the investigated pro-inflammatory markers; TNF-α, IL-6, IL-1β, and MMP-9. RUPP resulted in microglial and astrocyte activation in the fetal brains, in addition to upregulation of Hif-1α and iNOS. Edaravone conferred a neuroprotective effect via alleviating the inflammatory response, restoring the neuronal structure and decreasing oxidative stress in the developing fetal brain. In conclusion, RUPP-placental ischemia mouse model could be a useful tool to further understand the underlying mechanisms of PE-induced child neuronal alterations. Edaravone could be a potential adjuvant therapy during PE to protect the developing fetal brain. The current study investigated the effects of a placenta-induced ischemia mouse model using reduced uterine perfusion pressure (RUPP) surgery on the fetal brain development and the potential neuroprotective effects of the drug edaravone. The study found that the RUPP model caused neurodegeneration and a pro-inflammatory response in the developing fetal brain, as well as hypoxia and oxidative stress. However, maternal injection of edaravone showed a strong ability to protect against these detrimental effects and target multiple pathways associated with neuronal damage. The current study suggests that the RUPP model could be useful for further study of the impact of preeclampsia on fetal brain development and that edaravone may have potential as a therapy for protecting against this damage.

DOI： 10.1007/s11481-023-10095-6

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive dysfunction and memory loss that is accompanied by pathological changes to white matter. Some clinical and animal research revealed that AD combined with chronic cerebral hypoperfusion (CCH) exacerbates AD progression by inducing blood-brain barrier dysfunction and fibrinogen deposition. Rivaroxaban, an anticoagulant, has been shown to reduce the rates of dementia in atrial fibrillation patients, but its effects on white matter and the underlying mechanisms are unclear. OBJECTIVE: The main purpose of this study was to explore the therapeutic effect of rivaroxaban on the white matter of AD+CCH mice. METHODS: In this study, the therapeutic effects of rivaroxaban on white matter in a mouse AD+CCH model were investigated to explore the potential mechanisms involving fibrinogen deposition, inflammation, and oxidative stress on remyelination in white matter. RESULTS: The results indicate that rivaroxaban significantly attenuated fibrinogen deposition, fibrinogen-related microglia activation, oxidative stress, and enhanced demyelination in AD+CCH mice, leading to improved white matter integrity, reduced axonal damage, and restored myelin loss. CONCLUSIONS: These findings suggest that long-term administration of rivaroxaban might reduce the risk of dementia.

DOI： 10.3233/JAD-230413

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

DOI： 10.1136/jnnp-2022-330851

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Carnosine (β-alanyl-L-histidine) is a natural dipeptide with multiple neuroprotective properties. Previous studies have advertised that carnosine scavenges free radicals and displays anti-inflammatory activity. However, the underlying mechanism and the efficacies of its pleiotropic effect on prevention remained obscure. In this study, we aimed to investigate the anti-oxidative, anti-inflammative, and anti-pyroptotic effects of carnosine in the transient middle cerebral artery occlusion (tMCAO) mouse model. After a daily pre-treatment of saline or carnosine (1000 mg / kg / day) for 14 days, mice (n = 24) were subjected to tMCAO for 60 min and continuously treated with saline or carnosine for additional 1 and 5 days after reperfusion. The administration of carnosine significantly decreased infarct volume 5 days after the tMCAO (*p < 0.05) and effectively suppressed the expression of 4-HNE, 8-OHdG, Nitrotyrosine 5 days, and RAGE 5 days after tMCAO. Moreover, the expression of IL-1β was also significantly suppressed 5 days after tMCAO. Our present findings demonstrated that carnosine effectively relieves oxidative stress caused by ischemic stroke and significantly attenuates neuroinflammatory responses related to IL-1β, suggesting that carnosine can be a promising therapeutic strategy for ischemic stroke.

DOI： 10.1016/j.jns.2023.120608

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記述言語：英語  

Myoclonus, a rare complication in patients with end-stage renal disease, is typically ameliorated through hemodialysis. The present case concerns an 84-year-old male with chronic renal failure undergoing hemodialysis, presenting involuntary movements in his limbs, which gradually worsened from the initiation of hemodialysis without constant elevation of serum blood urea nitrogen and electrolytes levels. Surface electromyography revealed characteristic findings consistent with myoclonus. He was diagnosed with subcortical-nonsegmental myoclonus related to hemodialysis, and the myoclonus was significantly alleviated after slightly increasing the post-dialysis target weight even though drug treatment was ineffective. This case suggests that drug-resistant myoclonus in patients with renal failure may be improved by adjusting hemodialysis settings, even in cases of atypical dialysis disequilibrium syndrome.

DOI： 10.7759/cureus.36104

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担当区分：責任著者   記述言語：英語  

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) is a neuromuscular disorder that presents muscle weakness in proximal extremities and/or the trunk with an elevation of creatine kinase (CK). Young and asymptomatic anti-HMGCR IMNM patients are very rare and a treatment regimen has not been established. The present case, a 17-year-old woman without any muscular symptoms, only showed hyperCKemia that was detected by chance. After close examinations, including a muscle biopsy and antibody search, she was diagnosed as anti-HMGCR IMNM, and initial treatment with methotrexate and continuous intravenous immunoglobulin seemed to be effective. The present case is the unusually young asymptomatic case of anti-HMGCR IMNM. The diagnosis was successfully made, leading to the early introduction of a treatment. Given the course of this case, we believe that the preceding antibody testing is one of the diagnostic option for rhabdomyolysis.

DOI： 10.1016/j.nmd.2022.12.012

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human cord blood-endothelial progenitor cells (hCB-EPCs) isolated from the human umbilical cord can be used to repair damaged arteries. In this study, we used an animal model with pathological changes that mimics artery wall damage caused by stent retrievers in humans. We injected hCB-EPCs to investigate their effect on endothelial hyperplasia and dysfunction during intimal repair. Four groups were established based on the length of reperfusion (3 and 28 days), as well as the presence or absence of hCB-EPC therapy. Damage to the internal carotid artery was evaluated by hematoxylin-eosin and immunohistochemical staining. Stroke volume was not significantly different between non-EPC and EPC groups although EPC treatment alleviated intimal hyperplasia 28 days after intimal damage. Vascular endothelial growth factor (VEGF) and eNOS expression were significantly higher in the EPC-treated group than in the non-EPC group 3 days after intimal damage. In addition, MMP9 and 4HNE expression in the EPC-treated group was significantly lower than in the non-EPC group. Ultimately, this study found that venous transplantation of hCB-EPCs could inhibit neointimal hyperplasia, alleviate endothelial dysfunction, suppress intimal inflammation, and reduce oxidative stress during healing of intimal damage.

DOI： 10.1177/09636897231193069

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.

DOI： 10.1177/09636897231214370

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: NADPH oxidase 2 (NOX2) is an important source of reactive oxygen species (ROS). Activated NOX2 may contribute to Alzheimer's disease (AD). Our previous studies showed that a novel vitamin E mixture, Tocovid, had potential neuroprotective effects in a stroke mice model and an AD cell model. OBJECTIVE: The aim of this study was two-fold: to assess whether long-term Tocovid treatment can regulate NOX2, and the therapeutic effects of long-term administration of Tocovid to an AD mice model. METHODS: Therapeutic effects of long-term administration of Tocovid (200 mg/kg /day) on an Aβ-overexpressed transgenic AD mice model (APP23, n = 8) was investigated. The therapeutic effect of Tocovid in 16-month-old mice compared with the no-treatment APP23 group (n = 9) was assessed. RESULTS: Tocovid treatment strongly improved motor and memory deficits of APP23 mice by attenuating NOX2 expression, oxidative stress, neuroinflammation, neurovascular unit dysfunction, synaptic alteration, and Aβ deposition after 16 months. CONCLUSION: These findings suggest that NOX2 is a potential target in AD pathology. Long-term administration of Tocovid may be a promising candidate for AD treatment.

DOI： 10.3233/JAD-220761

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In this case report, we describe a 60-year-old man who presented with headaches for 1 year and mild confusion for 3 weeks and was initially diagnosed as having a cerebral tumor on the basis of finding a round lesion in the right lenticular nucleus with ring enhancement on gadolinium-enhanced T1-weighted brain magnetic resonance imaging. However, the discovery of positive serology for Treponema pallidum infection on routine tests on admission prompted analysis of cerebrospinal fluid, which was also positive on Treponema pallidum hemagglutination (TPHA), rapid plasma reagin (RPR), and treponemal antibody absorption (FTA-ABS) tests. Thus, he was diagnosed as having an intracranial syphilitic gumma. After commencing treatment with penicillin G, the lesion temporarily increased in size, but subsequently resolved completely with continuing antibiotic treatment. In the present era of increasing prevalence of syphilitic infection and because they are eminently treatable, syphilitic gummas should be included in the differential diagnosis of apparent brain tumors. Additionally, temporary enlargement of a probable gumma after instituting antibiotic treatment should not prompt cessation or change of the antibiotics.

DOI： 10.1016/j.ensci.2022.100436

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective During the coronavirus disease 2019 (COVID-19) pandemic, many social activities have moved online using applications for digital devices (e.g. computers, smartphones). We investigated the needs of telemedicine and trends in medical status and social care situations of Japanese patients with neurological disorders in order to estimate their affinity for an online telemedicine application. Methods We designed an original questionnaire for the present study that asked participants what problems they had with hospital visits, how the COVID-19 pandemic had affected their lives, and whether or not they would like to receive telemedicine. Patients The present study included volunteer caregivers, participants with Parkinson's disease (PD), epilepsy, stroke, dementia, immune-mediated neurological disease (IMMD), spinocerebellar degeneration (SCD), amyotrophic lateral sclerosis (ALS), headache, myopathy, and other neurological diseases from Okayama University Hospital. Results A total of 29.6% of patients wanted to use telemedicine. Patients with headaches (60.0%) and epilepsy (38.1%) were more likely to want to use telemedicine than patients with PD (17.8%) or stroke (19.0%). Almost 90% of patients had access to a digital device, and there was no association between favoring telemedicine, ownership of a digital device, hospital visiting time, or waiting time at the hospital, although age was associated with motivation to telemedicine use (52.6 vs. 62.2 years old, p <0.001*). Conclusion We can contribute to the management of the COVID-19 pandemic and the medical economy by promoting telemedicine, especially for young patients with headaches or epilepsy.

DOI： 10.2169/internalmedicine.9702-22

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

We report a case of a symptomatic female carrier of X-linked adrenoleukodystrophy (ALD) with a novel ABCD1 gene mutation. She has developed slowly progressive gait disturbance since age 40, and her father and sister had similar symptoms. When admitted to our hospital at age 66, blood analysis showed slight increase of very long-chain fatty acids (VLCFA), and DNA analysis of ABCD1 gene revealed a novel heterozygous missense mutation (c.1700 A>C, p.Gln567Pro). The genetic testing for ABCD1 gene can be considered in female patients over middle age presenting spastic gait, because female ALD carriers tend to be symptomatic beyond age 60.

DOI： 10.1111/ncn3.12667

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12667

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alzheimer's disease (AD) is a degenerative disorder characterized by the loss of synapses and neurons in the brain, and results in the accumulation of amyloid-based neurotic plaques. Amyloid-β oligomers (AβO) are widely accepted as the main neurotoxin that induces oxidative stress and neuronal loss in AD. In this study, an oxidative stress model of the neuroblastoma SH-SY5Y cell line exposed to AβO was established to simulate an AD cell model. Exposure to AβO significantly reduced the viability of cultured SH-SY5Y cells (p < 0.05) and significantly increased intracellular reactive oxygen species (ROS) (p < 0.01). AβO exposure also induced oxidative stress in SH-SY5Y cells. Furthermore, AβO significantly increased the level of hyperphosphorylation of tau at sites T181 and T205 in SH-SY5Y cells (p < 0.01). Using edaravone, a free radical scavenger with neuroprotective properties, as the control, the possible protective and anti-oxidative effects of curcumin (40 μM) and resveratrol (20 μM) were evaluated. The results suggest that curcumin and resveratrol decreased ROS generation, attenuated oxidative stress, inhibited tau hyperphosphorylation, and protected SH-SY5Y cells from AβO damage. Both curcumin and resveratrol are promising supplements or medicine as therapeutic agents for the treatment of AD.

DOI： 10.1016/j.jns.2022.120356

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Charcot-Marie-Tooth disease type 2Z (CMT2Z) shows highly variable clinical features. We report the first Japanese CMT2Z patient with a c.754C>T (p.R252W) substitution of the MORC2 gene, complicating severe retinitis pigmentosa. The MORC2 mutants were involved in a decrease in cell survival through induction of apoptosis. Thus, the MORC2 mutation might be involved in the degeneration of photoreceptors and the development of retinitis pigmentosa.

DOI： 10.1111/ncn3.12660

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掲載種別：研究論文（学術雑誌）  

Focal and segmental areas of glomerular sclerosis (FSGS) have various subcategories. Here, we report on a 35-year-old man who suffered from Charcot-Marie-Tooth disease (CMT) with FSGS carrying the INF2 mutation (c.206 T > C, p.L69P). The INF2 mutation might cause abnormal actin filaments of the podocytes and Schwann cells, leading to CMT associated with FSGS. He successfully underwent living donor kidney transplantation from a mother with a normal INF2 gene without any serious adverse events. Following genetic testing, the identification of the INF2 mutation allows a recipient to reduce the use of immunosuppressive drugs. Genetic testing may provide a treatment plan for kidney transplantation.

DOI： 10.1111/ncn3.12651

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. METHODS: We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). RESULTS: We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. INTERPRETATION: This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

DOI： 10.1038/s10038-022-01019-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The feasibility of transcranial sonothrombolysis has been demonstrated, although little is known about the relationships between thermal or mechanical mechanisms and thrombolytic outcomes. Therefore, the present study aims to reveal the effect and safety of temperature and ultrasound through in vitro and in vivo thrombolysis models. Artificial clots in microtubes were heated in a water bath or sonicated by ultrasound irradiation, and then clots weight decrease with rising temperature and sonication time was confirmed. In the in vitro thrombotic occlusion model, based on spot heating, clot volume was reduced and clots moved to the distal side, followed by recanalization of the occlusion. In the in vivo study, the common carotid artery of rats was exposed to a spot heater or to sonication. No brain infarct or brain blood barrier disruption was shown, but endothelial junctional dysintegrity and an inflammatory response in the carotid artery were detected. The present spot heating and ultrasound irradiation models seem to be effective for disintegrating clots in vitro, but the safety of the in vivo model was not fully supported by the data. However, the data indicates that a shorter time exposure could be less invasive than a longer exposure.

DOI： 10.1177/0271678X221079127

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

BACKGROUND: Alzheimer's disease (AD) is the most frequent cause of dementia among the elderly. The accumulation of amyloid beta (Aβ) and its downstream pathological events such as oxidative stress play central roles in AD. Recent studies revealed that Aβ oligomer (AβO)-induced strong neurotoxicity in SH-SY5Y cells via the induction of oxidative stress. OBJECTIVE: In the present study, we investigated the effect of two antioxidants, Tocovid and Twendee-X, on AβO-induced SH-SY5Y cell damage. METHODS: AβOs (2.5 μM) were applied to induce cellular damage in the SH-SY5Y cell line. Cell viability following AβO toxicity, Tau protein phosphorylation, cell morphology, and intracellular reactive oxygen species were assayed with or without different concentrations of Tocovid or Twendee-X. RESULTS: Tocovid (60 μg/mL) and Twendee-X (150 μg/mL) significantly recovered cell viability from AβO toxicity (**p < 0.01, vs. control), attenuated Tau protein phosphorylation (**p < 0.01, vs. AβOs), improved cell morphology (**p < 0.01, vs. AβOs), and suppressed intracellular ROS (**p < 0.01, vs. AβOs) in SH-SY5Y cells. CONCLUSION: These findings suggest the neuroprotective and therapeutic potential of Tocovid and Twendee-X for AD treatment.

DOI： 10.1159/000523983

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Cerebral cavernous malformations (CCMs) are congenital abnormalities of cerebral vessels. Surgical resection is rarely considered for the control of epilepsy in a first seizure patient with vascular malformation. In contrast, lesions that produce repetitive or progressive symptoms should be considered for surgical resection as treatment. Herein, we report a Japanese patient with a CCM2 mutation, c.609G>A (p.K203K) substitution, who showed drug-resistant epilepsy and dramatic improvement after surgical resection.

DOI： 10.1111/ncn3.12649

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer's disease (AD) patients. OBJECTIVE: However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20-30% among the dementia society, were still elusive. METHODS: In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH. RESULTS: The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-β pathology, regulated neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M. CONCLUSION: These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH.

DOI： 10.3233/JAD-215246

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掲載種別：研究論文（学術雑誌）  

Mutations in the ATP-binding cassette subfamily C member 6 (ABCC6) gene are responsible for pseudoxanthoma elasticum (PXE). PXE is a rare genetic metabolic disease with autosomal recessive inheritance that shows ectopic mineralization in skin, eyes, and blood vessels and causes cerebrovascular disease. There are few reports of intracranial hemorrhages in patients with the ABCC6 mutation. We report the first Japanese case with a heterozygous ABCC6 mutation displaying recurrent ischemic strokes and intracranial hemorrhages. We propose that the ABCC6 mutation may be one cause of neurovascular diseases with a family history.

DOI： 10.1111/ncn3.12575

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia. OBJECTIVE: To evaluate the therapeutic effect of makeup therapy. METHODS: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n = 16) or skin care plus makeup therapy (makeup therapy group, n = 18) once every 2 weeks for 3 months were assessed. RESULTS: Three months of makeup therapy significantly improved the Mini-Mental State Examination (MMSE) score compared with control patients ( *p <  0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression ( *p <  0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r = 0.43,  *p <  0.05). CONCLUSION: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software.

DOI： 10.3233/JAD-215385

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer's disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. OBJECTIVE: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. METHODS: In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. RESULTS: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. CONCLUSION: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.

DOI： 10.3233/JAD-215318

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune meningoencephalomyelitis. Case 1 is a 26–year-old (yo) woman with a bilateral ovarian teratoma. She presented neck stiffness, hyperreflexia, bilateral postural tremor, and urinary retention. Three courses of a methylprednisolone pulse and subsequent enucleation of the bilateral ovarian teratoma improved her neurological symptoms with no recurrence. Case 2 is a 46-year-old man who showed infectious-like symptoms with elevated creatine kinase. Case 3 is a 76-year-old man with preceding weight loss, a hyperintensity lesion in the hypothalamus, and increased uptake of the spinal cord, assessed by Fluorine18 fluorodeoxyglucose positron emission tomography (18F-FDG PET). We compared the clinical features of the present three cases with previous reports. Consciousness disturbance, neck stiffness, tremors, and urinary dysfunction were observed in all three cases. These findings suggest widespread damage of the brain and spinal cord.

DOI： 10.1111/ncn3.12559

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12559

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alzheimer's disease (AD) is a common neurodegenerative disease that is characterized by the abnormal accumulation of intracellular and extracellular amyloid-β (Aβ) as well as disruption of the blood brain barrier (BBB). Fibrinogen plays an essential role in regulating thrombosis, wound healing, and other biological functions. In the present study, we investigated the relationship between three polypeptide chains α, β, and γ (FGA, FGB, and FGG) and Aβ deposition in the APP23 plus chronic cerebral hypoperfusion (CCH) mice model as well as the human AD brain. FGA, FGB, and FGG accumulated when Aβ was deposited in neural cells and cerebral vessels. This deposition was significantly higher in AD plus CCH mice models relative to wild-type brains, and in human AD brains compared to control brains. The present study demonstrates that FGA, FGB, and FGG are associated with AD progress, and can thus be potential targets for the diagnosis and therapy of AD.

DOI： 10.1016/j.brainres.2021.147569

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Scallop-derived plasmalogen (sPlas) has both anti-oxidative and anti-inflammation activities, but its efficacy has not been investigated in ischemic stroke models where oxidative stress, inflammation, and neurovascular unit (NVU) damage accelerates pathophysiological progression. Therefore, in the present study, we aimed to assess the neuroprotective effects of sPlas in ischemic stroke by using a transient middle cerebral artery occlusion (tMCAO) mouse model. After the pretreatment of vehicle or sPlas (10 mg/kg/day) for 14 days, adult male mice were subjected to tMCAO for 60 min, then continuously treated with vehicle or sPlas during reperfusion and for an additional 5 days. The administration of sPlas significantly improved motor deficits (corner and rotarod tests, *p < 0.05 vs vehicle), enhanced serum antioxidative activity (OXY-adsorbent and d-ROMs tests, *p < 0.05 vs vehicle), reduced infarction volume (*p < 0.05 vs vehicle), decreased the expression of two oxidative stress markers, 4-HNE (*p < 0.05 vs vehicle) and 8-OHdG (*p < 0.05 vs vehicle), decreased the expression of pro-inflammatory markers Iba-1 (**p < 0.01 vs vehicle), IL-1β (**p < 0.01 vs vehicle), and TNF-α (**p < 0.01 vs vehicle), and alleviated NVU damage (collagen IV, MMP9, and GFAP/collagen IV, *p < 0.05 vs vehicle). Our present findings are the first to demonstrate the neuroprotective effects of sPlas on acute ischemic stroke mice at 5 d after tMCAO via anti-oxidative stress, anti-inflammation, and improvement of NVU damage, suggesting the potential of sPlas in preventing and treating ischemic stroke.

DOI： 10.1016/j.brainres.2021.147516

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Anti-glutamic acid decarboxylase (GAD) antibody (Ab)-associated autoimmune cerebellar ataxia (CA) is a rare neurological disorder, and a standardized therapy has not been established. Here, we report on a 58 year-old man with type 1 diabetes mellitus, who developed progressive CA with high levels of serum and cerebrospinal fluid (CSF) anti-GAD-Ab. He was initially treated with intravenous high-dose methylprednisolone and intravenous immunoglobulin (IVIg), but his CA was gradually worsened. Additional combined immunotherapies with plasma exchange, intravenous cyclophosphamide, and rituximab finally stabilized the progressive CA and suppressed the CSF anti-GAD-Ab index. Our case suggests the effectiveness of combined immunotherapies against progressive CA and the usefulness of the CSF anti-GAD-Ab index as a therapeutic indicator.

DOI： 10.1111/ncn3.12541

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Due to an increasing number of dementia patients, the development of a rapid and sensitive method for cognitive assessment is awaited. Here, we examined the usefulness of a novel and short (3 min) eye tracking device to evaluate the cognitive function of normal control (NC, n = 52), mild cognitive impairment (MCI, n = 52), and Alzheimer's disease (AD, n = 70) subjects. Eye tracking total score declined significantly in MCI (**p < 0.01 vs NC) and AD (**p < 0.01 vs NC, ##p < 0.01 vs MCI), and correlated well with the mini-mental state examination (MMSE) score (r = 0.57, *p < 0.05). Furthermore, the eye tracking test, especially memory and deductive reasoning tasks, effectively discriminated NC, MCI and AD. The present novel eye tracking test clearly discriminated cognitive functions among NC, MCI, and AD subjects, thereby providing an advantage for the early detection of MCI and AD in screening.

DOI： 10.1016/j.jns.2021.117529

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Immune checkpoint inhibitors occasionally cause various side effects, but the occurrence of a severe immune-related adverse event (irAE) is rare in neurology. We report on a 56-year-old woman who suffered from rheumatoid arthritis and recurrent uterine cancer. After treatment with pembrolizumab, she showed visual disturbance followed by acute fever and consciousness disturbance with high-intensity lesions around the midbrain aqueduct and bilateral caudate heads on FLAIR images of a brain MRI. Her symptoms improved after steroid therapy. However, symptoms relapsed leading to an elevation of the anti-CCP antibody index. Pembrolizumab-induced rheumatoid meningoencephalitis was suspected, so additional steroid therapy was provided. This improved her symptoms, turning the anti-CCP antibody index negative. The present case is the first case of rheumatoid meningoencephalitis induced by pembrolizumab. The combination of MRI findings and elevated anti-CCP index seems useful for diagnosing rheumatoid meningoencephalitis.

DOI： 10.1111/ncn3.12540

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We herein report a 75-year-old man who developed disturbed consciousness with polynuclear cell dominant pleocytosis and low glucose and extremely high interleukin (IL)-6 levels in his cerebrospinal fluid. The biopsy specimen from his right supraclavicular lymph node showed the infiltration of inflammatory cells positive for IgG, IgG4 and IL-6. Prednisolone and azathioprine administered under suspicion of IgG4-related disease (IgG4-RD) or multicentric Castleman's disease (MCD) successfully remitted the symptoms. However, he developed myelodysplastic syndrome (MDS) and died 18 months later. The extremely high IL-6 may have been related to the rare neurological manifestations and development of MDS in the present case.

DOI： 10.2169/internalmedicine.6098-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Treatment with MG132 or 3MA significantly increased the clinical hanging wire score and exacerbated α-motor neuron loss at 18 weeks in G93A mice, and increased the amount of ubiquitin, p62 aggregates, and BAG3 expression. This study's results demonstrate that the molecular switch from UPS to autophagy occurred not only in motor neurons but also in astroglia at the end stage (18 weeks) when the autophagic flux was impaired in G93A mice. This finding suggests that the defense system was disrupted against aggregate-prone protein production in ALS.

DOI： 10.1016/j.neuroscience.2021.04.034

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We report on a 35-year-old man who had gender dysphoria following unilateral ovariectomy and then received continuous testosterone injection for nine years, inducing chronic inflammatory demyelinating polyneuropathy (CIDP). He developed recurrent muscle weakness and numbness in the extremities and displayed demyelinating neuropathy, detected by nerve conduction studies and a sural nerve biopsy. Repeated intravenous immunoglobulin (IVIg) therapy and the administration of oral prednisolone improved symptoms and inhibited their recurrence. A relatively high level of serum testosterone as a genetic female might have caused the neurotoxicity of the peripheral nerve, leading to CIDP.

DOI： 10.1111/ncn3.12514

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記述言語：英語  

DOI： 10.1038/s41598-021-91963-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Hypoxic stress is suspected as the pathogenesis of ALS, however, no positron emission tomography (PET) study for hypoxic stress has been conducted in the spinal cord of ALS patients.Methods: In the present study, we examined cervical spinal hypoxic stress of nineALS patients with upper extremity (U/E) atrophy by18F-fluoromisonidazole (FMISO) PET.Results: On the ipsilateral side of C1 and C5 levels, 18F-FMISO uptake increased significantly compared with the contralateral side (*p < 0.05) and the control subject (**p < 0.01). In addition, a strong correlation was found between 18F-FMISO uptake of the C5 level and the rate of progression of the ALS FRS-R score (R = 0.781, *p = 0.013).Conclusion: These results indicate that hypoxic stress increased in the spinal cord of ALS patients with a close link to ALS progression. Both hypoxic stress and a compromised response to hypoxia, which may lead to subsequent motor neuron death, could be a potential therapeutic target for ALS.

DOI： 10.1080/01616412.2020.1866383

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

White matter lesions (WMLs) caused by cerebral chronic hypoperfusion (CCH) may contribute to the pathophysiology of Alzheimer's disease (AD). However, the underlying mechanisms and therapeutic approaches have yet to be totally identified. In the present study, we investigated a potential therapeutic effect of the free radical scavenger edaravone (EDA) on WMLs in our previously reported novel mouse model of AD (APP23) plus CCH with motor and cognitive deficits. Relative to AD with CCH mice at 12 months (M) of age, EDA strongly improved CCH-induced WMLs in the corpus callosum of APP23 mice at 12 M by improving the disruption of white matter integrity, enhancing the proliferation of oligodendrocyte progenitor cells, attenuating endothelium/astrocyte unit dysfunction, and reducing neuroinflammation and oxidative stress. The present study demonstrates that the long-term administration of EDA may provide a promising therapeutic approach for WMLs in AD plus CCH disease with cognitive deficits.

DOI： 10.1177/0271678X20968927

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cu-diacetyl-bis (N4-methylthiosemicarbazone) (CuATSM) has both anti-oxidative and anti-inflammatory activities, but its therapeutic efficacy for oxidative stress has not been thoroughly investigated in acute ischemic stroke. Here, the present study was designed to assess the efficacies of CuATSM in acute ischemic stroke by comparing with the standard neuroprotective reagent edaravone. Mice were subjected to transient middle cerebral occlusion (tMCAO) for 60 min, and then intravenously administrated with CuATSM (1.5 mg/kg) or edaravone (3 mg/kg) just after the reperfusion, and examined at 1 and 3 d. Compared with the vehicle group, CuATSM treatment decreased infarct volumes and oxidative stress at 3d after tMCAO, which was further enhanced by combined CuATSM + edaravone treatment as compared with single CuATSM group, but not improve neurobehaviors. The present study demonstrated that CuATSM showed strong antioxidative and neuroprotective effects in acute ischemic stroke, which was enhanced by the combination with edaravone.

DOI： 10.1016/j.neures.2020.05.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: Because behavioral and psychological symptoms of dementia (BPSD) are sometimes prodromal symptoms of dementia, it is important to investigate the relationship between BPSD and subsequent cognitive decline.Methods: We examined the cognitive and affective functions of 76 cognitively normal subjects at initial assessment (baseline) and 1-year follow-up. Cognitive function was assessed using clinical dementia rating (CDR) and Mini-Mental State Examination (MMSE), and affective function was assessed using Abe's BPSD score (ABS) and mild behavioral impairment (MBI).Results: Although there was no change in MMSE, ABS, or MBI after 1 year, the mean CDR score of 0 at baseline increased to 0.1 +/- 0.2 at 1-year follow-up (**P < 0.01 vs baseline). No significant change in MMSE was found in both baseline ABS and MBI positive- or negative-groups. In contrast, baseline MBI-dependent CDR change showed a 13.2% of worsening in MBI-negative subjects and a 62.5% of MBI-positive subjects (dagger dagger P < 0.01), but ABS not.Conclusion: The present data indicate that positive baseline BPSD with MBI was closely related to a subsequent CDR exacerbation. Examining BPSD may be useful for screening cognitively normal population for subsequent dementia development in local communities.

DOI： 10.1111/ncn3.12492

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.

DOI： 10.3390/cells10040961

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Only a few studies have investigated changes in the dose of long-acting injectable second-generation antipsychotics (LAI-SGAs) over the long term in the maintenance treatment of schizophrenia. In this retrospective cohort study, we examined longitudinal changes in antipsychotic dose over a 3-year period in patients with schizophrenia who had been taking LAI-SGAs for at least 1 year. We compared the total daily chlorpromazine equivalent dose of antipsychotics at 12, 24 and 36 months with the baseline dose at 3 months after initiation of LAI-SGAs. We also performed multiple regression analysis to explore factors associated with change in total daily dose 12 months after treatment initiation. A total of 154 patients fulfilled the inclusion criteria. There was no significant difference in total daily antipsychotic dose between 3 months and 12, 24 or 36 months after treatment initiation. Total daily dose was increased in 43 (27.9%), 31 (34.8%) and 22 patients (36.7%) at 12, 24 and 36 months, respectively. Age and total antipsychotic dose at 3 months were significantly negatively associated with change in total daily dose. Antipsychotic dose was basically unchanged during long-term treatment in patients treated with LAI-SGAs in the maintenance phase, although there was an increase in some patients.

DOI： 10.1097/YIC.0000000000000347

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: Telestroke network can provide rapid access to specialized treatment and improves on-site management of acute stroke patients through the "hub-and-spoke" model. In the northern part of Okayama Prefecture, there has been a regional gap of stroke care due to the shortage of stroke specialists and facilities. In addition, due to the novel coronavirus disease 2019 (COVID-19), it is required to reduce the unnecessary contact with stroke patients from other hospitals.Aim: We organized a novel cost-free telestroke network with an image and video sharing for neurological diseases in the northern part of Okayama Prefecture to improve the stroke management in the area.Method: We prepared the tablet device on which Skype(R) application was installed for each hospital and recruited the patients who visited or hospitalized in the spoke hospitals and were suspected to have some neurological diseases from April 2019 to May 2020. The patient's clinical data were recorded and analyzed.Results: During the study period, 5 patients were recruited including the cases with the initial diagnosis of stroke or brain tumor. Among them, 2 cases were transferred to the hub hospital, 2 cases were transferred to other hospitals, and 1 case was treated on site under specialist's advice.Conclusion: The new telestroke network system may be beneficial for acute stroke management and reducing the unnecessary patient's transfer in the rural area, especially under coexistence with COVID-19.

DOI： 10.1111/ncn3.12475

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The relationship between stroke etiology and clot pathology remains controversial. MATERIALS AND METHODS: We performed histological analysis of clots retrieved from 52 acute ischemic stroke patients using hematoxylin and eosin staining and immunohistochemistry (CD42b and oxidative/hypoxic stress markers). The correlations between clot composition and the stroke etiological group (i.e., cardioembolic, cryptogenic, or large artery atherosclerosis) were assessed. RESULTS: Of the 52 clots analyzed, there were no significant differences in histopathologic composition (e.g., white blood cells, red blood cells, fibrin, and platelets) between the 3 etiological groups (P = .92). By contrast, all large artery atherosclerosis clots showed a localized pattern with the oxidative stress marker 4-hydroxyl-2-nonenal (P < .01). From all 52 clots, 4-hydroxyl-2-nonenal expression patterns were localized in 28.8% of clots, diffuse in 57.7% of clots, and no signal in 13.5% of clots. CONCLUSIONS: A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).

DOI： 10.1016/j.jstrokecerebrovasdis.2020.105583

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Growing evidence indicates that reduced uterine perfusion pressure (RUPP) triggers the cascade of events leading to preeclampsia. Edaravone is a powerful free radical scavenger used for the treatment of ischemia/reperfusion diseases due to its anti-oxidative stress and anti-inflammatory properties. Here we investigate the effect of edaravone (3 mg/kg) on different maternal and fetal outcomes of RUPP-induced placental ischemia mice model. RUPP surgery was performed on gestation day (GD) 13 followed by edaravone injection from GD14 to GD18, sacrifice day. The results showed that edaravone injection significantly decreased the maternal blood pressure (113.2 ± 2.3 mmHg) compared with RUPP group (131.5 ± 1.9 mmHg). Edaravone increased fetal survival rate (75.4%) compared with RUPP group (54.4%), increased fetal length, weights, and feto-placental ratio (7.2 and 5.7 for RUPP and RUPP-Edaravone groups, respectively) compared with RUPP group. In addition, RUPP resulted in many fetal morphological abnormalities as well as severe delayed ossification, however edaravone decreased the morphological abnormalities and increased the ossification of the fetal endoskeleton. Edaravone improved the histopathological structure of the maternal kidney and heart as well as decreased the elevated blood urea and creatinine levels (31.5 ± 0.15 mg/dl (RUPP), 25.6 ± 0.1 mg/dl (RUPP+edaravone) for urea and 5.4 ± 0.1 mg/dl (RUPP), 3.5 ± 0.1 mg/dl (RUPP+edaravone) for creatinine) and decreased cleaved caspase-3 expression in the maternal kidney. In conclusion, this study demonstrated that our RUPP mice model recapitulated preeclampsia symptoms and edaravone injection ameliorated most of these abnormalities suggesting its effectiveness and potential application in preeclampsia treatment regimes.

DOI： 10.1186/s12958-021-00707-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Combined central and peripheral demyelination (CCPD) causes demyelination in both the central and peripheral nervous systems. Anti-neurofascin 155 antibody plays an important pathogenic role in CCPD, but evidence concerning an association between this antibody and CCPD remains inconclusive. Although there have been no reports of precedent optic neuritis developing into CCPD, we herein report a Japanese man in whom optic neuritis recurred four times over nine years and who developed CCPD without positive anti-neurofascin 155 antibody. This case suggests the possibility of developing CCPD after optic nerve neuritis and the existence of an unknown antibody that induces CCPD.

DOI： 10.2169/internalmedicine.5536-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), frequently observed in the Kii peninsula of Japan, is pathologically characterized by widespread tau pathology in the cerebrum and brainstem. Here, we report a case of Kii ALS/PDC predominantly presenting progressive parkinsonism. Tau positron emission tomography (PET) imaging with F-18-PM-PBB3 suggested tau deposition in the substantia nigra of the midbrain and subcortical areas, but not in the cerebral cortex, which was similar to progressive supranuclear palsy (PSP), suggesting that parkinsonism-predominant type of Kii ALS/PDC may have a similar area of tau deposition to PSP.

DOI： 10.1111/ncn3.12463

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions. NIID presents highly variable clinical manifestations such as dementia, ataxia, convulsion, neuropathy, and autonomic dysfunction. A 60-year-old woman developed recurrent severe cerebellar ataxia (SARA score: 30/40 points). She was diagnosed with adult-onset NIID by a characteristic brain diffusion-weighed imaging hyperintensity lesion in subcortical white matter and intranuclear inclusion bodies in a skin biopsy. Her ataxia was more severe and lasted longer (additional 19 days) than a previous case, although she showed remarkable improvement.

DOI： 10.1111/ncn3.12454

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

A 76-year-old man presented with subacute onset of progressive cognitive impairment, anorexia, tremor, ataxic gait, and urinary dysfunction. He had lost 17 kg in 9 months before his admission (due to persistent anorexia). A brain MRI showed a typical radial pattern of periventricular gadolinium enhancement and longitudinally extensive hyperintensity from cervical to lumbar spinal cord. F-18-FDG PET newly revealed an increased uptake of the tracer in the cervical and lower thoracic cords. After an intravenous methylprednisolone (1000 mg/d for 3 days) followed by oral prednisolone 40 mg/d, his clinical symptoms and abnormal MRI lesions improved. Anti-GFAP antibodies were subsequently identified in CSF obtained on admission, confirming the diagnosis of autoimmune GFAP astrocytopathy.

DOI： 10.1111/ncn3.12441

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Possible benefits of makeup therapy, in terms of immediate and late effects on cognitive and affective functions, have not been fully proved for dementia patients. OBJECTIVE: To evaluate the immediate effect of makeup therapy on dementia patients. METHODS: Female nursing home residents with dementia received either only skin care treatment (control group, n = 17) or skin care plus makeup therapy treatment (makeup therapy group, n = 19). Cognitive, affective, and activity of daily living (ADL) scores were evaluated before and just after treatments. Apparent age and emotion were also evaluated with artificial intelligence (AI) software. RESULTS: Makeup therapy significantly improved Abe's behavioral and psychological symptoms of dementia (BPSD) score (ABS, *p < 0.05). AI software judged that makeup therapy significantly made the apparent age younger (*p < 0.05). In particular, patients with moderate ADL scores had a significantly higher happiness score in makeup therapy (*p < 0.05), with a modest correlation to the Mini-Mental State Examination (MMSE, r = 0.42, *p < 0.05). The severe baseline MMSE group reported a greater feeling of satisfaction following makeup therapy (*p < 0.05). CONCLUSION: The present makeup therapy is a promising non-pharmacological approach to immediately alleviate BPSD in female dementia patients, and the present AI software quickly and quantitatively evaluated the beneficial effects of makeup therapy on facial appearance.

DOI： 10.3233/JAD-210284

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cost-effective and noninvasive methods for in vivo imaging of amyloid deposition are needed to screen Alzheimer's disease (AD). Although retinal amyloid is a possible diagnostic marker of AD, there are very few studies on in vivo retinal amyloid imaging. OBJECTIVE: To examine the usefulness of in vivo imaging of retinal amyloid in AD patients. METHODS: To examine amyloid deposition, 30 Japanese subjects (10 normal control (NC), 7 with mild cognitive impairment (MCI), and 13 with AD) underwent a complete ophthalmic examination, including fundus imaging by scanning laser ophthalmoscopy before and after oral curcumin intake. RESULTS: Retinal amyloid deposition was greater in AD than in NC subjects (*p < 0.05) while MCI showed a slight but insignificant increase of retinal amyloid deposition relative to NC subjects. Retinal amyloid deposition was correlated with whole gray matter atrophy (r = 0.51, *p < 0.05) but not with the cognitive score of the Mini-Mental State Examination, nor with medial temporal lobe atrophy. CONCLUSION: The present noninvasive in vivo detection of retinal amyloid deposition is useful for screening AD patients.

DOI： 10.3233/JAD-210327

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cerebral microbleeds (CMBs) in patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied. OBJECTIVE: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99 mTc-ECD SPECT subtraction images of these two diseases. METHODS: We examined 112 patients with PD (53 males and 59 females; age: 77.4±3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1±6.7 years) using brain magnetic resonance imaging (MRI) and 99 mTc-ECD SPECT subtraction imaging. RESULTS: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7±1.1) than the latter (0.2±0.5, p < 0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7-17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99 mTc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB. CONCLUSION: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB.

DOI： 10.3233/JAD-201495

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tocilizumab (TCZ; Actemra/RoActemra) is an anti-interleukin (IL)-6 receptor antibody for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases and cytokine storms. The present case is a 63-year-old female well-controlled RA patient, who presented with a progressive cognitive impairment after 34 months of TCZ administration. Brain magnetic resonance imaging (MRI) showed leukencephalopathy with a lactic acid peak in magnetic resonance spectroscopy (MRS), a decreased blood flow in single photon emission computed tomography (SPECT), and a decreased accumulation in fluorodeoxyglucose positron emission tomography (FDG-PET). The discontinuation of TCZ improved her cognitive function and brain MRI findings at 3 months after drug cessation. The present case suggests that TCZ may sometimes cause leukoencephalopathy after long-term administration, and thus the early discontinuation of TCZ is recommended to achieve a good prognosis.

DOI： 10.2169/internalmedicine.5288-20

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記述言語：英語  

DOI： 10.1016/j.jns.2020.117150

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 104 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.

DOI： 10.1038/s41598-020-74216-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mechanical thrombectomy (MT) is a standard treatment for acute ischemic stroke that could cause hemorrhagic complications. We aimed to evaluate the pathology of MT-induced arterial damage and neurovascular unit (NVU) disruption in relation to tissue-type plasminogen activator (tPA) injection for acute ischemic stroke. We induced transient middle cerebral artery occlusion in male SHR/Izm rats for 2 hr. This was followed by reperfusion with/without tPA (3 mg/kg) and "rough suture" insertion that mimicked MT once or thrice (MT1 or MT3). Compared with the control group, the tPA + MT3 group presented with an increase in the cerebral infarct and hemorrhage with severer IgG leakage. Moreover, structural damage reaching the tunica media was detected in the MT3 and tPA + MT3 groups. The tPA + MT3 group presented with increased matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression with some MMP9-positive cells expressing a neutrophil marker myeloperoxidase. Furthermore, basal lamina detachment from astrocyte foot processes was observed in the tPA + MT1 and tPA + MT3 groups. These findings suggest that MT causes direct arterial damage, as well as VEGF and MMP9 upregulation, which results in NVU disruption and hemorrhagic complications in acute ischemic stroke, especially when combined with tPA.

DOI： 10.1002/jnr.24671

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

DOI： 10.1038/s42003-020-01251-2

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記述言語：英語  

DOI： 10.1016/j.jns.2020.117043

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aggregation and cellular mislocalization of several RNA-binding proteins (RBPs) have been identified as the major hallmarks of neurodegenerative diseases such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, it remains obscure whether these pathological changes also occur during cerebral ischemia. In this study, we report that RBPs increased significantly compared with the sham group (*p < 0.05 and **p < 0.01 vs sham), with nuclear depletion and cytoplasmic deposition in neurons in the acute phase of cerebral ischemia. On the other hand, such nucleocytoplasmic mislocalization were not observed in astrocytes. We provide evidence of the alteration of these neurodegeneration-related RBPs after cerebral ischemia, suggesting a potential association between cerebral ischemia and neurodegenerative diseases.

DOI： 10.1016/j.brainres.2020.146862

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ASEAN Neurological Association  

Palmoplantar pustulosis is a chronic inflammatory skin disease involving the palms and soles where mild accumulation of helper T cells and neutrophils in the dermis histologically are observed. Leukoencephalopathy is a brain disease affecting white matter but is rarely accompanied by skin lesion. Here we report a unique case of leukoencephalopathy accompanied by palmoplantar pustulosis with identical pathological feature of helper T cell accumulation in both the brain and skin, suggesting a possible link in the pathogenesis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We report on a 35-year-old woman who complained of myasthenia in ocular, bulbar, and limb muscles, but who was negative for antibodies against acetylcholine receptor, muscle-specific kinase, or low-density lipoprotein receptor-related protein 4, accompanied by the suppression of thyroid-stimulating hormone with elevated free T3 and free T4. Administration of edrophonium significantly ameliorated blepharoptosis, and electromyography revealed 13.9% waning after 3 Hz repetitive stimulation in the left accessory nerve. Thus, she was suspected of having triple seronegative myasthenia gravis or thyrotoxic myasthenia. She was remitted after the resection of her enlarged thymus with an elevated uptake in fluorine-18 fluorodeoxyglucose positron emission tomography, suggesting an unknown autoimmune target that escaped detection by current autoantibody screens. Consequently, thymectomy may still be effective in patients with seronegative MG plus hyperthyroidism.

DOI： 10.1111/ncn3.12414

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記述言語：英語  

DOI： 10.1016/j.jns.2020.116885

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The free radical scavenger edaravone is a proven neuroprotective drug for patients with amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the therapeutic effects of edaravone for oxidative stress and anti-oxidative activity in ALS patients. METHODS: Twenty-two ALS patients with a disease duration of 2 years, treated by edaravone, and 25 control participants were evaluated according to their clinical scores, including ALS functional rating scale-revised (ALSFRS-R), and serum and cerebrospinal fluid (CSF) markers of oxidative stress dROM and anti-oxidative activity OXY. RESULTS: Serum and CSF markers of anti-oxidative activity OXY were significantly decreased in ALS patients at pre-treatment compared with controls (##p < .01), which was improved in the course of edaravone treatment. Both serum and CSF OXY were significantly correlated with ALS clinical scores including ALSFRS-R (*p < .05, **p < .01, ***p < .001). Furthermore, serum OXY at pre-treatment was significantly correlated with a change in the ALSFRS-R score in the sixth cycle of edaravone treatment (*p < .05). CONCLUSIONS: The present study suggests significant correlations between anti-oxidative activity and ALS clinical severity, and the therapeutic efficacy of edaravone for decreased anti-oxidative activity in ALS.

DOI： 10.1016/j.jns.2020.116906

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: During an acute stroke, reactive oxygen species are overproduced and the endogenous antioxidative defense systems are disrupted. Therefore, antioxidative therapy can be a promising scheme to reduce the severity of stroke. Neumentix is a novel antioxidative supplement produced from a patented mint line and contains a high content of rosmarinic acid (RA). Although Neumentix has proven diverse efficacy and safety in clinical trials, its effect on strokes is unclear. METHODS: Mice that were treated with Neumentix or vehicle for 14 days underwent transient middle cerebral artery occlusion (tMCAO) for 60 min. Mice were sacrificed 5 days after tMCAO. RESULTS: Neumentix preserved body weight after tMCAO, showed a high antioxidative effect in serum, and reduced infarction volume compared to the vehicle. The expression of 4-hydroxy-2-nonenal, Nε-(carboxymethyl) lysine, and 8-hydroxy-2'-deoxyguanosine was reduced in Neumentix-treated mice. CONCLUSION: The antioxidative effect of Neumentix was confirmed. This is the first report to demonstrate the antioxidative effect of Neumentix on strokes.

DOI： 10.1016/j.jstrokecerebrovasdis.2020.104818

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.

DOI： 10.1016/j.neuron.2020.04.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There is thought to be a strong relationship between sphingosine-1-phosphate (S1P) signaling and pathophysiolosy of cerebral ischemia. We examined the change of expression and distribution of S1P receptors (S1PRs) and sphingosine kinases (SphKs) after cerebral ischemia in male C57BL6/J mice using immunohistochemical analysis at 1, 5, 14, and 28 days after 30 min of transient middle cerebral artery occlusion (tMCAO). S1PR1, 3, and 5 were transiently induced in the cells, which were morphologically similar to neurons in the peri-infarct lesion with a peak seen at 1 day after tMCAO (p < 0.01 vs. sham control). S1PR2 appeared in the inner layer of vessels in the ischemic core (p < 0.01 vs. sham control) and the peri-infarct lesion (p < 0.01 vs. sham control) at the acute phase after tMCAO. However, SphK1 was strongly induced at 1 and 5 days after tMCAO (p < 0.01 vs. sham control) in the peri-infarct lesion, whereas SphK2 expression did not change. Western blot analysis at 1 and 5 days after 30 min of tMCAO revealed that the expression of S1PRs were transiently enhanced at the acute phase, which was consistent with the immunohistochemical results. Double immunofluorescent analysis revealed S1PR2/NG2- and S1PR2/CD31-, S1PR3/CD31-, and S1PR5/CD31-double positive cells in the peri-infarct lesion 1 day after tMCAO. The present results suggest that S1PRs and SphK1 may be important therapeutic targets for rescuing the peri-infarct lesion.

DOI： 10.1016/j.brainres.2020.146831

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We report a new case of familial dropped head syndrome (DHS) due to myopathy. The proband is a 63-year-old woman, and her younger sister and son also showed DHS. She was not good at sport since elementary school and showed unique muscle weakness in her paraspine and four limbs. A blood test showed a slight increase in creatine kinase (237 IU/mL) and myoglobin (95 ng/mL). An electromyogram showed myogenic change, and computed tomography revealed a normal muscle volume of the neck but paraspinal muscle atrophy. Muscle biopsy of the right femoral muscle found type 2 fiber atrophy. Based on these unique clinical features, this is the first report of familial DHS which probably due to congenital myopathy.

DOI： 10.1111/ncn3.12382

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We report a 31-year-old woman with ring chromosome 20 syndrome who presented with epilepsy staring from 16 years old and loss of consciousness from 30 years old. Her neurological examinations and psychological testing were normal, without dysmorphic features. No abnormalities were found in neuroimaging. Electroencephalogram recording showed typical non-convulsive status epilepticus associated with alteration of consciousness. Her diagnosis was based on the cytogenetic analysis indicating that her karyotype was 46, XX, r(20)(p13q13.3)[9]/46, XX[21]. She had refractory epilepsy and improved by a combination of valproate and lacosamide.

DOI： 10.1111/ncn3.12389

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer's disease (AD) are associated with a lower quality of life. OBJECTIVE: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients. METHODS: In the present study, we evaluated the efficacy of sertraline (n = 11; average dose = 31.8 mg), escitalopram (n = 13; average dose = 7.3 mg), and nicergoline (n = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) (>5) or a high Apathy Scale (AS) (>16) scores. RESULTS: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p = 0.05); however, no significant changes were noted in patients receiving nicergoline. CONCLUSION: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD.

DOI： 10.3233/JAD-200247

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Statin-associated necrotizing myopathy (SANM) is a rare autoimmune disorder caused by administration of statins. SANM is characterized by weakness due to necrosis and regeneration of myofibers. Here we report the first case of SANM with acute respiratory failure treated with noninvasive pressure support ventilation in addition to immunosuppressants. CASE PRESENTATION: A 59-year-old woman who had been treated with 2.5 mg/day of rosuvastatin calcium for 5 years stopped taking the drug 4 months before admission to our hospital due to elevation of creatine kinase (CK). Withdrawal of rosuvastatin for 1 month did not decrease the level of CK, and she was admitted to our hospital due to the development of muscle weakness of her neck and bilateral upper extremities. Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies were positive. Magnetic resonance imaging showed myositis, and muscle biopsy from the right biceps brachii muscle showed muscle fiber necrosis and regeneration without inflammatory cell infiltration, suggesting SANM. After the diagnosis, she received methylprednisolone pulse therapy (mPSL, 1 g/day × 3 days, twice) and subsequent oral prednisolone therapy (PSL, 30 mg/day for 1 month, 25 mg/day for 1 month and 22.5 mg/day for 1 month), leading to improvement of her muscle weakness. One month after the PSL tapering to 20 mg/day, her muscle weakness deteriorated with oxygen desaturation (SpO2: 93% at room air) due to hypoventilation caused by weakness of respiratory muscles. BIPAP was used for the management of acute respiratory failure in combination with IVIG (20 g/day × 5 days) followed by mPSL pulse therapy (1 g/day × 3 days), oral PSL (30 mg/day × 3 weeks, then tapered to 25 mg/day) and tacrolimus (3 mg/day). Twenty-seven days after the start of BIPAP, she was weaned from BIPAP with improvement of muscle weakness, hypoxemia and hypercapnia. After she achieved remission with improvement of muscle weakness and reduction of serum CK level to a normal level, the dose of oral prednisolone was gradually tapered to 12.5 mg/day without relapse for 3 months. CONCLUSIONS: Our report provides new insights into the role of immunosuppressants and biphasic positive airway pressure for induction of remission in patients with SANM.

DOI： 10.1186/s12890-020-01195-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cerebral ischemia causes strong inflammatory response. Neumentix is a dietary supplement containing 14.9% rosmarinic acid and 29.9% total phenolic content, which was proved to be beneficial against inflammatory response. Therefore, we investigated Neumentix's effect on anti-inflammatory and blood brain barrier (BBB) disruption in transient middle cerebral artery occlusion (tMCAO) model mice. METHODS: After the pretreatment of vehicle or Neumentix 134 mg/kg/d, intraperitoneal injection (i.p.) (containing rosmarinic acid 20mg/kg/d) for 14 days, mice were subjected to tMCAO for 60 min and kept receiving vehicle or Neumentix daily 5 days afterwards. RESULTS: Neumentix treatment ameliorated neurobehavioral impairment in the corner test (5d after tMCAO, **p<0.01), reduced infarct volume (#p<0.05), suppressed expression of ionized calcium-binding adapter molecule-1 (Iba-1), tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) (### p <0.001), and improved the integrity of BBB (§p<0.05) at the 5 days after tMCAO. Conclusios: Our present study provided an evidence of Neumentix's anti-inflammatory and neuroprotection effect against BBB disruption on experimental tMCAO model mice, suggesting that Neumentix could be potential therapeutic agent for stroke.

DOI： 10.2174/1567202617666200517105727

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bone marrow stromal cell (BMSC) transplantation is a promising therapeutic approach for cerebral ischemia, as it elicits multiple neuroprotective effects. However, it remains unclear how BMSC transplantation modulates the ubiquitin-proteasome system (UPS) and autophagy under cerebral ischemia. METHODS: In the present study, an intermediate level of cerebral ischemia (30 minutes) was chosen to examine the effect of BMSC transplantation on the molecular switch regulating UPS and autophagy. BMSC or vehicle was stereotactically injected into the penumbra 15 minutes after sham operation or transient middle cerebral artery occlusion (tMCAO). RESULTS: Thirty minutes of tMCAO artery occlusion significantly increased TUNEL-, ubiquitin-, and p62-positive cells (which peaked at 72 hours, 2 hours, and 2 hours after reperfusion, respectively) and ratios of both BAG3/BAG1 and LC3-II/LC3-I at 24 hours after reperfusion. However, intracerebral injection of BMSCs significantly reduced infarct volume and numbers of TUNEL- and p62-positive cells, and improved BAG3/BAG1 and LC3-II/LC3-I ratios. In addition, observed increases in ubiquitin-positive cells 2 hours after reperfusion were slightly suppressed by BMSC transplantation. CONCLUSIONS: These data suggest a protective role of BMSC transplantation, which drove the molecular switch from autophagy to UPS in a murine model of ischemic stroke.

DOI： 10.1016/j.jstrokecerebrovasdis.2020.104743

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Truncal neuropathy is a rare phenotype of diabetic neuropathy. Here, we report the first case of diabetic painful truncal neuropathy complaining of back pain with hypohidrosis confirmed by a sweat test accompanied by cranial nerve palsy. The patient had poorly controlled type 2 diabetes mellitus and suffered from back pain followed by facial palsy. After pulse therapy with methylprednisolone facial palsy improved, but back pain was intractable with a loss of body weight. The sweat test showed hypohidrosis on the back and soles on his feet. Sural nerve biopsy revealed decreased small fibers and mild axonopathy. After palliative therapy, his symptoms gradually improved.

DOI： 10.1111/ncn3.12370

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Anti-galactocerebroside (Gal-C) antibody is characteristic of encephalomyelitis and Guillain-Barre syndrome subsequent to mycoplasma infection. Here, we report a 75-year-old Japanese man who presented somnolence, signs of meningeal irritation, and parkinsonian features with positive serum inflammatory markers and cerebrospinal fluid (CSF) pleocytosis. Although anti-Mycoplasma pneumoniae antibody was negative, anti-Gal-C antibody was later detected in his serum. The present case recovered spontaneously without any other specific therapies.

DOI： 10.1111/ncn3.12379

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

There is a strong relationship between Alzheimer's disease (AD) and sleep problems, and a sleep condition is informative for evaluating the AD status. In the present study, we evaluated subjective sleep problems in AD and mild cognitive impairment (MCI) with self-check questionnaires and objective sleep problems with a convenient home-based portable device, WatchPAT. A total of 63 subjects with normal cognition (NC) (n = 22), MCI (n = 20), and AD (n = 21) were cross-sectionally investigated. AD patients showed a better self-check Pittsburgh sleep quality index (PSQI) score (*p < 0.05) than NC and MCI patients. On the other hand, WatchPAT analysis showed a significantly reduced rapid eye movement (REM) sleep (*p < 0.05) and increased light sleep in AD patients (*p < 0.05) compared with NC subjects, and mildly reduced REM and increased light sleep in MCI subjects. The present study revealed a gap between the subjective self-check sleep questions and the objective WatchPAT analysis in AD patients. Thus, a home-based sleep study with WatchPAT is a useful tool to detect an objective sleep problem in AD and the risk of MCI conversion into AD.

DOI： 10.1016/j.jocn.2020.01.085

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Leucine-rich glioma-inactivated 1 (LGI1) antibody-associated limbic encephalitis is a rare autoimmune encephalitis. Here, we report a 39-year-old woman presented with generalized tonic-clonic seizures, night delirium, bilateral upper limb tremor, and hyponatremia. Her symptoms did not improve with initial steroid therapy, and brain magnetic resonance imaging (MRI) showed a progression of abnormalities from right basal ganglia to medial temporal lobe and insula. The presence of LGI1 antibodies in the patient's serum confirmed the clinical diagnosis. After the combined treatments of methylprednisolone, plasma exchange, and intravenous immunoglobulin, her clinical symptoms resolved completely.

DOI： 10.1111/ncn3.12351

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

The accurate diagnosis of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases is sometimes challenging due to its various central nervous system (CNS) lesions. Here, we report a 22-year-old man with positive anti-MOG antibody presenting multiple brain lesions including a brainstem tumefactive demyelinating lesion (TDL), cortical edematous lesions, and a periventricular white matter lesion. These variety of lesions made the diagnosis challenging, especially because TDL is quite rare among MOG antibody-associated disease patients. The present case suggests the importance to check anti-MOG antibody for patients presenting atypical multiple CNS lesions.

DOI： 10.1111/ncn3.12364

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Idiopathic hypertrophic pachymeningitis (HP) is a rare inflammatory disorder characterized by local or diffuse thickening of the cranial or spinal dura mater, which is primarily reported in adults. Here, we report a juvenile idiopathic HP case presenting diplopia and multiple cranial nerve palsies. Although cranial magnetic resonance imaging (MRI) shows evident lesions in cavernous sinus and preganglionic segment of trigeminal nerve, only cerebrospinal fluid (CSF) showed elevated protein (55 mg/dL) and myelin basic protein (MBP, 355 pg/mL) but negative systemic inflammatory markers. Steroid therapy greatly improved the symptom and the CSF data in 1 month.

DOI： 10.1111/ncn3.12355

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autosomal dominant amyloid precursor protein (APP) mutations in familial Alzheimer's disease accelerate the amyloid beta (Aβ) pathology. Here we describe Japanese siblings with a new N-terminal mutation (a heterogeneous c.674T>C, p.Val225Ala) of the APP gene, developing a progressive dementia at 57 years and Aβ and tau pathologies in cerebrospinal fluid studies. However, the brother and sister showed different clinical and neuroimaging features, suggesting different Aβ pathologies for each sibling.

DOI： 10.1016/j.jocn.2019.11.009

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記述言語：英語  

DOI： 10.1016/j.jns.2019.116460

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The ubiquitin-proteasome system (UPS) and autophagy are two major pathways to degrade misfolded proteins that accumulate under pathological conditions. When UPS is overloaded, the degeneration pathway may switch to autophagy to remove excessive misfolded proteins. However, it is still unclear whether and how this switch occurs during cerebral ischemia. In the present study, transient middle cerebral artery occlusion (tMCAO) resulted in accelerated ubiquitin-positive protein aggregation from 0.5 h of reperfusion in mice brain after 10, 30 or 60 min of tMCAO. In contrast, significant reduction of p62 and induction of LC3-II were observed, peaking at 24 h of reperfusion after 30 and 60 min tMCAO. Western blot analyses showed an increase of BAG3 and HDAC6 at 1 or 24 h of reperfusion that was dependent on the ischemic period. In contract, BAG1 decreased at 24 h of reperfusion after 10, 30 or 60 min of tMCAO after double immunofluorescent colocalization of ubiquitin, HSP70, p62 and BAG3. These data suggest that a switch from UPS to autophagy occurred between 10 and 30 min of cerebral ischemia depending on the BAG1/BAG3 ratio and level of HDAC6.

DOI： 10.1177/0271678X18810617

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

The authors report on a 22-year-old Japanese woman who started oral administration of 1000 mg levetiracetam (LEV) for her epilepsy after the second convulsive seizure. She was free from seizures for the subsequent 111 days, but a third tonic-clonic seizure happened and she was transferred to our hospital (Day 1). Her consciousness state was drowsy and 1000 mg LEV continued for two days, but intravenously. Although her state became clear, her serum creatine kinase (CK), myoglobin (Mb), and creatine (Cre) levels were significantly elevated (18 179 IU/L, 2783 ng/mL, and 0.8 mg/mL) with a peak at Day 5 of CK 26, 189 IU/L. After stopping intravenous injection of LEV, serum CK returned to its normal level promptly. The present case suggests that we should take more care in monitoring for rhabdomyolysis on switching from oral to intravenous administration of LEV.

DOI： 10.1111/ncn3.12336

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer's disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established. OBJECTIVE: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology. METHODS: With only 1.5μl of serum, we examined a new target plate "BLOTCHIP®" plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains. RESULTS: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains. CONCLUSION: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

DOI： 10.3233/JAD-191016

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The world is rapidly aging and facing an increase in the number of dementia patients, so it is important to detect the preclinical stage of dementia in such countries. We examined both cognitive and affective functions among cognitively normal control (n = 218), mild cognitive impairment (MCI, n = 146), and Alzheimer's disease (AD, n = 305) subjects using two evaluation tools for behavioral and psychological symptoms of dementia (BPSD) [Abe's BPSD score (ABS) and mild behavioral impairment (MBI)]. BPSD were present in 12.4% (ABS) and 9.6% (MBI) of cognitively normal people, 34.9% and 32.2% in MCI subjects, and 66.2% and 51.1% in AD patients. Both ABS (§p<0.05) and MBI (§§p < 0.01) score showed worse score with cognitive decline of the Mini-Mental State Examination in the AD group in BPSD-positive participants. Similar correlations were found in all participants in AD group (||||p < 0.01 versus ABS and MBI). Among the subscales in BPSD-positive participants, an apathy/indifference score of ABS and a decreased motivation of MBI showed significant differences in AD patients compared to the control and MCI subjects (**p<0.01). In addition, subscale analyses further showed a downward trend from the control to MCI and AD subjects in four ABS subscales and three MBI subscales. The present study showed the preclinical presence of BPSD in cognitively normal people, more so in MCI subjects, and ABS detected BPSD more sensitively than MBI in all three groups.

DOI： 10.3233/JAD-190669

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Associations of sarcopenia and physical frailty in cognitive and affective (depression, apathy, and behavioral and psychological symptoms of dementia) functions of mild cognitive impairment (MCI) and Alzheimer's disease (AD) were not fully evaluated previously, especially not for gender differences. 165 AD, 84 MCI, and 48 control participants (175 female, 122 male) were evaluated for cognitive, affective, activities of daily living (ADL), and physical functions associated with sarcopenia and physical frailty. In both sexes, cognitive and affective functions, ADL, and physical functions worsened in MCI and AD compared to control subjects. Physical dysfunctions, especially slow gait speed (3 m up and go test), were significantly associated with cognitive, affective, and ADL declines in participants (control subjects, MCI, and AD) of each gender, which were especially noticeable in females. The present study may be the first to suggest significant associations of sarcopenia and physical frailty with cognitive and affective functions of MCI and AD, especially in females.

DOI： 10.1016/j.jocn.2019.08.062

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ASEAN NEUROLOGICAL ASSOC  

A fungal carotid aneurysm is an infrequently occurring infectious aneurysm that is usually treated by antifungal therapy plus surgical debridement of the infected vessel. We herein report an extremely rare case involving a patient with a medical history of bladder cancer treated by Bacillus Calmette-Guerin (BCG) who developed a fungal aneurysm of the internal carotid artery and thrombosis of the superior ophthalmic vein caused by maxillary Aspergillus sinusitis. The patient was successfully treated by antifungal, anticoagulant, and antiplatelet drugs combined with internal carotid artery ligation therapy. Internal carotid artery fungal aneurysm is associated with a high mortality rate, but the present case suggests that it can be successfully treated by antifungal therapy combined with a less invasive endovascular therapy.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abnormal accumulation of amyloid-β (Aβ) peptide defines progression of Alzheimer's disease (AD) pathology in brain. Here, we investigated expressive changes of two main Aβ transport receptors low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE) in a novel AD mice (APP23) with chronic cerebral hypoperfusion (CCH) model, moreover, examined a protective effect of a free radical scavenger edaravone (Eda). In contrast to wild type (WT) and APP23 mice, CCH strongly accelerated abnormal Aβ40 depositions and cerebral amyloid angiopathy (CAA) pathology, increased both LRP1 and RAGE expressions in brain parenchyma, while a decrease of LRP1 and an increase of RAGE were observed in vascular endothelial cells at age 12 months (M) of AD mice. Furthermore, CCH strongly increased expressions of two hypoxia-related proteins hypoxia inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1), two oxidative-related proteins 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and decreased both two vital nutrient transporter proteins major facilitator super family domain containing 2a (Mfsd2a) and glucose transporter 1 (Glut1) expressions. Such the above abnormal pathological changes were significantly ameliorated by edaravone treatment. The present study demonstrated that CCH strongly enhanced primary AD pathology causing double imbalances of Aβ efflux and influx transport related proteins in the cortical blood vessels in AD mice, and that such a neuropathologic abnormality was greatly ameliorated by Eda.

DOI： 10.1016/j.brainres.2019.146379

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A complicated form of spastic paraplegia is a neurodegenerative disorder presenting as progressive spasticity in the bilateral lower limbs accompanied by some clinical features. The present case showed spastic paralysis and hyperreflexia in all extremities as well as lead pipe rigidity in the neck and bilateral upper extremities (R < L), decreased scores on frontal cognitive tests, a decreased accumulation of the right dorsal putamen on a DAT scan, and hypoperfusion of the bilateral frontal lobes on 99mTc-ECD single photon emission computed tomography (SPECT). The present case provides a new spectrum of spastic paraplegia based on the evidence of clinical scores and the findings of brain functional imaging.

DOI： 10.2169/internalmedicine.2765-19

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: Increased attention is being paid to Asian medicine in balanced total health care. We investigated the effects of mixed exercise including yoga ('Yoga-plus') among elderly individuals. Methods: A total of 385 subjects (72 males and 313 females, 75.5 ± 8.7 years old) participated in a 12-month (M) exercise program at a health and welfare center, a day service center, and a nursing home. Cognitive, affective, and physical functions, and activities of daily living (ADL), were compared at baseline (0M), 6M and 12M of exercise intervention. Results: Mean scores on the frontal assessment battery, clock drawing test, cube copying test, letter fluency, and category fluency significantly improved after the Yoga-plus intervention, while mini-mental state examination, Hasegawa dementia score-revised, and trail-making test performance were relatively stable. Affective scores on the geriatric depression scale (GDS), apathy scale (AS) and Abe's behavioral and psychological symptoms of dementia were not significantly affected by exercise therapy, but subgroups with higher baseline GDS (GDS ≥ 5) and AS (AS ≥ 16) scores showed a significant improvement after intervention. One-leg standing time and 3-m timed up and go test performance significantly improved after 12M intervention. Discussion: Yoga-plus improved cognitive, affective, ADL, and physical functions in a local elderly population, particularly among below-baseline individuals, indicating the benefits of dementia prevention among elderly individuals.

DOI： 10.1080/01616412.2019.1672380

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

In 1993, a mutation in the superoxyde dismutase gene, SOD1, was found causative for familial ALS, suggesting that free radical-related injury may be involved in ALS pathogenesis. Therefore, clinical trials were conducted with ALS patients using a free radical scavenger, edaravone, which was already approved for acute phase treatment of cerebral infarction in Japan. Because edaravone showed a therapeutic effect in suppressing the progression of ALS symptoms, it was approved as a new therapeutic agent in Japan, in June, 2015. In this article, we discuss the recent progress of basic and clinical research for the development of new ALS treatments.

DOI： 10.11477/mf.1416201434

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

An 83-year-old man developed acute ischemic stroke. Brain magnetic resonance imaging (MRI) showed ischemic stroke in the left parietal lobe gyri, but fluid-attenuated inversion recovery (FLAIR) showed hyperintensity in the contralateral right temporal-occipital lobe sulci. Follow-up FLAIR image showed the gradual disappearance of the sulcal hyperintensity in the sulci and changed to linear serpiginous structures. This is a unique stroke case showing transitioned FLAIR findings suggesting that the sulcal hyperintensity findings are more severe and an earlier ischemic condition than the linear serpiginous structures.

DOI： 10.1111/ncn3.12327

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder caused by mutations in the valosin-containing protein (VCP) gene. IBMPFD usually presents progressive limb muscle weakness resulting in wheelchaired after mean course of 9 years with myopathy, and Paget's osteolytic lesions and frontotemporal dementia (FTD) rarely present respiratory failure. Different from previous reports, we reported a Japanese IBMPFD patient with a VCP mutation c.290G > A (p.G97E), presenting a progressive respiratory failure accompanied by wheelchaired in only 6 years after myopathy onset, suggesting unique relationship between clinical severity and c.290G > A (p.G97E) mutation of VCP gene in Japanese.

DOI： 10.1111/ncn3.12330

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX). METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry. RESULTS: The present study revealed that the expressions of phospho-tau and phospho-α-synuclein were significantly increased in the APP23 + CCH mice group as compared with wild type and APP23 mice groups (*P < .05 and ⁎⁎P < .01 versus WT; #P < .05 and ##P < .01 versus APP23). In addition, CCH significantly exacerbated MMP-9 activation relating to blood-brain barrier destruction (⁎⁎P < .01 versus WT; #P < .05, and ##P < .01 versus APP23), enhanced neurovascular remodeling, and impaired a neurovascular trophic coupling in the vascular endothelial BDNF expression of the APP23 + CCH group. TwX treatment (20 mg/kg/day, from 4.5 to 12 months) significantly reduced tau and α-synuclein pathologies, ameliorated neurovascular dysfunction compared with APP23 + CCH group. CONCLUSIONS: Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.

DOI： 10.1016/j.jstrokecerebrovasdis.2019.104310

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Subacute myelo-optico neuropathy (SMON) patients typically suffer from sequelae that cause sleep disturbances. We sought to examine the prevalence of sleep problems among SMON patients. We conducted a questionnaire-based survey concerning sleep problems among 106 SMON patients, and 110 age- and gender-matched control participants. The prevalence of subjective insomnia (6 ≤ Athens Insomnia Scale score) was 89.6% among SMON patients, which was significantly higher than among control participants 54.4%. Sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI) revealed that the prevalence of poor sleepers (6 ≤ PSQI score) was higher among SMON patients than control participants (75.6% vs 39.6%, respectively). Subscale analyses of rapid eye movement sleep behavior disorder screening questionnaire revealed that scores on two items ("dreams match nocturnal behavior" and "limb movements") were significantly higher among SMON patients than control participants. In addition, daytime sleepiness scores were significantly higher among SMON patients than control participants (4 ≤ Epworth Sleepiness Scale scores: 54.0% vs 29.0%, respectively). The current study revealed that most SMON patients suffer from insomnia with dissatisfactory sleep quality, likely due to their long-term physical sequelae. Moreover, SMON patients showed higher rates of daytime sleepiness and sleep medication intake, which could be related to reduced activity during the day, as well as insomnia.

DOI： 10.1016/j.jocn.2019.07.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alzheimer's disease (AD) in the elderly is frequently accompanied by chronic cerebral hypoperfusion (CCH), which impairs the clearance of amyloid beta (Aβ) due to the dysfunction of the blood-brain barrier (BBB) and accelerates the AD pathology. Since the coagulation and complement cascades are associated with BBB dysfunction and AD pathology, we investigated the expression changes of coagulation (fibrinogen alpha chain-FGA, coagulation factor XIII A chain-Factor XIIIα) and complement (plasma protease C1 inhibitor-C1-INH, Complement component 3-C3) factors in the brain of novel AD model (APP23) mice with CCH at 12 months of age. Immunohistochemical and immunofluorescent analysis showed that the expressions of FGA, Factor XIIIα, C1-INH and C3 were significantly increased in cerebral neocortex, hippocampus, and thalamus of APP23 + CCH group (n = 12) as compared with wild type (WT, n = 10) and APP23 (n = 10) groups (⁎P < .05 and ⁎⁎P < .01 vs WT; #P < .05 and ##P < .01 vs APP23), especially near and inside of neurovascular unit. The present study suggests that CCH activated both the coagulation and complement cascades in a novel AD model mice brain accompanied by the acceleration of AD pathology.

DOI： 10.1016/j.neuroscience.2019.07.050

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hypoxia inducible factor-1α (HIF-1α) is a key transcription factor that maintains oxygen homeostasis. Hypoxic stress is related to the pathogenesis of amyotrophic lateral sclerosis (ALS), and impaired HIF-1α induces motor neuron degeneration in ALS. Dimethyloxalylglycine (DMOG) upregulates the stability of HIF-1α expression and shows neuroprotective effects, but has not been used in ALS as an anti-hypoxic stress treatment. In the present study, we investigated hypoxic stress in ALS model mice bearing G93A-human Cu/Zn superoxide dismutase by in vivo HIF-1α imaging, and treated the ALS mice with DMOG. In vivo HIF-1α imaging analysis showed enhanced hypoxic stress in both the spinal cord and muscles of lower limbs of ALS mice, even at the pre-symptomatic stage. HIF-1α expression decreased as the disease progressed until 126 days of age. DMOG treatment significantly ameliorated the decrease in HIF-1α expression, the degeneration of both spinal motor neurons and myofibers in lower limbs, gliosis and apoptosis in the spinal cord. This was accompanied by prolonged survival. The present study suggests that in vivo bioluminescence resonance energy transfer (BRET) HIF-1α imaging is useful for evaluating hypoxic stress in ALS, and that the enhancement of HIF-1α is a therapeutic target for ALS patients.

DOI： 10.1016/j.neuroscience.2019.06.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We found a late presented congenital myasthenic syndrome (CMS) patient with novel CHRNE gene mutations. Although our patient has shown blepharoptosis since youth, fatigable muscle weakness began at age 71. Genetic analysis revealed novel compound heterozygous CHRNE mutations (c.1032+2T>G, c.1306_1307 delGA). His myasthenic symptoms were well managed by oral anti-cholinesterase drug until he died at 82-year-old. The present case showed mild myasthenic symptoms with very late presentation and slow progression. Late presented CMS is often underdiagnosed; therefore, genetic testing is important to distinguish it from other myasthenic disease.

DOI： 10.1111/ncn3.12317

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vertebral artery (VA) dissection is one major cause of brain infarction in young and middle-aged adults. Risk factors for VA dissection are hypertension, diabetes mellitus, hyperlipidemia, trauma, and genetic factors. A 32-year-old man with familial Hirschsprung disease at the age of 2 presented cerebellar ischemic stroke due to bilateral VA dissections. A stroke recurred within 17 days despite oral dual antiplatelet therapy. Bilateral VA dissections and recurrent dissections are related to genetic mutations associated with connective tissue diseases. A part of familial Hirschsprung disease has genetic factors in common with cerebrovascular disease. There may be a common genetic background between his VA dissection and Hirschsprung disease.

DOI： 10.1016/j.jstrokecerebrovasdis.2019.04.035

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The therapeutic effect of in vivo direct reprogramming on ischemic stroke has not been evaluated. In the present study, a retroviral solution (1.5-2.0 × 107 /ul) of mock pMX-GFP (n = 13) or pMX-Ascl1/Sox2/NeuroD1 (ASN) (n = 14) was directly injected into the ipsilateral striatum and cortex 3 days after 30 min of transient cerebral ischemia. The reprogrammed cells first expressed neuronal progenitor marker Dcx 7 and 21 days after viral injection, then expressed mature neuronal marker NeuN. This was accompanied by morphological changes, including long processes and synapse-like structures, 49 days after viral injection. Meanwhile, therapeutic improvement was not detected both in clinical scores or infarct volume. The present study provides a future novel self-repair strategy for ischemic stroke with beneficial modifications of the inducer-suppressor balance.

DOI： 10.1038/s41598-019-47482-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Multiple pathogeneses are involved in Alzheimer's disease (AD), such as amyloid-β accumulation, neuroinflammation, and oxidative stress. The pathological impact of chronic cerebral hypoperfusion on Alzheimer's disease is still poorly understood. METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive chronic cerebral hypoperfusion (CCH). The effects of the administration of Twendee X (TwX) were evaluated by behavioral analysis, immunohistochemical analysis, and immunofluorescent histochemistry. RESULTS: In the present study, chronic cerebral hypoperfusion, which is commonly found in aged Alzheimer's disease, significantly exacerbated motor dysfunction of APP23 mice from 5 months and cognitive deficit from 8 months of age, as well as neuronal loss, extracellular amyloid-β plaque and intracellular oligomer formations, and amyloid angiopathy at 12 months. Severe upregulations of oxidative markers and inflammatory markers were found in the cerebral cortex, hippocampus, and thalamus at 12 months. Twendee X treatment (20 mg/kg/d, from 4.5 to 12 months) substantially rescued the cognitive deficit and reduced the above amyloid-β pathology and neuronal loss, alleviated neuroinflammation and oxidative stress. CONCLUSIONS: The present findings suggested a potential therapeutic benefit of Twendee X for Alzheimer's disease with chronic cerebral hypoperfusion.

DOI： 10.1016/j.jstrokecerebrovasdis.2019.03.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Streptococcus pneumoniae is a major cause of bacterial meningitis usually in children or elder adults. We report a case of a 38-year-old man having pneumococcal meningoencephalitis with a small spleen (35 cm(3)), compared to seven previous patients with pneumococcal meningitis in our department. Among the eight patients, four cases were due to sinusitis, but the origin could not be identified in the other four cases, including the present case who was the youngest patient with the smallest splenic size. Of interest in the present analysis was the negative or positive correlation between splenic size and age, with or without sinusitis. This is the first report on pneumococcal meningoencephalitis that takes into consideration age, splenic size, and the origin of infection.

DOI： 10.1111/ncn3.12290

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cerebral neuroinflammation defines a novel pathway for progressing Alzheimer's disease (AD) pathology. We investigated immunohistological changes of neuroinflammation with nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3), activated caspase-1 and interleukin-1 beta (IL-1β) in a novel AD (APP23) mice with chronic cerebral hypoperfusion (CCH) model from 4 months (M) of age, moreover, examined protective effect of galantamine. CCH strongly enhanced NLRP3, activated caspase-1 and IL-1β expressions in hippocampus and thalamus at age 12 M of AD mice. CCH also exaggerated amyloid-beta (Aβ) 40 depositions in cerebral cortex. Furthermore, CCH exacerbated a marked dissociation of neurovascular unit (NVU). These pathological changes were ameliorated by galantamine treatment. The present study demonstrated that CCH strongly enhanced primary AD pathology including neuroinflammation, Aβ accumulations and NVU dissociation in AD mice, which was greatly protected by an allosterically potentiating ligand galantamine.

DOI： 10.1016/j.neures.2018.06.002

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記述言語：英語  

DOI： 10.1016/j.jns.2019.03.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Oxidative stress is associated with the degeneration of both motor neurons and skeletal muscles in amyotrophic lateral sclerosis (ALS). A free radical scavenger edaravone has been proven as a therapeutic drug for ALS patients, but the neuroprotective mechanism for the oxidative stress of ALS has not been fully investigated. In this study, we investigated oxidative stress in ALS model mice bearing both oxidative stress sensor nuclear erythroid 2-related factor 2 (Nrf2) and G93A-human Cu/Zn superoxide dismutase (Nrf2/G93A) treated by edaravone. In vivo Nrf2 imaging analysis showed the accelerated oxidative stress both in spinal motor neurons and lower limb muscles of Nrf2/G93A mice according to disease progression in addition to the enhancement of serum oxidative stress marker dROMS. These were significantly alleviated by edaravone treatment accompanied by clinical improvements (rotarod test). The present study suggests that in vivo optical imaging of Nrf2 is useful for detecting oxidative stress in ALS, and edaravone alleviates the degeneration of both motor neurons and muscles related to oxidative stress in ALS patients.

DOI： 10.1002/jnr.24368

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Ischemic stroke (IS) due to giant cell arteritis (GCA) is rare, but highly mortal. Here, we report a 72-year-old man who showed frequent IS with GCA. Initial therapy with prednisolone increased the frequency of IS, which disappeared after continuous multi-modal combination therapy with corticosteroids, immunosuppressive agents, antiplatelets, and statin. The present case was discharged with independent walk, suggesting that a multi-modal combination therapy rescued the GCA patient from frequent IS.

DOI： 10.1111/ncn3.12266

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Here we present the first report of solitary primary peripheral nerve onset cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (PTCL) diagnosed after nerve biopsy. An 84-year-old female with rheumatoid arthritis (RA) complained of asymmetric severe tenderness in her upper limbs. The biopsy pathology revealed a direct invasion of CM-positive PTCL. When RA patients complain of numbness, tenderness, or weakness, lymphomatic peripheral nerve invasion should be considered.

DOI： 10.1111/ncn3.12280

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective We evaluated the clinical effects of a telephone call service for psychological symptoms such as anxiety, depression or apathy in subacute myelo-optico-neuropathy (SMON) patients living alone or with a single caregiver. Methods Up to 16 SMON patients (4 men, 12 women) and 32 control subjects were evaluated by the geriatric depression scale (GDS), apathy scale (AS) and state and trait anxiety inventory (STAI) forms X-I, including the P and A values for depression, apathy and state anxiety including disturbed peace of mind and enhanced anxiety, respectively, before (pre) and three months after (post) the telephone call service. Results The SMON patients, especially women, had significantly worse baseline scores in GDS (depression), AS (apathy) and STAI (state anxiety) than control subjects. The automated telephone call service significantly improved the high baseline STAI scores, including the P and A scores (disturbed peace of mind and enhanced anxiety), of SMON patients but not the GDS or AS scores. Conclusion SMON patients, especially women, living alone or with a single caregiver showed higher baseline depression, apathy and anxiety scores than the control subjects. The present automated telephone call service proved to be a useful care tool for improving the anxiety of SMON patients with high STAI P and A scores.

DOI： 10.2169/internalmedicine.1554-18

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Werner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in the WRN gene (WRN). Most Japanese WS patients are born from a consanguineous marriage with homozygous WRN mutations. We herein report a rare WS patient born from non-consanguineous parents with compound heterozygous WRN mutations with a novel heterogeneous c.1720+1G>A substitution plus the most frequent heterogeneous c.3139-1G>C substitution among Japanese. Although the present case showed clinical characteristics common to previous Japanese WS patients, he had not developed any malignant tumors as of 43 years of age, suggesting that WS patients with this particular genetic mutation have a different phenotype than others.

DOI： 10.2169/internalmedicine.1816-18

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Klinefelter syndrome is a chromosomal disorder with a typical karyotype of 47, XXY, accompanied by various neurological symptoms. We herein report the first case of Klinefelter syndrome with a rare mosaic form of 47, XXY and 48, XXXY, combined with both spastic paraplegia and peripheral motor neuropathy. This case showed spasticity and hyperreflexia with pathological reflexes and ankle clonus as well as muscle weakness in all extremities. A motor nerve conduction study and the magnetic motor evoked potential suggested motor axonal neuropathy and corticospinal tract disorders. The present case suggests that Klinefelter syndrome can present with both upper and lower motor neuron degeneration.

DOI： 10.2169/internalmedicine.1048-18

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

BACKGROUND: Autoantibodies against glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) cause chylomicronemia by blocking the ability of GPIHBP1 to bind lipoprotein lipase (LPL) and transport the enzyme to its site of action in the capillary lumen.OBJECTIVE: A patient with multiple sclerosis developed chylomicronemia during interferon (IFN) beta 1a therapy. The chylomicronemia resolved when the IFN beta 1a therapy was discontinued. Here, we sought to determine whether the drug-induced chylomicronemia was caused by GPIHBP1 autoantibodies.METHODS: We tested plasma samples collected during and after IFN beta 1a therapy for GPIHBP1 autoantibodies (by western blotting and with enzyme-linked immunosorbent assays). We also tested whether the patient's plasma blocked the binding of LPL to GPIHBP1 on GPIHBP1-expressing cells.RESULTS: During IFN beta 1a therapy, the plasma contained GPIHBP1 autoantibodies, and those autoantibodies blocked GPIHBP1's ability to bind LPL. Thus, the chylomicronemia was because of the GPIHBP1 autoantibody syndrome. Consistent with that diagnosis, the plasma levels of GPIHBP1 and LPL were very low. After IFN beta 1a therapy was stopped, the plasma triglyceride levels returned to normal, and GPIHBPI autoantibodies were undetectable.CONCLUSION: The appearance of GPIHBP1 autoantibodies during IFN Pla therapy caused chylomicronemia. The GPIHBP1 autoantibodies disappeared when the IFN beta 1a therapy was stopped, and the plasma triglyceride levels fell within the normal range. (C) 2018 National Lipid Association. All rights reserved.

DOI： 10.1016/j.jacl.2018.10.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Malignant lymphoma sometimes involves peripheral nerves due to paraneoplastic syndrome associated with anti-ganglioside antibodies. We report a very rare case of malignant lymphoma accompanied by an asymmetrical and isolated hypoglossal nerve palsy associated with a new subset of anti-ganglioside antibodies. Magnetic resonance imaging and 18F-2-deoxy-2-fluoro-D-glucose position emission tomography showed no abnormalities of the hypoglossal nerve nucleus; however, the patient' s serum was positive for anti-sulfated glucuronyl paragloboside IgM antibodies as well as anti-GM1 IgM and anti-GQ1b IgM antibodies. The present case might suggest a paraneoplastic asymmetrical and isolated hypoglossal nerve palsy associated with a new subset of anti-ganglioside antibodies.

DOI： 10.2169/internalmedicine.1269-18

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer's disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. Seventy-eight subjects with MCI were randomized into placebo (n = 37) and TwX (n = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI.

DOI： 10.3233/JAD-190644

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alzheimer's disease (AD) is the most common dementia and a progressive neurodegenerative disorder aggravated by chronic hypoperfusion (HP). Since numerous evidence suggests that inflammation is related with AD pathology, we investigated the expression change of two anti-inflammatory markers, inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and alpha-2-HS-glycoprotein (AHSG), in a novel AD model (APP23) with HP at 12 month of age. As compared with wild type (WT, n = 10), immunohistochemical analysis showed a higher ITIH4 and a lower AHSG expressions in the cerebral cortex, hippocampus, and thalamus of the APP23 + HP group (n = 12) than the simple APP23 (n = 10) group (*p < 0.05 and **p < 0.01 versus WT; #p < 0.05 and # #p < 0.01 versus APP23). The present study provides an upregulation of anti-inflammatory ITIH4 and a downregulation of pro-inflammatory TNFα-dependent AHSG in a novel AD plus HP mice model.

DOI： 10.3233/JAD-181218

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis.

DOI： 10.3233/JAD-190369

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掲載種別：研究論文（学術雑誌）  

© 2018 National Lipid Association Background: Autoantibodies against glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1) cause chylomicronemia by blocking the ability of GPIHBP1 to bind lipoprotein lipase (LPL) and transport the enzyme to its site of action in the capillary lumen. Objective: A patient with multiple sclerosis developed chylomicronemia during interferon (IFN) β1a therapy. The chylomicronemia resolved when the IFN β1a therapy was discontinued. Here, we sought to determine whether the drug-induced chylomicronemia was caused by GPIHBP1 autoantibodies. Methods: We tested plasma samples collected during and after IFN β1a therapy for GPIHBP1 autoantibodies (by western blotting and with enzyme-linked immunosorbent assays). We also tested whether the patient's plasma blocked the binding of LPL to GPIHBP1 on GPIHBP1-expressing cells. Results: During IFN β1a therapy, the plasma contained GPIHBP1 autoantibodies, and those autoantibodies blocked GPIHBP1's ability to bind LPL. Thus, the chylomicronemia was because of the GPIHBP1 autoantibody syndrome. Consistent with that diagnosis, the plasma levels of GPIHBP1 and LPL were very low. After IFN β1a therapy was stopped, the plasma triglyceride levels returned to normal, and GPIHBP1 autoantibodies were undetectable. Conclusion: The appearance of GPIHBP1 autoantibodies during IFN β1a therapy caused chylomicronemia. The GPIHBP1 autoantibodies disappeared when the IFN β1a therapy was stopped, and the plasma triglyceride levels fell within the normal range.

DOI： 10.1016/j.jacl.2018.10.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 46-year-old woman developed slowly progressive tongue weakness with a pseudohypertrophic change on the right side of her tongue. She subsequently developed weakness in her proximal lower extremities, skin erythema and a sustained increase of muscle enzymes at 11 M after the onset. A biopsy of the quadriceps muscle showed necrotizing myopathy and a skin biopsy showed erythema nodosum. The present case showed characteristic clinical manifestations that may represent a rare variant of sarcoidosis.

DOI： 10.4081/ni.2018.7852

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neurolymphomatosis is a rare form of extranodal malignant lymphoma defined as the infiltration of malignant lymphocytes into the central or peripheral nerve. We herein report a case of neurolymphomatosis in the cauda equina diagnosed by an open surgical biopsy. He presented with muscle weakness, atrophy, numbness and hypoesthesia in the bilateral lower extremities with the accumulation of 18fluoro-2-deoxyglucose (FDG) in the bilateral cauda equina. Cerebrospinal fluid cytology (three times) and flow cytometry (two times) and biopsies of the left sural nerve, bone marrow, paranasal sinus and left testis were all negative for malignancy, so finally we performed a surgical open biopsy of the cauda equina by laminectomy and diagnosed him with diffuse large B-cell lymphoma in the cauda equina. He was successfully treated with the disappearance of the FDG accumulation for a long time. The present case suggested that an early open biopsy of the cauda equina may be considered for cases of suspected neurolymphomatosis in the cauda equina for a good outcome.

DOI： 10.2169/internalmedicine.1049-18

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stachybotrys microspora triprenyl phenol (SMTP)-44D has both anti-oxidative and anti-inflammatory activities, but its efficacy has not been proved in relation to the pathological changes of neurovascular unit (NVU) and neurovascular trophic coupling (NVTC) in ischemic stroke. Here, the present study was designed to assess the efficacies of SMTP-44D, moreover, compared with the standard neuroprotective reagent edaravone in ischemic brains. ICR mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, SMTP-44D (10 mg/kg) or edaravone (3 mg/kg) was intravenously administrated through subclavian vein just after the reperfusion, and these mice were examined at 1, 3, and 7 d after reperfusion. Compared with the vehicle group, SMTP-44D treatment revealed obvious ameliorations in clinical scores and infarct volume, meanwhile, markedly suppressed the accumulations of 4-HNE, 8-OHdG, nitrotyrosine, RAGE, TNF-α, Iba-1, and cleaved caspase-3 after tMCAO. In addition, SMTP-44D significantly prevented the dissociation of NVU and improved the intensity of NAGO/BDNF and the number of BDNF/TrkB and BDNF/NeuN double positive cells. These effects of SMTP-44D in reducing oxidative and inflammatory stresses were similar to or stronger than those of edaravone. The present study demonstrated that SMTP-44D showed strong anti-oxidative, anti-inflammatory, and anti-apoptotic effects, moreover, the drug also significantly improved the NVU damage and NVTC in the ischemic brain.

DOI： 10.1002/jnr.24326

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Facioscapulohumeral muscular dystrophy (FSHD) 2 is caused by a combination of heterozygous structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) mutation plus DNA hypomethylation on D4Z4. Here we report two Japanese FSHD2 siblings (brother and sister) with a new SMCHD1 nonsense mutation (a heterogeneous c. 1654C > T substitution, leading to a stop codon Arg552∗). They showed the typical phenotype of FSHD2 such as asymmetric muscle weakness and atrophy in bilateral facial, scapular and humeral muscles, but different clinicopathological features between them. The brother and asymptomatic mother showed normal D4Z4 methylation plus the same SMCHD1 mutation, but the sister showed the SMCHD1 mutation plus D4Z4 hypomethylation, suggesting an interesting correlation of the new SMCHD1 nonsense mutation and D4Z4 hypomethylation.

DOI： 10.1016/j.jocn.2018.10.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both thrombolytic and anti-inflammatory effects, but its neuroprotective effects on cerebral ischemia are still unclear. The present study assessed the antioxidative and neurovascular unit (NVU) protective effects of SMTP-7 using transient middle cerebral artery occlusion (tMCAO) mice. METHODS: After 60 minutes tMCAO, 0.9% NaCl, tissue-type plasminogen activator (tPA), SMTP-7 or tPA + SMTP-7 was intravenously administrated through subclavian vein just before the reperfusion, and these mice were examined at 24 hours after reperfusion. We histologically assessed the hemorrhage and expressive changes of antioxidative markers in brains. RESULTS: SMTP-7 treatment showed a similar antithrombotic effect to tPA, but significantly decreased the hemorrhage volumes and the number of 4-HNE, 3-NT and 8-OHdG positive cells, meanwhile, ameliorated the decrease of collagen IV in the ischemic brains. However, tPA + SMTP-7 treatment did not decrease hemorrhage volumes nor showed NVU protective effect. CONCLUSIONS: The present study suggested that SMTP-7 provided therapeutic benefits for ischemic stroke through antioxidative and NVU protective effects unlike tPA alone or tPA + SMTP-7.

DOI： 10.1016/j.jstrokecerebrovasdis.2018.08.018

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The primary treatment for hydrocephalus is ventricular shunt placement, and a programmable valve is widely used for ventriculoperitoneal (VP) shunt surgery to reduce over/under drainage of cerebrospinal fluid (CSF). Here, we report a rare case of a patient who developed successive VP shunt malfunction causing spastic muscle weakness in extremities associated cervical epidural venous distension and compressive myelopathy due to over-drainage of CSF through a defective VP shunt valve a decade after the initial shunt was placed. One should be aware and cognizant of this complication and carefully follow the symptoms and potentially utilize brain MRI with and without contrast to look at over drainage stigmata to avoid the development of neurological complications.

DOI： 10.1016/j.inat.2018.08.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both potentials of thrombolytic and neuroprotective effects, but its detailed neuroprotective mechanisms in ischemic stroke are still unclear. Here, we assessed the neuroprotective effects of SMTP-7 for anti-inflammatory and antiapoptosis mechanisms after 60 minutes of transient middle cerebral artery occlusion (tMCAO) in mice. METHODS: After 60minutes of tMCAO, 0.9% NaCl, tissue-type plasminogen activator (tPA), SMTP-7 or tPA+SMTP-7 was intravenously administrated through subclavian vein just before the reperfusion, and these mice were examined at 24hours after reperfusion. We histologically assessed the antineuroinflammatory effect of SMTP-7 on the expressive changes of inflammatory markers in ischemic mouse brains. RESULTS: Compared with the vehicle and tPA groups, SMTP-7 treatment significantly improved clinical scores and decreased the infarct volume and the numbers of TNF-α, nuclear factor-κB (NF-κB), nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), and cleaved caspase-3-positive cells in the brain of mice at 24hours after tMCAO but not p62-positive cells. However, tPA+SMTP-7 treatment did not show such effects. CONCLUSIONS: The present study suggested that SMTP-7 provides a therapeutic benefit for ischemic stroke mice through anti-inflammatory and antiapoptotic effects but not antiautophagic effect.

DOI： 10.1016/j.jstrokecerebrovasdis.2018.06.039

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

The prompt and accurate diagnosis of orbital apex syndrome (OAS) is very important because of its fatality. Here we report an old man with aspergillotic OAS diagnosed after two biopsies by nasal endoscopy and craniotomy. Only craniotomy leads to the appropriate diagnosis, suggesting an immediate need of additional biopsy for the accurate diagnosis and saving the patient.

DOI： 10.1111/ncn3.12226

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記述言語：英語  

DOI： 10.1016/j.jns.2018.08.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mitochondrial dynamically undergo massive fusion and fission events to continuously maintain their function in cells. Although an impaired balance of mitochondrial fission and fusion was reported in in-vitro and in-vivo Alzheimer's disease (AD) model, changes of mitochondrial fission and fusion proteins have not been reported in AD with chronic cerebral hypoperfusion (HP) as an etiological factor related to the development of elder AD. To clarify the impacts of HP on mitochondrial fission and fusion, related oxidative stress in the pathogenesis of AD, and protective effect of galantamine, the novel AD with HP mouse model (APP23 + HP) was applied in this project. Compared with APP23 mice, APP23 + HP mice greatly enhanced the number of Aβ oligomer-positive/phosphorylated tau (pTau) cells, the expression of mitochondrial fission proteins (Drp1 and Fis1), and decreased the expression of mitochondrial fusion proteins (Opa1 and Mfn1) in the cerebral cortex (CTX) and thalamus (TH) at 12 month (M) of age. Moreover, the expression of peroxidation products (4-HNE and 8-OHdG) showed a significant increase in CTX and TH of APP23 + HP mice at 12 M. However, above neuropathological characteristics were retrieved by galantamine (Gal) treatment, detected through immunohistochemical analyses. The present study demonstrates that cerebral HP shifted the balance in mitochondrial morphology from fusion to fission with increasing Aβ oligomer/pTau accumulations in APP23 mice, and such neuropathologic processes were strongly attenuated by Gal treatment.

DOI： 10.1016/j.brainres.2018.06.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sigma-1 receptor (Sig-1R) is expressed at endoplasmic reticulum (ER) membranes, where it regulates a variety of specific physiological functions. However, the profile and exact roles of ER stress-related molecules after Sig-1R agonist treatment in an in vivo stroke model are largely unknown. The aim of this study is to investigate the effect of a novel Sig-1R agonist, aniline derivative compound (Comp-AD), on the ER stress response following ischemic stroke. Male C57BL/6J mice received transient middle cerebral artery occlusion for 90 min, and were then treated with vehicle saline or Comp-AD at reperfusion. At 3 hr, 1 day, and 7 days after reperfusion, immunohis- tochemistry was performed for Sig-1R and ER stress-related proteins including phospho protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), phospho inositol requiring enzyme 1α (p- IRE1α), and activating transcription factor 6 (ATF6). Neurobehavioral analysis showed improved functional recovery at 1 day and 7 days after reperfusion, and the infarct volume was significantly smaller at 7 days (p < .05), in the Comp-AD group compared with the vehicle group. Comp-AD treatment upregulated Sig-1R immunoreactivity at 3 hr and 1 day (p < .05), and reduced p-PERK and p-IRE1α expression at 1 day (p < .05, respectively), in the peri-ischemic region compared with the vehicle group. Treatment with the novel Sig-1R agonist Comp-AD was neuroprotective after transient middle cerebral artery occlusion, and was associated with upregulation of Sig-1R and a reduction of ER stress.

DOI： 10.1002/jnr.24270

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neurological disease patients living alone or with a single caregiver need a support system to care for their psychological symptoms. We evaluated the clinical effects of a unique telephone call system that automatically called participants at their desired times once a week for 3 months. In total, 104 neurological disease patients and caregivers were evaluated by the geriatric depression scale, apathy scale and state and trait anxiety inventories (STAI) forms X-I for depression, apathy and state anxiety, respectively. High baseline STAI scores (40≥) significantly improved in the Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and spinocerebellar degeneration (SCD) + multiple system atrophy (MSA) patients (p = 0.001, p = 0.013 and p = 0.046, respectively) after patients/caregivers used the telephone call service. The baseline (pre) STAI score significantly correlated with the score change (post-pre) in PD, ALS, SCD + MSA, Alzheimer' s disease patients (ADp), and caregivers for ADp (p < 0.0001, p = 0.001, p = 0.011, p = 0.025 and p = 0.020, respectively). The geriatric depression scale and apathy scale did not significantly improve. The present study suggests that there is a positive effect of using an automated telephone call service for anxiety in neurological disease patients and caregivers, especially in ALS, SCD + MSA and PD patients with high STAI scores (40≥).

DOI： 10.1016/j.jocn.2018.07.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Bilateral upward and ipsilateral downward gaze palsy due to a unilateral thalamomesencephalic stroke is called vertical one-and-a-half syndrome (VOHS). Here, we report a valiant VOHS case who presented contralateral upward and ipsilateral downward gaze palsy due to a unilateral thalamomesencephalic stroke. The neuronal fiber connections associated with vertical gaze are not completely understood, so the present case provides an important proof to obtain a better understanding of vertical gaze mechanisms.

DOI： 10.1111/ncn3.12210

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Vogt-Koyanagi-Harada disease (VKHD) is a systemic autoimmune disease that targets melanocyte-rich tissues such as eye, central nervous system, inner ear, and skin. Here, we report a case of VKHD accompanied by polyneuropathy. After VKHD was diagnosed, depending on the involvement of bilateral ocular, auditory, and central nervous systems, he expressed muscle weakness, pain, and numbness in bilateral lower extremities. Nerve conduction studies suggested sensorimotor polyneuropathy, while a skin, muscle, and nerve biopsy suggested vasculitis. Steroid therapy improved his symptoms. The present case might suggest a relationship between VKHD and polyneuropathy.

DOI： 10.1111/ncn3.12213

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The authors report a man who developed oral dyskinesia at 46 years of age, followed by slowly progressive choreic movement and mild cognitive impairment over 20 years. He showed caudate atrophy and four types of intracranial calcification in the hippocampus (dot-like), cerebellar white matter (vague-mass), occipital cortices (laminar), and cerebral white matter (linear). Linear-calcification in the corona radiata seems to be deposition along small veins, which may be related to the white matter changes and to the decreased regional cerebral blood flow in the frontal and parietal lobes. The present case shows a slowly progressive disease with caudate atrophy and characteristic brain calcifications.

DOI： 10.2169/internalmedicine.9454-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Japanese encephalitis (JE) survivors often present with nigrostriatal aftereffects with parkinsonian features. A 67-year-old woman with JE showed right-dominant clinical parkinsonism and left-dominant substantia nigra lesions after magnetic resonance imaging (MRI). Dopamine transporter (DAT) imaging using 123I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT) revealed a corresponding left-dominant decrease. The present case is the first to reveal a clear match of laterality between clinical parkinsonism, MRI-based substantia nigra lesions, and impaired DAT in presynaptic dopaminergic neurons in JE.

DOI： 10.2169/internalmedicine.0337-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Dietary supplement is an attempt to reduce the risk of ischemic stroke in high-risk population. A new mixed vitamin E-Tocovid that mainly contains tocotrienols other than tocopherol, attenuated the progression of white matter lesions by oral in humans. However, the effect of Tocovid on ischemic stroke has not been examined. In the present study, we assessed the therapeutic effects of Tocovid pretreatment on transient middle cerebral artery occlusion (tMCAO) in mice. MATERIALS AND METHODS: After pretreatment with Tocovid (200 mg/kg/d) or vehicle for 1 month, 60-minute tMCAO was performed, and these mice were examined at 1 day, 3 days, and 7 days after reperfusion. We histologically assessed the effects of Tocovid pretreatment on the expressive changes of oxidative stress markers, cleaved caspase-3, and LC3-II after tMCAO in mice. RESULTS: We observed that Tocovid pretreatment significantly improved the rotarod time, reduced infarct volume, decreased the number of 4-HNE, nitrotyrosine, and 8-OhdG positive cells, inhibited advanced glycation end products biomarkers RAGE, CMA, and CML expressions, and increased Nrf2 and MRP1 levels with GSSG/GSH ratio decrease. Furthermore, Tocovid pretreatment greatly decreased cleaved caspase-3 and LC3-II expressions after tMCAO. CONCLUSIONS: The present study obviously demonstrated that Tocovid pretreatment showed neuroprotective effects against oxidative stress and at least in part by antiapoptotic/autophagic cell death in ischemic mice brain.

DOI： 10.1016/j.jstrokecerebrovasdis.2018.03.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The objective of this study was to determine alteration of corticospinal tract in patients with amyotrophic lateral sclerosis (ALS) using diffusion tensor tractograhy (DTT) focusing on the cervical spinal cord (C5) and transcranial magnetic stimulation (TMS). We recruited 38 ALS, 6 spinal and bulbar muscular atrophy (SBMA), 7 spastic paraplegia (SP) patients, and 8 age-matched normal controls, and then ALS were divided into two subgroups according to their clinical type: 28 ALS-limb and 10 ALS-bulbar. DTT was performed using the diffusion tensor image (DTI) track module to reconstruct two fiber tracts via C5. The fractional anisotropy (FA) values of ALS-total and ALS-limb patients were significantly reduced compared with normal controls, and SBMA patients. On the other hand, the mean diffusivity (MD) values were not significantly different among normal controls and the three disease groups. The rate of disease progression (ΔFRS-R) of ALS patients was significantly correlated with FA values and central motor conduction time (CMCT). In conclusion, the present study demonstrated a significant reduction of FA values in ALS patients, and the ΔFRS-R of ALS patients showed distinct regressions with FA values and CMCT, suggesting that this DTT analysis could be useful for detecting disease progression of ALS patients.

DOI： 10.1016/j.neures.2017.11.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Tocovid is a new combination of tocotrienols and tocopherol, both of which are neuroprotective agents for preventing cerebral infarction in mice. However, the effects of tocovid on anti-inflammation in ischemic model remain elusive. In the present study, we assessed the effects of Tocovid pretreatment on anti-inflammatory effects after transient middle cerebral occlusion (tMCAO) in mice. MATERIALS AND METHODS: We evaluated the therapeutic and anti-inflammatory effects of tocovid pretreatment (200 mg/kg per day, for 1 month) on mice brain under 60 minutes of tMCAO. The expressive changes of inflammatory markers were observed after tMCAO in mice. RESULTS: Tocovid pretreatment greatly improved the mice neurobehaviors, reduced infarct volumes and decreased expressions of inflammatory markers such as tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1) and ionized calcium binding adapter molecule-1 (Iba-1), and improved the damage of neurovascular units including matrix metallopeptidase 9, IgG and collagen IV after tMCAO. CONCLUSIONS: Our present findings demonstrated that oral tocovid pretreatment showed obviously neuroprotective and at least in part by anti-inflammatory effects in ischemic mice brain.

DOI： 10.1016/j.jstrokecerebrovasdis.2018.03.014

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記述言語：英語  

DOI： 10.1016/j.jns.2018.04.003

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記述言語：英語  

DOI： 10.1016/j.jns.2018.04.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We report a case of a 77-year-old Japanese man with a fever of up to 39.0 degrees C, which subsided after 5 days. The patient showed fulminant Guillain-Barre syndrome (GBS), severe autonomic dysfunction with a labile blood pressure, an unstable heart rate from onset to death, and Takotsubo cardiomyopathy. Although Takotsubo cardiomyopathy was ameliorated by Day 14 (from admission in the hospital) with a normalized electrocardiogram, his blood pressure became markedly more variable and he died on Day 26. In the present report, we describe an autopsied case of GBS with Takotsubo cardiomyopathy.

DOI： 10.1111/ncn3.12197

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: Despite a rapidly increasing prevalence of dementia, social support systems for dementia patients and their caregivers are insufficient.Aim: To investigate a telephone support system for dementia patients and their caregivers managed by a local public association, the Okayama Dementia Call Center (ODCC).Methods: A total of 1485 phone calls were retrospectively surveyed over 4 years (from June 2011 to May 2014) and were divided into four annual periods.Results: The average consulting time of each of the 1485 phone calls was 20.2 14.7 min. The chief complaint was distress related to dementia symptoms (56.2%), mainly from the children (66.7%) and spouses (17.5%) of dementia patients. With respect to management of ODCC for these clients, the proportion of providing advice has decreased (66.1 to 47.7%) as that of listening time increased (22.7 to 46.1%).Conclusion: The present unique telephone call system (ODCC) may supplement an insufficient social support, and may play an important role in the community care system, enabling people with dementia to live comfortably in their local community.

DOI： 10.1111/ncn3.12200

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Rates of disease progression differ among patients with Alzheimer's disease (AD), but prognostic predictions remain a challenge. We carried out a clinic-based retrospective study to investigate the clinical factors for AD progression. METHODS: The 748 AD patients, who attended our hospital for >1 year and were given the Mini-Mental State Examination (MMSE) at least three times, were divided into three groups according to the annual change rate of MMSE score (G): Aggravater group (G < -2), Stabler group (-2 ≤ G ≤ 2) and Improver group (2 < G). We compared the three groups on cognitive, affective and activities of daily living functions, response to medication, clinical fluctuations, serum levels of metabolic factors, and neuroimaging data. RESULTS: We found no significant differences in age, sex, educational attainment or body mass index across the groups. The Aggravater group showed better baseline MMSE (P < 0.01) and Abe's behavioral and psychological symptoms of dementia (P < 0.01) scores than the Improver group, but its MMSE improvement after drug treatment was the worst among the three groups (P < 0.01 vs Stabler/Improver). Fluctuations in MMSE (P < 0.01), apathy scale (P < 0.05) and activities of daily living (P < 0.01) scores were smaller in the Improver group than in the Aggravater or Stabler groups. Serum docosahexaenoic acid levels tended to be lower (trend P < 0.05) and voxel-based specific regional analysis system for Alzheimer's disease Z-scores tended to be higher (trend P < 0.05) in the Improver group than in the Stabler or Aggravater groups. CONCLUSIONS: Initial responses to medication, fluctuations in cognitive, affective and activities of daily living functions, serum docosahexaenoic acid levels, and medial temporal atrophy are clinical factors related to AD prognosis. Geriatr Gerontol Int 2018; 18: 929-936.

DOI： 10.1111/ggi.13286

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記述言語：英語  

DOI： 10.1016/j.jns.2018.02.040

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 37-year-old man with anti-muscle-specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) presented with subacute progressive dysphagia and muscle weakness of the neck and bilateral upper extremities. Conventional immune-suppressive treatments and high-dose intravenous immunoglobulin were ineffective. He then displayed repeated exacerbations and remissions over the course of two years, despite two to four sessions of plasma exchange (PE) every two months. The patient was successfully treated with outpatient periodic weekly blood purification therapy with alternative PE and double-filtration plasmapheresis using an internal shunt. This case report suggests the benefits of blood purification therapy with an internal shunt against anti-MuSK antibody-positive MG.

DOI： 10.2169/internalmedicine.9466-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Internal carotid artery (ICA) dissection is a major cause of cerebral infarction in young adult and usually presents cervical pain and headache, but rarely presents cranial nerve palsy. Here, we report a case of rare bilateral ICA dissections in young adult with cranial nerve IX and X palsies as initial symptom. He presented dysarthria and nasal voice at an early stage, followed by a small brain infarction. The cranial nerve palsy was improved in parallel with the improvement of ICA stenosis and dilatation. It is important to know that cranial nerve palsy can be one of the symptoms of ICA dissection for appropriate treatment.

DOI： 10.1111/ncn3.12187

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Acromegaly patients usually show impaired vision, the enlargement of hands and feet, heart failure, and diabetes and rarely show myopathy (weakness and muscle pain) and arthropathy (joint pain). Here, we report an acromegaly patient who showed progressive myopathy and arthropathy long after a Hardy operation. The symptoms of myopathy and arthropathy occurred under normal GH and high IGF-1 levels, but these symptoms improved when the IGF-1 level was normalized by a treatment of octreotide with an increased dose of 30-40 mg. Thus, strict and immediate control of IGH-1 may be pivotally important to prevent and treat acromegalic myopathy and arthropathy.

DOI： 10.1111/ncn3.12191

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記述言語：英語  

DOI： 10.1016/j.jns.2018.01.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & OBJECTIVE: Parietal ataxia has been mainly reported as a consequence of acute ischemic stroke, while degenerative parietal ataxia has not been reported. METHODS: We investigated clinical characteristics, neuroimaging data, and genetic analysis of patients with cerebellar ataxia plus parietal atrophy. RESULTS: We identified seven patients, including five patients from two families, with chronic progressive cerebellar ataxia due to degenerative parietal atrophy but not stroke. Age at onset of ataxia was 57.6 ± 6.9 years. All patients showed chronic progressive cerebellar ataxia with severity of ataxic gait > limb ataxia > dysarthria. Patients showed no cognitive dysfunction, muscle weakness, or parkinsonism, and only two patients showed mild sensory disturbances. The seven patients showed lateralized limb ataxia with greater contralateral parietal lobe atrophy by magnetic resonance imaging, and hypoperfusion by single photon emission computed tomography, without any abnormal cerebellar pathology (i.e., crossed cerebellar diaschisis). Pathogenic mutations in the microtubule-associated protein tau gene were not found using two single nucleotide polymorphisms. CONCLUSIONS: This is the first description showing unique clinical features of familial and sporadic chronic progressive degenerative parietal ataxia.

DOI： 10.1016/j.jns.2018.01.031

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/STROKEAHA.117.019216

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

A 70-year-old women presented classical CEFOM1 phenotypes such as bilateral ptosis and external ophthalmoplegia, but also progressive cerebellar ataxia, carrying a previously reported heterozygous missense mutation of KIF21A p.Arg941Gln. The present case is the first report of CFEOM1 showing cerebellar atrophy with hypoperfusion, mainly of the vermis, indicating that cerebellar function should be carefully evaluated in CFFOM1 patients.

DOI： 10.1111/ncn3.12178

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This prospective study investigated the superiority of transarterial chemoembolization (TACE) with miriplatin over TACE with epirubicin regarding overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). METHODS: Patients with unresectable HCC were randomized 1:1 to receive TACE with miriplatin or epirubicin in lipiodol. The primary endpoint was OS; secondary endpoints were percentages of patients who achieved treatment effect (TE) 4 (100% necrotizing effect or tumor reduction), duration of time to TACE failure, and adverse events (AEs). OS was compared using a stratified log-rank test adjusted for clinical stage, Child-Pugh class, and institution. RESULTS: Of 257 patients enrolled from August 2008 to August 2010, 247 were analyzed for efficacy and toxicity (miriplatin, n = 124; epirubicin, n = 123). Baseline characteristics were well balanced between the two groups. Median OS times were 1111 days for miriplatin and 1127 days for epirubicin (adjusted hazard ratio 1.01, 95% confidence interval 0.73-1.40, P = 0.946). TE4 rates were 44.4% for miriplatin and 37.4% for epirubicin. Median times to TACE failure were 365.5 days for miriplatin and 414.0 days for epirubicin. AEs of grade 3 or higher, including elevated aspartate aminotransferase (miriplatin, 39.5%; epirubicin, 57.7%) and elevated alanine aminotransferase (miriplatin, 31.5%; epirubicin, 53.7%), were less frequent in the miriplatin than the epirubicin group. CONCLUSIONS: OS after TACE with miriplatin was not superior to that after TACE with epirubicin; however, hepatic AEs were less frequent with miriplatin. CLINICAL TRIAL REGISTRATION: JapicCTI-080632.

DOI： 10.1007/s00535-017-1374-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND PURPOSE: Cognitive and cerebrovascular diseases are common in the elderly, but differences in the plasma levels and associations of plasma biomarkers in these diseases remain elusive. METHODS: The present study investigated differences in plasma fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], adiponectin, reptin, plasma markers of inflammation [high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (serum AA)], and plasma lipids [high-density lipoprotein and low-density lipoprotein (LDL)] in patients with Alzheimer's disease (AD) (n=266), mild cognitive impairment (MCI) (n=44), vascular dementia (VaD) (n=33), and ischemic stroke (IS) (n=200) in comparison to normal controls (n=130). RESULTS: The serological data showed that lower EPA and DHA levels and higher reptin and LDL levels were associated with AD and IS, the reptin/adiponectin ratio was strongly associated with IS, the hsCRP level was more strongly associated with VaD and IS, and the serum AA level was associated with all three cognitive diseases and IS. CONCLUSIONS: This is the first report of differences in the expression levels of plasma biomarkers and peripheral arterial tonometry among AD, MCI, VaD, and IS patients and normal controls. These different associations indicate that diverse pathological mechanisms underlie these diseases.

DOI： 10.3988/jcn.2018.14.1.29

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

A pituitary abscess is a rare intracranial infection, and direct transsphenoidal surgery is common for the therapy. Intracranial rupture of the pituitary abscess is usually fatal. Here, we report a 76-year-old woman with a pituitary abscess who showed headaches, left eyelid ptosis, periorbital swelling and external eye movement disturbances in the left eye. Although her symptoms initially improved after therapy with systemic antibiotics, the pituitary abscess suddenly developed an intraventricular rupture on admission day 27. However, emergency ventricular drainage in combination with different antibiotics gradually improved her condition. The present case suggests that the combination of emergency ventricular drainage and systemic antibiotic administration could serve as an alternative choice to manage pituitary abscesses of ventricular ruptures, especially in elderly patients.

DOI： 10.1111/ncn3.12167

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We herein report the case of a 46-year-old pregnant woman with anti-muscle specific kinase (MuSK) antibody-positive myasthenia gravis (MG) who showed pregnancy-induced hypertension and developed respiratory failure at 30 weeks and 5 days of pregnancy, and who underwent an emergency caesarean section (CS). Her MG symptoms gradually improved in the subsequent weeks. The premature baby with positive MuSK antibodies was successfully delivered, but the male baby required temporary artificial ventilation. However, his condition also gradually improved over time. The present case suggests that an emergency CS could rescue both the mother, who was in critical condition, and the prematurely born baby, even when suffering from acute respiratory insufficiency.

DOI： 10.2169/internalmedicine.8636-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) is an endemic disease observed in the Kii peninsula, Guam, and Papua. We report a case of a 76-year old man with ALS/PDC of the Kii peninsula of Japan (Kii ALS/PDC). The patient was born and grew up in the Kii peninsula. He moved out at age three, and developed symptoms 73years later. He showed pyramidal sign, parkinsonian symptoms, and mildly impaired cognitive function. 131I-metaiodobenzylguanidine myocardial scintigraphy showed decreased cardiac sympathetic nerve function, and dopamine transporter single photon emission computed tomography imaging showed decreased 123I-N-ω-fluoropropyl-2β-carbomethoxy3β-(4-iodophenyl) nortropane accumulation. Cerebral blood flow showed hypoperfusion. Positron emission tomography showed widespread tau deposition in his brain. This is a migration case of Kii ALS/PDC with the shortest stay in the endemic area and the longest delay to develop the disease, indicating a genetic factor for the disease development in a considerable degree.

DOI： 10.1016/j.jocn.2017.08.057

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To evaluate the therapeutic effects of switching from one acetylcholinesterase inhibitor (ChEI), donepezil, galantamine or rivastigmine, to another in Alzheimer's disease patients. METHODS: We retrospectively enrolled 171 Alzheimer's disease patients, whose ChEI medication was changed. The patients were evaluated on three major aspects of dementia - cognitive, affective and activities of daily living (ADL) measures - at 6 months (M) before the drug switch, at the time of drug switch (baseline), and at 3 M and 6 M after the drug switch. RESULTS: The doses of the three ChEI were significantly lower at 6 M after the switch compared with the pre-switch doses. Improvements in apathy were found at 3 M when switching from donepezil to galantamine, but not to rivastigmine, but this switch had adverse effects on ADL. Improvements in cognitive scores at 3 M were also found when switching from galantamine to rivastigmine, but not to donepezil. However, both of these changes improved Abe's Behavioral and Psychological Symptoms of Dementia scores (ABS), except ADL. Switching from rivastigmine to donepezil worsened ABS at 6 M, but preserved cognitive and ADL scores. CONCLUSIONS: The present study suggests that despite a relatively lower dose of ChEI after the switch, switching from donepezil or rivastigmine preserved cognitive functions for at least 6 M. Switching from galantamine to rivastigmine improved Mini-Mental State Examination and ABS at 3 M, but did not improve ADL scores. Geriatr Gerontol Int 2017; 17: 1843-1848.

DOI： 10.1111/ggi.12971

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To examine the clinical effect of four antidementia drugs (donepezil, galantamine, rivastigmine and memantine) in Alzheimer's disease patients who were divided into subgroups based on their periventricular hyperintensity (PVH) severity. METHODS: A total of 551 Alzheimer's disease patients (201 men and 350 women) were divided into four subgroups based on their PVH severity (0-III). They received monotherapy for 12 months. We compared the clinical effects at the baseline, and at 3, 6 and 12 months after initiation. RESULTS: The baseline age became higher with PVH grades, and the Mini-Mental State Examination and Hasegawa Dementia Scale-Revised showed a decrease that was dependent on white matter severity. Although the PVH 0 subgroup showed stable cognitive, affective and ADL functions until 12 months in all four drug groups, the PVH I subgroup showed an improved Apathy Scale from the baseline in response to memantine at 3 and 9 months (P < 0.05), and galantamine at 9 months (P < 0.01). In the PVH II subgroup, the Mini-Mental State Examination showed a significant improvement from the baseline in response to galantamine (P < 0.05) at 9 months and Hasegawa Dementia Scale-Revised (P < 0.05) at 3 months. In the PVH III subgroup, cognitive and affective functions were preserved in all four drug groups until 12 months, but activities of daily living deteriorated in the riverstigmine group at 6 and 12 months (P < 0.05). CONCLUSIONS: The present study shows that these four drugs showed sensitivity dependent on white matter severity that clinically affected cognitive, affective and activities of daily living functions. Geriatr Gerontol Int 2017; 17: 1991-1999.

DOI： 10.1111/ggi.13007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

We report mother-daughter cases of type 2 Alexander disease with a novel glial fibrillary acidic protein gene mutation. The mother (proband) began to show slowly progressive gait disturbance. However, after an incidental medical checkup, it took just 9 months for the diagnosis. Different from the previous reports, she showed a unique phenotype in points of scoliosis without palatal myoclonus, decreased regional cerebral blood flow in the frontal lobe and mild cognitive impairment. Her second daughter showed mild intellectual disability. Genetic analysis of the mother and the second daughter showed the same novel glial fibrillary acidic protein gene mutation (c.371_372insAGA).

DOI： 10.1111/ncn3.12146

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Unlike in Western countries, only a few familial multiple sclerosis cases have been reported from Asian countries. Herein, we report on the characteristics of siblings with multiple sclerosis. Their parents were consanguineous, and the siblings showed different first symptoms of gait disturbance or double vision, with a clinical phenotype of primary progressive multiple sclerosis or relapse-remitting multiple sclerosis. Their human leukocyte antigen showed unique subtypes of DPB1 (0501/0901 or 0901/0901) and DRB1 (0406/1502 or 1502/1502).

DOI： 10.1111/ncn3.12145

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

As the number of elderly people increases, Alzheimer's disease and hypertension have become more common. This is an important case report that shows severe hyponatremia induced by a combination of angiotensin II receptor blocker and thiazide, causing the deterioration of cognitive functions in an elderly patient. In rapidly aging societies around the world, more attention should be paid to hyponatremia under combination therapy of angiotensin II receptor blocker plus thiazide to assist elderly patients.

DOI： 10.1111/ncn3.12161

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Evaluating the cognitive and behavioral features in amyotrophic lateral sclerosis (ALS) patients is important for therapy and care. Fifty-seven ALS, 5 ALS with the behavioral variant of frontotemporal dementia (FTD) (ALS-FTD), 12 FTD patients, and 35 control subjects were evaluated by 10 different tests for cognitive and behavioral (mini-mental state examination (MMSE), Hasegawa dementia rating scale - revised (HDS-R), frontal assessment battery (FAB), Montreal cognitive assessment (MoCA), ALS-frontotemporal dementia-Questionnaire (ALS-FTD-Q), and anosognosia scale), affective (depression, apathy, and behavioral and psychological symptoms of dementia (BPSD)), and activities of daily living (ADL) assessments. The motor functions of ALS patients were evaluated by ALS functional rating scale - revised (ALSFRS-R) and modified Norris scale. ALS-FTD-Q scores showed intermediate behavioral disturbances of ALS patients between ALS-FTD and FTD patients and control subjects, but FAB, MoCA, and anosognosia scales did not. Both FAB and MoCA scores were significantly correlated with MMSE and HDS-R in ALS patients, but ALS-FTD-Q was not. ALS-FTD-Q score was significantly correlated with ALSFRS-R, apathy, BPSD, and ADL scores in ALS patients. Thus, in ALS patients, both FAB and MoCA tests were useful to assess frontal cognitive impairments, while ALS-FTD-Q was useful to detect mild behavioral and affective disturbances.

DOI： 10.1016/j.jns.2017.08.024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in cellular defense against oxidative stress damage after ischemic stroke. In the present study, we examined the time-dependent change of in vivo optical imaging of oxidative stress after stroke with Keap1-dependent oxidative stress detector (OKD) mice. OKD mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 45 min, and in vivo optical signals were detected during the pre-operative period, 12 h, 1 d, 3 d, and 7 d after tMCAO. Ex vivo imaging was performed immediately after obtaining in vivo optical signals at 1 d after tMCAO. Immunohistochemical analyses and infarct volume were also examined after in vivo imaging at each period. The in vivo signals showed a peak at 1 d after tMCAO that was slightly correlated to infarct volume. The strong ex vivo signals, which were detected in the peri-ischemic area, corresponded to endogenous Nrf2 expression. Moreover, endogenous Nrf2 expression was detected mainly in neurons followed by oligodendrocytes and pericytes, but only slightly in astrocytes, microglia, endothelial cells. The present study successfully demonstrated the temporal change of in vivo imaging of oxidative stress after tMCAO, which is consistent with strong expression of endogenous Nrf2 in the peri-ischemic area with a similar time course. © 2017 Wiley Periodicals, Inc.

DOI： 10.1002/jnr.24047

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The coexistence of Alzheimer's disease (AD) and cerebrovascular disease pathology increases age-dependently. We comprehensively analyzed the clinical effects of galantamine or cilostazol monotherapy to the add-on combination therapy on three major factors of dementia, such as cognitive, affective and activities of daily living functions in AD patients with asymptomatic lacunar infarction. METHODS: We divided 101 AD patients with asymptomatic lacunar infarction into two subgroups: group A (n = 61, first treated with galantamine and then cilostazol added) and group B (n = 40, first treated with cilostazol and galantamine added). We compared the clinical effects before and after combination therapy of galantamine and cilostazol (i.e. 3 months [M] before (-3 M), baseline (0 M), 3 and 6 M after the add-on combination). RESULTS: Galantamine monotherapy increased cognitive Hasegawa dementia score-revised scores, which were further improved with add-on cilostazol. Cilostazol monotherapy also increased the cognitive tests, which were further improved with add-on galantamine. Add-on cilostazol significantly improved Geriatric Depression Scale and Abe's behavioral and psychological symptoms of dementia scores after galantamine monotherapy. Cilostazol monotherapy also significantly improved Geriatric Depression Scale scores, with further improvements in Geriatric Depression Scale, apathy scores and Abe's behavioral and psychological symptoms of dementia scores by add-on galantamine. Activities of daily living scores continuously improved with galantamine monotherapy and add-on cilostazol. CONCLUSIONS: The present study provides a clinical possibility that galantamine or cilostazol monotherapy and the combination therapy maintained or even improved cognitive, affective, and activities of daily living functions in AD with asymptomatic lacunar infarction. Geriatr Gerontol Int 2017; 17: 1384-1391.

DOI： 10.1111/ggi.12870

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spinocerebellar ataxia type 36 is a late-onset, slowly progressive cerebellar syndrome with motor neuron degeneration that is caused by expansions of a hexanucleotide repeat (GGCCTG) in the noncoding region of NOP56 gene, with a histopathological feature of RNA foci formation in postmortem tissues. Here, we report a cellular model using the spinocerebellar ataxia type 36 patient induced pluripotent stem cells (iPSCs). We generated iPSCs from spinocerebellar ataxia type 36 patients and differentiated them into neurons. The number of RNA-foci-positive cells was increased in patient iPSCs and iPSC-derived neurons. Treatment of the 2'-O, 4'-C-ethylene-bridged nucleic acid antisense oligonucleotides (ASOs) targeting NOP56 pre-mRNA reduced RNA-foci-positive cells to ∼50% in patient iPSCs and iPSC-derived neurons. NOP56 mRNA expression levels were lower in patient iPSCs and iPSC-derived neurons than in healthy control neurons. One of the ASOs reduced the number of RNA-foci-positive cells without altering NOP56 mRNA expression levels in patient iPSCs and iPSC-derived neurons. These data show that iPSCs from spinocerebellar ataxia type 36 patients can be useful for evaluating the effects of ASOs toward GGCCTG repeat expansion in spinocerebellar ataxia type 36.

DOI： 10.1016/j.omtn.2017.06.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder that mainly involves in the brainstem, basal ganglia and cerebellum. We herein report the case of a patient with CLIPPERS, which was diagnosed based on the clinical and radiological features. After initially responded to steroid treatment, the patient developed limbic encephalitis. The patient presented with memory disturbance, a delirious state and emotional incontinence. A cerebrospinal fluid study revealed interleukin-6 elevation and enhanced bilateral hippocampal lesions were observed on MRI. The patient was successfully treated with methylprednisolone pulse therapy. This is the first case of CLIPPERS with limbic encephalitis involving the bilateral hippocampus.

DOI： 10.2169/internalmedicine.8533-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The diagnosis of aortic dissection (AD) is sometimes difficult within the limited time window of recombinant tissue plasminogen activator (tPA) for ischemic stroke (IS). A 60-year-old man developed sudden left hemiparesis due to IS. During tPA infusion, his blood pressure dropped and consciousness declined. After transfer to our hospital, carotid duplex ultrasonography led to a diagnosis of AD. Emergency surgery was postponed because of the risk of hemorrhagic transformation. The patient successfully underwent aortic surgery on day 5 and was discharged with a remarkable improvement in his symptoms. Delayed surgery may avoid hemorrhagic transformation in patients with AD-induced IS who have received tPA.

DOI： 10.2169/internalmedicine.8438-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.

DOI： 10.1002/jnr.24013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nuclear pore complexes (NPCs) play an important role in coordinating the transport of proteins and nucleic acids between the nucleus and cytoplasm, and are therefore essential for maintaining normal cellular function and liability. In the present study, we investigated the temporal immunohistochemical distribution of five representative components of NPCs-Ran GTPase-activating protein 1 (RanGap1), glycoprotein-210 (Gp210), nucleoporin 205 (Nup205), nucleoporin 107 (Nup107), and nucleoporin 50 (Nup50)-after 90 min of transient middle cerebral artery occlusion (tMCAO) up to 28 days after the reperfusion in rat brains. Single immunohistochemical analyses showed ring-like stainings along the periphery of the nucleus in sham control brains. After tMCAO, Gp210 and Nup107 immunoreactivity continuously increased from 1 day, and RanGap1, Nup205, and Nup50 increased from 2 days until 28 days, which also displayed progressive precipitations within the nucleus in the peri-ischemic area, while the ischemic core showed scarce expression with collapsed structure. Double immunofluorescent analyses revealed nuclear retention and apparent colocalization of RanGap1 with Nup205, Gp210 with Nup205, and partial colocalization of Nup205 with Nup107; most of the ischemic changes above were similar to those observed in patients with C9orf72-genetic amyotrophic lateral sclerosis. Taken together, these observations suggest that the mislocalization of these nucleoporins may be a common pathogenesis of both ischemic and neurodegenerative disease. © 2016 Wiley Periodicals, Inc.

DOI： 10.1002/jnr.24005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Progressive myelopathy is caused by infectious, inflammatory, autoimmune, paraneoplastic, demyelinating, vascular, hereditary, degenerative, metabolic and toxic properties. Here, we report a case of a 53-year-old woman who showed a progressive cervical and thoracic myelopathy with muscle weakness in all limbs, and hypoesthesia in all limbs and trunk below the Th8 level without any evident magnetic resonance imaging lesions. She displayed rheumatoid factor, anti-double stranded DNA antibody and hepatitis B surface antigen, as well as an elevated cerebrospinal fluid protein level. The paraneoplastic antibodies that we examined were negative. Our treatments (plasma exchange, steroid pulse therapy and immunoglobulin therapy) were slightly effective, but the symptoms did not improve completely. The present case suggests that the presence of a cervical and thoracic lesion without evident magnetic resonance imaging abnormalities required a careful follow up to discover occult lesions.

DOI： 10.1111/ncn3.12136

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Patients with progressive supranuclear palsy often suffer from dysphagia, and percutaneous endoscopic gastrostomy is a treatment option for the advanced stage of this disease. The present percutaneous endoscopic gastrostomy patient had slightly impaired glucose tolerance, but the condition became considerably worse with normal nutrients due to limited activity and an infection after percutaneous endoscopic gastrostomy, resulting in a non-ketotic hyperosmolar coma. After receiving supplementary fluid, intravenous insulin, antibiotics and endotracheal intubation, the patient recovered from the non-ketotic hyperosmolar coma state. Percutaneous endoscopic gastrostomy placement at an advanced stage of a neurodegenerative disorder, such as progressive supranuclear palsy, should have a careful follow-up, especially when glucose tolerance worsens.

DOI： 10.1111/ncn3.12139

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Dementia and parkinsonism are rarely observed in dural arteriovenous fistula. Here, we report a case of a 63-year-old man with recurrent dural arteriovenous fistula, who developed progressive dementia and parkinsonism as a result of a dural arteriovenous fistula at the torcular herophili. A sinus thrombosis induced the abnormal cortical venous reflux from the isolated straight sinus, resulting in the deep venous congestion of the thalamus and basal ganglia, which led to dementia and parkinsonism. However, the third endovascular embolization ameliorated memory disturbance and apathy with a slight improvement of parkinsonism. Although recoveries from dural arteriovenous fistula-associated neurological deficits are variable depending on the severity, duration and, furthermore, selective vulnerability of the responsible ischemic lesions, early treatment should be essential for better recovery.

DOI： 10.1111/ncn3.12138

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

A 72-year-old woman developed a subacute series of encephalitis, cerebellar ataxia, and combined symptoms of both myasthenia gravis and Lambert-Eaton myasthenic syndrome. Seven different neuronal antibodies were detected for Hu, glutamic acid decarboxylase, acetylcholine receptor, P/Q-type voltage-gated calcium-channels, Zic4, Titin and SOX1 in her serum with intrathecal synthesis of glutamic acid decarboxylase antibodies. Although she showed classical manifestations with onconeural antibodies, she was diagnosed with not paraneoplastic but autoimmune neurological syndrome because of no underlying tumor and good response to immunotherapies. The present case is very unique and rare for complex neurological disorders including myasthenia gravis and Lambert-Eaton myasthenic syndrome overlap syndrome with multiple neuronal antibodies.

DOI： 10.1111/ncn3.12134

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Oxidative stress and inflammation are important aggravating factors in acute ischemic stroke. METHODS: In the present study, the neuroprotective effects of a novel antioxidant mixture Twendee X containing multiple antioxidative ingredients, such as coenzyme Q10, ascorbic acid, and cystine, were evaluated. After the pretreatment of a vehicle or Twendee X (20 mg/kg/d) for 14 days, mice were subjected to transient middle cerebral artery occlusion for 60 minutes and further treated with vehicle or Twendee X for 1 or 5 days. RESULTS: Twendee X administration reduced the infarct size, and reduced oxidative stress markers such as 8-hydroxy-2'-deoxyguanosine, 4-hydroxy-2-nonenal, and Nε-(carboxymethyl) lysine (one of advanced glycation end products), as well as inflammatory markers such as ionized calcium binding adapter molecule-1, tumor necrosis factor-α, and monocyte chemotactic protein-1. CONCLUSIONS: In the present study, the neuroprotective effects of Twendee X were shown on transient middle cerebral artery occlusion mice via antioxidative and anti-inflammatory pathways, providing a potential of Twendee X as one preventive and therapeutic treatment.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.01.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Among several types of ischemic stroke (IS), branch atheromatous disease (BAD) is known to be the leading cause of disability. METHODS: A total of 1919 patients with acute IS were retrospectively analyzed, and BAD patients were classified into anterior or posterior BAD, depending on the responsible vascular territories. These patients were further subcategorized with or without early neurologic deterioration (END or no-END). RESULTS: Of all IS patients, 14.3% had BAD, and 202 patients (73.7%) were further classified as anterior BAD and 72 patients (26.3%) as posterior BAD. The prevalence of diabetes mellitus and END was significantly higher in posterior than in anterior BAD (44.4% vs 26.4%, P < .01; 18.1% vs 5.4%, P < .01, respectively). Posterior BAD showed a higher proportion of female patients and an older age (69.2% vs 39.0%, P < .05; 79.1 ± 7.7 vs 70.5 ± 10.7, P < .01, respectively) in END than in no-END. The modified Rankin Scale was worse in posterior BAD at 90 days (2.5 ± 1.6, P < .01) than in anterior BAD (1.6 ± 1.4). CONCLUSIONS: Our present study shows that posterior BAD is a worse clinical outcome than anterior BAD, with more vascular risk factors. Older female patients with posterior BAD showed a higher risk of END, leading to a worse clinical outcome.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.02.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients. Compared with wild type (WT), these proteins displayed age-dependent and progressive nuclear precipitations, and cytoplasmic aberrant expressions in motor neurons of lumbar cord in SOD1-Tg mice from 10 to 18weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPl with NUP205 and NUP205 with NUPl07, meanwhile, GP210 with NUP205 mainly co-localized in the nuclear envelope (NE) of motor neurons. Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons. The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention.

DOI： 10.1016/j.neuroscience.2017.03.024

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

Background and purpose: Few studies have examined why some patients with dementia stop attending medical consultations. We conducted a retrospective study to investigate factors associated with discontinuous clinic attendance. Methods: Participants were 988 patients with dementia from university hospital (UH) clinics and affiliated local hospital (LH) clinics. We compared continuous and discontinuous attenders on cognitive and affective functions and activities of daily living (ADL), and also compared UH and LH patients (UH: continuous, n = 176
discontinuous, n = 207
LH: continuous, n = 418
discontinuous, n = 187). Results: The total annual rate of discontinuation was 8.0%, and the mean period of attendance before discontinuation was 2.2 ± 2.4 years (UH, 2.8 ± 3.0
LH, 1.5 ± 1.3, P &lt
0.01). Scores for the Mini-Mental State Examination, Hasegawa Dementia Scale – Revised, Geriatric Depression Scale, apathy scale, Abe's behavioral and psychological symptoms of dementia (BPSD) score, and ADL were significantly worse in the discontinuous group than the continuous group for both UH and LH patients (P &lt
0.01). The best predictor of discontinuation was ADL decline (UH and LH) and Abe's BPSD score (UH). The most common reason for discontinuation was returning to the family doctor (39.1% for UH), and cessation of hospital attendance at their own discretion (35.3% for LH). Conclusions: We identified the main reasons for discontinuation of attendance as returning to the family doctor and cessation of hospital attendance at their own discretion. The best predictors of discontinuation were ADL decline and worsening BPSD. There were significant differences in discontinuation between UH and LH patients with dementia.

DOI： 10.1111/ene.13268

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The number of people with dementia is rapidly increasing as populations around the world age. It is important to grasp the characteristic features of mild cognitive impairment (MCI) for early detection and prevention of dementia. METHODS: We examined 408 individuals recruited from a health checkup for metabolic syndrome, which comprised three groups: normal (n = 325), MCI (n = 55) and apparent cognitive decline (ACD; n = 28). We compared cognitive/affective functions and exercise/hobby habits with assessments of vascular risk factors and results from computerized touch-panel tests. RESULTS: Among the 408 individuals, 93.1% showed normal scores on the Mini-Mental State Examination, and 6.9% had ACD. Among the normal Mini-Mental State Examination participants, 14.5% had MCI (13.5% of all participants). The three groups of participants showed significant differences in age, education, systolic blood pressure, glycosylated hemoglobin and high-density lipoprotein cholesterol level. Even within the normal range, those in the MCI group showed significantly lower cognitive function than those in the normal group. Scores on the Geriatric Depression Scale were greater in the MCI group, and "day-night reversal" was worse in the ACD group. Scores on touch-panel screening tests were significantly worse in the MCI and ACD groups than in the normal group. Participants showed better cognitive and affective function if they exercised regularly or had hobbies. CONCLUSIONS: Incidental MCI and ACD had prevalences of 13.5% and 6.9%, respectively, in the population-based study. Participants with these conditions showed cognitive/affective decline and impairment on computerized touch-panel tests in relation to vascular risk factors and exercise/hobbies. Geriatr Gerontol Int 2017; 17: 722-729.

DOI： 10.1111/ggi.12778

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

The majority of amyotrophic lateral sclerosis patients have the sporadic form, but 5-10% of those have familial amyotrophic lateral sclerosis. A total of 15-20% of familial amyotrophic lateral sclerosis patients have genetic mutations in the superoxide dismutase 1 gene. In 2012, Kobayashi et al. reported the first case of a familial amyotrophic lateral sclerosis patient carrying a G37V superoxide dismutase 1 mutation, who showed rapid progression and died within 1.2 years of onset from respiratory failure. In contrast, here we report the second case of familial amyotrophic lateral sclerosis carrying the G37V superoxide dismutase 1 mutation, showing a very slow progression, and his father and aunt also had longer disease durations from 4 to 6 years. Further clinical and biological studies will clarify the detailed pathological role of the G37V superoxide dismutase 1 mutation for amyotrophic lateral sclerosis.

DOI： 10.1111/ncn3.12123

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems.

DOI： 10.1016/j.jns.2017.02.058

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. In ALS, both glucose consumption and neuronal intensity reportedly decrease in the cerebral motor cortex when measured by positron emission tomography (PET). In this study, we evaluated cervical spinal glucose metabolism, blood flow, and neuronal intensity of 10 ALS patients with upper extremity (U/E) atrophy both with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) PET and 11C-flumazenil (11C-FMZ) PET. On the ipsilateral side of C5 and T1 levels, 18F-FDG uptake increased significantly (*p < 0.05), and was correlated with the rate of progression of the ALS FRS-R-U/E score (R = 0.645, *p = 0.041). Despite this hyperglucose metabolism, the 11C-FMZ PET study did not show a coupled increase of spinal blood flow even though neuronal intensity did not decrease. These results indicate a strong correlation between hyperglucose metabolism and ALS progression alongside the uncoupling of flow-metabolism. This mechanism, which could result in subsequent motor neuronal death, may be a potential therapeutic target for ALS.

DOI： 10.1007/s10072-017-2823-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The number of patients with insomnia is rapidly increasing as society ages. The influence of insomnia on cognitive, affective, and activities of daily living (ADL) functions has not been fully studied. METHODS: Participants were 142 residents of a local super-aged community who underwent health check-ups provided by the local government. Participants completed cognitive, affective and ADL function tests including the MMSE. We divided participants into two subgroups based on Athens Insomnia Scale (AIS) scores (AIS ≤3 and AIS ≥4) and compared cognitive, affective, and ADL functions by sex and age. RESULTS: Subjective insomnia (AIS ≥4) was found in 36.2% of participants and was more frequent in females than males. No differences were found in cognitive function between the AIS subgroups. For both sexes, Geriatric Depression Scale scores were significantly higher in the AIS ≥4 subgroup than the AIS ≤3 subgroup. Apathy Scale scores were significantly higher in males in the AIS ≥4 subgroup. Of the AIS subscales, 'sleepiness during the day' was significantly higher in females than males (**p < 0.01), especially in those aged  ≥75 years (**p < 0.01). This group of older females also showed a significantly lower Trail Making Test scores (*p < 0.05). DISCUSSION: Insomnia was present in 36.2% of the population in a Japanese super-aged community. Those with insomnia showed more depressive symptoms (both sexes) and males showed more apathy. The most distinct characteristic of females aged  ≥75 years was a high frequency of daytime sleepiness, possibly related to a decline in attention and executive function.

DOI： 10.1080/01616412.2017.1281200

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Somatic cells can be directly converted into induced neural stem cells (iNSCs) by defined transcription factors. However, the therapeutic effect of undifferentiated iNSCs on ischemic stroke has not been demonstrated. In this study, we used a mouse model of transient middle cerebral artery occlusion (tMCAO). iNSCs (5 × 105) were injected directly into the ipsilateral striatum and cortex 24 h after tMCAO. Histological analysis was performed at 7 days, 28 days, and 8 months after tMCAO. We found that iNSC transplantation successfully improved the survival rate of stroke model mice with significant functional recovery from the stroke. The fate of engrafted iNSCs was that the majority of iNSCs had differentiated into astroglial cells but not into neural cells in both the sham-operated brain and the poststroke brain without forming a tumor up to 8 months after tMCAO. Our data suggest that the directly converted iNSCs can be regarded as a candidate of safe cell resource for transplantation therapy in patients suffering from ischemic stroke.

DOI： 10.3727/096368916X692988

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記述言語：英語  

DOI： 10.1016/j.jns.2016.12.069

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To evaluate a potential multisystem involvement of neurodegeneration in Asidan, in addition to cerebellar ataxia and signs of motor neuron disease. METHODS: We compared the new Asidan patients and those identified in previous studies with Parkinson's disease (PD, n=21), and progressive supranuclear palsy (PSP, n=13) patients using 123I-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy (Asidan, DAT: n=10; MIBG: n=15). RESULTS: Both the PD and PSP groups served as positive controls for DAT decline. The PD and PSP groups served as a positive and negative control, respectively, of MIBG decline in the early phase H/M ratio. Of the Asidan patients, 60.0% showed DAT decline without evident parkinsonian features and 6.7% showed impaired MIBG in only the delayed phase H/M ratio. Combined with a normal range of the early phase H/M ratio, this phenotype was newly named Declined DAT Without Evident Parkinsonism (DWEP). INTERPRETATION: The results of present study including DWEP suggest a wider spectrum of neurodegeneration for extrapyramidal and autonomic systems in Asidan patients than expected, involving cerebellar, motor system and cognitive functioning.

DOI： 10.1016/j.jns.2017.01.003

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jns.2016.12.052

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記述言語：英語  

DOI： 10.1016/j.jns.2016.12.040

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記述言語：英語  

DOI： 10.1016/j.jns.2016.11.074

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Springer Japan  

The discovery of iPS indicated that overexpression of master transcriptional factors might change cell fate. Recent developments in reprogramming methods have shown that somatic cells can be directly reprogrammed to various kinds of neuronal cells directly. Moreover, overexpression of a neuron-specific transcriptional factor with a viral vector can change the fate of endogenous glial cells to neuronal cells in vivo. In this chapter, we discuss the advantages, issues, and possibility for clinical application of these reprogramming methods for cell transplantation/replacement therapy.

DOI： 10.1007/978-4-431-56059-3_4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

We report the unusual case of a 63-year-old man with spinocerebellar ataxia (SCA) type 31 who developed neuromyelitis optica spectrum disorder (NMOSD) 14 years after the onset of cerebellar symptoms. In addition to cerebellar atrophy, magnetic resonance imaging showed multiple high-intensity areas in the brain and a long thoracic cord lesion from Th1/2 to Th11. The combination of NMOSD and SCA31 is accidental. However, our case suggests that inflammatory processes could be involved in the pathogenesis of NMOSD and SCA31. (C) 2017 The Author(s) Published by S. Karger AG, Basel.

DOI： 10.1159/000475657

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)P413L allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHGBP413L variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGBL413 protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGBL413 transgene in SOD1G37R mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGBL413 variant also slowed down disease progression in SOD1G37R mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1D90A alleles and two variant CHGBP413L and CHGBR458Q alleles. In contrast, overexpression of the common CHGBP413 allele in SOD1G37R mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGBP413L allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGBL413 allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.

DOI： 10.1093/hmg/ddw304

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記述言語：英語  

DOI： 10.1016/j.jns.2016.08.051

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: We compared the behavioral and psychological symptoms of Alzheimer's disease (AD) and Parkinson's disease (PD) in order to determine the characteristic features of each disorder. METHODS: For this retrospective cohort study, we compared the behavioral and psychological symptoms of 288AD patients and 189 PD patients (mean age, 74.6±5.9 and 73.0±8.7years respectively). Symptoms were evaluated using the geriatric depression scale (GDS), apathy scale (AS), and Abe's behavioral and psychological symptoms of dementia score (ABS). RESULTS: AD patients had higher AS and ABS scores than PD patients. A gender-dependent comparison showed that ABS scores were worse in female AD patients than in female PD patients (p=0.001). A subscale analysis of ABS scores revealed that male AD patients were only significantly different from male PD patients in 1 item, whereas female AD patients were significantly different from female PD patients in 4 items. Among patients with mild cognitive decline, no differences in affective scores were observed. Alternatively, among patients with moderate cognitive decline, affective scores on all 3 scales were worse in PD patients than in AD patients. CONCLUSIONS: The present age- and gender-matched retrospective analysis identified greater behavioral and psychological disease severity in female AD patients relative to female PD patients, and greater affective severity in PD patients versus AD patients with a similar degree of cognitive decline.

DOI： 10.1016/j.jns.2016.08.053

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Stress proteins have been found to play important protective roles against ischemic brain injury under hypoxic, oxidative, heat shock, and proteasome stresses. METHODS: In the present study, we investigated the temporal profiles of the major stress proteins including hypoxia-inducible factor-1α (HIF-1α), glutathione (GSH), heat shock protein 72 (HSP72), constitutive heat shock cognate protein 73 (HSC73), and ubiquitin after 45 minutes of transient middle cerebral artery occlusion (tMCAO) in the mice brain up to 7 days after reperfusion. RESULTS: Immunohistochemical analyses of HIF-1α, GSH, HSP72, and ubiquitin showed little immunoreactivity of neural cells in sham control brain, whereas HSC73 showed a constitutive immunoreactivity. After tMCAO, HSC73 showed the fastest increase at 12 hours in the peri-ischemic area, followed by HIF-1α with a peak at 24 hours, GSH, HSP72, and ubiquitin with a peak at 72 hours. All these stress proteins returned toward the baseline levels until 7 days. In the ischemic core, these stress proteins showed a similar change with less reaction compared to the peri-ischemic area. CONCLUSIONS: These data showed temporal expressions of HIF-1α, GSH, HSP72, HSC73, and ubiquitin in the mice brain after tMCAO, which might provide a better understanding of neuroprotective mechanisms and novel targets for therapeutic intervention of brain ischemic disease.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.05.031

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記述言語：英語  

DOI： 10.1016/j.jns.2016.07.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.

DOI： 10.1016/j.neuropharm.2016.03.035

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain. METHODS: Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation. RESULTS: Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups. CONCLUSIONS: Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.04.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study evaluates endothelial functions of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). The reactive hyperemia index (RHI) of peripheral arterial tonometry and serological data were compared between age- and gender-matched normal controls (n=302) and five disease groups (ALS; n=75, PD; n=180, PSP; n=30, MSA; n=35, SCA; n=53). Correlation analyses were performed in ALS with functional rating scale-revised (FRS-R), and in PD with the Hehn-Yahr scale (H-Y) and a heart to mediastinum ratio using (123)I-MIBG scintigraphy (MIBG). The RHI of ALS and PD, but not of PSP, MSA or SCA, were significantly lower than normal controls (p<0.01). ALS showed a negative correlation of RHI with serum triglycerides (TG) and immunoreactive insulin (IRI) levels, but not with disease severity (FRS-R) or rates of disease progression (∆FRS-R). On the other hand, PD showed a negative correlation of RHI with a progressive disease severity (H-Y) and a positive correlation of RHI with early/delayed MIBG scintigraphy, but not with serological data. The present study demonstrated significant declines of peripheral arterial endothelial functions in ALS and PD. The RHI of ALS was more correlated with disease duration and serum parameters while the RHI of PD was more correlated with disease severity and MIBG, suggesting different mechanisms of endothelial dysfunction.

DOI： 10.1016/j.jns.2016.04.042

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To compare age-dependent changes in cognitive and affective functions related to white matter changes between patients with Alzheimer's disease (AD) and Parkinson's disease (PD). METHODS: We retrospectively compared age-dependent cognitive and affective functions in 216 AD patients, 153 PD patients, and 103 healthy controls with cerebral white matter lesions (WMLs), periventricular hyperintensity (PVH), deep white matter hyperintensity (DWMH), micro-bleeds (MBs), and lacunar infarcts (LIs). RESULTS: The average mini-mental state examination (MMSE) scores were 19.6±6.1 and 26.8±3.6 in AD and PD patients, respectively. Significant decreases were found in the MMSE score, Hasegawa's dementia scale-revised (HDS-R) score, frontal assessment battery score, and Abe's BPSD score (ABS) among the age-dependent AD subgroups and in the MMSE, HDS-R, Montreal cognitive assessment, geriatric depression scale, and ABS scores among the age-dependent PD subgroups; they were worse in AD patients. White matter changes were observed in >88% and >72% of patients with AD and PD, respectively. An age-dependent direct comparison of AD and PD showed significant differences in the PVH and DWMH grades, and numbers of MBs and LIs. CONCLUSION: WML-related cognitive and affective functions worsen with age in AD and PD patients; however, the abnormalities were more frequent and stronger in AD patients.

DOI： 10.1016/j.jns.2016.03.031

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記述言語：英語  

DOI： 10.1016/j.jns.2016.03.044

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action.

DOI： 10.3233/JAD-160345

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. METHODS: Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. RESULTS: We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. CONCLUSIONS: G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.01.022

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記述言語：日本語   出版者・発行元：(株)メディカ出版  

(1)エダラボンは急性期脳梗塞患者の神経症候を改善する効果がある。(2)エダラボンはt-PA療法との併用において、出血性合併症軽減や再開通率向上に寄与する可能性がある。(3)エダラボンはALSの治療薬としても認可され、その効果が期待されている。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J03120&link_issn=&doc_id=20160609170008&doc_link_id=issn%3D0917-1495%26volume%3D26%26issue%3D6%26spage%3D621&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0917-1495%26volume%3D26%26issue%3D6%26spage%3D621&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Nav1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier's nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action.

DOI： 10.3233/JAD-160120

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: The world is rapidly aging, and is facing an increase of late-elderly dementia patients. It is important to investigate the characteristic features of late-elderly dementia in a super-aged country. METHODS: We examined 1554 patients with cognitive decline in Department of Neurology, Okayama University Hospital, Okayama, Japan, divided into three subgroups according to the age: young-elderly (age ≤64 years), middle-elderly (age 65-74 years) and late-elderly (age 75 years), and investigated the cognitive, affective and activities of daily living functions (ADL), especially in late-elderly patients compared with young-elderly and middle-elderly patients. RESULTS: Among 1554 patients, Alzheimer's disease dominated at 62%, and age-dependently increased up to 69% in the late-elderly group. The total scores of four cognitive tests were significantly worse with aging for specific subscales of orientation, recall, visual retention, word fluency and so on. In contrast, total scores of the affective tests showed only an increase in the apathy scale in the late-elderly group. Each subgroup showed depressive/depression in 63.2-55.2%, and apathy in 44.2-54.8%. Furthermore, instrumental ADL items significantly deteriorated in the late-elderly group, which statistically correlated with Mini-Mental State Examination score. CONCLUSIONS: These results show that the late-elderly group is characterized by significant cognitive declines, increasing apathy, and instrumental ADL decrease. The cognitive decline may be related to such affective and ADL declines.

DOI： 10.1111/ggi.12492

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: The aim of this study was to analyze the association between the variations of coenzyme Q2 4-hydroxybenzoate polyprenyltransferase gene (COQ2) and Japanese patients with multiple system atrophy (MSA). METHODS: We investigated the genetic variations in exons 1, 2, 6, and 7 of the COQ2 gene in 133 Japanese patients with MSA and 200 controls and analyzed the association between the variations and MSA. RESULTS: Six DNA variations (G21S, L25V, V66L, P157S, V393A, and X422K) were found in the 133 patients with MSA, and G21S and X422K were new variations that had never been reported. V66L was a common variation that was found in all 133 patients with MSA. G21S, P157S, V393A, and X422K did not show gene frequency differences between patients with MSA and controls. On the other hand, L25V was newly proven to be the only risk factor of sporadic MSA with predominant olivopontocerebellar ataxia. CONCLUSIONS: The present study suggests L25V variant of COQ2 gene as a genetic risk factor in Japanese patients with MSA with cerebellar ataxia.

DOI： 10.1212/NXG.0000000000000054

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Cell replacement therapy is attractive as a novel strategy for stroke patients. To realize this therapy, safer and more effective cell resources are now required. Since both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can retain high replication competence and pluripotency when they differentiate into various kinds of cells, they are regarded as a promising cell source for cell replacement therapy. Recent progress includes the combination of novel transcriptional factors that can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring embryonic stem fate. In this paper, we would like to discuss the advantage, issues, and possibility of clinical application of these cells for cell replacement therapy for post-stroke patient.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Clinical data from Japan on the safety and real-world outcomes of alteplase (tPA) thrombolysis in the extended therapeutic window are lacking. The aim of this study was to assess the safety and real-world outcomes of tPA administered within 3-4.5 h of stroke onset. The study comprised consecutive acute ischemic stroke patients (n = 177) admitted across five hospitals between September 2012 and August 2014. Patients received intravenous tPA within <3 or 3-4.5 h of stroke onset. Endovascular therapy was used for tPA-refractory patients. In the 3-4.5 h subgroup (31.6 % of patients), tPA was started 85 min later than the <3 h group (220 vs. 135 min, respectively). However, outcome measures were not significantly different between the <3 and 3-4.5 h subgroups for recanalization rate (67.8 vs. 57.1 %), symptomatic intracerebral hemorrhage (2.5 vs. 3.6 %), modified Rankin Scale score of 0-1 at 3 months (36.0 vs. 23.4 %), and mortality (6.9 vs. 8.3 %). We present data from 2005 to 2012 using a therapeutic window <3 h showing comparable results. tPA following endovascular therapy with recanalization might be superior to tPA only with recanalization (81.0 vs. 59.1 %). Compared with administration within 3 h of ischemic stroke onset, tPA administration within 3-4.5 h of ischemic stroke onset in real-world stroke emergency settings at multiple sites in Japan is as safe and has the same outcomes.

DOI： 10.1007/s12975-016-0448-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The aim of the present study was to compare the effects of a galantamine only therapy and a combination therapy with galantamine plus ambulatory cognitive rehabilitation for Alzheimer's disease patients. METHODS: For this retrospective cohort study, we enrolled 86 patients with Alzheimer's disease, dividing them into two groups - a galantamine only group (group G, n = 45) and a combination with galantamine plus ambulatory rehabilitation group (group G + R, n = 41). The present cognitive rehabilitation included a set of physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. We compared the Mini-Mental State Examination and Frontal Assessment Battery for cognitive assessment, and Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia score for affective assessment in two groups over 6 months. RESULTS: The baseline Mini-Mental State Examination score was 20.2 and 18.7 in groups G and G + R, respectively. Other baseline data (Frontal Assessment Battery, Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia) were not different between the two groups. Although group G kept all the scores stable until 6 months of the treatment, the Apathy Scale score showed a significant improvement in group G + R as early as 3 months, followed by the Mini-Mental State Examination and Frontal Assessment Battery improvements at 6 months (*P = 0.04 and *P = 0.02, respectively). The Geriatric Depression Scale and Abe's Behavioral and Psychological Symptoms of Dementia did not show any changes. CONCLUSION: The combination therapy of galantamine plus ambulatory cognitive rehabilitation showed a superior benefit both on cognitive and affective functions than galantamine only therapy in Alzheimer's disease patients.

DOI： 10.1111/ggi.12488

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer's disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on an AD mouse model in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of α7 subunit of nicotinic acetylcholine receptors (α7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities.

DOI： 10.3233/JAD-151126

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We recently experienced 2 young adult patients who developed ischemic stroke after regular intravenous immunoglobulin (IVIg) therapy for agammaglobulinemia with diagnosis of common variable immunodeficiency (CVID) in their childhood. Patient 1 was 26-year-old woman, who developed Wallenberg's syndrome 6 days after the last IVIg therapy, but had no further stroke recurrence with cilostazol later. Patient 2 was 37-year-old man, who developed recurrent cerebral infarction in the territory of bilateral lenticulostriate branches like branch atheromatous disease (BAD) several days after the IVIg therapy. However, he had no further stroke recurrence after bone marrow transplantation (BMT) therapy for his lymphoproliferative disorder. It was suggested that IVIg therapy was associated to these different types of ischemic stroke in our 2 young adult patients with minimal vascular risk factors. Although IVIg therapy is widely used as a relatively safe medication for immunodeficiency disorders or autoimmune diseases, we need to pay more attention to stroke occurrence with regular IVIg therapy.

DOI： 10.1016/j.jns.2015.12.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

Background and purpose: The influence of metabolic syndrome (MetS) on cognitive and affective functions in patients with Alzheimer's disease (AD) was examined. Methods: A total of 570 AD patients were divided into two subgroups depending on waist circumference (WC) (normal versus achieving Japanese diagnostic criteria of MetS). Afterwards, the AD control subgroup was defined as those normal WC patients with no vascular risk factors (VRFs). The AD with MetS (AD-MetS) subgroup was defined as the MetS WC group who had two or more VRFs to qualify as having MetS. Cognitive and affective functions, insulin resistance, vascular endothelial function and white matter changes between AD-MetS and AD controls were compared. Results: Scores on the Mini-Mental State Examination, Hasegawa Dementia Score - Revised, Frontal Assessment Battery and Montreal Cognitive Assessment were worse in the AD-MetS group than in AD controls, but the difference was not significant. Some analyses were conducted twice, once including all patients and once including only late-elderly patients. Scores on the Geriatric Depression Scale were found to be significantly higher for AD-MetS than for AD controls (all ages, late-elderly), as were those for apathy (late-elderly). Furthermore, both the homeostasis model assessment of insulin resistance and reactive hyperemia index scores were significantly worse in AD-MetS than in AD controls, whilst white matter changes showed a tendency to be worse. Conclusions: Greater cognitive and affective decline occurs in patients with AD-MetS than in those without. Further, insulin resistance and vascular endothelial dysfunction are strongly correlated with AD-MetS before pathological white matter changes can be observed. Click here to view the accompanying paper in this issue.

DOI： 10.1111/ene.12845

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTS: Alzheimer's disease (AD) is one of the most important diseases in aging society, and non-drug therapy might be an alternative therapeutic approach. Thus, we evaluated the add-on effect of cognitive rehabilitation on AD patients under donepezil treatment. METHODS: We retrospectively analyzed 55 AD patients with a Mini-Mental State Examination score of 15-25, dividing them into two groups depending on whether they were receiving ambulatory cognitive rehabilitation (group D + R, n = 32) or not (group D, n = 23) in Kurashiki Heisei Hospital over 1 year. The present cognitive rehabilitation included physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. RESULTS: Between group D and group D + R, there was no significant difference in baseline data, such as age, Mini-Mental State Examination score, periventricular hyperintensity on magnetic resonance imaging, deep white matter hyperintensity on magnetic resonance imaging or donepezil dose (4.1 mg/day). At 1 year later, however, the Mini-Mental State Examination score improved only in group D + R from 21.7 to 24.0 (**P < 0.001), whereas that of group D remained at 21.5 with both groups of donepezil 5.0 mg/day. CONCLUSION: The combination of cognitive rehabilitation plus a choline esterase inhibitor donepezil showed a better effect for the cognitive function of AD patients than drug only therapy at 1 year.

DOI： 10.1111/ggi.12455

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

Background and purpose: A novel TYPE of prion disease associated mainly with autonomic-sensory polyneuropathy was reported by us previously. Methods: Here the autopsy pathology for patient 1 (the sister) and the clinical characteristics of her younger brother (patient 2) are newly reported. Polymerase chain reaction based restriction fragment length polymorphism analysis of the prion protein gene (PRNP) was performed on both patients and their father (normal control). Results: Polymerase chain reaction based restriction fragment length polymorphism analysis revealed a 2-bp deletion (CT) in codon 178 that causes an additional variable 25 amino acids at the C terminal, from the mutation site to the premature stop codon at codon 203, in both patients 1 and 2 but not in their father. The autopsy of patient 1 showed remarkable prion protein (PrP) deposits in the sympathetic ganglion and peripheral nerves, correlated to her severe autonomic sensory failure. PrP deposits were also found in the central nervous system and peripheral organs such as the heart, lung, stomach, jejunum, ileum, colon, urinary bladder and adrenal gland. The symptoms and biopsy findings of patient 2 were nearly the same as those reported previously for patient 1. His cognitive function was well preserved, but autonomic functions were severely impaired. His biopsied samples showed PrP deposits in the sural nerve and nerve plexuses of the stomach and colon. Conclusion: The present unique 2-bp deletion (CT) in codon 178 induced a 'PrP systemic deposition disease' such as pan-autonomic failure, sensory neuropathy and mild cognitive impairment with a specific pathology.

DOI： 10.1111/ene.12905

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The objective of this study is to determine whether diffusion tensor imaging (DTI) tractography analysis is a potential method for differentiating cerebellar ataxia patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) and cortical cerebellar atrophy (CCA). Forty-one MSA-C patients (62.7 ± 8.1 years old, mean ± SD) and age- and gender-matched 15 CCA patients (63.0 ± 8.6 years old) were examined.Tractography was performed using the DTI track module provided in the MedINRIA version 1.9.4, and regions of interest were drawn manually to reconstruct an efferent fiber tract and two afferent fiber tracts via the cerebellum. Compared with CCA, MSA-C patients showed significant declines of fractional anisotropy (FA) values of afferent 1 and 2 (p<0.01, respectively) and a significant increase of the radial diffusivity (RD) value in afferent 1 (p<0.05). Receiver-operator characteristic curve analysis showed 85.7 % sensitivity and 75.0 % specificity of FA values in afferent 1 (cutoff value 0.476). Linear regressions showed strong correlations between FA value and disease duration in CCA patients (efferent 1, r = -0.466; afferent 2, r = -0.543; both p<0.05), and between the FA value and the ratio of the standardized scale for the assessment and rating of ataxia (SARA)/disease duration in MSA-C patients (afferent 1, r = -0.407; p<0.01). The present DTI tractography newly showed that the FA values of two afferent fiber tracts showed significant declines in MSA-C patients, and afferent 1 showed good diagnostic sensitivity and specificity. When combining the FA values of efferent 1 with disease duration, the present DTI tractography analysis could be useful for differentiating MSA-C and CCA patients.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Possible strategies for treating stroke include neuroprotection in the acute phase of cerebral ischemia and stem cell therapy in the chronic phase of cerebral ischemia. Previously, we have studied the temporal and spatial expression patterns of c-fos, hypoxia inducible factor-1α (HIF-1α), heat shock protein 70 (HSP70), and annexin V after 90 min of transient middle cerebral occlusion in rats and concluded that there is a time window for neuroprotection from 12 to 48 h after ischemia. In addition, we have estimated the neuroprotective effect of glial cell line-derived neurotrophic factor (GDNF) by injecting Sendai viral vector containing the GDNF gene into the postischemic brain. This Sendai virus-mediated gene transfer of GDNF showed a significant neuroprotective effect in the ischemic brain. Additionally, we have administered GDNF and hepatocyte growth factor (HGF) protein into the postischemic rat brain and estimated the infarct size and antiapoptotic and antiautophagic effects. GDNF and HGF significantly reduced infarct size, the number of microtubule-associated protein 1 light chain 3 (LC3)-positive cells, and the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick-end labeling (TUNEL)-positive cells, indicating that GDNF and HGF were greatly associated with not only the antiapoptotic effect but also the antiautophagic effects. Finally, we have previously transplanted undifferentiated iPSCs into the ipsilateral striatum and cortex at 24 h after cerebral ischemia. Histological analysis was performed at 14 and 28 days after cell transplantation, and we found that iPSCs could supply a great number of doublecortin-positive neuroblasts but also formed tridermal teratoma in the ischemic brain. Our results suggest that iPSCs have a potential to provide neural cells after ischemic brain injury if tumorigenesis is properly controlled. In the future, we will combine these strategies to develop more effective therapies for the treatment of strokes.

DOI： 10.3727/096368916X690548

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n = 52) and DLB (n = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2±4.8) and better frontal assessment battery (FAB) scores (11.3±4.1) compared with DLB (17.0±6.4, p = 0.013 and 8.6±4.7, p = 0.039, respectively). DLB patients performed worse than PDD patients in "orientation to place" tasks. In affective functions, DLB patients had worse GDS (7.6±3.4) and ABS (9.9±5.3) scores than PDD patients (5.1±4.1 and 4.8±3.0, respectively). 99mTc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients' lower average scores for "repetition" (MMSE), "recent memory" (HDS-R), and "lexical fluency" (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients' poorer average subscale scores of "orientation to place" (MMSE) and "similarities", "conflicting instructions", and "go-no go" (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD.

DOI： 10.3233/JAD-150952

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although changes to gait are an important clinical feature of progressive supranuclear palsy (PSP), systematic analyses have not been well examined, especially in comparison to Parkinson's disease (PD). METHODS: The characteristics of gait in 20 PSP patients (14 males and 6 females) were evaluated in comparison to 124 PD patients (64 males and 60 females) and 24 controls, that is, healthy age-matched adults (5 males and 19 females). Gait in patients was recorded in a 10-m walking test at a self-selected speed. During this time, patients felt most comfortable while wearing a new portable triaxial accelerometer rhythmogram device. Gait variables among the 3 groups were compared. RESULTS: Both PSP and PD patients shared the following similar hypokinetic gait characteristics: decreased velocity, step length, cadence and mean acceleration. Step time and variability in step time were mutually related. However, among the 3 groups, PSP patients showed characteristically low vertical displacement and a higher acceleration than PD patients at the same cadence. CONCLUSION: Although PSP and PD patients showed similar hypokinetic gait, a reduced vertical displacement characterized walking in PSP patients, differing substantially from the characteristics of walking displayed by PD patients.

DOI： 10.1159/000445111

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The discovery of induced pluripotent stem (iPS) cells opened the gate for reprogramming technology with which we can change the cell fate through overexpression of master transcriptional factors. Now we can prepare various kinds of neuronal cells directly induced from somatic cells. It has been reported that overexpression of a neuron-specific transcriptional factors might change the cell fate of endogenous astroglia to neuronal cells in vivo. In addition, some research groups demonstrated that chemical compound can induce chemical-induced neuronal cells, without transcriptional factors overexpression. In this review, we briefly review recent progress in the induced neuronal (iN) cells, and discuss the possibility of application for cell transplantation therapy.

DOI： 10.2176/nmc.ra.2015-0309

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

CONCLUSION: The prevalence of low-tone hearing loss (LTHL) is significantly high in spinocerebellar degeneration (SCD) with cerebellar predominance, including multiple-system atrophy C (MSA-C) and cortical cerebellar atrophy (CCA). OBJECTIVE: This study aimed to test the hypothesis that SCD with cerebellar predominance, MSA-C and CCA may cause auditory symptoms. METHODS: The shape and threshold of pure-tone audiograms were evaluated for MSA-C (n = 47; mean (± SD) age, 61.6 ± 8.9 years), CCA (n = 16; 62.8 ± 9.5 years), and age-matched controls (n = 169; 62.5 ± 10.7 years). To differentiate specific hearing loss for MSA-C and CCA from presbycusis, the shape of audiograms was examined based on previously established audiological criteria. RESULTS: When audiogram shape was defined according to audiological criteria, the odds ratio for LTHL in SCD compared to controls was 2.492 (95% confidence interval (CI) = 1.208-5.139; p < 0.05, Pearson's Chi-square test) in MSA-C and 2.194 (95% CI = 0.709-6.795) in CCA. When the selection of audiogram shape according to these criteria was verified by three certified audiologists, odds ratios for LTHL in MSA-C and CCA were 3.243 (95% CI = 1.320-7.969) and 3.692 (95% CI = 1.052-12.957), respectively, significantly higher than in controls.

DOI： 10.3109/00016489.2015.1104722

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記述言語：英語   出版者・発行元：TAYLOR & FRANCIS INC  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The purpose of this study was to clarify the difference between PSP and PD from the viewpoint of dynamic cerebrospinal fluid (CSF) flow focusing on the midbrain aqueduct. METHODS: Thirty-three PD patients (mean age 69.2±7.9) and 35 PSP patients (mean age 70.5±6.6) were included in this study. CSF flow was calculated by 15 images in an equidistant magnetic resonance imaging (MRI) sequence that was taken throughout a cardiac cycle. RESULTS: Absolute values of the velocity (time points of 2-6 and 12-15, *p<0.05), and the width of the CSF velocity (Vheight) (PSP, 5.1±2.3cm/s; PD, 6.0±1.6cm/s, p<0.05) effectively discriminated PSP from PD patients. On the other hand, conventional MRI measurements discriminated well the midbrain aqueduct area (Area) (PSP, 7.7±2.6mm(2); PD, 5.4±1.8mm(2), p<0.01). Two cutoff value lines (Vheight: 4.75, Area: 5.77) of the ROC curve analysis established two areas for discriminating PSP from PD. CONCLUSION: In the present dynamic CSF flow study, it was newly found that mean velocity of each time point and Vheight showed a more significant decline in PSP than in PD patients, providing a sensitive biomarker for differentiating them. The combination of Vheight and Area could further discriminate PSP from PD patients.

DOI： 10.1016/j.jns.2015.07.026

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: Subacute myelo-optico neuropathy was the first epidemic drug intoxication that affected many people in Japan in the 1970s. Aim: More than 40 years later, we assessed the real conditions of subacute myelooptico neuropathy patients. Methods: The present study examined current cognitive and affective functions, activities of daily living, and vascular endothelial function in aged subacute myelooptico neuropathy patients (n = 28) compared with age-,sex-,body mass indexand years of schooling-matched normal controls (n = 141).Results: Mini-Mental State Examination, Hasegawa Dementia Scale-Revised, Montreal Cognitive Assessment and Frontal Assessment Battery scores were not significantly lower in subacute myelo-optico neuropathy patients, but the Geriatric Depression Scale was significantly higher without apathy. Computerized touchpanel tests showed poor performance in the flipping cards game, arranging pictures game and beating devils game, whereas activities of daily living and vascular endothelial function were within normal limits.Conclusion: The present study shows that subacute myelo-optico neuropathy patients showed essentially normal cognitive function using standard cognitive assessments, although the touch- panel tests detected some decline in subacute myelo- optico neuropathy patients. Subacute myelo- optico neuropathy patients presented a higher depression score without evident apathy, activities of daily living decline or vascular endothelial dysfunction.

DOI： 10.1111/ncn3.12000

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

The primary clinical manifestations of synovitis, acne, pustulosis, hyperostosis and osteitis syndrome are skin lesions and osteitis. We describe a 53-year-old woman patient suffering from overlapping refractory headache and polyneuritis (cranial nerves I, II and VII). She complained of headaches, which recurred every month, followed by bilateral anosmia and left vision loss approximately 1 year later. Prednisolone therapy improved her symptoms; however, her refractory headache, pain in the right shoulder and left hip joint, and rash recurred 1 year after prednisolone withdrawal. Also, the patient presented with left sensorineural deafness and extensive acne on her body, and bone scintigraphy and bone biopsy showed synovitis, acne, pustulosis, hyperostosis and osteitis syndrome. After treatment, her symptoms improved without recurrence. Although synovitis, acne, pustulosis, hyperostosis and osteitis syndrome induced by polyneuritis is rare, it should be considered when clinicians encounter patients presenting with headache and polyneuritis of unknown cause.

DOI： 10.1111/ncn3.171

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記述言語：英語  

DOI： 10.1016/j.jns.2015.06.006

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Springer Japan  

The human brain utilizes large amounts of O2, which means that the rate of blood flow has to be maintained at a consistently high level. This is made possible by "cerebral autoregulation," the process by which the cerebral and spinal blood vessels keep cerebral blood flow constant, even under change in systemic blood pressure. In addition, cerebral and spinal blood flow and its regulation appear to be closely related not only to vascular disease phenotype but also the pathophysiology of various neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. In this review, we briefly highlight cerebral and spinal blood flow and its autoregulation and show its relationship to neurological diseases.

DOI： 10.1007/978-4-431-54490-6_2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study investigated the incidence of current poststroke dementia (PSD), the annual conversion ratio into PSD, and the risk factors for conversion. METHODS: In a 4.8-year follow-up period, 112 poststroke patients (ischemic stroke and intracerebral hemorrhage) were retrospectively investigated in cognitive examinations. They were categorized into 3 subgroups: converters into PSD, nonconverters who maintained their normal cognitive functions, and reverters who recovered to the normal mentality range. The clinical and demographic characteristics of these 3 subgroups were analyzed. RESULTS: Among all 112 poststroke patients (61.6% male, 73.6 ± 10.4 years old), 16.1% had PSD. During the follow-up period, a part of the normal baseline mentality group (83.9% of 112 original patients) newly developed PSD (subdivided into converters) with an annual conversion rate of 7.6%. The reversion rate from the baseline PSD group was 11.3%. There were significant differences in age (P < .05), baseline mini-mental state examination scores (P < .05), body mass index (P < .05), and periventricular and deep white matter hyperintensity grades (P < .05 and P = .01, respectively) between converters and nonconverters. The annual rate of stroke recurrence was only 2.2% in all stroke subtypes. CONCLUSIONS: In comparison with stroke recurrence (2.2%), 7.6% of the annual PSD conversion rate was very high. Therefore, prevention of direct conversion into PSD without stroke recurrence may be another important aspect of poststroke clinics, especially in late elder society.

DOI： 10.1016/j.jstrokecerebrovasdis.2015.03.037

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Hypertension is a crucial risk factor for both stroke and dementia, including Alzheimer's disease (AD). We inspected the effect of telmisartan on the neurovascular unit (NVU) and related inflammatory responses in spontaneously hypertensive rat stroke resistant (SHR-SR) by observing the components of NVU such as N-acetyl glucosamine oligomer (NAGO), collagen IV, astrocytes, and matrix metalloproteinase-9 (MMP-9), as well as inflammasome NOD-like receptors family protein 3 (NLRP3). METHODS: In the present study, we examined the effect of a highly selective angiotensin type 1 (AT-1) antagonist of angiotensin 2 receptor with high lipid solubility, telmisartan, on NVU and related inflammatory responses in SHR-SR with a low dose (0.3 mg/kg/day) only for improving metabolic syndrome, and a high dose (3 mg/kg/day) for improving both metabolic syndrome and SHR-SR hypertension. RESULTS: Compared to normotensive Wistar rats, long-lasting hypertension in SHR-SR disrupted NVU by changing immunohistological components such as NAGO, collagen IV, astrocytes, and MMP-9. SHR-SR also strongly induced AD-related inflammasome NLRP3 in neuronal cells with age. However, such NVU disruption and inflammasome activation were greatly improved with dose-dependent telmisartan treatments. DISCUSSION: These results suggest that telmisartan comprehensively protected the NVU components by reducing inflammatory reactions relative to AD in hypertensive rats, which could also preclude the risk of AD under hypertension.

DOI： 10.1179/1743132815Y.0000000002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cognitive impairment and affective dysfunction of multiple system atrophy (MSA) and cortical cerebellar atrophy (CCA) have not been simultaneously examined comparing standard test batteries and a sensitive tool to detect subtle cognitive decline in patients. In the present study, we simultaneously examined cognitive and affective ability in MSA with predominant cerebellar ataxia (MSA-C, n=25), MSA with predominant parkinsonism (MSA-P, n=8), and CCA (n=14) patients using computerized touch panel screening tests. Mini-mental state examination (MMSE), Hasegawa dementia scale-revised (HDS-R), frontal assessment battery (FAB), and Montreal cognitive assessment (MoCA) scores were significantly lower in MSA-C patients than in age-and gender-matched normal controls. One MSA-C patient showed a decrease in the regional cerebral blood flow (rCBF) of the frontal lobe. MSA-P patients showed no such cognitive decline. Only FAB and MoCA scores were significantly lower in the CCA patients. MSA and CCA patients also showed a mild to moderate depressive state. Touch-panel screening tests demonstrated a significant decline of beating devils game in all three disease groups including MSA-P patients, and a significant extension of the flipping cards game only in MSA-C patients. The present study demonstrated different cognitive and affective functions among MSA-C, MSA-P, and CCA patients, and a sensitive screening method for cognitive assessment using touch-panel tests.

DOI： 10.1016/j.jns.2015.02.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Telmisartan is expected to reduce not only the level of blood pressure but also neuroinflammation and neurotoxicity via pleiotrophic effects as a metabo-sartan. We examined the effects of telmisartan on Alzheimer's disease (AD) pathology in spontaneously hypertensive rat stroke resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO) by giving either telmisartan at 0 (vehicle), 0.3 mg/kg/day (low dose, with no reduction of blood pressure), or 3 mg/kg/day (high dose, with a significant reduction of blood pressure) p.o. from 3 months (M) of age, and performed immunohistological analysis at 6, 12, and 18 M of age. The numbers of amyloid β (Aβ)-positive neurons in the cerebral cortex and hippocampus and senile plaque (SP) in the ipsilateral cerebral cortex progressively increased with age until 18 M in the SHR-SR after tMCAO. On the other hand, low-dose telmisartan significantly reduced the number of Aβ-positive neuron as well as SP at 6, 12, and 18 M. High-dose telmisartan showed further reductions of the above AD pathology. The present study suggests that telmisartan reduced both intracellular Aβ and extracellular SP accumulations after tMCAO in SHR-SR, with a further improvement by combined BP lowering. Such a strong effect of telmisartan could provide a preventative approach for AD in post-stroke patients with hypertension.

DOI： 10.1007/s12975-013-0321-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.09.037

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Tumefactive demyelination is sometimes difficult differentiate from malignant tumors. Positron emission tomography with C-11-methionine is useful for diagnosing cerebral malignant tumors, but there are previous reports for tumefactive demyelination. We experienced a 32-year-old man who suffered from subacute onset dysarthria and left hemiparesis with magnetic resonance image of a large lesion (5.3 x 4.2 cm) in the right frontal lobe. Positron emission tomography with F-18-fluorodeoxyglucose showed a high ring-shaped glucose uptake in the lesion and C-11-methionine showed a remarkable methionine uptake in the whole lesion. Although a malignant tumor was suspected, the patient was finally diagnosed with tumefactive demyelinating disease based on brain biopsy results, and was treated completely by methylpredonisolone therapy. Although C-11-methionine uptake with positron emission tomography commonly suggests a malignant tumor, there can still be a possibility of tumefactive demyelinating disease.

DOI： 10.1111/ncn3.150

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

Diabetes mellitus (DM) is associated with a decline in cognitive and affective functions. Methods: In all, 182 outpatients with DM were investigated for associations of cognitive and affective functions with diabetes-related factors and cerebral white matter abnormalities. In addition, the difference in cognitive decline of age-matched late elderly normal subjects and DM patients was investigated. Results: The present study revealed that cognitive and affective functions declined in some DM patients. Furthermore, the decline in these functions was unrelated to fasting blood sugar level but was related to glycosylated hemoglobin (HbA1c) and insulin resistance. Poor HbA1c control was associated with a significant decline in the 'calculation' subscale and insulin resistance for 'naming', 'read list of letters' and 'delayed recall' Montreal Cognitive Assessment (MoCA) subscale scores. Magnetic resonance imaging scans showed that both periventricular hyperintensity (PVH) and deep white matter hyperintensity were associated with Mini Mental State Examination (MMSE) and MoCA scores, but only PVH was related to homeostasis model assessment of insulin resistance scores. Compared with age-matched late elderly normal subjects, 'orientation to time' and 'registration' MMSE subscales declined in late elderly DM patients. Conclusions: These results suggest that cognitive and affective decline in DM patients was mostly related to glucose control and insulin resistance, whilst amongst late elderly subjects the impairment of 'attention' and 'orientation' were characteristic features of DM patients.

DOI： 10.1111/ene.12568

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/OBJECTIVE: To examine comprehensive clinical evaluations of frontotemporal dementia (FTD) patients compared with Alzheimer's disease (AD) patients. METHODS: We used eight batteries and the touch panel test to retrospectively analyze 41 FTD patients compared with 121 AD patients. Furthermore, 34 FTD and all 121 AD patients were evaluated with a frontotemporal dementia-Alzheimer's disease index (FA index), which we developed for novel diagnosis with magnetic resonance imaging. RESULTS: Frontal assessment battery, geriatric depression scale, and Abe's behavioral and psychological symptom of dementia score were significantly worse in FTD patients than in AD patients ( **p <  0.01 in FAB,  **p <  0.01 in the geriatric depression scale, and  ***p <  0.001 in Abe's behavioral and psychological symptom of dementia score), although there was no significant difference in the other five scores. The finding mistakes game score of the touch panel test was worse in FTD than in AD ( *p <  0.05). The receiver operating characteristic curve of the FA index showed 91.4% sensitivity and 89.3% specificity with the FA index ≤0.6015 to discriminate FTD from AD. CONCLUSION: Combining clinical scores, a computerized touch panel test, and the FA index will help to provide a more accurate diagnosis of FTD in contrast to AD.

DOI： 10.3233/JAD-150416

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an anti-hypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor γ (PPAR-γ) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-γ, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three-months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-γ and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-γ activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR-γ in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-γ activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/OBJECTIVE: To compare the effectiveness of combination therapy with cholinesterase inhibitors (ChEI) plus memantine in all AD patients and in older AD patients (age >75 years). METHODS: The Okayama Memantine Study was used to compare the clinical effects of combination therapy of donepezil plus memantine (n = 61) or galantamine plus memantine (n = 53) in all AD patients, and in older AD patients separately, with six batteries at baseline, at 6 months with ChEI only monotherapy, and at 3, 6, and 12 months after addition of memantine to the treatment schedule (18 months total). RESULTS: The addition of memantine resulted in stabilization of the Mini-Mental State Examination scores and Hasegawa dementia rating for 6 months, and then significantly declined at 12 months in both subgroups. Frontal assessment battery (FAB) declined significantly at 12 months after memantine addition in the donepezil subgroup, while the galantamine subgroup significantly improved at 6 months. Affective functions were well preserved after memantine addition until 12 months, except for the apathy scale at 12 months after memantine addition in the galantamine subgroup. The combination therapy of donepezil plus memantine was better for apathy in older AD patients, and galantamine plus memantine was better for cognitive functions. CONCLUSIONS: The addition of memantine stabilized cognitive scores for 6 months and affective scores for 12 months in the donepezil subgroup. Additionally, memantine significantly improved FAB at 6 months in the galantamine subgroup although apathy scale became significantly worse at 12 months.

DOI： 10.3233/JAD-143084

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The increasing population of elderly people in Japan has accelerated the demand for a simple screening test to detect cognitive and affective declines in mild cognitive impairment (MCI) and the early stage of dementia. Methods We compared the cognitive and affective functions, activities of daily living (ADLs) and the results of four computerized touch-panel screening tests in 41 MCI subjects, 124 patients with Alzheimer's disease (AD) and 75 age- and gender-matched normal controls. RESULTS: All computerized touch-panel games were successfully used to discriminate the AD patients from the normal controls (** p<0.01). Although there were no differences in the findings of the conventional cognitive assessments, the results of the flipping cards game were significantly different (** p<0.01) between the normal controls (19.3 ± 9.5 sec) and MCI subjects (30.9 ± 18.4 sec). Three conventional affective assessments, the ADL score, Abe's behavioral and psychological symptoms of dementia (ABS) (** p<0.01) and the apathy scale (AS) (* p<0.05), could be used to discriminate the MCI subjects (ABS, 0.9 ± 1.5; AS, 12.8 ± 5.9) from the normal controls (ABS, 0.1 ± 0.4; AS, 8.9 ± 5.3). CONCLUSION: In the present study, all four touch-panel screening tests could be employed to discriminate AD patients from normal controls, whereas only the flipping cards game was effective for distinguishing MCI subjects from normal controls. Therefore, this novel touch-panel screening test may be a more sensitive tool for detecting MCI subjects among elderly patients.

DOI： 10.2169/internalmedicine.54.3931

PubMed

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 57-year-old man was admitted to our hospital because of bradykinesia. He was diagnosed with Parkinson disease (Hoehn and Yahr grade 2) and administered levodopa at the maximum dose of 800 mg. However, his condition did not improve. While his symptoms were responsive to levodopa therapy, the sensitivity to the drug was poor. Brain MRI revealed atrophy of the upper vermis and cerebral hemispheres, and brain SPECT revealed low perfusion in both parietal lobes. I(123)-metaiodobenzylguanidine scintigraphy showed a decrease in the heart/mediastinum ratio. Striatal dopamine transporter (DAT) density was evaluated using I(123)-FP-CIT. The patient showed moderately reduced DAT density, which suggested nigrostriatal dopaminergic damage. His mother was found to have pure cerebellar ataxia without parkinsonism, and her two siblings also had celebellar type of multiple system atrophy (MSA-C) and progressive supranuclear palsy, respectively. Genetic testing revealed that the patient, his mother and the uncle with MSA-C had spinocerebellar ataxia type 6 (SCA6). SCA6 presenting parkinsonism without ataxia is very rare and important for the pathomechanism of disease.

DOI： 10.5692/clinicalneurol.55.243

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MicroRNAs (miRNAs) are critically important in both normal neuronal development and neurological diseases. Although cerebral ischemia has been shown to alter the miRNA profiles of rats, the role of miRNA in the cornu ammonis 1 region of the gerbil hippocampus under ischemic tolerance has not been studied. In the present study, Mongolian gerbils were subjected to one or three times the nonlethal dose of 2-min transient common carotid artery occlusion (tCCAO). miRNA microarray technology detected 251 miRNAs and the expression of seven of these in terms of ischemic tolerance. They were compared at different time points: 1 day, 7 days, 1 month, and 6 months. mmu-miR-15a-5p, related to neurogenesis, showed increased expression after one dose of 2-min tCCAO and was much higher after three doses. An increase in sha-miR-24 and oan-let-7b-3p, related to transactivation response DNA-binding protein (TDP43), was observed after one dose of 2-min tCCAO, but the peak was accelerated to an earlier period of reperfusion after three doses. In contrast, mmu-miR-125b-5p and mmu-miR-132-5p, related to fused in sarcoma/translocated in liposarcoma (FUS/TLS), showed similar increases at both doses. mmu-miR-181c-5p and mmu-miR-378a-5p, related to heat shock protein 70 (HSP70), also showed accelerated expression after three doses. This data set provides new insight about miRNA expression during neurogenesis, and related to TDP43, FUS/TLS, and HSP70, which may be useful when pursuing further studies on the possible use of miRNAs as biomarkers in cerebral ischemic tolerance and neuroregeneration.

DOI： 10.3727/096368915X686869

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We experienced a unique case of familial prion disease with a prion gene mutation that caused pan-autonomic failure, sensory neuropathy and mild cognitive impairment. No abnormal sites of intensity were observed on diffusion-weighted magnetic resonance image (MRI) over six to 11 years or fluid attenuated inversion recovery MRI at six or nine years. However, (99m)Tc-ethylcysteinate dimer single photon emission computed tomography (SPECT) showed a decreased cerebral blood flow in the bilateral parietal and occipital lobes at nine years, which then expanded at 11 years, corresponding to mild atrophy in these areas on MRI. In some cases of prion mutations, particularly the slowly progressive type, SPECT may show abnormalities, while MRI does not.

DOI： 10.2169/internalmedicine.54.3378

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in real world dementia clinics, have not been completely examined. We performed the "Okayama Memantine Study II (OMS II)" to retrospectively evaluate the clinical effects of memantine monotherapy (n = 38) in Alzheimer's disease (AD) patients using seven batteries to assess dementia at the baseline, at 3, 6, and 12 months. Additionally, we divided 163 AD patients treated with memantine into two subgroups depending on the baseline cognitive score of the Mini-Mental State Examination (MMSE): the MMSE <15 group (n = 36) and the baseline MMSE ≥15 group (n = 127). We also analyzed 71 AD patients based on the baseline behavioral and psychological symptoms of dementia (BPSD) severity using Abe's BPSD score (ABS). Memantine monotherapy maintained cognitive functions until 6 months of treatment, but showed a decrease at 12 months ( *p <  0.05 versus baseline). However, memantine monotherapy greatly improved BPSD symptoms until 12 months ( *p <  0.05,  **p <  0.01) and maintained other affective functions as well as the activity of daily living. Memantine treatment showed similar effects, regardless of the baseline cognitive functions, but showed better effects on ABS for higher baseline cognitive functions. Memantine treatment greatly improved ABS depending on baseline BPSD severity. Our present OMS II showed that memantine monotherapy improved BPSD until 12 months. The higher baseline cognitive subgroup (MMSE ≥15) and the worse baseline BPSD subgroup were expected to show better effects with memantine.

DOI： 10.3233/JAD-150094

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Alzheimer's disease (AD) is one of the most significant diseases affecting an increasingly aging society. OBJECTIVE: To determine the long-term efficacy of galantamine treatment in a Japanese population. METHODS: We performed "Okayama Galantamine Study (OGS)" to retrospectively analyze the clinical effects of galantamine in 279 AD patients using 7 batteries for assessing dementia at baseline, 3, 6, 12, and 24 months. We further analyzed the effects of galantamine based on gender and the severity of their baseline cognitive, affective, and activity of daily living (ADL) functions. RESULTS: In all 279 AD patients (80.6 ± 7.2 years old, MMSE 20.0 ± 4.5), cognitive functions were well preserved until 12 months and even frontal assessment battery improved after 12 months although Hasegawa dementia scale-revised finally worsened at 24 months ( *p <  0.05) with galantamine treatment. Affective and ADL functions were also well maintained after galantamine treatment with significant improvement of Geriatric Depression Scale scores at 3 months ( *p <  0.05). Subanalyses showed the better response to galantamine for male and lower baseline function subgroups. CONCLUSIONS: Our present study (OGS) revealed a long-term efficacy of galantamine in very elderly AD patients, and suggested a better efficacy for male and baseline lower cognitive, affective, and ADL functions.

DOI： 10.3233/JAD-150308

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記述言語：英語  

Here, we report a unique case of late-onset myotonic dystrophy type 1 in a 64-year-old woman, with selective disappearance of the medial lower back muscles. We compared the clinical features of this patient with those of a cohort of 29 patients with myotonic dystrophy type 1 to clarify the correlation between clinical features and lower back muscle atrophy. After classification into three subgroups according to muscle atrophy pattern, medial muscle atrophy was present in 17.2% of the patients. Affected patients were older at onset than non-affected patients, and limb muscle power and respiratory function decreased with atrophy progression.

DOI： 10.1016/j.jns.2015.04.020

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The purpose of this study was to examine a new MRI technology, dynamic cerebrospinal fluid (CSF) flow, to examine sporadic cerebellar ataxia patients with cortical cerebellar atrophy (CCA) and multiple system atrophy-cerebellar type (MSA-C). METHODS: Nine CCA patients (3 men and 6 women; mean age: 64.2±6.9 years) and 31 MSA-C patients (13 men and 18 women; mean age: 62.7±6.8 years) were examined by a dynamic CSF flow analysis. All CSF flow data were evaluated by phase contrast-MRI using a 1.5T MRI scanner. The CSF flow was calculated by 15 images in the equidistant MRI sequence which was taken through a cardiac cycle. RESULTS: Compared with the CCA patients, the absolute values of the mean velocity of the MSA-C patients were significantly reduced at time points 5 (CCA, 0.24±0.14 cm/s; MSA-C, 0.13±0.11 cm/s; (*) p<0.05) and 13 (CCA, -0.60±0.37 cm/s; MSA-C, -0.31±0.17 cm/s; (**) p<0.01). Significant correlations in Spearman's rank correlation coefficient were also found in MSA-C patients between the disease duration and the difference between the maximum and minimum velocities (Vheight) (r=-0.429, (*) p<0.05), the minimum velocity of the CSF (Vmin) (r=0.486, (**) p<0.01) or the length of the minor axis of the pons (r=-0.529, (**) p<0.01). The linear regressions between the disease duration and Vheight or Vmin revealed a significant strong correlation only in the MSA-C patients. CONCLUSION: The present CSF flow study showed for the first time that Vheight and Vmin revealed good correlations with the disease duration in the MSA-C patients. Furthermore, the velocity of the prepontine CSF flow tended to decrease in the MSA-C patients compared with the CCA patients, suggesting that this particular CSF flow analysis may be a new surrogate marker for differentiating both types of cerebellar ataxia.

DOI： 10.2169/internalmedicine.54.4747

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) is one of the most important diseases in an aging society, but the clinical effects of rivastigmine have not been fully examined in real world domestic clinics. METHODS: We performed the "Okayama Rivastigmine Study (ORS)" to retrospectively analyze the clinical effects of rivastigmine (n = 75) or donepezil (n = 71) on AD patients with seven dementia assessment batteries at the baseline, 3, 6, and 12 months. In addition, we divided the rivastigmine group into two subgroups at the baseline: the mild behavioral and psychological symptoms of dementia (BPSD) group (Abe's BPSD score (ABS) <6) and the severe BPSD group (6≤ABS). In these two subgroups, baseline scores and changes were also retrospectively analyzed until 12 months. RESULTS: Rivastigmine significantly improved the Mini-Mental State Examination score at 3 months (*p <  0.05 versus baseline) and at 6 months (*p <  0.05), the Frontal Assessment Battery (FAB) at 6 months (*p <  0.05), and ABS at 3 months (**p <  0.01) while donepezil only stabilized the three cognitive scores. On the other hand, the Geriatric Depression Scale and the Apathy Scale were stable until 12 months in both groups. Baseline BPSD severity-dependent analysis showed a small improvement of FAB at 6 months in the mild BPSD subgroup (*p <  0.05) and a great improvement of ABS at 3 months in the severe BPSD subgroup (**p <  0.01) in the rivastigmine group. CONCLUSIONS: Our present study showed that rivastigmine improved both cognitive and affective functions at 3 and 6 months, and suggested an advantage at 3 and 6 months compared to donepezil in real world dementia clinics.

DOI： 10.3233/JAD-150518

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/OBJECTIVE: There are few reports on the effects of anti-Alzheimer's disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting. METHODS: "Okayama Late Dementia Study (OLDS)" is a retrospective clinical cohort study focusing on older AD patients (n = 373; age≥75 years) treated with monotherapy donepezil (n = 55), galantamine (n = 222), rivastigmine (n = 63), or memantine (n = 33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy. RESULTS: All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine ( *p <  0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months ( *p <  0.05), and memantine (3 and 6 months, *p <  0.05) and rivastigmine (3 months, **p <  0.01) improved Abe's Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months ( *p <  0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil ( *p <  0.05), as did female Geriatric Depression Scale scores at 6 months ( *p <  0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months ( *p <  0.05), while male ADL scores became worse with rivastigmine at 12 months ( *p <  0.05). CONCLUSION: OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.

DOI： 10.3233/JAD-150175

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier B.V.  

In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients. This studywas designed for a newsimple assessment of BPSD. Wefirst employed a clinical survey for the local community with sending an inquiry letter to all members (n= 129) of dementia caregiver society, and then attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Inter-rater reliabilitywas examined comparing scores between main and second caregivers (n = 70) for AD. Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abe's BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1-9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r = 0.716,p &lt
0.01) in 792 AD patients (age 78.6 ± 7.0 years, MMSE 19.0 ± 5.9), and took a shorter time as only 56.8 ± 38.8 s (p &lt
0.01) than NPI score (132.7 ± 94.0 s) with 136 AD patients. A high inter-rater reliability was obtained (r = 0.964,p &lt
0.01) with a little smaller score (0.877 time) of ABS in secondary than the main caregivers. ABS provides a new simple and quick test for BPSD assessment, with a good correlation to NPI but a shorter time, and with a high inter-rater reliability. Thus ABS is useful for evaluating BPSD for mild to moderate dementia patients.

DOI： 10.1016/j.jns.2015.01.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To identify clinical and demographic predictors for mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD) or reversion to normal cognition, and sustained MCI. METHODS: In total, 74 baseline MCI subjects were retrospectively investigated and categorized into three subgroups: conversion to AD, sustained MCI, or reversion to normal cognition during one year. The clinical and demographic characteristics assessed were age, gender, educational attainment, vascular risk factors, white matter lesions (WMLs), and parahippocampal gyrus atrophy (PGA), analyzed by magnetic resonance imaging (MRI) using the voxel-based specific regional analysis system for AD (VSRAD). RESULTS: Of the 74 MCI subjects, 29 (39.2%) were classified as "converters", 39 (52.7%) as "sustained MCI", and 6 (8.1%) as "reverters". Among the three subgroups, there were significant differences in educational attainment (years) (*p = 0.03), baseline mini-mental state examination (MMSE) scores (***p<0.001), and periventricular and deep white matter hyperintensity grades (*p = 0.02 and *p = 0.03, respectively). Baseline PGA showed a significant increasing trend among the three subgroups (reverters<sustained MCI<converters, (###)p<0.001). MCI subjects with higher educational attainment and low VSRAD Z-scores without WMLs were associated with reversion to normal cognitive function. CONCLUSIONS: Risk factors for MCI conversion to AD were low educational attainment, low baseline MMSE scores, high grade WMLs, and high VSRAD Z-scores. High educational attainment, low VSRAD Z-scores, and no WMLs characterized reversion to normal cognition.

DOI： 10.1016/j.jns.2014.09.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

Background and purpose: Spinocerebellar ataxia type 36 (SCA36), also called Asidan, is an autosomal-dominant neurodegenerative disorder identified as a hexanucleotide GGCCTG repeat expansion in the first intron 1 of the NOP56 gene. In the present study, for the first time an autopsy sample from an Asidan patient was examined and cytoplasmic inclusions and (GGCCUG)n repeat RNA foci were detected. Methods: Hematoxylin and eosin staining, immunohistochemical staining, as well as fluorescence in situ hybridization were used to investigate the cytoplasmic inclusions of ubiquitin and p62 and the (GGCCUG)n repeat RNA foci. Results: The present study showed both ubiquitin- and p62-positive inclusions in the cytoplasm of the inferior olivary nucleus of the Asidan patient, (GGCCUG)n RNA foci in neuronal nuclei of the cerebrum, cerebellum, inferior olive, spinal cord and temporal muscle, and three types of RNA foci, i.e. single small, multiple small and giant. Of interest is that the giant RNA foci, nearly 10 μm in diameter, that were detected in Purkinje cells, spinal motor neurons and most frequently in the inferior olivary nucleus, may be responsible for pivotal clinical symptoms of Asidan. Conclusions: The present study is the first report to show neuronal cytoplasmic inclusion bodies and giant RNA foci in an Asidan patient. The relationships between the giant RNA foci and neurodegeneration have yet to be studied.

DOI： 10.1111/ene.12491

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pericytes play a pivotal role in contraction, mediating inflammation and regulation of blood flow in the brain. In this study, changes of pericytes in the neurovascular unit (NVU) were examined in relation to the effects of exogenous tissue plasminogen activator (tPA) and a free radical scavenger, edaravone. Immunohistochemistry and Western blot analyses showed that the overlap between platelet-derived growth factor receptor β-positive pericytes and N-acetylglucosamine oligomers (NAGO)-positive endothelial cells increased significantly at 4 days after 90 min of transient middle cerebral artery occlusion (tMCAO). The number of pericytes and the overlap with NAGO decreased with tPA but recovered with edaravone 4 days after tMCAO with proliferation. Thus, tPA treatment damaged pericytes, resulting in the detachment from astrocytes and a decrease in glial cell line-derived neurotrophic factor secretion. However, treatment with edaravone greatly improved tPA-induced damage to pericytes. The present study demonstrates that exogenous tPA strongly damages pericytes and destroys the integrity of the NVU, but edaravone treatment can greatly ameliorate such damage after acute cerebral ischemia in rats.

DOI： 10.1002/jnr.23420

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We evaluated the neuroprotective effects of an anti-oxidative nutrient rich enteral diet (AO diet) that contained rich polyphenols (catechins and proanthocyanidins) and many other anti-oxidative ingredients. Wistar rats were treated with either vehicle, normal AO diet (containing 100kcal/100mL, catechin 38.75mg/100mL and proanthocyanidin 19mg/100mL, 1mL/day), or high AO diet (containing 10 times the polyphenols of the normal AO diet) for 14 days, and were subjected to 90min of transient middle cerebral artery occlusion. The AO diet improved motor function, reduced cerebral infarction volume, and decreased both peroxidative markers such as 4-hydroxynonenal, advanced glycation end products, 8-hydroxy-2-deoxyguanosine and inflammatory markers such as monocyte chemotactic protein-1, ionized calcium-binding adapter molecule-1, and tumor necrosis factor-α. Our study has shown that an AO diet has neuroprotective effects through both anti-oxidative and anti-inflammatory mechanisms, indicating that nutritional control with polyphenols could be useful for patients with acute ischemic stroke.

DOI： 10.1016/j.brainres.2014.08.056

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE AND IMPORTANCE: Although ketogenic diet therapy is effective in refractory seizures in childhood, its effect on adult encephalitis with similar refractory seizures and prolonged encephalopathy has not been well reported. CLINICAL PRESENTATION: We report here a case of a 22-year-old man with acute encephalitis with refractory repetitive partial seizures (AERRPS). INTERVENTION: Partial seizures of the face developed to repeated generalized convulsions, which were refractory against anti-epileptic drugs and a high dose of propofol. After struggling for 9 months, he dramatically recovered after ketogenic diet therapy. CONCLUSION: Ketogenic diet therapy may be an important tool to help cure AERRPS.

DOI： 10.1179/1743132814Y.0000000371

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Telmisartan is a unique angiotensin II type 1 receptor blocker with a partial peroxisome proliferator-activated receptor-γ (PPARγ) agonistic property to exert not only antihypertensive effect but also antimetabolic syndrome effect. METHODS: We examined the long-term effect of telmisartan on cholesterol transport-related proteins (low-density lipoprotein receptor [LDL-R]/apolipoprotein E [ApoE]) and microtubule-associated proteins 2 (MAP2) in the brains of stroke resistant spontaneously hypertensive rats (SHR-SRs), which were divided into 3 experiment groups including vehicle group (SHR/Ve), low-dose telmisartan group (SHR/Low, .3 mg/kg/day), and high-dose telmisartan group (SHR/High, 3 mg/kg/day). RESULTS: The numbers of LDL-R- and immuno-ApoE-positive neurons increased in both cerebral cortex and hippocampus of SHR/Ve throughout 6, 12, and 18 months of age, compared with age-matched normotensive Wistar rats. On the other hand, telmisartan significantly reduced the numbers of LDL-R- and ApoE immuno-positive neurons in both cerebral cortex and hippocampus, with similar effectiveness in the SHR/Low group without blood pressure (BP) lowering to BP lowering (SHR/High). The decrease of MAP2-positive neuron in SHR/Ve was recovered by telmisartan in both cerebral cortex and hippocampus. CONCLUSIONS: These findings suggest that a long-term treatment with telmisartan directly improved neuronal lipid metabolism in the cerebral cortex and hippocampus of SHR-SR, mainly improving LDL-R and ApoE metabolism (SHR/Low) with a small additive benefit by BP lowering (SHR/High), which could provide a preventative approach in patients with hypertension at risk of Alzheimer disease.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.05.033

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.

DOI： 10.1002/jnr.23406

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Telmisartan, an angiotensin receptor blocker also called metabosartan, is a promising solution for preventing cognitive decline or the incidence of dementia. METHODS: We examined the effects of telmisartan on cholesterol transport-related proteins (apolipoprotein E [ApoE]/low-density lipoprotein receptor [LDL-R]) and microtubule-associated protein 2 (MAP2) in the brain of spontaneously hypertensive stroke resistant (SHR-SR). SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes at 12 weeks of age and then was divided into 3 experiment groups including a vehicle, low-dose telmisartan (.3 mg/kg/day), and high-dose telmisartan (3 mg/kg/day). RESULTS: The low dose served to improve the metabolic syndrome of SHR-SR without lowering the blood pressure (BP) whereas the high dose was used to improve metabolic syndrome while lowering BP. Immunohistologic analysis showed that ApoE expression of cortical neurons was strong in the vehicle group at 6, 12, and 18 months of age, and that this ApoE expression pattern was very similar between the ipsilateral and contralateral sides of cerebral ischemia. On the other hand, LDL-R expression of cortical neurons was transiently increased at 6 months of age only on the ipsilateral side. Telmisartan dramatically suppressed the expression of ApoE/LDL-R at both doses. There was no remarkable difference in neuronal MAP2 staining between the 3 groups. CONCLUSIONS: These findings suggest that both low and high doses of telmisartan prevented the activation of ApoE/LDL-R in SHR-SR after tMCAO, and that the antimetabolic effect was regarded as the most important mechanism with few additional benefits by lowering BP in this transient stroke model.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.04.010

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記述言語：日本語   出版者・発行元：医学図書出版(株)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND PURPOSE: This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo. METHODS: Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography. RESULTS: The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarin-pretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban- and apixaban-pretreated rats. CONCLUSIONS: This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.

DOI： 10.1161/STROKEAHA.114.005316

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Previously, we reported that reactive oxygen species and signaling molecules of angiotensin II produced lipid peroxides, degenerated proteins, and injured DNA after cerebral ischemia in normotensive Wistar rats. Here, we investigated the long-term effect of the angiotensin II type I receptor blocker telmisartan on oxidative stress and hyperphosphorylated α-synuclein accumulation in stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 3 months, SHR-SR were divided into 3 treatment groups: SHR-SR vehicle (SHR/Ve), SHR-SR low-dose telmisartan (.3 mg/kg/day) (SHR/low), and SHR-SR high-dose telmisartan (3 mg/kg/day) (SHR/high). Immunohistologic analyses were conducted in these groups and Wistar rats at the age of 6, 12, and 18 months. The SHR/Ve group demonstrated more progressive increase in advanced glycation end product (AGE)-, 4-hydroxy-2-nonenal (4-HNE)-, and phosphorylated α-synuclein (pSyn)-positive cells in the cerebral cortex and hippocampus compared with the Wistar group at 18 months. These expressions were reduced in the SHR/low group even without lowering blood pressure (BP), and expressions were dramatically suppressed in the SHR/high group with lowering of BP. These data suggest that persistent hypertension in SHR-SR strongly potentiate the markers of oxidative damage (AGEs and 4-HNE) and abnormal accumulation of pSyn, which were greatly suppressed by telmisartan in a dose-dependent manner without and with lowering of BP.

DOI： 10.1016/j.jstrokecerebrovasdis.2013.12.052

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Telmisartan is an angiotensin receptor blocker with high lipid solubility, also called metabosartan, which exerts a special protective effect on both acute brain damage and chronic neurodegeneration. We examined the effects of telmisartan on oxidative stress by advanced glycation end product (AGE) and 4-hydroxynonenal (4-HNE) assays and the accumulation of phosphorylated α-synuclein (pSyn) in the brain of stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 12 weeks, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups: the vehicle group, the low-dose telmisartan group (.3 mg/kg/day), and the high-dose telmisartan group (3 mg/kg/day, postoperatively). Immunohistologic analysis was performed when rats were 6, 12, and 18 months old. AGE, 4-HNE, and pSyn-positive cells (per square millimeter) increased with age in the cerebral cortex and hippocampus of the vehicle group, in the low-dose telmisartan group, these parameters decreased without lowering blood pressure (BP), and in the high-dose telmisartan group, these parameters increased with lowering BP. The present study suggests that a persistent hypertension after tMCAO caused a progressive oxidative stress with the abnormal accumulation of pSyn, and that telmisartan reduced oxidative stress and the accumulation of pSyn without lowering BP (low dose) or improved these conditions with a reduction in BP (high dose) via its pleiotropic effects through a potential peroxisome proliferator-activated receptor gamma stimulation in the brain of SHR-SR.

DOI： 10.1016/j.jstrokecerebrovasdis.2013.12.051

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke-prone spontaneously hypertensive rats (SHR-SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP-9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP-9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR-SP.

DOI： 10.1002/jnr.23327

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study assesses the risks and benefits of tissue plasminogen activator (tPA) treatment under oral anticoagulation with dabigatran compared with warfarin or vehicle control in transient middle cerebral artery occlusion (tMCAO). After pretreatment with warfarin (0.2 mg/kg/day), dabigatran (20 mg/kg/day), or vehicle (0.5% carboxymethyl cellulose sodium salt) for 7 days, tMCAO was induced for 120 min, followed by reperfusion and tPA (10 mg/kg/10 ml). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. At 24 hr after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and MMP-9 activity was measured by zymography. Paraparesis and intracerebral hemorrhage volume were significantly improved in the dabigatran-pretreated group compared with the warfarin-pretreated group. A marked dissociation between astrocyte foot processes and the basal lamina or pericyte was observed in the warfarin-pretreated group, which was greatly improved in the dabigatran-pretreated group. Furthermore, a remarkable activation of MMP-9 in the ipsilateral warfarin-pretreated rat brain was greatly reduced in dabigatran-pretreated rats. The present study reveals that the mechanism of intracerebral hemorrhage with warfarin-pretreatment plus tPA in ischemic stroke rats is the dissociation of the neurovascular unit, including the pericyte. Neurovascular protection by dabigatran, which was first shown in this study, could partially explain the reduction in hemorrhagic complication by dabigatran reported from clinical study.

DOI： 10.1002/jnr.23302

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The 43-kDa transactivation response DNA binding protein (TDP43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), heat shock protein 70 (HSP70), and β-amyloid (Aβ) are induced and involved in cerebral ischemia, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), but their relationships in ischemic tolerance have never been examined, although they could be involved in endogenous neuroprotection under ischemic preconditioning. In the present study, Mongolian gerbils were subjected to one or three incidents of basically nonlethal 2-min transient common carotid arteries occlusion (tCCAO). Hippocampal CA1 neurons were lost only in the 2-min three times group at 3 and 7 days, which then gradually recovered from 1 to 6 months. Inductions of TDP43 and FUS/TLS were accelerated from 3 months to 7 days or from 7 days to 1 day, respectively, after 2-min three times ischemia compared with once. The cytoplasmic stainings of TDP43 and FUS/TLS showed a further acceleration of the peaks from 1 months to 3 days or from 1 months to 7 days, respectively, after 2-min three times ischemia compared with once. In contrast, HSP70 was induced only at 7 days after 2-min tCCAO for three times, with no expression for Aβ. These data show that ischemic preconditioning offers a way to induce endogenous neuroprotection and neurogenesis in gerbils, with TDP43, FUS/TLS, and HSP70 involved in this function.

DOI： 10.1002/jnr.23301

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

AIM: The purpose of this study was to determine the relationship between the combined presence of medial temporal atrophy (MTA) and white matter lesions (WMLs: periventricular hyperintensity (PVH) and deep white matter hyperintensity) and the cognitive/emotional function in Alzheimer's disease (AD) patients. METHODS: The subjects included 193 patients with AD and 30 normal elderly controls. On MRI, MTA was rated using the Voxel-based specific regional analysis system for AD (VSRAD). WMLs was also estimated using the Fazekas scale. The MRI measurements were classified as follows: MTA=VSRAD<2 or ≥2; WML absent (-) 0/1 or present (+) 2/3. A total of five groups were assessed, including four groups with AD and a control group. The cognitive and emotional functions were evaluated with neuropsychological tests (Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Geriatric Depression Scale (GDS) and Apathy scale). RESULTS: Four AD groups showed significant declines in the both the MMSE and FAB scores compared to that observed in the control group ((***)p<0.001, (**)p<0.01, (*)p<0.05). Among these four AD groups, the MMSE and FAB scores of in the VSRAD<2 and WML (-) groups significantly declined to VSRAD≥2 and WML (+), respectively group ((*)p<0.05). VSRAD≥2 and WML (+) groups showed demonstrated significantly higher scores than the control group on the GDS ((*)p<0.05), and the PVH (+) group exhibited significantly higher scores than the control group on the apathy scale ((*)p<0.05). Multiple regression analysis identified a VSRAD score of ≥2 and the presence of WMLs to be most significantly associated with the cognitive and emotional functions. CONCLUSIONS: Combined presence of MTA and WML is associated with lower MMSE and FAB scores. Furthermore, depression is also associated with MTA and WML, while PVH independently affects the degree of apathy.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W.B. Saunders  

Telmisartan is expected to ameliorate not only hypertension, but also metabolic syndrome as a metabosartan. We examined the effects of telmisartan on metabolic syndrome-related molecules such as insulin receptor (IR), peroxisome proliferatoractivated receptor gamma (PPAR-g), and angiotensin 2 type 1 receptor (AT1R) in stroke-resistant spontaneously hypertensive rat (SHR-SR) after transient middle cerebral artery occlusion (tMCAO), by administering telmisartan at either 0 (vehicle), .3 mg/kg/day (low dose), or 3 mg/kg/day (high dose), postoperatively, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months of age. Compared with the vehicle group, the 2 telmisartan groups dose dependently decreased the number of IR- and AT1R-positive neurons in the cerebral cortex in the ipsilateral cerebral cortex from 6 to 18 months after tMCAO. On the other hand, the number of PPAR-g-positive neurons increased in a dose-dependent manner in the 2 telmisartan groups from 6 to 18 months. The present study suggests that telmisartan dose-dependently ameliorated metabolic syndrome-related changes in the poststroke brain of SHR-SR with a direct protective effect (low dose) and an additive benefit, an antihypertensive effect at a high dose, for long-term protection after tMCAO.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.06.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W.B. Saunders  

Telmisartan, an angiotensin receptor blocker with high lipid solubility, also called metabo-sartan, not only reduces blood pressure (BP), but also ameliorates inflammation in the cerebral cortex and in adipose tissue. We examined the effects of telmisartan on inflammatory responses of monocyte chemotactic protein-1, tumor necrosis factor-a, and ionized calcium-binding adapter molecule 1 in the brain of spontaneously hypertensive rat stroke-resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO). At 12 weeks of age, SHR-SR received tMCAO for 90 minutes and were divided into 3 groups, that is, the vehicle group, a low-dose telmisartan group (.3 mg/kg/day), and a high-dose telmisartan group (3 mg/kg/ day). Immunohistological analysis was performed when rats became 6, 12 and 18 months old. Monocyte chemotactic protein-1, tumor necrosis factor-a, and ionized calcium-binding adapter molecule 1 cells (/mm2) immunoreactivities increased with age in the cerebral cortex and hippocampus of the vehicle group, suggesting strong and persistent inflammatory changes in SHR-SR after tMCAO up to 18 months of age. On the other hand, a low dose of telmisartan significantly reduced such inflammatory changes without lowering BP, whereas a high dose of telmisartan showed a few additional improvements, including the lowering of BP throughout 6-18 months of age. The present study suggests that persistent hypertension after tMCAO caused a long-lasting inflammatory response in the SHR-SR brain, and that even a low dose of telmisartan reduced continuous inflammation without lowering BP via its pleiotropic effects in the SHR-SR brain. A high dose of telmisartan had a few additional benefits, including lowering BP.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.02.019