Masashi Nakamura

Tohoku University, Sendai-shi, Miyagi-ken, Japan

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Publications (8)38.27 Total impact

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    ABSTRACT: Neuromyelitis optica (NMO) is characterized by severe optic neuritis and transverse myelitis. The relationship of NMO to multiple sclerosis (MS) has long been debated, but NMO has been classified as a demyelinating disease. Since the discovery of an NMO‐specific autoantibody to aquaporin 4 (AQP4), a dominant water channel in the central nervous system densely expressed on end‐feet of astrocytes, the clinical, magnetic resonance imaging and laboratory findings to distinguish NMO from MS have been clarified. Furthermore, pathological studies showed an extensive loss of immunoreactivities to astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), and perivascular deposition of immunoglobulins and activated complements with a relative preservation of the staining of myelin basic protein (MBP) in acute NMO lesions, but not in MS. In support of these pathological findings, the GFAP levels in the cerebrospinal fluid (CSF) during acute exacerbation of NMO are remarkably elevated compared with MBP and neurofilament, whereas the CSF‐GFAP in MS is not different from those in controls. Additionally, recent experimental studies have convincingly shown that AQP4 antibody is pathogenic in causing astorocytic destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that damage of astrocytes is far more severe than those of myelin and neurons, and that autoimmune astrocytopathy is the primary pathology in NMO. Based on these accumulated data, we propose that NMO should be classified as an astrocytopathic disease rather than a demyelinating disease.
    Clinical and Experimental Neuroimmunology. 01/2012; 3(2):58-73.
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    ABSTRACT: The protein profiles in the cerebrospinal fluid of 10 patients with multiple sclerosis (MS), 10 patients with neuromyelitis optica (NMO), 8 inflammatory disease control patients, and 4 noninflammatory disease control patients were screened by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Peaks of 12.5 kDa were significantly lower in multiple sclerosis, NMO, and inflammatory disease control patients than in noninflammatory disease control patients, and 13.4 kDa peaks were higher in NMO than in inflammatory disease control patients. Further analyses demonstrated that both peaks were cystatin C. Enzyme-linked immunosorbent assay showed that the cystatin C levels tended to be lower in multiple sclerosis and NMO. Alterations of cystatin C may relate to the pathogeneses of demyelinating diseases.
    Annals of Neurology 09/2007; 62(2):197-200; discussion 205. · 11.19 Impact Factor
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    ABSTRACT: The aim of the present study was to detect antigenic proteins that react specifically with cerebrospinal fluid (CSF)-IgG from oligoclonal IgG bands (OB)-positive multiple sclerosis (MS) patients. To identify such antigenic proteins, we developed a rat brain proteome map using 2-DE and applied it to the immunoscreening of brain proteins that react with CSF-IgG but not with serum-IgG in OB-positive MS patients. After sequential MALDI-TOF mass spectrometry, eight proteins [two neuronal proteins (tubulin β-2 and γ enolase-2), HSP-1, Tpi-1 protein and cellular enzymes (creatine kinase, phosphopyruvate hydratase, triosephosphate isomerase and phosphoglycerate kinase-1)] were identified as candidate antigens in seven MS patients. Reactivity to tubulin was seen in Western blotting in four patients, and CSF-specific anti-tubulin IgG was detected in one patient. In addition, CSF-specific anti-gamma enolase IgG was found in another patient. These findings suggest that intrathecal immune responses may occur against a broad range of proteins in MS.
    Proteomics. Clinical applications 07/2007; 1(7):681-7. · 2.93 Impact Factor
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    ABSTRACT: NMO-IgG is a disease-specific autoantibody for neuromyelitis optica (NMO) and its target antigen is aquaporin-4 (AQP4) water channel. Recently, we established a sensitive anti-AQP4 antibody assay using human AQP4-transfected cells, which appeared more sensitive than the original NMO-IgG assay. So far, there has been no large-scale study on anti-AQP4 antibody titre in NMO and related disorders. We tested 148 sera of patients with NMO, high-risk syndrome of NMO, multiple sclerosis (MS), clinically isolated syndrome suggestive of MS and miscellaneous diseases. We analysed the relation of anti-AQP4 antibody titres and clinical and laboratory parameters. The sensitivity of anti-AQP4 antibody assay was 91% (95% CI 79-100) for NMO and 85% (65-100) for high-risk syndrome, and the specificity was 100% (91-100) for NMO and high-risk syndrome, that is, none with the other disorders was positive. Among 21 anti-AQP4 antibody-positive cases whose NMO-IgG were tested, 15 were NMO-IgG-positive and 6 were NMO-IgG-negative. Higher anti-AQP4 antibody titres were associated with complete blindness and extensive or large cerebral lesions on MRI. The lengths of spinal cord lesions on MRI were positively correlated with the titres of anti-AQP4 antibody at the nadir of exacerbations. A few patients who had short (approx. one to two vertebral segments) spinal cord lesions on MRI were also seropositive with low anti-AQP4 antibody titres, but did have other clinical and MRI features of NMO. Anti-AQP4 antibody titres became lower after high-dose methylprednisolone, and a follow-up showed anti-AQP4 antibody titres remained low in relapse-free periods under immunosuppression. Cerebrospinal fluid (CSF)-anti-AQP4 antibody was detected when the serum-antibody titres exceeded 512x, at the ratio of 1 (CSF) to 500 (serum). Using a sensitive assay, the results of the present study suggest that NMO and high-risk syndrome may be essentially anti-AQP4 antibody-associated disorders, and that the anti-AQP4 antibody titres have significant clinical and immunological implications in NMO.
    Brain 06/2007; 130(Pt 5):1235-43. · 10.23 Impact Factor
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    ABSTRACT: Neuromyelitis optica (NMO) is a devastating neurologic disease characterized by severe optic neuritis and transverse myelitis. Recently, its disease-specific serum autoantibody, NMO-IgG, was discovered with indirect immunofluorescence. However, the substrates of the immunofluorescence assay were not human but mouse brain tissues, which could influence the sensitivity and specificity of the antibody. The target antigen of NMO-IgG was recently identified as aquaporin-4 (AQP4) water channel protein, which is mainly expressed in brain and spinal cord. In the present study, we have established human cell lines that stably express human AQP4 and used these cells to detect and titrate anti-AQP4 antibody present in the sera of patients with NMO by immunofluorescence assay. The results were compared with those of the original NMO-IgG assay. We tested the sera from 10 patients with NMO, 10 with MS and five with other neurological disorders. Among the patients with NMO, six were NMO-IgG-positive. However, using the new anti-AQP4 antibody assay, we showed that eight patients with NMO including the six NMO-IgG-positives were positive for anti-AQP4 antibody. The staining pattern of AQP4-expressing cells treated with each serum of these eight NMO patients corresponded to that with a commercially available anti-AQP4 antibody. The antibody titer (maximum serum dilution for positive staining) ranged from 64x to 16,384x. The serum dilution titers were reproducible in blinded studies. In contrast, the patients with MS or other neurological disorders showed negative for anti-AQP4 antibody. Thus, the newly developed anti-AQP4 antibody assay appears to have a higher sensitivity for NMO than the original NMO-IgG assay and is expected to be useful for the diagnosis of NMO.
    The Tohoku Journal of Experimental Medicine 01/2007; 210(4):307-13. · 1.37 Impact Factor
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    ABSTRACT: The protein profiles in the cerebrospinal fluid of 10 patients with multiple sclerosis (MS), 10 patients with neuromyelitis optica (NMO), 8 inflammatory disease control patients, and 4 noninflammatory disease control patients were screened by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Peaks of 12.5kDa were significantly lower in multiple sclerosis, NMO, and inflammatory disease control patients than in noninflammatory disease control patients, and 13.4kDa peaks were higher in NMO than in inflammatory disease control patients. Further analyses demonstrated that both peaks were cystatin C. Enzyme-linked immunosorbent assay showed that the cystatin C levels tended to be lower in multiple sclerosis and NMO. Alterations of cystatin C may relate to the pathogeneses of demyelinating diseases. Ann Neurol 2007
    Annals of Neurology 08/2006; · 11.19 Impact Factor
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    ABSTRACT: Neuromyelitis optica (NMO) is clinically characterized by severe optic neuritis and transverse myelitis. In Japan, NMO has been named optic-spinal multiple sclerosis (OSMS) and it has been thought to be a subtype of multiple sclerosis (MS). However, several clinical and laboratory findings suggest NMO or OSMS is distinct from MS. Recently, the disease-specific antibody (NMO-IgG) was found in the serum from NMO patients, and its target antigen was identified as aquaporin-4 (AQP4) water channel protein which is mainly expressed in astroglial foot processes. However, the pathogenetic role of AQP4 in NMO remains unknown. We herein report a typical case of NMO in which immunohistochemical analysis showed a lack of AQP4 in the spinal cord lesions. The loss of AQP4 was evident in the central gray matter, especially in the perivascular lesions where immunoglobulins and complements were deposited, and glial fibrillary acidic protein (GFAP) staining was weak in those lesions. However, GFAP was strongly stained at the reactive astrogliosis surrounding the lesions. Myelin basic protein (MBP)-stained myelinated fibers were relatively preserved in the lesions where AQP4 was lost. In contrast to these NMO lesions, AQP4 was expressed predominantly in the gray matter in control spinal cords, and AQP4 was preserved in demyelinating MS lesions. Our findings suggest that astrocytic impairment associated with humoral immunity against AQP4 may be primarily involved in the lesion formation of NMO, and that the pathomechanisms of NMO are different from those of MS in which demyelination is the primary pathology.
    The Tohoku Journal of Experimental Medicine 08/2006; 209(3):269-75. · 1.37 Impact Factor
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    ABSTRACT: We report a 44-year-old woman with toxoplasma encephalitis that occurred during cyclosporine monotherapy for Behçet disease. She had been treated with cyclosporine for 8 years. She experienced headache and, nausea, and then consciousness disturbance developed. Brain MRI showed high-signal intensity lesions on T1-weighted MRI with Gd-enhancement in the left temporoparietal lobe, right thalamus and right frontal and temporal lobes. The pathological examination of the biopsied brain specimens suggested toxoplasma encephalitis. She improved rapidly after the administration of antibiotics for toxoplasma gondii. Anti-toxoplasma specific protein antibodies were positive in the serum and CSF, supporting a diagnosis of acute toxoplasmosis. Toxoplasma encephalitis due to cyclosporine mono-therapy has not been reported yet. The measurement of anti-toxoplasma specific protein antibodies may be useful for the early, accurate diagnosis of toxoplasmosis.
    Rinsho shinkeigaku = Clinical neurology 03/2005; 45(2):105-10.