RESUMO
Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. Cases comprised six females and two males, with a median age of 56.5 years (range, 46-71 years) and a median disease duration of 62.5 months (range, 0.6-252 months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for GFAP: (i) astrocyte lysis: extensive loss of astrocytes with fragmented and/or dust-like particles; (ii) progenitor recruitment: loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (iii) protoplasmic gliosis: presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (iv) fibrous gliosis: lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2 months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD.
Assuntos
Astrócitos/patologia , Encéfalo/patologia , Ativação do Complemento/fisiologia , Neuromielite Óptica/patologia , Idoso , Aquaporina 4/imunologia , Astrócitos/imunologia , Autoanticorpos , Encéfalo/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologiaRESUMO
BACKGROUND: The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated. METHODS: We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells. RESULTS: Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease. CONCLUSIONS: Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.
Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/fisiologia , Sistema Nervoso Central/citologia , Citocinas/farmacologia , Esclerose Múltipla/patologia , Linfócitos B/classificação , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Feminino , Feto/citologia , Citometria de Fluxo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Esclerose Múltipla/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologiaRESUMO
BACKGROUND: The low level of disease activity and manageable safety profile seen with fingolimod versus placebo in a 6-month, phase 2, randomized controlled trial in Japanese patients with relapsing multiple sclerosis (MS; ClinicalTrials.gov Identifier NCT00537082) were maintained in the initial 6-month observational study extension. Here, we report long-term safety and efficacy results of the 3-year follow-up to the phase 2 study extension. METHODS: The 6-month core study was completed by 147 patients, of whom 143 entered the extension and took at least one dose of fingolimod. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg (n = 23) or 0.5 mg (n = 27). During the extension, the patients taking fingolimod 1.25 mg (n = 46) were switched to open-label fingolimod 0.5 mg, and those originally randomized to fingolimod 0.5 mg (n = 47) continued with open-label fingolimod 0.5 mg. RESULTS: Continuous fingolimod treatment was associated with a sustained low level of MRI and relapse activity for the duration of the extension phase; 75-100% (range across all assessment time points up to end of study) of patients remained free of Gd-enhanced T1 lesions, 88-100% remained free of new/newly enlarged T2 lesions, and 45-62% remained relapse-free. In patients who switched to the active treatment, a 79.5% decrease in annualized relapse rate (ARR; from 1.131 before switch to 0.232 6-months after switch) was observed in the first 6 months of the extension phase and thereafter remained low until the end of study (0.16-0.31 across all assessment time points after switch up to end of study). The mean number of Gd-enhanced T1 and new/newly enlarged T2 lesions decreased up to month 9 and thereafter remained low until the end of study (0.0-0.1 and 0.0-0.3, respectively, across all assessment time points after switch up to end of study). Fingolimod was generally well-tolerated and the safety profile was consistent with the core and 6-month extension. Serious adverse events were reported in 13.3% of patients during the extension study, with the range in the continuous fingolimod and placebo-fingolimod switch groups (3.7-21.7%) being similar to that reported in the core study for the placebo and fingolimod groups (5.3-20.4%). CONCLUSION: Continuous fingolimod treatment over 36 months was associated with maintained efficacy and a manageable safety profile with no new safety signals. These results indicate that fingolimod provides long-term treatment benefit for Japanese patients with relapsing MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT00670449 (April 28, 2008).
Assuntos
Cloridrato de Fingolimode/farmacologia , Imunossupressores/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Adulto , Feminino , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Japão , Masculino , Pessoa de Meia-Idade , Adulto JovemAssuntos
Desastres , Terremotos , Esclerose Múltipla/psicologia , Neuromielite Óptica/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Estresse Psicológico/epidemiologia , Adulto , Feminino , Habitação/estatística & dados numéricos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/mortalidade , Neuromielite Óptica/complicações , Neuromielite Óptica/mortalidade , Recidiva , Estresse Psicológico/complicaçõesRESUMO
A number of persons with an intractable disease (ID) experience work-related problems that could lead to job loss. The aim of this study was to ascertain perceptions regarding a range of work-related issues and corresponding support needs of individuals with an ID. Potential participants were people ages 15 to 64 with one of the 130 intractable chronic diseases designated in the Act to Comprehensively Support the Daily and Social Activities of Persons with Disabilities (Comprehensive Support for the Disabled Act). Participants completed a self-administered questionnaire. With the assistance of patients' organizations, 3,000 questionnaires were mailed to potential participants. Questions included demographic characteristics, family concerns, employment/supported employment, work accommodations, and other aspects of life. Responses were received from 889 (29.6%) participants, and respondents had 57 IDs. Forty-six-point-seven percent of respondents reported being unemployed due to fatigue and/or long-term treatment. Nearly half of the unemployed respondents reported that they had been unable to work despite their willingness to do so. Common requests for accommodation included flexible work hours, working at home, and job/workplace modifications. Only 30% of respondents knew about job training programs and supported work available for persons with disabilities. The results of the study are relevant for employees, employers, and occupational health/human resource professionals. The issue of reasonable accommodations for persons with an ID needs to be addressed in future research in order to promote continued work by those persons.
RESUMO
Our objective was to confirm the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients. We conducted a 36-week confirmatory study, consisting of 12-week pre-observation period followed by 24-week treatment period. Patients received placebo or edaravone i.v. infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6. The efficacy primary endpoint was changed in the revised ALS functional rating scale (ALSFRS-R) scores during the 24-week treatment. Patients were treated with placebo (n = 104) and edaravone (n = 102). Changes in ALSFRS-R during the 24-week treatment were -6.35 ± 0.84 in the placebo group (n = 99) and -5.70 ± 0.85 in the edaravone group (n = 100), with a difference of 0.65 ± 0.78 (p = 0.411). Adverse events amounted to 88.5% (92/104) in the placebo group and 89.2% (91/102) in the edaravone group. In conclusion, the reduction of ALSFRS-R was smaller in the edaravone group than in the placebo group, but efficacy of edaravone for treatment of ALS was not demonstrated. Levels and frequencies of reported adverse events were similar in the two groups.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antipirina/análogos & derivados , Sequestradores de Radicais Livres/uso terapêutico , Adulto , Idoso , Análise de Variância , Antipirina/uso terapêutico , Método Duplo-Cego , Edaravone , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: A 6-month phase 2 study of fingolimod demonstrated efficacy and safety in Japanese patients with relapsing-remitting multiple sclerosis (MS). Here we report a 6-month observational extension that evaluated efficacy and safety in patients who received fingolimod continuously for 12 months or who switched from placebo to fingolimod. METHODS: Of 147 patients who completed the 6-month core study, 143 entered the extension. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg or 0.5 mg. During the extension, all patients were switched to open-label fingolimod 0.5 mg. RESULTS: Magnetic resonance imaging (MRI) and relapse outcomes were maintained or improved in patients treated with fingolimod for 12 months versus those treated for 6 months. No new safety events were reported over 12 months of treatment. Infections occurred in similar proportions of continuously treated and switched patients, while cardiac and liver adverse events occurred in fewer continuously treated than switched patients. Four patients were aquaporin-4 (AQP4) antibody-positive, three of whom showed rapid disease exacerbations within 10 days of fingolimod initiation. CONCLUSION: Continuous fingolimod treatment for up to 12 months was associated with maintained or improved efficacy and a manageable safety profile, consistent with that previously seen. Results in a small number of patients suggest lack of benefit in AQP4 antibody-positive patients. Meaningful statistical interpretation was limited by the small sample size in each treatment group, owing to the number of patients who completed the core study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00670449.
Assuntos
Povo Asiático/etnologia , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/etnologia , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Adolescente , Adulto , Método Duplo-Cego , Feminino , Cloridrato de Fingolimode , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esfingosina/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Neuromyelitis optica (NMO) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally extensive myelitis. Until recently, NMO was considered an acute aggressive variant of multiple sclerosis (MS), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody (NMO-IgG), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other central nervous system (CNS) inflammatory demyelinating disorders. The target antigen of NMO-IgG was confirmed to be aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, mainly expressed on astrocytic foot processes at the blood-brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid (CSF) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF-GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO.
Assuntos
Astrócitos/patologia , Imunoglobulina G/metabolismo , Neuromielite Óptica/patologia , Animais , Aquaporina 4/imunologia , Aquaporina 4/metabolismo , Astrócitos/imunologia , Astrócitos/metabolismo , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Humanos , Imunoglobulina G/imunologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/metabolismoRESUMO
OBJECTIVES: To analyze aquaporin-4 (AQP4) antibody-positive patients who do not fulfill the current diagnostic criteria of neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD). METHODS: We used a cell-based assay (CBA) with AQP4-transfected cells to detect AQP4 antibody in 298 consecutive patients with inflammatory CNS disorders seen at Tohoku University Hospital from 2007 to 2012. The patients were diagnosed as NMO, NMOSD, multiple sclerosis, or others using the respective current diagnostic criteria. The seropositive samples by CBA were also tested using a commercial ELISA. RESULTS: Seventy-two patients were AQP4 antibody positive. Among them, 18.1% (13/72) did not meet the NMO or NMOSD criteria (7 with monophasic optic neuritis, 2 with attacks restricted to the brainstem, and 4 with myelitis with less than 3 vertebral segments) and 84.6% (11/13) of these had only a single attack. The ELISA results were negative in 38.4% (5/13) of those patients, and they had lower antibody titers by CBA than patients with NMO/NMOSD. Although these patients had a shorter follow-up and few attacks, they shared some clinical features with NMO/NMOSD patients such as onset age, female predominance, presence of other autoantibodies, severe optic neuritis attacks, centrally located spinal cord lesions, persisting hiccups, and nausea or vomiting episodes. CONCLUSIONS: AQP4 antibody-positive patients with single or recurrent attacks of optic neuritis, myelitis, or brain/brainstem disease not fulfilling the current criteria of NMO or NMOSD may not be uncommon, and they should also be included in the NMO spectrum.
Assuntos
Aquaporina 4/imunologia , Neuromielite Óptica/diagnóstico , Adulto , Idoso , Autoanticorpos/sangue , Biomarcadores/sangue , Estudos Transversais , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Seguimentos , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologiaRESUMO
Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial. Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient. We have distinguished six different lesion types. The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2). Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6). In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis. Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes. Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion.
Assuntos
Encéfalo/patologia , Neuromielite Óptica/metabolismo , Neuromielite Óptica/patologia , Medula Espinal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 1/fisiologia , Aquaporina 4/fisiologia , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Estudos de Coortes , Feminino , Proteína Glial Fibrilar Ácida/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/etiologia , Medula Espinal/metabolismo , Adulto JovemRESUMO
OBJECTIVE: Dysphagia is one of the cardinal symptoms of Parkinson's disease (PD). It is closely related to the quality of life and longevity of PD patients. The aim of the study is to clarify the pathophysiological mechanisms responsible for dysphagia in PD. DESIGN: A cross-sectional and longitudinal comparative study. SETTING: Tohoku University Hospital. PARTICIPANTS: Eight patients with dysphagia, 15 patients without dysphagia and 10 normal control subjects. MAIN OUTCOME MEASURES: The time needed for swallowing initiation and changes in brain glucose metabolism at baseline and after a 3-year follow-up period. RESULTS: The time needed for swallowing initiation was significantly longer in the patients with dysphagia compared with the patients without dysphagia at baseline and after the 3-year follow-up period (p<0.05). The patients with dysphagia exhibited hypometabolism in the supplementary motor area (SMA) and the anterior cingulate cortex (ACC) compared with the 10 normal control subjects at baseline (uncorrected p<0.001). After the 3-year follow-up period, the number of brain areas showing hypometabolism increased, involving not only the SMA and the ACC but also the bilateral medial frontal lobes, middle cingulate cortex, thalamus and right superior, middle, inferior and orbital frontal gyri (uncorrected p<0.001). In contrast, the patients without dysphagia showed virtually no regional hypometabolism at baseline (uncorrected p<0.001) and only a small degree of hypometabolism in the SMA and ACC after the 3-year follow-up period (uncorrected p<0.001). CONCLUSIONS: These results suggest that dysphagia in PD patients is mainly related to a difficulty in swallowing initiation that is based on a combination of poor movement planning due to SMA dysfunction and impaired cognitive processing due to ACC dysfunction.
RESUMO
Complement is thought to play a pivotal role in neuromyelitis optica (NMO) pathogenesis. Anaphylatoxins (C3a, C4a, and C5a), produced in complement activation, have proinflammatory potential, and thereby may play an important role. We measured concentrations of anaphylatoxins in CSF and sera, obtained from patients with NMO (n=15), multiple sclerosis (MS) (n=15), and other neurological disease (OND) (n=12), and evaluated their clinical implications. The CSF-C5a levels were elevated significantly in NMO patients, especially in patients with multiple enhanced lesions on MRI. The CSF-C5a levels correlated with the severity of exacerbation. Our results may provide a rationale for anti-complement therapies of NMO.
Assuntos
Complemento C5a/líquido cefalorraquidiano , Neuromielite Óptica/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Encéfalo/patologia , Feminino , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/patologia , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/patologia , Neuromielite Óptica/patologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.
Assuntos
Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Mutação/genética , Mutação/fisiologia , Adolescente , Adulto , Idade de Início , Povo Asiático , Creatina Quinase/sangue , Disferlina , Feminino , Testes de Função Cardíaca , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Testes de Função Respiratória , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons. Approximately 20% of familial ALS cases are linked to mutations in Cu/Zn superoxide dismutase (SOD1) gene. Previously, we developed a transgenic rat model of ALS overexpressing mutant SOD1 protein. The rat model facilitates preclinical ALS research employing various therapeutic approaches such as intrathecal administration, cell transplantation, and viral vector-mediated gene transduction to the affected central nervous system. Hepatocyte growth factor (HGF) is a pleiotropic growth factor and also a potent survival-promoting factor for motor neurons. To examine its therapeutic effect on ALS, we administered human recombinant HGF (hrHGF) to the transgenic ALS rats. In contrast with vehicle-treated rats, continuous intrathecal infusion of hrHGF attenuated spinal motor neuron degeneration and prolonged the duration of the disease, even with administration from the onset of symptoms. To translate the strategy to human treatment, we performed dose-finding and safety studies using non-human primate model of contusive cervical spinal cord injury. Introducing exogenous HGF protein also revealed a distinct therapeutic effect with functional recovery. Given the therapeutic potential of hrHGF on ALS, we started a novel phase I clinical trial for ALS patients in Tohoku University Hospital.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Fator de Crescimento de Hepatócito/administração & dosagem , Animais , Ensaios Clínicos Fase I como Assunto , Humanos , Ratos , Ratos Transgênicos , Proteínas Recombinantes/administração & dosagem , Pesquisa Translacional BiomédicaRESUMO
Hereditary neuropathy with liability to pressure palsy (HNPP) is characterized by recurrent focal neuropathies, which usually become symptomatic in the second or third decade of life. However, clinical phenotypic heterogeneity among patients with HNPP has recently been reported. Certain patients show polyneuropathy-type diffuse nerve injuries, whereas others remain asymptomatic at older ages. We present two cases of elderly-onset bilateral peroneal nerve palsies with diffuse muscle weakness in the lower limbs and glove-and-stocking type sensory disturbance. Both patients were diagnosed with HNPP by genetic analyses that detected deletions of chromosome 17p11.2 in peripheral myelin protein 22 genes. Their clinical courses suggested that the Japanese sitting style termed 'seiza', a way of sitting on the floor with the lower legs crossed under the thighs, was a precipitating factor for the bilateral peroneal nerve palsies.
Assuntos
Aquaporina 4/imunologia , Cauda Equina/imunologia , Neuromielite Óptica/complicações , Radiculopatia/imunologia , Medula Espinal/imunologia , Idoso , Cauda Equina/patologia , Feminino , Gadolínio , Humanos , Imunoglobulina G/líquido cefalorraquidiano , Imageamento por Ressonância Magnética , Radiculopatia/etiologia , Radiculopatia/patologia , Medula Espinal/patologiaRESUMO
Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-ß (IFN-ß) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-ß may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-ß 1a and subcutaneous IFN-ß 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-ß preparations in MS patients have only been performed in Caucasian populations. NAbs positivity has been reported to be associated with HLA-DRB1 alleles, suggesting that the positivity might differ among populations with distinct genetic backgrounds. Clinical information and sera were collected from 229 consecutive MS patients treated with IFN-ß in 4 centers in Japan. Sera were tested for NAbs using a luciferase reporter gene assay. In total, 5.2% of IFN-ß-1a-treated patients (4/77) and 30.3% of IFN-ß-1b-treated patients (46/152) were positive for Nabs. The frequency of NAbs was highest in patients treated for 13 to 24 months. Clinical relapse and contrast-enhancing lesions in the magnetic resonance imaging increased together with NAbs titers in this group. In conclusion, the prevalence of NAbs in Japanese MS patients is similar to that in Caucasian populations and is associated with an increase in disease activity. Therefore, routine NAbs testing is recommended also in Asian populations to ensure the early identification of patients who would benefit from a change in therapy.
Assuntos
Anticorpos Neutralizantes/sangue , Interferon beta/farmacologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Anticorpos Neutralizantes/imunologia , Povo Asiático , Humanos , Interferon beta/imunologia , Interferon beta/uso terapêutico , Luciferases , Imageamento por Ressonância Magnética , Fatores de TempoRESUMO
BACKGROUND: The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration. RESULTS: In this study, we have demonstrated that α-synuclein (αSYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- and concentration-dependent manner. Once incorporated, the extracellular αSYN was immediately assembled into high-molecular-weight oligomers and subsequently formed cytoplasmic inclusion bodies. Furthermore, αSYN uptake by neurons and cells of the oligodendroglial lineage was markedly decreased by the genetic suppression and pharmacological inhibition of the dynamin GTPases, suggesting the involvement of the endocytic pathway in this process. CONCLUSIONS: Our findings shed light on the mode of αSYN uptake by neuronal and oligodendroglial cells and identify therapeutic strategies aimed at reducing the propagation of protein misfolding.
Assuntos
Dinaminas/antagonistas & inibidores , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , alfa-Sinucleína/metabolismo , Animais , Western Blotting , Linhagem Celular , Técnicas de Cocultura , Endocitose , Inibidores Enzimáticos , Imunofluorescência , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Camundongos , Microscopia Confocal , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Oligodendroglia/patologiaRESUMO
The attentional set-shifting deficit that has been observed in Parkinson's disease (PD) has long been considered neuropsychological evidence of the involvement of meso-prefrontal and prefrontal-striatal circuits in cognitive flexibility. However, recent studies have suggested that non-dopaminergic, posterior cortical pathologies may also contribute to this deficit. Although several neuroimaging studies have addressed this issue, the results of these studies were confounded by the use of tasks that required other cognitive processes in addition to set-shifting, such as rule learning and working memory. In this study, we attempted to identify the neural correlates of the attentional set-shifting deficit in PD using a compound letter task and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography during rest. Shift cost, which is a measure of attentional set-shifting ability, was significantly correlated with hypometabolism in the right dorsolateral prefrontal cortex, including the putative human frontal eye field. Our results provide direct evidence that dysfunction in the dorsolateral prefrontal cortex makes a primary contribution to the attentional set-shifting deficit that has been observed in PD patients.