Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 116
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
BMC Neurol ; 24(1): 282, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138414

RESUMO

BACKGROUND: Primary lateral sclerosis (PLS) is an extremely rare condition; therefore, to date no clinical studies have been conducted. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) was developed in the United States of America. The PLSFRS is a crucial assessment scale for international collaborative research and future clinical trials for PLS. It is useful for evaluating medical conditions through face-to-face assessments and telephone interviews such as when a face-to-face assessment is not possible due to disasters or the burden of hospital visits. This study assessed the reliability and consistency of in-person and telephone interviews using the Japanese version of the PLSFRS. METHODS: We enrolled 19 Japanese patients who met the specific criteria for inclusion at the six collaborating institutions. The PLSFRS assessments were performed by two evaluators at defined time points and analyzed for intra-rater and inter-rater reliability and consistency between the in-person and telephone interviews. RESULTS: The Japanese version of the PLSFRS was developed by a specialized company and translator, and modified to consider the Japanese lifestyle through a consensus among motor neuron specialists. The quadratic-weighted kappa coefficients for the intra-rater and the inter-rater agreement were substantial (intra-rater: 0.691-1.000, inter-rater: 0.634-1.000). Moreover, the intraclass correlation coefficient for the PLSFRS total score was 0.997 (95% confidence interval, 0.992-0.999). CONCLUSIONS: This study provides results regarding the Japanese version of the PLSFRS intra-rater and inter-rater reliability and consistency between in-person and telephone interviews.


Assuntos
Índice de Gravidade de Doença , Humanos , Reprodutibilidade dos Testes , Feminino , Masculino , Pessoa de Meia-Idade , Japão , Adulto , Idoso , Avaliação da Deficiência , População do Leste Asiático
2.
J Neurochem ; 166(3): 547-559, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37005741

RESUMO

Astrocytes are the most abundant glial cell type in the brain, where they participate in various homeostatic functions. Transcriptomically, diverse astrocyte subpopulations play distinct roles during development and disease progression. However, the biochemical identification of astrocyte subtypes, especially by membrane surface protein glycosylation, remains poorly investigated. Protein tyrosine phosphatase receptor type zeta (PTPRZ) is a highly expressed membrane protein in CNS glia cells that can be modified with diverse glycosylation, including the unique HNK-1 capped O-mannosyl (O-Man) core M2 glycan mediated by brain-specific branching enzyme GnT-IX. Although PTPRZ modified with HNK-1 capped O-Man glycans (HNK-1-O-Man+ PTPRZ) is increased in reactive astrocytes of demyelination model mice, whether such astrocytes emerge in a broad range of disease-associated conditions or are limited to conditions associated with demyelination remains unclear. Here, we show that HNK-1-O-Man+ PTPRZ localizes in hypertrophic astrocytes of damaged brain areas in patients with multiple sclerosis. Furthermore, we show that astrocytes expressing HNK-1-O-Man+ PTPRZ are present in two demyelination mouse models (cuprizone-fed mice and a vanishing white matter disease model), while traumatic brain injury does not induce glycosylation. Administration of cuprizone to Aldh1l1-eGFP and Olig2KICreER/+ ;Rosa26eGFP mice revealed that cells expressing HNK-1-O-Man+ PTPRZ are derived from cells in the astrocyte lineage. Notably, GnT-IX but not PTPRZ mRNA was up-regulated in astrocytes isolated from the corpus callosum of cuprizone model mice. These results suggest that the unique PTPRZ glycosylation plays a key role in the patterning of demyelination-associated astrocytes.


Assuntos
Astrócitos , Doenças Desmielinizantes , Animais , Camundongos , Astrócitos/metabolismo , Encéfalo/metabolismo , Cuprizona/toxicidade , Cuprizona/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Modelos Animais de Doenças , Glicosilação , Camundongos Endogâmicos C57BL , Polissacarídeos/metabolismo , Proteínas Tirosina Fosfatases/metabolismo
3.
J Neurol Neurosurg Psychiatry ; 94(10): 816-824, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37142397

RESUMO

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.


Assuntos
Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Esclerose Lateral Amiotrófica/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Estudo de Associação Genômica Ampla , População do Leste Asiático , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Neurônios Motores/patologia
4.
J Peripher Nerv Syst ; 28(4): 597-607, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37555797

RESUMO

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.


Assuntos
Eritromelalgia , Doenças do Sistema Nervoso Periférico , Humanos , Células HEK293 , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Eritromelalgia/genética , Eritromelalgia/patologia , Dor , Mutação/genética
5.
Genomics ; 114(5): 110469, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36041634

RESUMO

We report two patients with autosomal dominant neuronal intranuclear inclusion disease (NIID) harboring the biallelic GGC repeat expansion in NOTCH2NLC to uncover the impact of repeat expansion zygosity on the clinical phenotype. The zygosity of the entire NOTCH2NLC GGC repeat expansion and DNA methylation were comprehensively evaluated using fluorescent amplicon length PCR (AL-PCR), Southern blotting and targeted long-read sequencing, and detailed genetic/epigenetic and clinical features were described. In AL-PCR, we could not recognize the wild-type allele in both patients. Targeted long-read sequencing revealed that one patient harbored a homozygous repeat expansion. The other patient harbored compound heterozygous repeat expansions. The GGC repeats and the nearest CpG island were hypomethylated in all expanded alleles in both patients. Both patients harboring the biallelic GGC repeat expansion showed a typical dementia-dominant NIID phenotype. In conclusion, the biallelic GGC repeat expansion in two typical NIID patients indicated that NOTCH2NLC-related diseases could be completely dominant.


Assuntos
Corpos de Inclusão Intranuclear , Doenças Neurodegenerativas , Receptor Notch2/metabolismo , Humanos , Corpos de Inclusão Intranuclear/genética , Doenças Neurodegenerativas/genética , Fenótipo
6.
J Neurol Neurosurg Psychiatry ; 91(3): 285-290, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31937581

RESUMO

OBJECTIVE: The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy. METHODS: We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group. RESULTS: From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy. CONCLUSION: We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.


Assuntos
Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/terapia , Respiração Artificial , Traqueostomia , Idoso , Esclerose Lateral Amiotrófica/complicações , Estudos de Casos e Controles , Feminino , Humanos , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento
7.
Brain ; 142(9): 2845-2859, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31312839

RESUMO

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.


Assuntos
Cerebrosídeo Sulfatase/fisiologia , Chaperonas Moleculares/metabolismo , Mutação de Sentido Incorreto , Doença de Parkinson/metabolismo , Mutação Puntual , alfa-Sinucleína/metabolismo , Adulto , Idoso , Animais , Animais Geneticamente Modificados , Encéfalo/enzimologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Células Cultivadas , Cerebrosídeo Sulfatase/sangue , Cerebrosídeo Sulfatase/genética , Demência/sangue , Demência/etiologia , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Técnicas de Inativação de Genes , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/genética , Doença de Parkinson/psicologia , Linhagem , Agregação Patológica de Proteínas/genética , Mapeamento de Interação de Proteínas , Proteínas Recombinantes/metabolismo
8.
BMC Neurol ; 19(1): 184, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382909

RESUMO

BACKGROUND: Pembrolizumab is an immune-checkpoints inhibitor that enhances the immune response against cancer cells and therefore is useful for the treatment of several carcinomas. However, pembrolizumab sometimes perturbs the immune system resulting in various autoimmune neurological complications. In this situation, autoimmune myositis due to pembrolizumab is a rare but not-negligible complication. Here, we report two cases of autoimmune myositis due to pembrolizumab, with systemic myositis involving levator palpebrae superioris, extraocular and hindneck muscles. CASE PRESENTATION: Case 1 was a 78-year-old man with advanced urinary cancer referred to the neurological ward presenting with bilateral ptosis, restriction of eye movements, dropped head and weakness in the lower extremities after pembrolizumab administration. His blood examination showed elevated serum levels of creatine kinase with positive anti-PM-Scl 75 and anti-signal recognition particle antibodies. Needle electromyography and MRI suggested systemic inflammatory myopathy. There were no findings to indicate myocardial involvement on electrocardiogram or echocardiogram. Administration of intravenous methylprednisolone following plasma exchange ameliorated creatine kinase levels and inhibited the progression of clinical symptoms. Case 2 was a 72-year-old female with lung cancer and multiple metastasis, including lymph nodes and brain. She presented with back pain, right-sided ptosis, weakness of her neck extensors and flexors and elevated serum creatine kinase after receiving pembrolizumab. Although myositis specific autoantibodies were negative, needle electromyography and MRI suggested systemic inflammatory myopathy and muscle biopsy indicated necrotizing myopathy. There were no signs indicating heart dysfunction and her electrocardiogram was normal. Clinical symptoms and serum creatine kinase levels were ameliorated after the administration of intravenous methylprednisolone. CONCLUSIONS: Both cases showed atypical extensive inflammatory myositis including levator palpebrae superioris, extraocular and hindneck muscles, resembling myasthenia gravis (MG), but they did not have MG-related antibodies. Edrophonium test was negative and showed no daily fluctuation. Two previously reported cases also presented with systemic necrotizing systemic myositis involving extraocular and facial muscles caused by pembrolizumab. Idiopathic inflammatory myositis evolving levator palpebrae superioris and ocular muscles is quite rare; however, myositis due to immune-checkpoint inhibitors may preferentially involve these muscles. This case report will alert physicians to the possibility of systemic inflammatory myopathy evolving levator palpebrae superioris, extraocular and hindneck muscles mimicking MG due to pembrolizumab.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Miosite/induzido quimicamente , Idoso , Feminino , Humanos , Masculino , Miastenia Gravis
9.
J Neural Transm (Vienna) ; 125(6): 937-944, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29644397

RESUMO

Coenzyme Q2, polyprenyltransferase (COQ2) variants have been reported to be associated with multiple system atrophy (MSA). However, the relationship between COQ2 variants and familial Parkinson's disease (PD) remains unclear. We investigated the frequency of COQ2 variants and clinical symptoms among familial PD and MSA. We screened COQ2 using the Sanger method in 123 patients with familial PD, 52 patients with sporadic PD, and 39 patients with clinically diagnosed MSA. Clinical information was collected from medical records for the patients with COQ2 variants. Allele frequencies of detected rare non-synonymous variants were compared by public database of the Exome Aggregation Consortium (ExAC) and Japanese genetic variation database, using Fisher's exact test. We detected two probands with rare variants in COQ2, the p.P157S from Family A, whose patient was clinically diagnosed as having juvenile PD, and the p.H15 N/p.G331S from Family B, whose patients shared common symptoms of PD. Furthermore, in an association study comparing these familial PD and MSA cases with a public variant database, eight non synonymous variants were detected in COQ2. Three of these were very rare variants, namely, p.P157S, p.L261Qfs*4, and p.G331S, and one variant, p.G21S, was found to show a significant association with familial PD. COQ2 variants rarely may associate with the disease onset of familial PD. Our findings contribute to an understanding of COQ2 variants in neurodegenerative disorders.


Assuntos
Alquil e Aril Transferases/genética , Predisposição Genética para Doença/genética , Atrofia de Múltiplos Sistemas/genética , Doença de Parkinson/genética , Adulto , Idoso , Animais , Povo Asiático/genética , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Coelhos
10.
BMC Neurol ; 18(1): 112, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30107829

RESUMO

BACKGROUND: Cutaneous and systemic plasmacytosis are skin disorders characterized by cutaneous polyclonal plasma cell infiltration accompanied by polyclonal hypergammaglobulinemia. Cutaneous plasmacytosis involvement is limited to the skin, mainly on the face and trunk, while systemic plasmacytosis also involves 2 or more organ systems. However, there have been no reports of inflammatory myositis due to plasmacytosis. Here, we report a patient with plasmacytosis who developed myalgia and easy fatigability due to inflammatory myositis. CASE PRESENTATION: A 54-year-old man with cutaneous plasmacytosis on the face, chest, and back complained of a history of atypical facial and lower leg pain and easy fatigability since the age of 45 years. Muscle-strength tests revealed bilateral trivial gastrocnemius weakness with myalgia. The results of routine blood analysis, including creatine kinase and thyroid function, were normal, but levels of several inflammation markers and autoantibodies were elevated. Additionally, lower leg magnetic resonance imaging and gastrocnemius muscle biopsy revealed inflammatory myositis mimicking polymyositis. His plasmacytosis, myalgia, and lower leg weakness were ameliorated by prednisolone. CONCLUSION: The patient was diagnosed with inflammatory myositis due to plasmacytosis. Given that plasmacytosis has previously been reported to disrupt the immune status, myositis in this patient might have been associated with abnormal autoimmune inflammation. Neurologists and physicians should thus be aware that plasmacytosis might be associated with inflammatory myositis accompanied by myalgia.


Assuntos
Mialgia/etiologia , Miosite/complicações , Plasmócitos/patologia , Doença Crônica , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Pele/patologia
11.
J Neurol Neurosurg Psychiatry ; 87(8): 851-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26746183

RESUMO

OBJECTIVE: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. METHODS: We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. RESULTS: We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34×10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10(-10)-1.1×10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). CONCLUSIONS: We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.


Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Conectina/genética , Predisposição Genética para Doença/genética , Alelos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único/genética , Prognóstico
12.
Front Neurol ; 15: 1340694, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38405402

RESUMO

Spinal and bulbar muscular atrophy (SBMA) is an X-linked recessive motor neuron disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the androgen receptor (AR) gene. It is thought that the nuclear translocation of abnormal AR proteins following binding to testosterone triggers the onset of the disease. We report the case of a patient who had SBMA coincident with Klinefelter syndrome. He developed SBMA symptoms rapidly after receiving androgen replacement therapy for Klinefelter syndrome. No cases of coincident SBMA and Klinefelter syndrome have been reported, and if confirmed by further patients in future, that androgen hormones are strongly associated with the development and progression of SBMA in fact in humans.

13.
Neuromuscul Disord ; 41: 56-58, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38954991

RESUMO

Myasthenia gravis (MG) is an autoimmune disease that targets neuromuscular junctions. While immunotherapy remains the cornerstone of treatment, the effects of Janus kinase (JAK) inhibitors on MG remain underexplored. In this report, we describe the case of a 58-year-old woman with ocular myasthenia gravis who received treatment with the JAK inhibitor, baricitinib for alopecia areata. The patient presented with left eyelid ptosis and an inadequate response to steroids and pyridostigmine, along with symptoms of alopecia areata. Following diagnosis, we initiated a treatment regimen consisting of baricitinib for six months. After initiation of baricitinib, we observed a complete resolution of the patient's MG symptoms, accompanied by hair regrowth, even when steroids were tapered and pyridostigmine was discontinued. Furthermore, the titer of the anti-acetylcholine receptor antibody was decreased. This report represents the first reported case of anti-acetylcholine receptor antibody-positive MG that was successfully treated through the inhibition of JAK activity.


Assuntos
Azetidinas , Miastenia Gravis , Purinas , Pirazóis , Sulfonamidas , Humanos , Miastenia Gravis/tratamento farmacológico , Azetidinas/uso terapêutico , Feminino , Pessoa de Meia-Idade , Sulfonamidas/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Resultado do Tratamento , Receptores Colinérgicos/imunologia
14.
J Neurol Neurosurg Psychiatry ; 84(9): 969-72, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23467416

RESUMO

BACKGROUND: In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed 'split hand'. Previous axonal excitability studies have suggested increased nodal persistent sodium current and reduced potassium current in motor axons in ALS, but the extent of excitability changes in APB and ADM axons in ALS has never been compared. OBJECTIVE: To elucidate the peripheral axonal pathophysiology of split hand. METHODS: In both APB and ADM motor axons of 21 patients with ALS and 17 age-matched normal controls, threshold tracking was used to measure excitability indices such as strength-duration time constant (SDTC; a measure of persistent sodium current) and threshold electrotonus. RESULTS: In normal controls, SDTC was significantly longer for APB than ADM axons, suggesting that axonal excitability is physiologically higher in APB axons. Compared with normal controls, patients with ALS had longer SDTC and greater threshold changes in depolarising threshold electrotonus in both APB and ADM axons. Furthermore, the difference in extent of SDTC prolongation between normal subjects and patients with ALS was greater in APB than ADM axons. CONCLUSIONS: APB axons have physiologically higher excitability than ADM axons, and, in ALS, the hyperexcitability is more prominent in APB axons. Although cortical mechanisms would also be involved, more prominent hyperexcitability of APB axons may contribute to development of split hand, and the altered axonal properties are possibly associated with motor neuronal death in ALS.


Assuntos
Esclerose Lateral Amiotrófica/complicações , Axônios , Mãos/inervação , Mãos/fisiopatologia , Neurônios Motores , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/fisiopatologia , Interpretação Estatística de Dados , Estimulação Elétrica , Fenômenos Eletrofisiológicos , Potencial Evocado Motor , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Refratário Eletrofisiológico
15.
J Neurol Neurosurg Psychiatry ; 84(4): 398-401, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23012445

RESUMO

BACKGROUND: A GGGGCC hexanucleotide repeat expansion in C9ORF72 occurs on a chromosome 9p21 locus that is linked with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in white populations. The diseases resulting from this expansion are referred to as 'c9FTD/ALS'. It has been suggested that c9FTD/ALS arose from a single founder. However, the existence of c9FTD/ALS in non-white populations has not been evaluated. RESULTS: We found two index familial ALS (FALS) patients with c9FTD/ALS in the Japanese population. The frequency of c9FTD/ALS was 3.4% (2/58 cases) in FALS. No patients with sporadic ALS (n=110) or control individuals (n=180) had the expansion. Neuropathological findings of an autopsy case were indistinguishable from those of white patients. Although the frequency of risk alleles identified in white subjects is low in Japanese, one patient had all 20 risk alleles and the other had all but one. The estimated haplotype indicated that the repeat expansion in these patients was located on the chromosome with the risk haplotype identified in white subjects. CONCLUSIONS: C9ORF72 repeat expansions were present in a Japanese cohort of ALS patients, but they were rare. Intriguingly, Japanese patients appear to carry the same risk haplotype identified in white populations.


Assuntos
Esclerose Lateral Amiotrófica/genética , Expansão das Repetições de DNA , Proteínas/genética , Alelos , Esclerose Lateral Amiotrófica/patologia , Autopsia , Encéfalo/patologia , Proteína C9orf72 , Evolução Fatal , Feminino , Genótipo , Haplótipos , Humanos , Corpos de Inclusão/patologia , Japão , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-myc/genética , Medula Espinal/patologia , Proteinopatias TDP-43/patologia
16.
Ann Hematol ; 92(2): 245-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23053181

RESUMO

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem disorder associated with plasma cell dyscrasia. Elevated serum levels of vascular endothelial growth factor (VEGF), which strongly promotes neovascularization and vasopermeability, are considered to be responsible for the characteristic symptoms such as angiomata, pleural effusion/ascites, edema, and organomegaly in the disorder. To study whether other angiogenetic factors are upregulated in POEMS syndrome, we measured serum levels of basic fibroblast growth factor and hepatocyte growth factor (HGF), as well as VEGF, in 17 patients with POEMS syndrome. All these factors were significantly upregulated in the POEMS syndrome patients. After the treatment with anti-VEGF antibody, the levels of HGF did not change, suggesting that elevation of HGF levels is not secondary to VEGF overproduction. These results suggest that different angiogenetic factors might contribute to the pathogenesis of POEMS syndrome, and this fact might contribute to the insufficient clinical effects obtained by suppression of VEGF alone.


Assuntos
Fator 2 de Crescimento de Fibroblastos/biossíntese , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/biossíntese , Síndrome POEMS/genética , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento de Hepatócito/genética , Humanos , Masculino , Melfalan/farmacologia , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Síndrome POEMS/sangue , Síndrome POEMS/tratamento farmacológico , Talidomida/farmacologia , Talidomida/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética
17.
Brain ; 135(Pt 3): 833-46, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22252998

RESUMO

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.


Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Citoplasma/metabolismo , Proteínas de Ligação a DNA/metabolismo , Animais , Atrofia , Comportamento Animal/fisiologia , Western Blotting , Cistatina C/metabolismo , Dependovirus , Modelos Animais de Doenças , Eletromiografia , Fenômenos Eletrofisiológicos , Vetores Genéticos , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Motores/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/patologia , Neuritos/patologia , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase em Tempo Real , Especificidade da Espécie , Medula Espinal/metabolismo , Técnicas Estereotáxicas
18.
Acta Neurol Belg ; 123(4): 1511-1517, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37273142

RESUMO

OBJECTIVE: If lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation at a constant speed, the lesion spread time should be proportional to the anatomical distance. We verify this model in the patients. METHODS: In 29 sporadic ALS patients with hand onset followed by spread to shoulder and leg, we retrospectively evaluated the inter/intra-regional spread time ratio: time interval of symptoms from hand-to-leg divided by that from hand-to-shoulder. We also obtained the corresponding inter-/intra-regional distance ratios of spinal cord from magnetic resonance imaging of 12 patients, and those of primary motor cortex from coordinates using neuroimaging software. RESULTS: Inter-/intra-regional spread time ratios ranged from 0.29 to 6.00 (median 1.20). Distance ratios ranged from 1.85 to 2.86 in primary motor cortex and from 5.79 to 8.67 in spinal cord. Taken together with clinical manifestations, of 27 patients with the requisite information available, lesion spreading was consistent with the model in primary motor cortex in 4 (14.8%) patients, and in spinal cord in only 1 (3.7%) patient. However, in more patients (12 of 29 patients: 41.4%), the inter-regional spread times in a long anatomical distance of hand-to-leg were shorter than or equal to the intra-regional spread times in a short anatomical distance of hand-to-shoulder. CONCLUSION: Contiguous cell-to-cell propagation at a constant speed might not play a major role at least in distant lesion spreading of ALS. Several mechanisms can be responsible for progression in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Estudos Retrospectivos , Mãos
19.
Clin Ther ; 45(12): 1251-1258, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37953075

RESUMO

PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration. METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated. FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported. IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www. CLINICALTRIALS: gov.


Assuntos
Esclerose Lateral Amiotrófica , Fármacos Neuroprotetores , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Edaravone/farmacocinética , Glucuronídeos/uso terapêutico , Fármacos Neuroprotetores/farmacocinética , Sulfatos/uso terapêutico
20.
Cell Rep Med ; 4(5): 101020, 2023 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-37080205

RESUMO

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.


Assuntos
Epilepsia , Receptores de AMPA , Humanos , Receptores de AMPA/fisiologia , Neurônios , Convulsões
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA