Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum disorders.

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.

Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis.

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.

Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study.

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.

Perceptions regarding a range of work-related issues and corresponding support needs of individuals with an intractable disease.

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).

Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients.

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.

Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension.

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.

The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica.

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.

Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders.

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.

Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica.

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.

Hypometabolism in the supplementary and anterior cingulate cortices is related to dysphagia in Parkinson's disease: a cross-sectional and 3-year longitudinal cohort study.

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.

Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.

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.

[Clinical translation of hepatocyte growth factor for amyotrophic lateral sclerosis].

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.

Two cases of elderly-onset hereditary neuropathy with liability to pressure palsy manifesting bilateral peroneal nerve palsies.

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.

Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica.

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.

Neutralizing antibodies are associated with a reduction of interferon-β efficacy during the treatment of Japanese multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-β (IFN-β) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-β may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-β 1a and subcutaneous IFN-β 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-β preparations in MS patients have only been performed in Caucasian populations.

Suppression of dynamin GTPase decreases α-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy.

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.

Attentional set-shifting deficit in Parkinson's disease is associated with prefrontal dysfunction: an FDG-PET study.

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.

Intramuscular interferon beta-1a is effective in Japanese patients with relapsing-remitting multiple sclerosis: a pre-treatment versus treatment comparison study of gadolinium-enhanced MRI brain lesions.

Background And Objective: Interferon beta (IFNβ) is standard therapy for multiple sclerosis (MS). The efficacy of intramuscular (IM) IFNβ-1a (AVONEX(®)) was assessed in 25 Japanese patients with relapsing-remitting MS (RRMS).

Methods: Patients with RRMS not previously treated with IFNβ or other disease-modifying therapies were included in this 36-week study.

Involvement of activated microglia in increased vulnerability of motoneurons after facial nerve avulsion in presymptomatic amyotrophic lateral sclerosis model rats.

Activated microglia are observed in various neurodegenerative diseases and are thought to be involved in the processes of neuronal cell death. Motoneuron damage in the facial nuclei after facial nerve avulsion is accelerated in presymptomatic transgenic rats expressing human mutant Cu(2+) /Zn(2+) superoxide dismutase 1 (SOD1), compared with that in wild-type rats. To reveal the functional role of microglia in motoneuronal death, we investigated the microglial response after facial nerve avulsion in presymptomatic mutant SOD1(H46R) (mSOD1(H46R) ) rats.

Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson's disease: a 3 year longitudinal study.

Dementia is one of the most debilitating symptoms of Parkinson's disease. A recent longitudinal study suggests that up to 80% of patients with Parkinson's disease will eventually develop dementia. Despite its clinical importance, the development of dementia is still difficult to predict at early stages.

Recurrent hypogeusia in a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Hypogeusia, a condition with diminished sense of taste, is caused by several conditions, including zinc deficiency and as a side-effect of drugs, but is not common in neurological disorders. A 55-year-old Japanese man with a 30-year history of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) presented with hypogeusia during hospitalization for a recurrence of CIDP. The hypogeusia improved after treatment with high-dose intravenous methylprednisolone (HIMP).

[Regenerative therapies for amyotrophic lateral sclerosis using hepatocyte growth factor].

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. We have developed rats that express a human SOD1 transgene with two different ALS-associated mutations develop striking motor neuron degeneration and paralysis.