Hitoshi Aizawa - Academia.edu (original) (raw)

Papers by Hitoshi Aizawa

Clinical and Experimental Neuroimmunology, 2021

Eculizumab, a humanized monoclonal antibody against complement protein C5, has been approved for ... more Eculizumab, a humanized monoclonal antibody against complement protein C5, has been approved for the treatment of myasthenia gravis (MG) in Japan since 2017. However, there are few reports on reducing the dose of prednisolone (PSL) and immunosuppressants after eculizumab administration.

BMC Neurology, 2020

Background We investigated the gait characteristics of patients with Parkinson’s disease (PD), un... more Background We investigated the gait characteristics of patients with Parkinson’s disease (PD), under free-living conditions, using a wearable device, and assessed their relationships with global cognitive function and motor abnormalities. Methods The study subjects comprised patients with PD aged < 80 years, with a Mini-Mental State Examination (MMSE) score of ≥20, free of any motor complications. A wearable sensor with a built-in tri-axial accelerometer was waist-mounted on each patient, and continuous, 24-h records were obtained. The mean gait cycle duration and mean gait acceleration amplitude, under free-living conditions, were computed and analyzed to determine their relationship with disease duration, MMSE score, Unified Parkinson’s Disease Rating Scale (UPDRS) Part III score, and postural instability and gait difficulty (PIGD) score. Results The study included 106 consecutive patients with PD. The mean gait cycle duration was 1.18 ± 0.12 s, which was similar to that of the...

Internal Medicine, 2021

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare condition of systemic vasculitis o... more Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare condition of systemic vasculitis of small to medium-sized blood vessels. We herein report the case of a 75-year-old man who presented with hemiplegia on his right side due to cerebral infarction following myalgia and a high fever. He had no history of asthma or allergic rhinitis. He was diagnosed with EGPA based on the presence of eosinophilia, sinusitis suggested by magnetic resonance imaging, and muscle pathology. His hemiplegia improved rapidly after corticosteroid therapy. This case suggests that EGPA should be a differential diagnosis of cerebral infarction with myalgia and eosinophilia.

Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018

Frontiers in Neurology, 2020

Journal of Neural Transmission, 2019

To determine the association of daily physical activity with cognition, mood disorders, and olfac... more To determine the association of daily physical activity with cognition, mood disorders, and olfactory function in treatmentnaive patients with early-stage Parkinson's disease (PD). The study subjects were 52 treatment-naive patients with earlystage PD (< 80 years). Daily physical activity was measured using a wearable sensor with a built-in triaxial accelerometer, and its association with cognition [mini-mental state examination (MMSE), clock-drawing test (CDT), frontal assessment battery (FAB), and behavioral assessment of the dysexecutive syndrome (BADS)], depressive symptoms [Beck Depression Inventory-Second Edition (BDI-II)], apathy [Starkstein Apathy Scale (AS)], and olfactory function [Odor Stick Identification Test for the Japanese (OSIT-J)] was analyzed using multiple linear regression after adjustment for age, sex, and education status. The daily physical activity (0.42 ± 0.11 m/s 2) of the PD group was significantly lower than that of healthy controls (p < 0.001). Moreover, the daily physical activity of the PD group was significantly associated with FAB (β = 0.337, p = 0.027) and BADS (β = 0.374, p = 0.017) scores, but not with MMSE, CDT, BDI-II, AS, and OSIT-J scores. The daily physical activity is significantly reduced in treatment-naive patients with early-stage PD, and the low activity correlates with frontal/ executive function.

Clinical Neurophysiology, 2020

Objective: Spike onset zone (SpOZ), which is considered the region where interictal spikes origin... more Objective: Spike onset zone (SpOZ), which is considered the region where interictal spikes originate, was analyzed by magnetoencephalography using gradient magnetic-field topography (GMFT). The aim of this study was to clarify the characteristics of SpOZ in various epileptogenic lesions. Methods: 41 patients with focal cortical dysplasia (FCD) (type I, 17; type IIa, 13; type IIb, 11), 6 with tumor-related epilepsy (Tumor), and 7 with tuberous sclerosis complex (TSC) were enrolled. SpOZ was analyzed GMFT. Spike peak was analyzed by conventional dipole analysis, and the distribution of dipoles was defined as spike peak zone (SpPZ). The distribution of SpOZ and the relationship between SpOZ and SpPZ were evaluated among lesions by gyral-unit level. Results: The distribution of SpOZ were significantly larger in than other lesions (P ¼ 0:004). In terms of the relationship between SpOZ and SpPZ, FCD type IIb were likely to show complete concordance, whereas type I and TSC had more discordant relationship (P ¼ 0:013). Conclusions: The distribution of SpOZ and the relationship between SpOZ and SpPZ indicates the characteristics of the epileptogenic zone in various epileptogenic lesions. FCD type IIb shows small and localized epileptogenic zone, while type I and TSC have broad and complicated epileptogenic zone/network.

Rinsho Shinkeigaku, 2022

菅原麻弓 1) 山田純司 1) 相澤仁志 2) 田口丈士 3) 南里和紀 3) 4)

Additional file 2. (a) Relationship between mean gait cycle duration and PIGD score, (b) Relation... more Additional file 2. (a) Relationship between mean gait cycle duration and PIGD score, (b) Relationship between mean gait acceleration amplitude and PIGD score.

Additional file 1. Results of measurements in a 77-year-old man with Parkinson's disease: (a)... more Additional file 1. Results of measurements in a 77-year-old man with Parkinson's disease: (a) The ordinate represents the gait cycle duration, and the abscissa represents time. (b) The ordinate represents the acceleration of all movements including gait, and the abscissa represents time. Note the decreased in acceleration amplitude during sleep (time from 23:30 to 06:00.

Journal of the Neurological Sciences, 2022

Clinical Neuropharmacology, 2018

Objectives: The objective of this study was to investigate the influence of treatment with cholin... more Objectives: The objective of this study was to investigate the influence of treatment with cholinesterase inhibitors (ChEIs) and calcineurin inhibitors (CNIs) on the occurrence of cramps in myasthenia gravis (MG) patients. Methods: The frequency and duration of cramp and serum electrolytes were evaluated in 81 patients with MG. The patients were classified using Myasthenia Gravis Foundation of America postintervention status scores based on the treatment and the responsiveness to the treatment. Quantitative MG score, MG activities of daily living score, MG composite score, or MG quality of life 15 score was used to assess the health-related quality of life (QOL). Results: Muscle cramps developed in 44 (54.3%) of 81 MG patients. The scores of MG activities of daily living, MG composite, or MG-QOL 15-item questionnaire in patients with cramp were significantly higher than those in patients without cramps (P = 0.002, P = 0.01, or P = 0.0022, respectively). The serum magnesium concentrations were lower in patients treated with CNI (n = 16) than in those not treated with CNI (n = 65) (P = 0.002). The probability of cramps was significantly higher in patients treated with ChEIs (≥180 mg/d) in addition to CNI than in patients who were treated with a low dose of ChEIs (≤60 mg/d) without concomitant CNI treatment (P = 0.017). Conclusions: Our data suggested that treatment with a high dose of ChEI and CNI accelerated the probability of cramps and reduced the QOL in MG patients.

Neuropathology, 2018

We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gamm... more We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA-binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

Journal of Neurology, 2020

Background Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebr... more Background Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebral microbleeds (CMBs) occur differently among stroke subtypes. The association of CMBs with cryptogenic stroke is essentially unknown. Methods CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) is a multicenter registry with comprehensive data including gradient-echo T2*-weighted magnetic resonance imaging of cryptogenic stroke patients who underwent transesophageal echocardiography. Patients' clinical characteristics were compared according to the presence and location of CMBs. Results A total of 661 patients (68.7 ± 12.7 years; 445 males) were enrolled, and 209 (32%) had CMBs. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04, p = 0.020), male sex (OR 1.85, 95% CI 1.18-2.91, p = 0.007), hypertension (OR 1.71, 95% CI 1.03-2.86, p = 0.039), chronic kidney disease (OR 1.64, 95% CI 1.11-2.43, p = 0.013), deep and subcortical white matter hyperintensity (OR 1.82, 95% CI 1.16-2.85, p = 0.009), and periventricular hyperintensity (OR 2.18, 95% CI 1.37-3.46, p = 0.001) were independently associated with the presence of CMBs. Aortic complicated lesions (OR 1.78, 95% CI 1.12-2.84, p = 0.015) were associated with deep and diffuse CMBs, whereas prior anticoagulant therapy (OR 7.88, 95% CI, 1.83-33.9, p = 0.006) was related to lobar CMBs. Conclusions CMBs were common, and age, male sex, hypertension, chronic kidney disease, and cerebral white matter diseases were related to CMBs in cryptogenic stroke. Aortic complicated lesions were associated with deep and diffuse CMBs, while prior anticoagulant therapy was related to lobar CMBs.

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2016

Mutations in the fused in sarcoma (FUS) gene can cause amyotrophic lateral sclerosis (ALS), and F... more Mutations in the fused in sarcoma (FUS) gene can cause amyotrophic lateral sclerosis (ALS), and FUS gene mutations have been reported in sporadic ALS patients with basophilic cytoplasmic inclusions. Deficiency of adenosine deaminase acting on RNA 2 (ADAR2), an enzyme that specifically catalyzes GluA2 Q/R site-editing, has been reported in considerable proportions of spinal motor neurons of the majority of sporadic ALS patients. We describe the relationship between GluA2 Q/R site-editing efficiency and FUS-positive inclusions in a patient with FUS(P525L). A 24-year-old woman with ALS presented with basophilic cytoplasmic inclusions, significantly reduced GluA2 Q/R site-editing efficiency in the spinal motor neurons, and markedly decreased ADAR2 mRNA levels. Neuropathologic examination showed that not all spinal motor neurons expressed ADAR2 and revealed FUS-positive cytoplasmic inclusions in motor neurons irrespective of ADAR2 immunoreactivity. There were no phosphorylated transactiv...

Neurology, Jan 24, 2016

We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM)... more We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM) in relation to anti-transcriptional intermediary factor 1 γ antibody (anti-TIF1-γ-Ab), a marker of cancer association. We retrospectively studied 349 patients with idiopathic inflammatory myopathies (IIMs), including 284 patients with pretreatment biopsy samples available. For the classification of IIMs, the European Neuromuscular Center criteria were applied. Patients with CAM with (anti-TIF1-γ-Ab[+] CAM) and without anti-TIF1-γ-Ab (anti-TIF1-γ-Ab[-] CAM) were compared with patients with IIM without cancers within and beyond 3 years of myositis diagnosis. Cancer was detected in 75 patients, of whom 36 (48%) were positive for anti-TIF1-γ-Ab. In anti-TIF1-γ-Ab(+) patients with CAM, cancers were detected within 1 year of myositis diagnosis in 35 (97%) and before 1 year of myositis diagnosis in 1. All the anti-TIF1-γ-Ab(+) patients with CAM satisfied the dermatomyositis (DM) criteria, incl...

$Research paper thumbnail of Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis$

Therapeutic Advances in Neurological Disorders, 2020

Background: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and ... more Background: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated damage at the neuromuscular junction. Recently, the REGAIN study showed that eculizumab was effective and well tolerated in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG). However, there is no consensus regarding which kind of patients with gMG are selected to preferentially receive eculizumab. Methods: Between January and December 2018, we followed 1388 patients with MG at seven hospitals located in Tokyo and Chiba. We evaluated the clinical features of MG and the patients’ quality of life. Clinical status and severity were determined by the recommendations of the Myasthenia Gravis Foundation of America. Results: Of 1388 patients with MG, 12 (0.9%) patients received eculizumab. A total of 11 patients who were anti-acetylcholine receptor antibody-positive with refractory gMG (M:F = 3:8) comp...

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Brain and nerve = Shinkei kenkyu no shinpo, 2019

Disease-specific and site-selective deficiency of an RNA editing enzyme, adenosine deaminase acti... more Disease-specific and site-selective deficiency of an RNA editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2), has been demonstrated in sporadic amyotrophic lateral sclerosis (sALS) motor neurons. ADAR2 regulates Ca2+ influx through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors via adenosine-to-inosine conversion at the glutamine/arginine site of GluA2 mRNA, which makes ADAR2 a key factor in acquired Ca2+ resistance in motor neurons. Deficient ADAR2 of sALS motor neurons is supposed to lead to excessive Ca2+ influx through AMPA receptors, resulting in TDP-43 pathology and nuclear pore complex pathology, and eventually motor neuronal death. We considered that AMPA receptor antagonists could strongly prevent excessive Ca2+ influx through AMPA receptors and block motor neuronal degeneration in sALS. Perampanel, a selective non-competitive AMPA receptor antagonist, has been reported to prevent deterioration in a mouse model for sALS, in which ADAR2 is con...

A single systemic injection of acromelic acid, one of kainoids, caused semipermanent severe spast... more A single systemic injection of acromelic acid, one of kainoids, caused semipermanent severe spastic paraparesis in the rat. One week after the injection, routine histological examination disclosed chromatoly-sis of small neurons with marked reactive gliosis in the spinal cord, particularly the lumbar and sacral segments. These changes were observed throughout the gray matter except the most dorsal margin of the posterior horn (I and II layers of Rexed). Glial processes were intensely stained by immunohistochemistry against glial fibrillary acidic protein (GFAP) which was maximal at the ventral part of the dorsal horn at the sacral and lumbar segment. Mild glial proliferation was visualized only by the immunohistochemistry of GFAP in the hippocampal CA4, but pyramidal cells appeared intact by ordinary staining. The remaining structures were not affected including large anterior horn cells and the white matter of the spinal cord. The following points are deduced from these results; 1) The selective loss of small neurons in the lower spinal cord is responsible for the marked spastic paraparesis produced by the injection of acromelic acid. Destroyed neurons may belong to a group of inhibitory intemeurons of spinal reflex arcs. 2) By analogy to the excitotoxic action of kainic acid, acromelic acid may have caused neural degeneration through excessive depolarization. This suggests that degenerated neurons might bear receptors with great affinity to acromelic acid. 3) Acromelic acid conceivably acts through a different glutamate receptor subtype from the kainate receptor in the rat central nervous system because of the different pattern of cell vulnerability from that following systemic kainic acid injection. 4) Selective destruction of small neurons of the spinal cord, possibly by extrinsic neurotoxin, might give a clue to the pathophysiology of human spastic paraparesis such as the ‘stiff-man syndrome’.

Scientific Reports, 2017

Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic... more Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca 2+permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca 2+mediated cell death signals may be a therapeutic strategy for ALS. Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease of unknown etiology. It has long been known that both nuclear volume and RNA contents of motor neurons are decreased in ALS patients compared to healthy control subjects 1. Recent findings of ALS-related genes encoding RNA-binding proteins (RBPs) such as TDP-43 and FUS and of a reduction or loss of these RBPs from the nuclei of anterior horn cells (AHCs) in ALS patients suggest a role of RNA dysregulation in ALS pathogenesis 2-4. RNAs and RBPs are transported between the nucleus and the cytoplasm, and the nuclear pore complex (NPC) functions as a gateway for nucleo-cytoplasmic transport of these molecules 5,6. Disruption of nucleo-cytoplasmic transport or the dysfunction of the NPC is a predicted mechanism underlying cell death 7-10 ; and its potential role in ALS pathogenesis has also been suspected. Indeed, the gene encoding the GLE1 protein, a nucleoporin (Nup) that is a constituent of the NPC, has been associated with ALS 11 , and morphological changes in the nuclear membrane upon disruption of Nups have been observed in motor neurons of patients with sporadic ALS or with SOD1-associated ALS 12,13. Moreover, nucleo-cytoplasmic transport through the NPC was found to be disrupted in cultured cells and in animals expressing the ALS-associated C9orf72 gene harboring an expanded GGGGCC (G 4 C 2) hexanucleotide repeat sequence 14-16. However, the manner in which NPC is disrupted in ALS motor neurons remains unclear. Adenosine deaminase acting on RNA (ADAR)2 is a member of the ADAR family, which catalyzes the adenosine-to-inosine (A-to-I) conversion in pre-mRNA. Progressive down-regulation of ADAR2 with resultant failure of the A-to-I conversion at the glutamine/arginine (Q/R) site of GluA2, the Ca 2+-regulating subunit of AMPA receptors, has been demonstrated in motor neurons of most patients with sporadic ALS 17-19. Furthermore, conditional ADAR2 knockout mice (AR2 mice) displayed the ALS phenotype resulting from progressive degeneration of motor neurons, and also exhibited TDP-43 mislocalization that resembled TDP-43 pathology 20,21 , the most reliable pathological hallmark of ALS. This behaviorally and pathologically ALS-like phenotype of AR2 mice results from excess influx of Ca 2+ through AMPA receptor complexes containing Q/R site-unedited GluA2 subunits 20,21 ; continuous Ca 2+ influx through these abnormal AMPA receptors activates the Ca 2+-dependent cysteine protease calpain, which cleaves TDP-43 into aggregation-prone fragments that serve as seeds for TDP-43 pathology 20-22. The above evidence indicates that the ADAR2-deficient motor neurons in AR2 mice mimic the pathogenetic mechanism of sporadic ALS. Notably, the motor neurons of AR2 mice possess abnormal vacuoles during the course of death, and these nuclear vacuoles disappear when Ca 2+ influx through AMPA receptors is normalized 23 .