Publications by authors named "Hitoshi Aizawa"

61 Publications

Persistent Hemichorea as a Preceding Symptom of Cerebral Infarction due to Middle Cerebral Artery Stenosis.

Intern Med 2021 Jun 12. Epub 2021 Jun 12.

Department of Neurology, Tokyo Medical University, Japan.

We herein report an 84-year-old woman with right middle cerebral artery (MCA) stenosis who presented with persistent left hemichorea preceding cerebral infarction. She visited our hospital on day 9 after the hemichorea onset. Magnetic resonance imaging (MRI) showed no acute cerebral infarction. Magnetic resonance angiography revealed right MCA stenosis. Her hemichorea persisted for 19 days and subsequently disappeared. On day 21, she developed left hemiplegia. Repeat MRI revealed a cerebral infarction in the right putamen. MCA stenosis can present with persistent hemichorea, even in the absence of cerebral infarction. Persistent hemichorea with MCA stenosis may presage cerebral infarction.
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http://dx.doi.org/10.2169/internalmedicine.7191-21DOI Listing
June 2021

Relationship between I-FP-CIT-SPECT and motor severity in drug-naive patients with Parkinson's disease.

J Neurol Sci 2021 Jul 6;426:117476. Epub 2021 May 6.

Department of Neurology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Introduction: Although functional imaging is useful for the diagnosis and pathophysiological evaluation of Parkinson's disease (PD), little is known about the relationship between functional imaging findings and PD clinical features. The objective of this study was to determine the relationship between I-FP-CIT-SPECT findings and motor symptoms, in particular gait disturbance.

Methods: The study included 46 drug-naive patients with early-stage PD. The specific binding ratios (SBRs) in the striatum and its subregions, namely anterior/posterior putamen and caudate nucleus, were calculated in patients who underwent I-FP-CIT-SPECT. Motor symptoms were evaluated using the modified Hoehn and Yahr (HY) stage and the Unified Parkinson's Disease Rating Scale (UPDRS) part III. Gait disturbance was evaluated by the mean gait cycle duration and the mean gait acceleration amplitude measured with a wearable sensor.

Results: The mean SBRs of the striatum and anterior putamen were significantly associated with the modified HY stage and UPDRS part III score. The mean SBR of the caudate nucleus was significantly associated with the UPDRS part III score. The mean striatal SBR was also significantly associated with the mean gait cycle duration and mean gait acceleration amplitude.

Conclusion: The mean striatal SBR, as determined by I-FP-CIT-SPECT, was significantly associated with motor severity and gait severity in drug-naive patients with PD.
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http://dx.doi.org/10.1016/j.jns.2021.117476DOI Listing
July 2021

[Posterior reversible encephalopathy syndrome during intravenous immunoglobulin therapy in Guillain-Barré syndrome].

Rinsho Shinkeigaku 2021 Jan 15;61(1):12-17. Epub 2020 Dec 15.

Department of Neurology, Tokyo Medical University.

A 63-year-old woman was diagnosed with Guillain-Barré syndrome (GBS), and intravenous immunoglobulin (IVIg) therapy was initiated. On the second day of IVIg therapy, she became less alert (JCS III-200) and had hyponatremia. Brain MRI showed vasogenic edema in bilateral occipital lobes, which disappeared afterwards. Her clinical course and MRI findings were consistent with those of posterior reversible encephalopathy syndrome (PRES). As a result of considering the timing of the onset of GBS and PRES and the degree of hyponatremia and hypertension in some documented patients, the cause of PRES onset in this case is considered to be IVIg therapy itself and IVIg therapy-induced hyponatremia.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001461DOI Listing
January 2021

Impact of the catechol-O-methyltransferase Val158Met polymorphism on the pharmacokinetics of L-dopa and its metabolite 3-O-methyldopa in combination with entacapone.

J Neural Transm (Vienna) 2021 01 2;128(1):27-36. Epub 2020 Nov 2.

Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical University, Asahikawa, 078-8510, Japan.

In the pharmacotherapy of patients with Parkinson's disease (PD), entacapone reduces the peripheral metabolism of L-dopa to 3-O-methyldopa (3-OMD), thereby prolonging the half-life (t) of L-dopa and increasing the area under the concentration curve (AUC). The effect of entacapone on the pharmacokinetics of L-dopa differs between patients with high-activity (H/H) and low-activity (L/L) catechol-O-methyltransferase (COMT) Val158Met polymorphisms, but the effects are unclear in heterozygous (H/L) patients. 3-OMD has a detrimental effect and results in a poor response to L-dopa treatment in patients with PD; however, the influence of this polymorphism on the production of 3-OMD remains unknown. Therefore, the present study aimed to clarify the effect of the COMT Val158Met polymorphism on the concentrations of L-dopa and 3-OMD in the presence of entacapone. We performed an open-label, single-period, single-sequence crossover study at two sites in Japan. The study included 54 Japanese patients with PD, who underwent an acute L-dopa administration test with and without 100 mg entacapone on two different days. Entacapone increased L-dopa AUC by 1.59 ± 0.26-fold in the H/H group, which was significantly higher than that in the H/L (1.41 ± 0.36-fold) and L/L (1.28 ± 0.21-fold) groups (p < 0.05). The concurrent administration of L-dopa with entacapone suppressed the increase in 3-OMD levels compared with L-dopa alone in all genotypes. Our results suggest that the COMT Val158Met polymorphism may be an informative biomarker for individualized dose adjustment of COMT inhibitors in the treatment of PD.
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http://dx.doi.org/10.1007/s00702-020-02267-yDOI Listing
January 2021

Cerebral Infarction and Myalgia in a 75-year-old Man with Eosinophilic Granulomatosis with Polyangiitis.

Intern Med 2020 Dec 4;59(23):3089-3092. Epub 2020 Aug 4.

Department of Neurology, Tokyo Medical University, Japan.

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.
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http://dx.doi.org/10.2169/internalmedicine.5099-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759697PMC
December 2020

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

Neurobiol Aging 2021 01 2;97:146.e1-146.e13. Epub 2020 Jul 2.

Department of Neurology, Jikei University Katsushika Medical Center, Tokyo, Japan.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.017DOI Listing
January 2021

Analysis of non-invasive gait recording under free-living conditions in patients with Parkinson's disease: relationship with global cognitive function and motor abnormalities.

BMC Neurol 2020 Apr 29;20(1):161. Epub 2020 Apr 29.

Department of Neurology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

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 normal controls. However, the mean gait acceleration amplitude of PD patients (1.83 ± 0.36 m/s) was significantly lower than that of the control (p < 0.001). In PD patients, the mean gait acceleration amplitude correlated with the MMSE (β = 0.197, p = 0.028), UPDRS Part III (β = - 0.327, p < 0.001), and PIGD (β = - 0.235, p = 0.008) scores.

Conclusions: The gait rhythm of PD patients is preserved at levels similar to those of normal subjects. However, the mean gait acceleration amplitude was significantly reduced in patients with PD. The results indicate that gait acceleration amplitude correlates with the severity of motor disorders and global cognitive function.
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http://dx.doi.org/10.1186/s12883-020-01729-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189597PMC
April 2020

Assessment and Rating of Motor Cerebellar Ataxias With the Kinect v2 Depth Sensor: Extending Our Appraisal.

Front Neurol 2020 11;11:179. Epub 2020 Mar 11.

Movement Disorders Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Current assessment of patients with cerebellar disorders is based on conventional neurological examination that is dependent on subjective judgements. Quantitative measurement of cerebellar ataxias (CAs) is essential for assessment of evidence-based treatments and the monitoring of the progress or recovery of diseases. It may provide us a useful tool to navigate future treatments for ataxia. We developed a Kinect v2. sensor system with a novel algorithm to measure and evaluate movements for two tests of Scale for the Assessment and Rating of Ataxia (SARA): the nose-finger test and gait. For the nose-finger test, we evaluated and compared accuracy, regularities and smoothness in the movements of the index finger and the proximal limbs between cerebellar patients and control subjects. For the task of walking, we evaluated and compared stability between the two groups. The precision of the system for evaluation of movements was smaller than 2 mm. For the nose-finger test, the mildly affected patients tended to show more instability than the control subjects. For a severely affected patient, our system quantified the instability of movements of the index finger using kinematic parameters, such as fluctuations and average speed. The average speed appears to be the most sensitive parameter that contrasts between patients with CAs and control subjects. Furthermore, our system also detected the adventitious movements of more proximal body parts, such as the elbow, shoulder and head. Assessment of walking was possible only in patients with mild CAs. They demonstrated large sways and compensatory wide stances. These parameters appeared to show higher accuracy than SARA. This examiner-independent device measures movements of the points of interest of SARA more accurately than eye and further provides additional information about the ataxic movements (e.g., the adventitious movements of the elbow, shoulder and head in the nose-finger test and the wide-based walking with large oscillation in the gait task), which is out of the scope of SARA. Our new system enables more accurate scoring of SARA and further provides additional information that is not currently evaluated with SARA. Therefore, it provides an easier, more accurate and more systematic description of CAs.
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http://dx.doi.org/10.3389/fneur.2020.00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078683PMC
March 2020

Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis.

Ther Adv Neurol Disord 2020 18;13:1756286420904207. Epub 2020 Mar 18.

Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

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) completed the 26-week treatment with eculizumab. The disease subtypes represented included five cases of early onset MG, one of late-onset MG, and five of thymoma-associated MG. Overall, seven patients had experienced myasthenic crisis. The mean quantitative MG score ranged from 18.6 at baseline to 9.1 at week 26 ( = 0.008). Similarly, the mean MG activities of daily living score ranged from 10.8 at baseline to 4.2 at week 26 ( = 0.002). There were marked improvements in all patients' quality of life status. Overall, seven patients were able to reduce the dose of prednisolone at week 26. All but one patient did not require additional rescue treatment. Overall, one patient with early onset MG could not continue the eculizumab treatment due to nausea and vertigo.

Conclusion: We demonstrate that eculizumab provided remarkable benefits for refractory gMG in practical real-world experience as well as in the REGAIN study. Patients with refractory gMG with myasthenia crisis and thymoma-associated MG are suitable for eculizumab administration.
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http://dx.doi.org/10.1177/1756286420904207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081459PMC
March 2020

Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke.

J Neurol 2020 May 3;267(5):1482-1490. Epub 2020 Feb 3.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

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.
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http://dx.doi.org/10.1007/s00415-020-09732-4DOI Listing
May 2020

[Perampanel for Sporadic Amyotrophic Lateral Sclerosis].

Brain Nerve 2019 Nov;71(11):1270-1278

Department of Neurology, Department of Neuropathogenesis, Tokyo Medical University.

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 conditionally knocked out in motor neurons. Because of the therapeutic potency of perampanel for sporadic ALS, we have performed a multicenter randomized, double-blinded, placebo-controlled, parallel-group phase 2 clinical trial. The primary outcome measure is the change in ALS functional rating scale-revised after 48 weeks of treatment. The results of this study will be available in early 2020.
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http://dx.doi.org/10.11477/mf.1416201437DOI Listing
November 2019

Association of daily physical activity with cognition and mood disorders in treatment-naive patients with early-stage Parkinson's disease.

J Neural Transm (Vienna) 2019 12 30;126(12):1617-1624. Epub 2019 Sep 30.

Department of Neurology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

To determine the association of daily physical activity with cognition, mood disorders, and olfactory function in treatment-naive patients with early-stage Parkinson's disease (PD). The study subjects were 52 treatment-naive patients with early-stage 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) 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.
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http://dx.doi.org/10.1007/s00702-019-02085-xDOI Listing
December 2019

Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein.

J Clin Neurol 2019 Jan;15(1):62-67

Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background And Purpose: Disruption of nucleoporins has been reported in the motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS). However, the precise changes in the morphology of nucleoporins associated with the pathology of the 43-kDa TAR DNA-binding protein (TDP-43) in the disease process remain unknown. We investigated the expression of nucleoporins that constitute the nuclear pore complex (NPC) in spinal motor neurons that exhibit sALS in relation to TDP-43 pathology, which is a reliable neuropathological hallmark of sALS.

Methods: Paraffin-embedded sections of the lumbar spinal cord were obtained for immunofluorescence analysis from seven control subjects and six sALS patients. Anti-TDP-43 antibody, anti-nucleoporin p62 (NUP62) antibody, and anti-karyopherin beta 1 (KPNB1) antibody were applied as primary antibodies, and then visualized using appropriate secondary antibodies. The sections were then examined under a fluorescence microscope.

Results: NUP62 and KPNB1 immunoreactivity appeared as a smooth round rim bordering the nuclear margin in normal spinal motor neurons that exhibited nuclear TDP-43 immunoreactivity. sALS spinal motor neurons with apparent TDP-43 mislocalization demonstrated irregular, disrupted nuclear staining for NUP62 or KPNB1. Some atrophic sALS spinal motor neurons with TDP-43 mislocalization presented no NUP62 immunoreactivity.

Conclusions: Our findings suggest a close relationship between NPC alterations and TDP-43 pathology in the degenerative process of the motor neurons of sALS patients.
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http://dx.doi.org/10.3988/jcn.2019.15.1.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325357PMC
January 2019

A controlled inflammation and a regulatory immune system are associated with more favorable prognosis of progressive multifocal leukoencephalopathy.

J Neurol 2019 Feb 3;266(2):369-377. Epub 2018 Dec 3.

Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima Bunkyo-ku, Tokyo, 113-8510, Japan.

Objective: In the present study, we analyzed the inflammatory profiles of brain tissues obtained from patients with progressive multifocal leukoencephalopathy (PML) due to John Cunningham (JC) virus infection to identify potential prognostic factors.

Methods: The study included seven patients (two men, five women) who had been pathologically diagnosed with PML, and all of whom were HIV negative. Fixed brain samples were analyzed via hematoxylin and eosin (HE) staining and Klüver-Barrera (KB) staining. We then performed immunohistochemistry (IHC) specific to JC virus capsid proteins (VP1 and VP2/3) and lymphocyte surface markers (CD4, CD8, CD138, and PD-1).

Results: The mean age at onset was 53.4, while the mean duration until biopsy/autopsy was 4.7 months. Four patients were included in the good prognosis (GP) group, while three were included in the poor prognosis (PP) group. Pathological analysis revealed a significantly larger number of CD4-positive T-cell infiltrations (P = .029) in the GP group, along with a preserved CD4:CD8 ratio. Larger numbers of CD138-positive plasma cells were also observed in the GP group (P = .029) than in the PP group. Linear regression analyses revealed a significant association between the numbers of CD138-positive plasma cells and PD-1-positive cells (R = 0.80).

Conclusions: Viral loads in the cerebrospinal fluid, a controlled inflammatory response mediated by CD4- and CD8-positive T cells, and plasma cells are associated with PML prognosis. Our findings further indicate that regulatory plasma cells may regulate inflammatory T-cell activity via a PD-1/PD-L1 immuno-checkpoint pathway, thereby protecting the uninfected brain from excessive immune-mediated damage during an active JC virus infection.
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http://dx.doi.org/10.1007/s00415-018-9140-0DOI Listing
February 2019

Treatment of Myasthenia Gravis With High-Dose Cholinesterase Inhibitors and Calcineurin Inhibitors Caused Spontaneous Muscle Cramps in Patients.

Clin Neuropharmacol 2018 Sep/Oct;41(5):164-170

Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.

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.
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http://dx.doi.org/10.1097/WNF.0000000000000295DOI Listing
December 2018

Autopsy-proven case of paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

Neuropathology 2018 Oct 19;38(5):568-573. Epub 2018 Aug 19.

Department of Neurology, Asahikawa Medical Center, Asahikawa, Japan.

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.
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http://dx.doi.org/10.1111/neup.12506DOI Listing
October 2018

Characteristics of apathy in treatment-naïve patients with Parkinson's disease.

Int J Neurosci 2019 Jan 29;129(1):16-21. Epub 2018 Nov 29.

a Department of Neurology , Tokyo Medical University , Shinjuku-ku , Tokyo , Japan.

Introduction: Although apathy is a common psychiatric symptom of Parkinson's disease (PD), there are many unknown aspects of its pathology. This study aimed to investigate the characteristics of apathy in treatment-naïve patients with early-stage PD.

Methods: Fifty treatment-naïve patients with early-stage PD were divided into 1 of 2 groups-apathetic or non-apathetic-based on Starkstein Apathy Scale (AS) scores. Cognitive function, depressive symptoms, olfactory function, and motor severity were compared between the two groups using validated assessment scales. Multiple linear regression was performed to assess the association between AS scores and clinical parameters.

Results: Apathy (AS score ≥16) was observed in 13 (26%) patients. Assessment scale scores (Beck Depression Inventory-Second Edition [p < .004]; modified Hoehn & Yahr stage [p = .039]; Unified Parkinson's Disease Rating Scale part III [p < .001]) were significantly higher in apathetic patients than in non-apathetic patients. Significant association between these scale scores and AS score was also evident (all p ≤ .001). There were no significant differences in the test scores derived from several other validated scales.

Conclusion: Apathy was observed in 26% of treatment-naïve patients with early-stage PD. Significant association between apathy and motor severity was found, suggesting that dysfunction of the dopaminergic pathway is involved in the pathology of apathy.
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http://dx.doi.org/10.1080/00207454.2018.1503184DOI Listing
January 2019

[A case of meningeal carcinomatosis mimicking subarachnoid hemorrhage on MRI].

Rinsho Shinkeigaku 2018 Jun 1;58(6):403-406. Epub 2018 Jun 1.

Department of Neurology, Tokyo Medical University.

We report a case of meningeal carcinomatosis that needed to be distinguished from subarachnoid hemorrhage. A 67-year-old female with acute severe headache was admitted to a previous hospital. Since high intensity signal was detected within the parietal cerebral sulci on the right side on brain FLAIR MRI, cerebral angiography was performed due to suspicion of subarachnoid hemorrhage. However, no vascular abnormality was observed. Then, cerebral spinal fluid was collected, which showed an increase in cell count, suggesting meningitis. She was transferred to our hospital for evaluation of neurological disease. After admission to our hospital, there was an episode of hematemesis. Upper gastrointestinal endoscopy was performed, and advanced gastric cancer was found. She was diagnosed as having meningeal carcinomatosis due to gastric cancer. Meningeal carcinomatosis should be considered in addition to subarachnoid hemorrhage when a patient with acute headache shows high intensity signal within the cerebral sulci on brain FLAIR MRI.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001151DOI Listing
June 2018

Progression level of extracapsular spread and tumor budding for cervical lymph node metastasis of OSCC.

Clin Oral Investig 2018 Apr 6;22(3):1311-1318. Epub 2017 Oct 6.

Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.

Objectives: The progression level of extracapsular spread (ECS) for cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) was previously divided into three types, and their relationships with the prognosis of patients were re-examined.

Patients And Methods: The Kaplan-Meier method was used to examine overall survival (OS) and relapse-free survival (RFS) curves. Prognosis factor for recurrence was analyzed with univariate and multivariate analysis.

Results: ECS was detected in 216 cases of OSCC and analyzed. The 5-year overall survival and RFS rates of patients with type C, which was microscopically defined as tumor invasion to perinodal fat or muscle tissue, were significantly poor at 40.6 and 37.8%, respectively. The results of a univariate analysis suggested that the prognosis of ECS in OSCC patients is associated with its progression level, particularly type C. The 5-year RFS rate of type C with tumor budding was significantly poor at 31.5%. Type C with tumor budding correlated with local and regional recurrence as well as distant metastasis. In a multivariate analysis, tumor budding was identified as an independent prognostic factor.

Conclusions: These results suggest that the progression level of ECS and tumor budding are useful prognostic factors in OSCC patients.

Clinical Relevance: This study indicated that the progression level and tumor budding of ECS for cervical lymph node metastasis were useful prognostic factors in OSCC patients.
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http://dx.doi.org/10.1007/s00784-017-2231-yDOI Listing
April 2018

Difference in glycogen metabolism (glycogen synthesis and glycolysis) between normal and dysplastic/malignant oral epithelium.

Arch Oral Biol 2017 Nov 2;83:340-347. Epub 2017 Sep 2.

Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

Background: The purpose of this study was to investigate a difference in glycogen metabolism (glycogen synthesis and glycolysis) between the iodine stained (normal non-keartinized) and the unstained (dysplasctic/malignant) oral epithelium.

Methods: Twenty-one frozen tissue samples of iodine-stained and unstained mucosal tissue were obtained from 21 OSCC patients. Serial frozen sections were cut and examined with the hematoxylin-eosin and periodic acid-Schiff methods and immunohistochemical (IHC) staining for Ki67, P53, molecules associated with glycogenesis (i.e., glycogen synthase (GS) and phospho-glycogen synthase (PGS)), and molecules associated with glycogenolysis (i.e., glycogen phosphorylase isoenzyme BB (GPBB) examine the glycogen metabolism in OSCC. Additionally, in vitro study, the expression levels of GS and GPBB in the cultured cells were analyzed by immunofluorescent staining, Western blot analysis, and the real-time quantitative polymerase chain reaction (PCR).

Results: There was no significant difference in GS and PGS immunoactivity between iodine stained and unstained area. On the other hand, significantly greater GPBB immunoreactivity was observed in the basal and parabasal layers of iodine-unstained epithelium, where higher positivity for p53 and Ki67 was also showed. Additionally, western blot analysis, immunofluorescent staining, and real-time quantitative PCR revealed that the oral squamous cancer cells exhibited greater expression of GPBB than normal epithelial cells.

Conclusions: The results of this study showed that GPBB expression, which resulted in up-regulation of glycogenolysis, is enhanced in oral dysplastic/malignant epithelium compared with non-keartinized normal epithelium, in spite of the fact that glycogenesis continues in both of them. Premalignant and malignant epithelial cells consume greater quantities of energy due to their increased proliferation, and hence, exhaust their glycogen stores, which resulting in negative stain reaction with iodine solution.
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http://dx.doi.org/10.1016/j.archoralbio.2017.08.014DOI Listing
November 2017

Limbic Encephalitis Associated with Human Herpesvirus-7 (HHV-7) in an Immunocompetent Adult: The First Reported Case in Japan.

Intern Med 2017 15;56(14):1919-1923. Epub 2017 Jul 15.

Division of Neurology, First Department of Medicine, Asahikawa Medical University, Japan.

A 35-year-old male who had not previously suffered any major illnesses was admitted to our hospital because of general fatigue, fever, headache, vomiting, consciousness disturbance, and seizures. A neurological examination showed that he was in a semi-comatose state and exhibited neck stiffness. Brain magnetic resonance imaging detected high-intensity areas in the bilateral hippocampi and periventricular white matter. A cerebrospinal fluid examination revealed mononuclear pleocytosis, an elevated protein level, and positivity for human herpesvirus-7 (HHV-7) DNA. The patient's condition improved after the administration of methylprednisolone, intravenous immunoglobulins, and acyclovir. This is the first known case of limbic encephalitis associated with HHV-7 in an immunocompetent Japanese adult.
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http://dx.doi.org/10.2169/internalmedicine.56.8185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548691PMC
January 2018

Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons.

Sci Rep 2017 01 3;7:39994. Epub 2017 Jan 3.

Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

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-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-mediated cell death signals may be a therapeutic strategy for ALS.
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http://dx.doi.org/10.1038/srep39994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206745PMC
January 2017

Secondary parkinsonism.

Nihon Rinsho 2017 Jan;75(1):63-70

Although many disorders are included in secondary parkinsonism, the mechanisms underlying parkinsonism vary and have yet to be elucidated. Herein, we introduced a group of diseases included among the forms of secondary parkinsonism and provide overviews of clinically significant drug-induced parkinsonism (DIP), vascular parkinson- ism (VP), and idiopathic normal pressure hydrocephalus (iNPH) with a focus on pathophysiology and symptoms. Although DIP has the highest frequency among the forms of secondary parkinsonism, it is overlooked in many patients due to lack of knowledge about drugs by the prescribing physicians. Both VP and iNPH present with "lower body parkinsonism, " showing the characteristic gait disturbance. DIP and iNPH are treatable, highlighting the importance of early diagnosis and treatment intervention.
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January 2017

A case of peri-implantitis and osteoradionecrosis arising around dental implants placed before radiation therapy.

Int J Implant Dent 2016 Dec 5;2(1):11. Epub 2016 Apr 5.

Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.

A little is known about the effect of radiotherapy on the dental implants that have previously been osseointegrated and charged. Here, we reported a case of osteoradionecrosis which arose around dental implants placed before radiation therapy.
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http://dx.doi.org/10.1186/s40729-016-0039-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005645PMC
December 2016

Anti-TIF1-γ antibody and cancer-associated myositis: A clinicohistopathologic study.

Neurology 2016 07 24;87(3):299-308. Epub 2016 Jun 24.

Objective: 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.

Methods: 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.

Results: 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, including 2 possible DM sine dermatitis cases, and were characterized histologically by the presence of perifascicular atrophy, vacuolated fibers (VFs), and dense C5b-9 deposits on capillaries (dC5b-9). In contrast, 39 anti-TIF1-γ-Ab(-) patients with CAM were classified into various subgroups, and characterized by a higher frequency of necrotizing autoimmune myopathy (NAM). Notably, all 7 patients with CAM classified into the NAM subgroup were anti-TIF1-γ-Ab(-) and exhibited no dC5b-9 or VFs.

Conclusions: CAM includes clinicohistopathologically heterogeneous disease entities. Among CAM entities, anti-TIF1-γ-Ab(+) CAM has characteristically shown a close temporal association with cancer detection and the histopathologic findings of dC5b-9 and VFs, and CAM with NAM is a subset of anti-TIF1-γ-Ab(-) CAM.
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http://dx.doi.org/10.1212/WNL.0000000000002863DOI Listing
July 2016

Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUS(P525L) mutation.

J Clin Neurosci 2016 Oct 21;32:128-9. Epub 2016 Jun 21.

Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Clinical Research Center of Medicine, International University of Health and Welfare, Minato-ku, Tokyo 108-8329, Japan.

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 transactive response (TAR) DNA-binding protein 43 kDa (TDP-43)-positive inclusions, indicating that there was no tight correlation between ADAR2 deficiency and TDP-43 deposition. ADAR2 deficiency can occur in ALS patients with a FUS(P525L) mutation and is unrelated to the presence of FUS-positive inclusions. FUS-associated ALS may share neurodegenerative characteristics with classical sporadic ALS.
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http://dx.doi.org/10.1016/j.jocn.2015.12.039DOI Listing
October 2016

Construction and characterization of human oral mucosa equivalent using hyper-dry amniotic membrane as a matrix.

Arch Oral Biol 2016 May 22;65:26-34. Epub 2016 Jan 22.

Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumato 390-8621, Japan. Electronic address:

Background: Human amniotic membrane(HAM) as a graft material has been used in various fields. Hyper-dry amniotic membrane (HD-AM) is a novel dried amniotic membrane that is easy to handle and can be preserved at room temperature without time limitation. The purpose of this study was to investigate the useful properties of HD-AM in reconstruction of the oral mucosa.

Methods: Human oral keratinocytes were isolated and seeded on HD-AM in serum-free culture system. Oral mucosa equivalent (OME) was developed and transplanted onto full-thickness wound on athymic mice. The wound healing was analyzed and the OME both before and after transplantation was analyzed with hematoxylin-eosin staining and immunohistochemical staining for Cytokines 10 (CK10), Cytokines 16 (CK16), and Ivolucrin (IVL).

Results: Oral keratinocytes spread and proliferated well on HD-AM. Two weeks after air-lifting, OME had formed with good differentiation and morphology. We confirmed immunohistochemically that the expression of CK10 was positive in all suprabasal layers, as was CK16 in the upper layers, while IVL was present in all cell layers. Three weeks after transplantation to athymic mice, the newly generated tissue had survived well with the smallest contraction. The epithelial cells of newly generated tissue expressed CK10 throughout in all suprabasal layers, IVL was mainly in the granular layer, and CK16 positive cells were observed in all spinous layer and granular layer but were not expressed in the mouse skin, all of which were similar to native gingival mucosa.

Conclusions: The OME with HD-AM as a matrix revealed a good morphology and stable wound healing. This study demonstrates that HD-AM is a useful and feasible biomaterial for oral mucosa reconstruction.
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http://dx.doi.org/10.1016/j.archoralbio.2016.01.011DOI Listing
May 2016

Oral cancer intraoperative detection by topically spraying a γ-glutamyl transpeptidase-activated fluorescent probe.

Oral Oncol 2016 Mar 19;54:e16-8. Epub 2016 Jan 19.

Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto 390-8621, Japan.

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http://dx.doi.org/10.1016/j.oraloncology.2015.12.003DOI Listing
March 2016

Kinematic analysis of 24-hour recording of walking pattern in patients with vascular parkinsonism.

Int J Neurosci 2015 2;125(10):733-41. Epub 2014 Dec 2.

a Department of Neurology , Tokyo Medical University , Tokyo , Japan.

Background: There is a need to define the basic characteristics of various kinematic parameters recorded during walking in patients with vascular parkinsonism (VP). The present study was designed to determine the kinematic features of walking in VP patients. For this purpose, gait acceleration and gait cycle were recorded continuously over 24-h period of daily living in VP patients, patients with Parkinson's disease (PD), and healthy subjects.

Methods: We used our newly developed 24-h monitoring device, the portable gait rhythmogram, which records gait during walking, and computes gait-induced accelerations with pattern matching algorithm. We studied nine VP patients with history of multiple lacunar infarcts (mean age ± standard deviation (SD): 72.6 ± 5.0 years, 7 men), 39 PD patients (mean age ± SD: 70.8 ± 5.8 years, 18 women), and 15 normal control subjects (mean age ± SD: 67.9 ± 4.7 years, 9 men).

Results: The "amount of overall movements per 24 h" was lower in VP and PD, compared with the control, with no significant differences between the two groups. Gait acceleration during walking was significantly lower (p < 0.01 in each case), while the gait cycle was the same in VP and PD patients compared with the control.

Conclusions: The results suggest that deficit in force production and preservation of gait rhythm are common features of walking patterns in VP and PD patients.
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http://dx.doi.org/10.3109/00207454.2014.967350DOI Listing
May 2016