Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Neurological Therapeutics  

<p>Most medical research is mainly clinical research conducted to gain knowledge that contributes to promoting the public's health, patients' recovery from diseases, or improving the quality of life through understanding the causes of diseases. The establishment of full–fledged ethical guidelines for clinical research was concentrated after 2000. However, the ethical guidelines are not legally binding, nor is administrative guidance for failing to comply. Under such circumstances, the need for a legal system was considered, and the “Clinical Trials Act” was enacted and issued after thorough consideration of the scope of the legal regulations and the content of specific regulations and measures, and came into effect in April 2018.</p><p>With the enactment of the Clinical Trials Act, clinical research in Japan now includes clinical trials conducted under the “Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices”, clinical trials conducted under the “Clinical Trials Act”, and other clinical researches conducted under the “Ethical Guidelines for Medical and Health Research Involving Human Subjects”. In this manuscript, after mentioning the Declaration of Helsinki, on which these laws and regulations are based, the laws and regulations that must be complied with in the above three types of clinical research are summarized.</p>

DOI： 10.15082/jsnt.42.1_13

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Neurological Therapeutics  

<p>Research and development for diseases in the field of neurology have dramatically advanced over the past two decades. This owes to the identification of disease causes through advances in genome research, the development of imaging and body fluid biomarkers, the enhancement of academia–led research such as physician–led clinical trials and registries, and the development of new modalities of therapeutic agents such as nucleic acid medicine and antibody therapy. In particular, genomics and biomarkers are undergoing extremely rapid technological innovation and are expected to be further utilized for diagnosis and prognosis prediction of diseases, and for stratification in clinical trials. Biotechnologies such as cell therapy, genome editing, and CAR–T, as well as bioengineering technologies such as robotics and brain–computer interfaces, are also being applied to neurological diseases. Further innovations are expected to emerge in the future, such as the integration of different modalities and the combination of pharmaceuticals and medical devices. The Japanese Society of Neurological Therapeutics established the Drug Discovery Working Group in 2020 with the aim of stimulating the development of treatments for neurological diseases, and in 2022, this working group became the Drug Discovery Promotion Committee, which has been promoting projects including the support for clinical trial execution, initiation of a consultation service for clinical research, and holding symposium. This article introduces the activities of the Drug Discovery Promotion Committee and explains the current status and prospects of drug discovery in the field of neurology, which is the background of the committee's activities.</p>

DOI： 10.15082/jsnt.42.1_33

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Neurosurgical Society  

Three anti-calcitonin gene-related peptide monoclonal antibodies (CGRP-mAbs) are available in Japan: galcanezumab, fremanezumab, and erenumab. Early-onset efficacy has been demonstrated for each CGRP-mAb in comparison with placebo, but differences among the drugs are unclear. Only galcanezumab requires 2 doses at the initial injection. This study is a multicenter, open-label, randomized, two-group comparison trial, consisting of the random selection of a CGRP-mAb and 6 consecutive injections, and then discontinuation of the CGRP-mAb after 6 injections. The primary outcome is a comparison of early-onset efficacy between galcanezumab and both fremanezumab and erenumab after the initial injection. The secondary outcomes are comparisons between galcanezumab and both fremanezumab and erenumab, and between fremanezumab and erenumab as follows: weekly number of headache days, migraine days, and acute medication use are compared to baseline during one month after initial injection; time of subjectively perceiving onset of effect after initial injection; monthly changes in headache status from baseline to after third (3rd) injections; effective rates after initial and 3rd injections; improvement rates of depression scores between baseline and after 3rd injections; changes in number of absenteeism and presenteeism days in each month from baseline to after 3rd injections; proportion of ineffective cases after 3rd injections; recurrence rates and time to recurrence after CGRP-mAb discontinuation; effective rates of CGRP-mAb re-injections; detection of clinical factors associated with effectiveness after the initial and 3rd injections. The aim of this study is to investigate differences in early-onset efficacy among the CGRP-mAbs, and when and to what extent headache symptoms recur after discontinuation.

DOI： 10.2176/jns-nmc.2024-0201

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neuroradiology  

Purpose: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics. Methods: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated. Results: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer’s disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively. Conclusion: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.

DOI： 10.1007/s00234-024-03432-w

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DOI： 10.1016/j.nmd.2024.07.434

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：English   Publishing type：Research paper (scientific journal)  

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BACKGROUND: Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray's 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology. RESULTS: Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement. CONCLUSIONS: This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.

DOI： 10.1186/s12859-024-05840-4

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DOI： 10.1136/jnnp-2024-333853

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BACKGROUND AND OBJECTIVES: This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. METHODS: Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. RESULTS: Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. DISCUSSION: Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.

DOI： 10.1212/NXI.0000000000200199

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Neurological Therapeutics  

<p>As a pioneer of investigator–initiated clinical trials in Japan, Nagoya University started a multi–institutional Phase III study (JASMITT trial) to evaluate the efficacy and safety of leuprorelin acetate in the patients with Spinal and Bulbar Muscular Atrophy (SBMA) in 2006. The JASMITT trial is a translational study based on basic research findings on animal models of SBMA. In investigator–initiated new drug developments, academic researchers often need help to prepare a complete clinical data package. Experience with PMDA may lead to better preparation of regulatory filings. The author joined the New Drug Review 2 of the Pharmaceutical and Medical Device Agency (PMDA) in April 2013, during the clinical development of leuprorelin acetate, and learned the actual operations of consultation and new drug reviews. After that, leuprorelin acetate got approval based on the investigator–initiated clinical trials in 2017.</p><p>In April 2021, the Department of Clinical Research Education (CRE) opened at the Nagoya University Graduate School of Medicine to promote clinical researches at Nagoya University. The two essential missions of CRE are “clinical research education” and “clinical research support”. CRE could be the only department to comprehensively deepen understanding and practice from observational researches to clinical trials.</p>

DOI： 10.15082/jsnt.41.3_411

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.41.6_s225

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Endocrine Society  

<p>This study aimed to evaluate the impact of periodic neck ultrasonography (US) on postoperative surveillance for locoregional disease control of patients with low- and intermediate-risk papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. This retrospective cohort study included patients with PTC who underwent total thyroidectomy and central neck dissection at our institution between January, 2000 and December, 2016. The patients were divided into two groups: the physical examination (PE) group (follow-up by PE without periodic US) and the US group (follow-up by PE with periodic US). Serum thyroglobulin levels were measured periodically in both groups. Propensity score matching was used to rigorously balance the significant variables and assess the 10-year postoperative outcomes between the groups. Of the 189 patients, 150 were included after matching (75 in each group). There were no significant differences between the two groups in terms of background characteristics. The median follow-up period was 127.9 months. There was no significant difference in locoregional relapse-free survival between the PE and US groups (97.0 <i>vs.</i> 98.7%, <i>p</i> = 0.541). The overall survival was 96.7% and 98.7% in the PE and US groups, respectively, with no significant difference (<i>p</i> = 0.364). This study demonstrated that the addition of periodic US to PE for postoperative surveillance of patients with low- and intermediate-risk PTC who underwent total thyroidectomy did not significantly affect locoregional control.</p>

DOI： 10.1507/endocrj.ej24-0194

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CiNii Research

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BACKGROUND: Spinal cord stimulation (SCS) is one of the neuromodulation therapies for chronic neuropathic pain. The conventional paresthesia-based SCS involves the application of tonic stimulation that induces a sense of paresthesia. Recently, new SCS stimulation patterns without paresthesia have been developed. Differential target multiplexed (DTM) stimulation and fast-acting subperception therapy (FAST) stimulation are the latest paresthesia-free SCS patterns. METHODS: A single-center, open-label, crossover, randomized clinical trial to investigate the superiority of SCS using the latest new stimulation patterns over conventional tonic stimulation for neuropathic pain is planned. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). In the SCS trial, participants will be randomly assigned to 4 groups receiving stimulation, including tonic, DTM, and FAST. Each stimulation will then be performed for 2 days, and a visual analog scale (VAS) for pain will be evaluated before and after each stimulation pattern. A stimulation-off period for 1 day is set between each stimulation pattern to wash out the residual previous stimulation effects. Pain improvement is defined as more than 33% reduction in the pain VAS. The primary analysis will compare pain improvement between the new stimulation patterns and the conventional tonic stimulation pattern in the SCS trial. The secondary outcomes will be evaluated as follows: (1) the relationships between causative disease and improvement rate by each stimulation pattern; (2) comparison of pain improvement between the DTM and FAST stimulation patterns in all cases and by causative disease; (3) changes in assessment items preoperatively to 24 months after the implantation; (4) preoperative factors associated with long-term effects defined as continuing for more than 12 months; and (5) adverse events related to this study 3 months after the implantation. DISCUSSION: This study aims to clarify the effectiveness of the latest new stimulation patterns compared to the conventional tonic stimulation. In addition, which stimulation pattern is most effective for which kind of causative disease will be clarified. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 1,042,220,094. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is an approved member of the Primary Registry Network of WHO ICTRP.

DOI： 10.1186/s13063-023-07637-x

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>A rare muscle disease, GNE myopathy is caused by mutations in the <jats:italic>GNE</jats:italic> gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (− 0.115 kg) was numerically smaller as compared with placebo (− 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (− 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy.</jats:p>
<jats:p><jats:italic>Trial registration number</jats:italic>: ClinicalTrials.gov (NCT04671472).</jats:p>
</jats:sec>

DOI： 10.1186/s13023-023-02850-y

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BACKGROUND: Neuropathic pain after spinal cord injury (SCI), both traumatic and non-traumatic, is refractory to various treatments. Spinal cord stimulation (SCS) is one of the neuromodulation therapies for neuropathic pain, although SCS has insufficient efficacy for neuropathic pain after SCI. The reasons are presumed to be inappropriate locations of SCS leads and conventional tonic stimulation itself does not have a sufficient analgesic effect for the pain. In patients with past spinal surgical histories, the cylinder-type leads are likely to be placed on the caudal side of the SCI because of surgical adhesions. Differential target multiplexed (DTM) stimulation is one of the latest new stimulation patterns that is superior to conventional stimulation. METHODS: A single-center, open-label, randomized, two-way crossover trial is planned to investigate the efficacy of SCS using DTM stimulation placing a paddle lead at the appropriate site for neuropathic pain after SCI in patients with spinal surgical histories. The paddle-type lead delivers energy more efficiently than a cylinder-type lead. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). The primary outcome is rates of achieving pain improvement with more than 33% reduction 3 months after SCS system implantation. The secondary outcomes are to be evaluated as follows: (1) effectiveness of DTM and tonic stimulations during the SCS trial; (2) changes of assessment items from 1 to 24 months; (3) relationships between the result of the SCS trial and the effects 3 months after SCS system implantation; (4) preoperative factors associated with a long-term effect, defined as continuing for more than 12 months; and (5) whether gait function improves from 1 to 24 months. DISCUSSION: A paddle-type lead placed on the rostral side of SCI and using DTM stimulation may provide significant pain relief for patients with intractable neuropathic pain after SCI in patients with past spinal surgical histories. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCT 1042220093. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is approved as a member of the Primary Registry Network of WHO ICTRP.

DOI： 10.1186/s13063-023-07433-7

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BACKGROUND: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far. OBJECTIVE: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy. METHODS: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point. RESULTS: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was -0.1 kg (-2.1 to 2.0) in the SA-ER group and -5.1 kg (-10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (-0.3 to 9.9; P = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed. CONCLUSIONS: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan.

DOI： 10.3233/JND-230029

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The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

DOI： 10.1093/braincomms/fcad296

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Neurological Therapeutics  

<p>Recent advancement in studies on pathogenesis led to development of disease–modifying therapies such as nucleic acid therapies for neuromuscular disorders. Such therapies target disease causing genes and proteins, but therapeutic benefits in clinic is limited at a symptomatic stage of disease. To overcome this, strategies for prevention have been actively developed for neurodegenerative disease. Before manifestation of core motor/cognitive symptoms, preclinical and then prodromal stages exist during the progression of neurodegeneration. At preclinical stage, molecular changes occurs but symptoms are hardly detectable. At prodromal stage, heralding symptoms appear prior to manifestation of core symptoms. In cohort studies on at–risk subjects, mild motor/cognitive symptoms emerge ∼20 years prior to the onset of subjective symptoms in various diseases. For instance, non–motor symptoms including REM sleep behavior disorder occurs approximately 15 years before clinical diagnosis of Parkinson disease, which is made on the basis of subjective motor symptoms. The effects of disease–modifying therapy for preventing neurodegeneration is clearly shown in a clinical trial of nusinersen, a nucleic acid therapy of spinal muscular atrophy, for pre–symptomatic subjects, in which initiation of disease–modifying therapy before manifestation achieved potent therapeutic effects particularly in mild patients. Currently, cohort studies, biomarker research, and novel therapies are being developed to further prevent various neurodegenerative diseases.</p>

DOI： 10.15082/jsnt.40.2_74

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.40.4_441

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本臨床薬理学会  

<p>新薬研究開発の国際競争力の低下などに対応して、本邦でも、創薬シーズを製薬企業のみならずアカデミアにも求める気運が高まってきた。「有効な医薬品を創り、患者さんに届ける」ことは医療人共通の願いでもあり、その気運にのり、アカデミアでの創薬は推進されてきたといえる。しかし、2014年度には20件あった医師主導治験の初回治験届け出数は、2019年度～2021年度には平均で9件を割り込んでおり、アカデミア発の創薬が活性化しているとは推定しにくい。一般に、創薬研究プロセスは、生体分子の新しい機能や病態における役割などの情報から創薬標的を同定する基礎研究と、同定した創薬標的に適切に作用する物質を開発化合物にまで最適化する応用研究に分類されるが、「アカデミア創薬」では、この基礎研究から応用研究まで、また可能であればその後の臨床開発も加え、一貫してアカデミア研究者が実施することになる。アカデミア基礎研究者の中には、自身の画期的な基礎的発見が、ただちに有望な創薬シーズとなるものと考えたが、その時に、創薬のためには不足する情報がたくさんあることを初めて知り、そのことこそ「死の谷（The Valley of Death）」というのだと思ってしまった研究者も多いものと想像される。医薬品開発は、新規薬剤の発見と合成、新規物質の有効性と安全性の研究に始まり、各種非臨床・臨床試験の計画・実施・解析、製造販売承認申請準備・申請、と多種多様で長い道のりである。本邦のアカデミア発医薬品開発を活性化するためには、これらの道程を一人で完全走破するアントレプレナーを育てることも重要ではあるが、医学研究者個々の研究リテラシー向上なく、スーパーアントレプレナーを育てるだけでは、全体としての医薬品開発力向上を見込むことは難しい。少なくとも、創薬研究に関わるすべての医学研究者が、医薬品開発の全景やその困難さを理解したうえで、自らの研究の、「医薬品開発の上での位置付け」を十分に理解し、その開発を遂行するために不足するmissing pieceを埋めるパートナーとうまく協業を進めていく術を知ることが、今後長い目で見た際に、アカデミア発の創薬を育てるために重要ではないかと考えられる。</p>

DOI： 10.50993/jsptsuppl.44.0_3-c-s35-1

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.40.6_s149

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder with progressive muscle weakness and atrophy, mainly caused by lower motor neuron degeneration resulting from decreased levels of the survival motor neuron protein. Recently, 3 disease-modifying therapies for SMA (nusinersen, onasemnogene abeparvovec, and risdiplam) were approved in Japan that are expected to improve the prognosis of patients with SMA. Long-term clinical follow-up of adult patients treated with disease-modifying therapies and the natural history of SMA are essential to assess the real-world effectiveness of available treatments. Until recently, nusinersen was the only treatment option for patients with SMA in Japan; however, because Japanese approval of nusinersen was based on global clinical trials in infants and children aged 0-15 years with SMA, the effectiveness of nusinersen in adult patients has not been fully assessed in Japan. In addition, longitudinal clinical data of adult patients have not been systematically collected in Japan. OBJECTIVE: This longitudinal observational study of adult patients with SMA who have been diagnosed with 5q-SMA in Japan aims to gain a better understanding of the natural history of SMA, as well as the long-term effectiveness of disease-modifying therapies. Here, we describe the protocol for the study. METHODS: The Japan Registry for Adult Subjects of Spinal Muscular Atrophy (jREACT-SMA) study is a longitudinal (prospective and retrospective) observational study with a 60-month prospective follow-up being conducted at 19 investigational sites using the newly established jREACT-SMA registry. Patients aged ≥18 years with genetically confirmed 5q-SMA were planned to be enrolled in the registry from December 2020 to May 2022. The planned enrollment was 100 patients. The protocol was approved on September 28, 2020 (approval 2020-0289) by the ethical review committee of Nagoya University. Registration, demographics, genetic diagnosis, motor functions, patient-reported outcomes/quality-of-life outcomes, and other clinical data have been or will be collected. RESULTS: As of May 2022, 113 patients had been enrolled, and the completion of patient registration has been extended from May 2022 to December 2022. Data at registration and during the follow-up period were and will be prospectively collected at least once a year until November 2025 (maximum 60 months). Data analyses will be conducted when all data have been collected. Results are expected to be available in 2026 and the study is expected to be completed by March 2027. CONCLUSIONS: This jREACT-SMA study will provide longitudinal prospective follow-up data in adult patients with SMA in Japan, including data on the natural history of the disease and data on the long-term effectiveness of disease-modifying therapies. TRIAL REGISTRATION: University Hospital Medical Information Network Center Clinical Trials Registry UMIN000042015; https://rctportal.niph.go.jp/en/detail?trial_id=UMIN000042015. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/38878.

DOI： 10.2196/38878

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：医歯薬出版(株)  

球脊髄性筋萎縮症(SBMA)は,X染色体に存在するアンドロゲン受容体遺伝子上のCAG繰返し配列数の異常伸長を原因とするポリグルタミン病である.緩徐進行性の筋萎縮,筋力低下を特徴とする神経筋疾患であり,成人男性に発症する.下位運動ニューロン徴候を主体とするが,体毛の減少,皮膚の女性化,睾丸萎縮などのアンドロゲン不全症状,深部覚異常なども合併することが特徴的である.筋力低下発現の前に,手指振戦や筋クランプを高頻度に認めるが,血液検査においても血清クレアチニン値の低下や血清CK値の上昇を認め,診断の契機となる.通常,無症状と考えられる女性保因者においても極軽度の臨床所見と神経原性変化の存在を疑う検査所見が認められており,SBMAの早期病態の解明に寄与する可能性がある.わが国では2017年に抗アンドロゲン療法(リュープロレリン酢酸塩)が承認を取得しており,現在,実臨床下での有効性・安全性を検討する臨床研究が継続中である.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00060&link_issn=&doc_id=20221206010019&doc_link_id=issn%3D0039-2359%26volume%3D283%26issue%3D10%26spage%3D1032&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D283%26issue%3D10%26spage%3D1032&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

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OBJECTIVE: Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. METHODS: In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). RESULTS: In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period. INTERPRETATION: Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency.

DOI： 10.1002/acn3.51667

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(株)医学書院  

＜文献概要＞COVID-19パンデミックは人類と社会に大きなインパクトを与えたが,パンデミック前と比べた最も大きな変化の1つが,オンライン会議システムの普及と活用である。その影響を受けているのは医学も例外ではなく,オンライン診療と並んでオンライン教育の試みも進んでいる。本稿では,東海国立大学機構(名古屋大学と岐阜大学)における脳神経内科領域の合同オンライン臨床実習の試みを紹介する。

Language：English   Publishing type：Research paper (scientific journal)  

This study aimed to develop a functional measurement that combines quantitative motor evaluation index of various body regions in patients with spinal and bulbar muscular atrophy (SBMA). We assessed subjects with SBMA and healthy controls with quantitative muscle strength measurements and functional scales. We selected tongue pressure, grip power, % peak expiratory flow (%PEF), timed walking test, and % forced vital capacity (%FVC) as components. By combining these values with Z-score, we created a functional composite (SBMA functional composite: SBMAFC). We also calculated the standardized response mean to compare the sensitivity of SBMAFC with that of existing measurements. A total of 97 genetically confirmed patients with SBMA and 36 age- and sex-matched healthy controls were enrolled. In the longitudinal analysis, the standardized response mean of SBMAFC was larger than that of existing rating scales. Receiver operating characteristic (ROC) analysis demonstrated that the SBMAFC is capable of distinguishing between subjects with early-stage SBMA and healthy controls. SBMAFC is more sensitive to disease progression than existing functional rating scales and is a potential outcome measure in clinical trials of SBMA.

DOI： 10.1038/s41598-022-22322-w

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To assess the clinical and electrophysiological features of female carriers and early-stage male subjects with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiological changes of the disease. METHODS: Female carriers, early-stage male subjects with SBMA and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between SBMA subjects and healthy male controls. Electromyography was also investigated in female carriers. RESULTS: We enrolled 21 female carriers and 11 early-stage male subjects. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and electromyography abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in male early-stage subjects with SBMA, but not in female carriers. CONCLUSION: The present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early-stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.

DOI： 10.1212/WNL.0000000000201342

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(株)中外医学社  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, slowly progressive, incurable, and hereditary neurodegenerative disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. After extensive review, two treatments for SBMA have recently been approved in Japan; this decision was based on the results of randomized controlled trials: First, anti-androgen therapy using leuprorelin acetate (leuprorelin), a disease-modifying drug that can inhibit the progression of dysphagia but has not yet been proved to improve gait function; second, cybernic treatment with a wearable cyborg hybrid assistive limb (HAL®) (Cyberdyne Inc. Tsukuba, Japan). The HAL is an innovative walking exercise system that has been shown to significantly improve gait function in eight neuromuscular diseases without reduction in muscle function, including SBMA. It is possible that the combination of these two approaches might yield better outcomes. However, the long-term effects of such a combined approach have yet to be clinically evaluated. Here, we describe the case of a 39-year-old male with SBMA who commenced anti-androgen therapy with leuprorelin 1 year previously; this was followed by cybernic treatment with HAL. The duration of walking exercise with HAL was 20–30 min a day in one session. Over 2 weeks, the patient underwent nine sessions (one course). The efficacy of HAL was evaluated by gait function tests before and after one course of cybernic treatment. Then, leuprorelin treatment was combined with cybernic sessions every 2 months for 2 years (13 courses in total). Walking ability, as evaluated by the 2-min walk test, improved by 20.3% in the first course and peaked 10 months after the commencement of combined therapy (a 59.0% improvement). Walking function was maintained throughout the period. Generally, SBMA is characterized by moderately increased serum levels of creatine kinase (CK), reflecting neuromuscular damage; interestingly, the patient's CK levels decreased dramatically with combined therapy, indicating remarkable functional improvement. Long-term combined therapy improved the patient's gait function with a steady reduction in CK levels. The combination of leuprorelin with cybernic treatment can, therefore, improve and maintain gait function without damaging the motor unit and may also suppress disease progression.

DOI： 10.3389/fneur.2022.905613

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While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

DOI： 10.1126/sciadv.abm5029

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DOI： 10.1136/jnnp-2021-328433

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OBJECTIVE: To quantitatively evaluate upper limb ataxia using a novel pen-like sensor device in patients with spinocerebellar ataxia (SCA) and to assess its validity, reliability, and sensitivity to disease progression. METHODS: We designed a cross-sectional and longitudinal study of patients with SCA and healthy controls. Upper limb ataxia was evaluated using a device that measures the three-dimensional position every 10 msec. Participants were instructed to move a pen-like part of the device iteratively between two buttons. We evaluated the time, length, velocity, and variation coefficient of the stroke, and calculated the distortion index using the mean squared error. The following scales were also evaluated: Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the nine-hole pegboard test. Subjects were followed 12 months after the baseline evaluation. RESULTS: A total of 42 patients with SCA and 33 healthy controls were enrolled and evaluated. For all ataxia indices measured using the device there were significant differences between healthy controls and patients with SCA. Among the ataxia indices, the distortion index showed the strongest correlation with the SARA and ICARS upper limb score (Pearson's r = 0.647 and 0.722, respectively). Test-retest reliability was high for most of the ataxia indices. In the longitudinal analysis, the distortion index showed high standardized response mean and adjusted effect size, regardless of disease severity. INTERPRETATION: Our study demonstrated that the distortion index is a reliable functional marker that is sensitive to longitudinal change in patients with SCA.

DOI： 10.1002/acn3.51528

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Neurological Therapeutics  

<p>Recent progress in molecular biology has elucidated the pathogenesis of neurodegenerative diseases, including SBMA, and this progression has led new disease–modifying drug development being active. In Japan, Nusinersen for spinal muscular atrophy and Leuprorelin acetate for spinal and bulbar muscular atrophy were approved in August 2017, and now, it is expected that many new disease–modifying drugs for neurological diseases will be launched.</p><p>In neurodegenerative disease, we could hardly obtain sufficient information about the efficacy and safety of the drug before drug approval, so we should continuously collect clinical data after approval. We are now developing a real–world database to create new evoidence of leuprorelin acetate for SBMA. In this symposium, we will present two activities that are still in progress.</p><p>First, we are creating a new functional composite using real–world data to overcome the weakness of the existing outcome measurements. Based on the results of previous clinical studies on SBMA, we selected the following five quantitative measurements to be integrated into the functional composite : tongue pressure for bulbar function ; grip power for upper limb function ; timed walking test for lower limb function ; peak expiratory flow for truncal function ; and vital capacity for respiratory function. Using Z–score, we computed the following formula as SBMAFC ; SBMAFC = (Tongue Pressure (kPa) − 41.6)/7.84 + (Grip Power (kgw) − 45.0)/6.4 + (%PEF − 116.4)/22.4 + (Timed Walking speed (km/hr) − 7.7)/2.0 + (%FVC − 112.0)/11.8. In the comparison of SBMAFC with the existing rating scales, SBMAFRS and ALSFRS–R, the effect size of SBMAFC was the largest, suggesting that SBMAFC was the most sensitive to the disease progression. Second, we are analyzing the longitudinal data to estimate drug efficacy by comparing the data before and after drug administration. Further accumulation of longitudinal real–world data will enable the development of new real–world evidence for SBMA treatment.</p><p>The development of disease–modifying drug for neurodegenerative diseases will continue to be active. However, many barriers to success clinical trials, such as extremely small number of patients or slow progression, make it difficult to detect drug efficacy. So, often, we have insufficient evidence of efficacy or safety of the new drugs even after drug approval. Continuous clinical evaluations after approval are essential to establish a new drug profile.</p>

DOI： 10.15082/jsnt.39.3_306

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.39.3_160

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To clarify whether serum neurofilament light chains (NfLs) serve as a biomarker of axonal damage in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), especially in patients with anti-neurofascin 155 (NF155) antibodies. METHODS: The Simoa system was used to examine serum NfL levels from 58 patients with CIDP, including 13 anti-NF155 antibody-positive patients, and from 14 age- and sex-matched healthy individuals. Serum NfL levels were evaluated before and after treatment in eight patients with anti-NF155 antibodies. Clinical features, electrophysiological findings, and cerebrospinal fluid (CSF) protein levels, were evaluated. The pathological features of sural nerves from 40 patients were also examined. RESULTS: Serum NfL levels were significantly higher in patients with CIDP than in healthy individuals (median 29.63 vs. 7.71 pg/mL, p < 0.001) and were correlated with both modified Rankin Scale scores (r = 0.584, p < 0.001) and CSF protein levels (r = 0.432, p = 0.001). The NfL levels of anti-NF155 antibody-positive patients were higher than those of antibody-negative patients (p = 0.005). Serum NfL levels were negatively correlated with compound muscle action potential amplitudes of the tibial nerves (r =  - 0.404, p = 0.004) and positively correlated with the degree of active axonal degeneration in the pathological findings (r = 0.485, p = 0.001). In the antibody-positive group, NfL levels and antibody titers decreased after treatment in all examined patients. CONCLUSION: Serum NfL correlated with pathological indices of axonal degeneration, and may serve as a biomarker that reflects active axonal damage of CIDP.

DOI： 10.1007/s00415-021-10537-2

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OBJECTIVE: We aimed to investigate the validity of urinary N-terminal titin fragment as a biomarker for amyotrophic lateral sclerosis (ALS). METHODS: We consecutively enrolled patients with ALS (n=70) and healthy controls (HC) (n=43). We assessed the urinary titin N-terminal fragment, urinary neurotrophin receptor p75 extracellular domain, serum neurofilament light chain (NfL), motor functional measurements and prognosis. We used urinary creatinine (Cr) levels to normalise the urinary levels of titin fragment. RESULTS: Compared with HC, patients with ALS had significantly increased urinary levels of titin N-terminal fragment normalised with Cr (titin/Cr) (ALS, 27.2 pmol/mg/dL; HC, 5.8 pmol/mg/dL; p<0.001), which were correlated with the scores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (r=-0.422, p<0.001). A Cox proportional hazards model demonstrated that the high urinary level of titin/Cr was a survival predictor in patients with ALS. Multivariate analysis of prognostic factors showed that the urinary titin/Cr and serum NfL were independent factors for poor prognosis. CONCLUSIONS: Our findings indicate that urinary N-terminal titin fragment is a non-invasive measure of muscle damage in ALS, which could be applied in disease monitoring and prediction of disease progression, in combination with serum NfL.

DOI： 10.1136/jnnp-2020-324615

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.38.6_s132

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

<jats:title>Abstract</jats:title><jats:p>Parkinson’s disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific.</jats:p>

DOI： 10.1038/s41598-020-77415-1

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経免疫学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公財)金原一郎記念医学医療振興財団  

＜文献概要＞近年の研究により,球脊髄性筋萎縮症(SBMA)では,純粋な下位運動ニューロン障害のみならず骨格筋や全身臓器も障害されることが明らかとなってきた。SBMAの治療法開発のためには,骨格筋の変性メカニズムや神経と筋の相互作用を解明することが重要である。本稿では,SBMAの病態とそのモデル,骨格筋障害と病態に即した治療法開発を中心に今後の展望について概説する。

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)  

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

DOI： 10.1136/jnnp-2020-322949

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA. OBJECTIVE: The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). METHODS: We analyzed longitudinal data of the specific binding ratio (SBR), a measure of striatal radiotracer uptake, in DAT SPECT from 7 patients with MSA-C, 5 patients with MSA-P, and 18 patients with PD. We performed 2.7±0.7 scans with an interval of 9.85±6.00 months for MSA and 2 scans with an interval of 2.16±0.16 years for PD. RESULTS: The rate of SBR decline was faster in both subtypes of MSA compared with PD, but the value was similar between MSA-P and MSA-C. The estimated SBR at the onset of initial motor symptoms was lower in PD and MSA-P than in MSA-C, especially in the predominantly affected side. SBR of the predominantly affected side starts to decrease before the onset of motor symptoms in PD and MSA-P, whereas the initiation of SBR decline is around the onset in MSA-C individuals. The decline of SBR in the less affected side was not clearly shown before the onset in MSA-P or MSA-C. CONCLUSIONS: Our results suggest that the SBR in DAT SPECT analysis is an important pathophysiological marker reflecting the disease- and subtype-specific progression of dopaminergic degeneration in MSA and PD.

DOI： 10.3233/JPD-191710

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：公益社団法人 日本理学療法士協会  

DOI： 10.14900/cjpt.47s1.f-171_2

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disease affecting only males characterized by progressive muscular atrophy and weakness in bulbar and limb muscles. The present study aimed to evaluate the features of velopharyngeal dysfunction (VPD) in SBMA subjects by an acoustic analysis of speech. Twenty-three genetically confirmed patients with SBMA were enrolled and assessed their speech by measuring the nasalance score with a Nasometer II. The nasalance scores of the SBMA group was higher than that of healthy controls (p = .035) and significantly correlated with the total score of the revised amyotrophic lateral sclerosis functional rating scale (rs = -0.520, p = .011). On the basis of the results of the VPD study, the efficacy of a palatal lift prosthesis (PLP) was assessed in two patients with SBMA to treat their VPD. The PLP improved dysarthria in both cases, although the impact of the prosthesis on dysphagia was not consistent. The present study suggested that the nasalance score is a useful quantitative measurement to evaluate VPD in patients with SBMA. A PLP may improve dysarthria in SBMA patients by reducing VPD, but the clinical application of this procedure should be considered carefully in view of its possible negative effect on dysphagia.

DOI： 10.1016/j.jns.2019.116503

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OBJECTIVE: To assess the changes of muscle-related biomarkers at the early stage of amyotrophic lateral sclerosis, and to confirm these findings in an experimental animal model. METHODS: Thirty-nine subjects with sporadic amyotrophic lateral sclerosis and 20 healthy controls were enrolled and longitudinally evaluated. We evaluated serum creatine kinase and creatinine levels and appendicular lean soft-tissue mass using dual X-ray absorptiometry. The levels of biomarkers at early ALS stages were estimated using linear mixed models with unstructured correlation and random intercepts. We also analyzed the longitudinal changes of serum creatine kinase and creatinine, together with the mRNA levels of acetylcholine receptor subunit γ (Chrng) and muscle-associated receptor tyrosine kinase, markers of denervation, in the gastrocnemius muscle of superoxide dismutase 1 (SOD1)G93A transgenic mice, an animal model of amyotrophic lateral sclerosis. RESULTS: The estimated levels of creatine kinase were higher in subjects with amyotrophic lateral sclerosis at the early stage than in healthy controls, although the estimated appendicular lean soft-tissue mass and creatinine levels were equivalent between both groups, suggesting that the elevation of creatine kinase precedes both muscular atrophy and subjective motor symptoms in sporadic amyotrophic lateral sclerosis. In SOD1G93A mice, the serum levels of creatine kinase were elevated at 9 weeks of age (peri-onset) when Chrng started to be up-regulated, and were then down-regulated at 15 weeks of age, consistent with the clinical data from patients with sporadic amyotrophic lateral sclerosis. INTERPRETATION: Creatine kinase elevation precedes muscular atrophy and reflects muscle denervation at the early stage.

DOI： 10.1007/s00415-019-09507-6

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

Spinal and bulbar muscular atrophy (SBMA) is a progressive hereditary neuromuscular disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. A 41-year-old man with SBMA received the androgen deprivation agent leuprorelin acetate for 7 years in clinical trials and underwent castration following the trial. Suppression of testosterone levels for 14 years resulted in a slower disease progression, as measured prospectively with quantitative measurements, than the historical control data reported in previous studies. This suggests that long-term androgen deprivation delays disease progression in SBMA.

DOI： 10.2169/internalmedicine.1592-18

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TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

DOI： 10.1172/JCI124481

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：南江堂  

DOI： 10.15106/j_naika123_1259

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BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied. METHODS: Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began. RESULTS: The primary endpoint difference between the leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, - 4.12% (95% CI, - 8.40-0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that leuprorelin acetate may be effective at each assessment point in both study groups. CONCLUSIONS: The efficacy of leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug.

DOI： 10.1007/s00415-019-09251-x

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Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG-rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper-methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over-expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper-methylation underlies the neurodegeneration in SBMA.

DOI： 10.15252/emmm.201708547

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DOI： 10.1016/S1474-4422(18)30359-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis. Although mexiletine hydrochloride administration has been shown to be effective for the treatment of several muscular diseases, its effectiveness in SBMA has not been validated to date. The trial will test it as a symptomatic drug for cold paresis. This study is the first trial to evaluate the efficacy and safety of mexiletine hydrochloride administration in patients with SBMA. METHODS AND ANALYSIS: A placebo-controlled, randomised, double-blind, multicentre, crossover clinical trial will be conducted to assess the safety and efficacy of mexiletine hydrochloride in patients with SBMA. The eligible patients will be assigned randomly in a 1:1 ratio to two groups in a double-blind manner. Participants will take mexiletine hydrochloride (300 mg/day) or a placebo orally three times a day for 4 weeks (period 1). After a 1-week washout period, participants will take the other drug for 4 weeks (period 2). The primary endpoint is the difference in distal latencies between room temperature and cold exposure conditions. ETHICS AND DISSEMINATION: This study will be conducted in compliance with the Helsinki Declaration and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Japanese government and has been approved by the ethics committee of Nagoya University Graduate School of Medicine, as a central institutional review board, and by each facility. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000026150; Pre-results.

DOI： 10.1136/bmjopen-2018-023041

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.107.1477

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Neurodegenerative diseases are disorders that are characterized by a progressive decline of the motor and/or cognitive function caused by a selective loss of neurons within the central nervous system. Recent advancements in the translational research have facilitated extensive insights into the molecular pathophysiology of neurodegenerative diseases. Nonetheless, a myriad of compounds that suppressed the disease progression in cellular and animal models did not exhibit efficacy in clinical trials. Perhaps, various biological, medical, and methodological factors could be attributed to unfavorable results of clinical trials of such disease-modifying therapies. Primarily, the fact that pathological changes at molecular and cellular levels precede the clinical onset by several years underscores a pressing need for the initiation of interventions before the emergence of neurological symptoms. Using exquisite biomarkers, recent studies revealed the preclinical and prodromal progression of pathophysiology, as well as compensatory brain responses in several neurodegenerative diseases. This review aims to discuss the recent advancement of biomarker studies on presymptomatic subjects and the perspective on a preventive trial of disease-modifying therapies for devastating neurological disorders.

DOI： 10.18999/nagjms.80.3.289

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OBJECTIVE: To identify a candidate biomarker reflecting biological changes during the preclinical progression of spinal and bulbar muscular atrophy (SBMA). METHODS: We analyzed longitudinal changes in biochemical parameters obtained during health examinations before and after the diagnosis of SBMA. We estimated trajectories of clinical markers across years from the onset of weakness using linear mixed models and compared these trajectories with those estimated for male healthy controls and patients with amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD). Moreover, we examined the relationship between serum creatinine level and the onset of symptoms using Kaplan-Meier curves. RESULTS: Between October 2014 and October 2017, we enrolled 40 patients with genetically confirmed SBMA, 48 healthy controls, 25 patients with ALS, and 20 patients with PD. In patients with SBMA, we evaluated the patients' data for a period of 17.3 ± 7.5 years, including 11.4 ± 7.1 years of preclinical phase. Decreases in serum creatinine occurred >10 years before the onset. The mean serum creatinine concentration was 0.56 mg/dL at the onset of weakness in patients with SBMA compared to 0.88 ± 0.10 mg/dL on final evaluation in healthy controls. Serum levels of alanine transaminase and aspartate transaminase showed tendencies to increase in preclinical SBMA. These preclinical changes of biomarkers were not observed in either ALS or PD. CONCLUSIONS: Our findings suggest that serum creatinine begins to decrease before the onset of clinical symptoms and is a biomarker for disease progression and the efficacy of therapeutics in preclinical SBMA.

DOI： 10.1212/WNL.0000000000005360

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BACKGROUND: Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness. OBJECTIVE: The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA. METHODS: A randomized, double-blind, placebo-controlled, three-armed clinical trial was conducted to assess the safety and efficacy of creatine therapy in patients with SBMA. Patients with SBMA eligible for this study were assigned randomly in a 1:1:1 ratio to each group of placebo, 10 g, or 15 g daily dose of creatine monohydrate in a double-blind fashion. Participants took creatine or placebo orally 3 times a day for 8 weeks. Outcome measurements were results of neurological assessments, examinations, and questionnaires collected at baseline and at weeks 4, 8, and 16 after a washout period. The primary endpoint was the change in handgrip strength values from baseline to week 8. The secondary endpoints included the following: results of maximum voluntary isometric contraction tests of extremities; tongue pressure; results of the 15-foot timed walk test and the rise from bed test; modified quantitative myasthenia gravis score; respiratory function test results; activities of daily living assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale and the Spinal and Bulbar Muscular Atrophy Functional Rating Scale; skeletal muscle mass measured with dual-energy X-ray absorptiometry; urinary 8-hydroxydeoxyguanosine levels; and questionnaires examining the quality of life, swallowing function, and fatigue. RESULTS: Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed. CONCLUSIONS: This is the first clinical trial evaluating creatine therapy in SBMA. Given that creatine serves as an energy source in skeletal muscles, recovery of intramuscular creatine concentration is expected to improve muscle strength. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000012503; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014611 (Archived by WebCite at http://www.webcitation.org/6xOlbPkg3).

DOI： 10.2196/resprot.8655

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Neurological Therapeutics  

<p>Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular degenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA is the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The ligand–dependent nuclear accumulation of the polyglutamine–expanded AR protein is central to the gender–specific pathogenesis of SBMA. The pathogenic AR–mediated neurodegeneration is suppressed by androgen inactivation, the efficacy of which has been tested in randomized controlled trials. Decreases in serum creatinine, a biomarker of SBMA, occurred approximately 15 years before the onset of subjective muscle weakness. The mean serum creatinine concentration is ∼0.6mg/dl and ∼0.8mg/dl at the onset of weakness and hand tremor, respectively. The low serum creatinine concentration in subjects with SBMA is caused by impaired muscle uptake of creatine due to the pathogenic AR–mediated down–regulation of creatine transporter SLC6A8, in addition to being caused by neurogenic atrophy.</p>

DOI： 10.15082/jsnt.35.4_427

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経治療学会  

DOI： 10.15082/jsnt.34.4_461

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

Objective This study aimed to evaluate swallowing dysfunction in patients with spinal and bulbar muscular atrophy and to identify the most appropriate method of assessing swallowing dysfunction using a videofluoroscopic swallowing study. Methods In the videofluoroscopic swallowing study, patients were instructed to swallow 3 mL of 40% weight/volume barium sulfate twice, and the pharyngeal residue was measured. We used three different methods to quantify the pharyngeal barium residue and an eight-point scale to evaluate the laryngeal penetration leading to aspiration pneumoniae. Patients We assessed 111 patients with spinal and bulbar muscular atrophy who weren't undergoing disease-specific treatment. Results Our results showed that the pharyngeal barium residue after initial swallowing correlated better with the bulbar-related functional rating scales than that after multiple deglutition. This correlation was vague when the data from patients whose barium residue was >50% were eliminated. In addition, evaluating the pharyngeal residue after initial swallowing proved to be the most sensitive method with regard to laryngeal penetration. Conclusion This study showed that the pharyngeal barium residue after initial swallowing was the most appropriate parameter for quantitatively assessing the degree of dysphagia using a videofluoroscopic swallowing study and suggests that this method may predict laryngeal penetration and aspiration in patients with spinal and bulbar muscular atrophy.

DOI： 10.2169/internalmedicine.8799-16

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OBJECTIVE: To evaluate the prognosis and progression of spinal and bulbar muscular atrophy (SBMA), a rare X-linked motor neuron disorder caused by trinucleotide repeat expansion in the AR (androgen receptor) gene, after long-term androgen suppression with leuprorelin acetate treatment. METHODS: In the present natural history-controlled study, 36 patients with SBMA treated with leuprorelin acetate for up to 84 months (leuprorelin acetate-treated group; LT group) and 29 patients with SBMA with no specific treatment (non-treated group; NT group) were analysed. Disease progression was evaluated by longitudinal quantitative assessment of motor functioning using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the modified Norris score. In addition, we selected two major clinical endpoint events, namely the occurrence of pneumonia requiring hospitalisation and death, to evaluate disease prognosis following long-term leuprorelin acetate treatment. RESULTS: In our analysis of the longitudinal disease progression using the random slope model, we observed a significant difference in the ALSFRS-R total score, the Limb Norris Score, and the Norris Bulbar Score (p=0.005, 0.026 and 0.020, respectively), with the LT group exhibiting a slower per-12-months decline compared with the NT group. As for the event analysis, the prognosis of the LT group was better in comparison to the NT group as for the event-free survival period (p=0.021). CONCLUSION: Long-term treatment with leuprorelin acetate appears to delay the functional decline and suppress the incidence of pneumonia and death in subjects with SBMA.

DOI： 10.1136/jnnp-2017-316015

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OBJECTIVE: To investigate the mechanisms of vasculitis in nonsystemic vasculitic neuropathy (NSVN) and microscopic polyangiitis (MPA), focusing on complement- and antineutrophil cytoplasmic antibody (ANCA)-associated pathogenesis. METHODS: Sural nerve biopsy specimens taken from twenty-four patients with NSVN and 37 with MPA-associated neuropathy (MPAN) were examined. Twenty-two patients in the MPAN group tested positive for ANCA. RESULTS: Immunostaining for complement component C3d deposition showed more frequent positive staining of epineurial small vessels in NSVN than in MPAN (p = 0.002). The percentages of C3d-positive blood vessels were higher in the NSVN group than those in the ANCA-positive MPAN and ANCA-negative MPAN groups (p = 0.002 and p = 0.009, respectively). Attachment of neutrophils to the endothelial cells of epineurial small vessels was frequently observed in the MPAN groups, irrespective of the presence or absence of ANCA, but was scarce in the NSVN group. Immunohistochemistry using antimyeloperoxidase (MPO) antibodies revealed that the number of MPO-positive cells attached to the endothelial cells of epineurial vessels was lower in the NSVN group than that in the ANCA-positive MPAN and ANCA-negative MPAN groups (p < 0.001 and p = 0.011, respectively). CONCLUSIONS: NSVN and MPA have distinct mechanisms of vasculitis. In MPA, the attachment of neutrophils to vascular endothelial cells seems to be an initial lesion of vasculitis, regardless of the presence or absence of ANCA. Complement participated in the pathogenesis of vasculitis in NSVN.

DOI： 10.1212/NXI.0000000000000407

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The objective of this study was to systematically investigate cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy (FAP ATTR Val30Met) patients from non-endemic areas. The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test with impedance cardiography, noradrenaline infusion test, and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy were assessed in eight patients. Although only four patients manifested orthostatic hypotension during the head-up tilt test, CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated a higher prevalence of cardiac sympathetic and parasympathetic dysfunction. Total peripheral resistance at 60° tilt did not increase from baseline values in five of six examined patients. An infusion of low-dose noradrenaline induced an increase in systolic blood pressure in all patients. The extent of the change in systolic blood pressure negatively correlated to that in total peripheral resistance (p < 0.05). Patients with poor vasoconstrictor responses to orthostatic stress tended to exhibit severe reduction of unmyelinated fibres in sural nerve biopsy specimens. In conclusion, both cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in late-onset FAP ATTR Val30Met patients from non-endemic areas, even in those without orthostatic intolerance. However, vasoconstriction by alpha-adrenoceptor agonists was preserved even after denervation, carrying important implications for the management of orthostatic hypotension in FAP.

DOI： 10.1007/s00415-017-8629-2

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DOI： 10.1016/j.jns.2017.08.3058

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DOI： 10.1016/j.jns.2017.08.588

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DOI： 10.1016/j.jns.2017.08.601

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DOI： 10.1016/j.jns.2017.08.606

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DOI： 10.1016/j.jns.2017.08.3512

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

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OBJECTIVE: We examined the characteristics of dysphagia in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease causing weakness of limb, facial, and oropharyngeal muscles via a videofluoroscopic swallowing study, and investigated the plausibility of using these outcome measures for quantitative analysis. METHODS: A videofluoroscopic swallowing study was performed on 111 consecutive patients with genetically confirmed spinal and bulbar muscular atrophy and 53 age- and sex-matched healthy controls. Swallowing of 3-mL liquid barium was analyzed by the Logemann's Videofluorographic Examination of Swallowing worksheet. RESULTS: Of more than 40 radiographic findings, the most pertinent abnormal findings in patients with spinal and bulbar muscular atrophy, included vallecular residue after swallow (residue just behind the tongue base), nasal penetration, and insufficient tongue movement (P < 0.001 for each) compared with healthy controls. Quantitative analyses showed that pharyngeal residue after initial swallowing, oral residue after initial swallowing, multiple swallowing sessions, and the penetration-aspiration scale were significantly worse in these patients (P ≤ 0.005 for each) than in controls. In patients with spinal and bulbar muscular atrophy, laryngeal penetration was observed more frequently in those without subjective dysphagia. INTERPRETATION: Dysphagia of spinal and bulbar muscular atrophy was characterized by impaired tongue movement in the oral phase and nasal penetration followed by pharyngeal residues, which resulted in multiple swallowing sessions and laryngeal penetration. Although major limitations of reproducibility and radiation exposure still exist with videofluoroscopy, pharyngeal residue after initial swallowing and the penetration-aspiration scale might serve as potential outcome measures in clinical studies.

DOI： 10.1002/acn3.425

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This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.

DOI： 10.1007/s00415-017-8405-3

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.48.141

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DOI： 10.1080/21678707.2017.1329088

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

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OBJECTIVE: The aim of this study was to explore the pathomechanism underlying the reduction of serum creatinine (Cr) concentrations in spinal and bulbar muscular atrophy (SBMA). METHODS: We evaluated blood chemistries, motor function, and muscle mass measured by dual-energy X-ray absorptiometry in male subjects with SBMA (n = 65), amyotrophic lateral sclerosis (ALS; n = 27), and healthy controls (n = 25). We also examined the intramuscular concentrations of creatine, a precursor of Cr, as well as the protein and mRNA expression levels of the creatine transporter (SLC6A8) in autopsy specimens derived from subjects who had SBMA and ALS and disease controls. Furthermore, we measured the mRNA expression levels of SLC6A8 in cultured muscle cells (C2C12) transfected with the polyglutamine-expanded androgen receptor (AR-97Q). RESULTS: Serum Cr concentrations were significantly lower in subjects with SBMA than in those with ALS (P < 0.001), despite similar muscle mass values. Intramuscular creatine concentrations were also lower in with the autopsied specimen of SBMA subjects than in those with ALS subjects (P = 0.018). Moreover, the protein and mRNA expression levels of muscle SLC6A8 were suppressed in subjects with SBMA. The mRNA levels of SLC6A8 were also suppressed in C2C12 cells bearing AR-97Q. INTERPRETATION: These results suggest that low serum Cr concentration in subjects with SBMA is caused by impaired muscle uptake of creatine in addition to being caused by neurogenic atrophy. Given that creatine serves as an energy source in skeletal muscle, increasing muscle creatine uptake is a possible therapeutic approach for treating SBMA.

DOI： 10.1002/acn3.324

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The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles.

DOI： 10.1371/journal.pone.0168846

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

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We describe the case of a 33-year-old man with a 4-year history of worsening muscle stiffness and weakness in his right hand. He showed elevated serum creatine kinase levels at the onset of muscle stiffness that was characterized by delayed muscle relaxation after voluntary contraction. This symptom often occurred during cold exposure, and was partially attenuated by sodium channel blockade. Electrodiagnostic findings in repetitive nerve stimulation, short-exercise, and cooling tests were normal. Electromyography showed chronic denervation potentials in his cranial, cervical, thoracic, and lumbosacral myotomes without myotonic discharge. He exhibited facial and tongue fasciculations, hypernasality, gynecomastia, neurogenic changes in muscle biopsy, and increased serum testosterone levels. Spinal and bulbar muscular atrophy (SBMA) was diagnosed on the basis of the CAG trinucleotide expansion in the gene coding androgen receptor. A myotonia-like symptom without myotonic discharge may present as an early neurological sign of SBMA, which possibly reflects a sodium channel dysfunction in skeletal muscles.

DOI： 10.1016/j.nmd.2015.08.006

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

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We aimed to develop, validate, and evaluate a disease-specific outcome measure for SBMA: the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). We examined the Japanese version (SBMAFRS-J) in 80 Japanese SBMA subjects to evaluate its validity and reliability. We then assessed this scale longitudinally in 41 additional SBMA subjects. The English version (SBMAFRS-E) was also tested in 15 US subjects. The total score of the SBMAFRS-J was distributed normally without an extreme ceiling or floor effect. For SBMAFRS-J, the high intra- and inter-rater agreement was confirmed (intra-class correlation coefficients [ICCs] 0.910 and 0.797, respectively), and internal consistency was satisfactory (Cronbach's alpha 0.700-0.822). In addition, SBMAFRS-J demonstrated concurrent, convergent, and discriminant validity, except for the respiratory subscale. The inter-rater reliability and internal consistency of SBMAFRS-E were also satisfactory. Longitudinally, SBMAFRS-J showed a higher sensitivity to disease progression than the existing clinical measures. In conclusion, we developed and validated a disease-specific functional rating scale for SBMA in both Japanese and English versions, although it needs to be re-assessed in interventional studies with a larger sample size including English speaking subjects.

DOI： 10.1016/j.nmd.2015.03.008

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BACKGROUND: Dysphagia due to bulbar involvement is a major symptom of patients with spinal and bulbar muscular atrophy (SBMA). The aim of this pilot study was to test the efficacy and safety of the head lift exercise for swallowing dysfunction in SBMA. METHODS: We enrolled 6 subjects with genetically confirmed SBMA and instructed them to perform the head lift exercise for 6 weeks. The efficacy outcome measures were the changes from baseline in tongue pressure, the scores of swallowing functional questionnaires, and the motor functional scales and parameters of videofluorography (VF). RESULTS: All subjects completed the study and no major adverse effects were recorded. Tongue pressure significantly increased by 19.2 ± 0.15% (p < 0.05) after the 6-week head lift exercise. The scores for oral dysphagia also improved, although there was no significant change in VF parameters or other variables examined pre- and post-exercise. CONCLUSION: Our findings suggested that the head lift exercise may improve swallowing dysfunction, particularly tongue pressure, in SBMA.

DOI： 10.1159/000431088

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Spinocerebellar ataxia type 3 (SCA3) is an inherited spinocerebellar ataxia caused by the expansion of trinucleotide CAG repeats in the gene encoding ataxin-3. The clinical manifestations of SCA3 include peripheral neuropathy, which is an important cause of disability in a subset of patients. Although the loss of neurones in the dorsal root ganglion (DRG) has been postulated to be the cause of this neuropathy, the precise mechanism remains to be elucidated. METHODS: To clarify the clinicopathological characteristics of SCA3-associated peripheral neuropathy, we performed nerve conduction studies and histopathological analyses. Nerve conduction studies were carried out in 18 SCA3 patients. Immunohistochemical analyses of the anterior and posterior roots of the spinal cord and peripheral nerves were performed in five SCA3 patients. We also employed immunohistochemistry and immunoelectron microscopy analyses with an anti-polyglutamine antibody. RESULTS: The mean sensory nerve action potentials of the SCA3 patients were half of the normal values. The motor conduction velocities were decreased, and the distal latencies were also significantly prolonged in the nerves studied relative to the those in normal controls. Histopathological analyses detected axonal sprouting and myelin thinning in all cases. Ataxin-3 aggregates were found in the cytoplasm of Schwann cells in all of the SCA3 patients examined but not in control subjects. CONCLUSIONS: In addition to the previously reported neuronopathy, the results of the present study indicate that Schwann cells are involved in the formation of the pathogenic intracytoplasmic ataxin-3 protein aggregates in patients with SCA3-associated neuropathy.

DOI： 10.1111/nan.12055

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The aim of this study was to clarify myocardial involvement and its clinical implications in subjects with spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease affecting both neuronal and nonneuronal tissues. METHODS: Two independent cardiologists evaluated ECGs from a total of 144 consecutive subjects with SBMA. We performed immunohistochemical, immunoblot, and quantitative real-time PCR analyses of autopsied myocardium. RESULTS: Abnormal ECGs were detected in 70 (48.6%) of 144 subjects. The most frequent findings were ST-segment abnormalities in V1-3 (19.4%), followed by ST-segment abnormalities in V5-6 (18.1%). We detected Brugada-type ECGs in 17 of 28 subjects with ST-segment abnormalities in V1-3. Of those, one subject presented with syncope that required an implantable cardioverter defibrillator and led to eventual sudden death, and another subject also died suddenly. No subjects with Brugada-type ECGs had mutations in SCN5A, CACNA1C, or CACNB2 genes. In autopsied cases, we detected nuclear accumulation of the mutant androgen receptor protein and decreased expression levels of SCN5A in the myocardium. CONCLUSIONS: Subjects with SBMA often show Brugada-type ECG. The accumulation of the pathogenic androgen receptor may have a role in the myocardial involvement in SBMA.

DOI： 10.1212/WNL.0000000000000434

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Laryngospasm is a sudden onset of transient respiratory difficulty that is perceived as life-threatening by patients with spinal and bulbar muscular atrophy (SBMA). The purpose of the study was to analyze the voice characteristics of SBMA patients with laryngospasm using acoustic voice analysis. METHODS: Acoustic measurements were obtained from 39 consecutive Japanese patients with genetically confirmed SBMA. A comparison was made between the acoustic voice profiles of 16 patients with laryngospasm and 23 patients without laryngospasm within 6 months before the evaluation. Computerized acoustic analysis was performed for a prolonged vowel (/a:/) using the Multi-Dimensional Voice Program (MDVP). RESULTS: SBMA patients with laryngospasm had smaller fluctuations of vocal fold vibration and the turbulent noise component, indicating stronger vocal fold closure than in those without laryngospasm. Receiver operating characteristic curve analysis showed that the noise-to-harmonic ratio, which globally measures the noise components of voice, is the most useful acoustic parameter to distinguish laryngospasm (area under the curve = 0.767, p = 0.007). CONCLUSIONS: The smaller noise component in patients with laryngospasm suggests that the vocal folds of these patients are more adducted during phonation than those of the patients without laryngospasm, even in the absence of laryngospasm. Quantitative laryngeal analysis using the MDVP helps to detect laryngeal dysfunction and provides physiological insight into the pathophysiology of laryngospasm in SBMA.

DOI： 10.1016/j.jns.2013.12.010

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: This study aimed to explore the reliability and validity of tongue pressure measurement as a quantitative evaluation of swallowing function in patients with spinal and bulbar muscular atrophy (SBMA). METHODS: This study enrolled 47 genetically confirmed patients with SBMA and 38 age- and sex-matched healthy controls. In both groups we measured tongue pressure using an intraoral pressure probe and assessed questionnaires that evaluated swallowing functions. We then analyzed the relationship between tongue pressure, functional scales, and the muscle weakness of other regions. RESULTS: Levels of tongue pressure were decreased in patients with SBMA within 3 years from the onset of the disease compared to healthy controls (SBMA 15.3 ± 6.4 kPa; healthy controls 37.3 ± 9.6 kPa; p < 0.001). Test-retest analysis showed a high reliability in patients with SBMA (intraclass correlation coefficient = 0.986). Tongue pressure showed a strong correlation with bulbar-related functional scales. Decrease of tongue pressure was detected in patients who reported no subjective dysphagia, and repetition of swallowing compensated for tongue weakness in such subjects. In patients with SBMA, tongue pressure more strongly correlates with the strength of pharyngeal, neck, and upper limb musculatures than with that of the lower limbs. CONCLUSION: Tongue pressure measurement is reliable and reflects swallowing function in patients with SBMA. The muscle strength of the tongue appears to decrease in SBMA before the awareness of subjective dysphagia, suggesting that tongue pressure measurement is a novel biomarker of SBMA and is applicable to early-stage detection.

DOI： 10.1212/WNL.0000000000000041

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本脳卒中学会  

【目的】回復期入院リハビリテーション(リハビリ)での脳梗塞branch atheromatous disease(BAD)の治療成績を検討した。【対象と方法】レンズ核線条体動脈領域(LSA-BAD)90例と傍正中橋動脈領域(PPA-BAD)21例に対し、入院時・退院時の脳卒中重症度(NIHSS)、機能的自立度評価法(FIM)、上肢・手指・下肢各Brunnstrom stage(BRS)を検討した。【結果】LSA-BAD群はPPA-BAD群に比べ入退院時NIHSSは有意に重症であり、手指・上肢の機能改善は不良であった(p<0.05)。LSA-BAD群は入院時上肢・手指BRSの退院時3段階以上の回復は稀だったが、両群とも退院時FIMは多くが100点以上であった。【結論】回復期リハビリでのBADを分類し検討することで、皮質脊髄路障害部位の違いによる運動麻痺と機能的自立度評価の回復過程を評価できた。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J01786&link_issn=&doc_id=20131129040007&doc_link_id=%2Fdh3strok%2F2013%2F003506%2F007%2F0441-0447%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdh3strok%2F2013%2F003506%2F007%2F0441-0447%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japan Stroke Society  

Purpose: We investigated inpatient convalescent rehabilitation outcomes of ischemic stroke especially for branch atheromatous disease (BAD).Subjects and Methods: Subjects were 90 lenticulostriate artery territory-BAD (LSA-BAD) and 21 paramedian pontine artery territory-BAD (PPA-BAD) patients. For all patients, National Institutes of Health Stroke Scale (NIHSS) and functional independence measure (FIM) scores, and Brunnstrom stages (BRS) of upper limb, fingers, and lower limb were measured both on admission and discharge.Results: There were no significant differences in clinical scores and characteristics on admission between LSA-BAD and PPA-BAD groups except for the higher proportion of female in PPA-BAD groups (p=0.043). The severities of PPA-BAD patients with NIHSS scores were significantly mild compared with those of LSA-BAD patients on admission (p=0.031) and at discharge (p=0.008). Significant lower improvements with LSA-BAD patients were found in the stages of BRS with upper limb (p=0.009) and fingers (p=0.010) at discharge and recovery changes of BRS with fingers (p=0.031) compared with those of PPA-BAD patients. The improvements of each BRS score with LSA-BAD patients had the tendency of the limitations within two up-grades however both LSA-BAD and PPA-BAD patients basically gained over 100 total-FIM scores at discharge.Conclusion: The investigation of rehabilitation outcomes with BAD patients in the convalescent period can assess the improvements of pure-motor hemiparesis and activities of daily living, because the disturbance of the corticospinal tract by ischemic infarction lesions may be different in LSA-BAD and PPA-BAD.

DOI： 10.3995/jstroke.35.441

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. The aim of this study was to verify whether urinary 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, is a biomarker for SBMA. METHODS: We measured the levels of urinary 8-OHdG in 33 genetically confirmed SBMA patients and 32 age-matched controls over a 24-month period at 6-month intervals. RESULTS: Urinary 8-OHdG levels in SBMA patients were significantly elevated compared with those of controls and correlated well with motor function scores. During the follow-up period, urinary 8-OHdG levels increased and correlated with motor function at each time-point. In addition, urinary 8-OHdG levels at baseline were correlated with changes in the 6-minute walk test during 24 months. CONCLUSIONS: Urinary 8-OHdG is a biomarker for SBMA, reflecting the severity and possibly predicting the deterioration of motor function.

DOI： 10.1002/mus.23413

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.101.2533

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PubMed

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Spinal and bulbar muscular atrophy is an adult-onset, hereditary motor neuron disease caused by the expansion of a trinucleotide CAG repeat within the gene encoding the androgen receptor. To date, several agents have been shown to prevent or slow disease progression in animal models of this disease. For the translational research of these agents, it is necessary to perform the detailed analysis of natural history with quantitative outcome measures and to establish sensitive and validated disease-specific endpoints in the clinical trials. To this end, we performed a prospective observation of disease progression over 3 years in 34 genetically confirmed Japanese patients with spinal and bulbar muscular atrophy by using quantitative outcome measures, including functional and blood parameters. The baseline evaluation revealed that CAG repeat length in the androgen receptor gene correlated not only with the age of onset but also with the timing of substantial changes in activity of daily living. Multiple regression analyses indicated that the serum level of creatinine is the most useful blood parameter that reflects the severity of motor dysfunction in spinal and bulbar muscular atrophy. In 3-year prospective analyses, a slow but steady progression was affirmed in most of the outcome measures we examined. In the analyses using random coefficient models that summarize the individual data into a representative line, disease progression was not affected by CAG repeat length or onset age. These models showed large interindividual variation, which was also independent of the differences of CAG repeat size. Analyses using these models also demonstrated that the subtle neurological deficits at an early or preclinical stage were more likely to be detected by objective motor functional tests such as the 6-min walk test and grip power or serum creatinine levels than by functional rating scales, such as the revised amyotrophic lateral sclerosis functional rating scale or modified Norris scale. Categorization of the clinical phenotypes using factor analysis showed that upper limb function is closely related to bulbar function, but not to lower limb function at baseline, whereas the site of onset had no substantial effects on disease progression. These results suggest that patients with spinal and bulbar muscular atrophy show a slow but steady progression of motor dysfunction over time that is independent of CAG repeat length or clinical phenotype, and that objective outcome measures may be used to evaluate disease severity at an early stage of this disease.

DOI： 10.1093/brain/aws170

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経治療学会  

Language：English   Publishing type：Research paper (scientific journal)  

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, and bulbar involvement. The aim of this study was to analyze the differential change of various outcome measures by comparing the progression of motor impairment in the two independent groups: placebo-treated group (PTG) and natural history group (NHG). For the PTG, we analyzed 99 patients who participated in a previous double-blind phase III clinical trial and received placebo. For the NHG, a total of 34 patients were followed with no specific treatment. The characteristics of both groups did not differ at baseline except for disease duration. Although the 6 min walk distance (6MWD) showed almost the same progression in both groups (-14.7 ± 7.3 m in NHG, -14.0 ± 4.7 m in PTG; NS), there was a significant difference of progression in the ALSFRS-R between the NHG and PTG (-1.18 ± 0.38, -0.14 ± 0.24; p = 0.03). A similar tendency was also seen in the subgroup analysis of the patients whose disease durations were less than 10 years. Although the relationship between the ALSFRS-R and 6MWD at week 48 was similar to that at baseline in the NHG, the slope of the regression at week 48 was significantly milder than at baseline in the PTG (p = 0.04). In conclusion, these two groups demonstrated a large difference in the chronological analysis of a motor function score, but showed similar changes in objective measures of walking capacity. These findings should be thoroughly considered when designing clinical trials for slowly progressive neurodegenerative diseases such as SBMA.

DOI： 10.1007/s00415-011-6251-2

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is an adult-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The testosterone-dependent nuclear accumulation of polyglutamine-expanded AR protein is central to the pathogenesis. This hypothesis is supported by pre-clinical studies showing that testosterone deprivation ameliorates motor neuron degeneration in animal modes of SBMA. In a randomized placebo-controlled multi-centric clinical trial, leuprorelin, which suppresses secretion of testosterone, showed no definite effect on motor functions, although there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. Elucidation of the entire disease mechanism, early initiation of therapeutic intervention, and sensitive outcome measures to evaluate drug effect appear to be the key to a successful translational research on SBMA.

DOI： 10.5692/clinicalneurol.52.1207

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PubMed

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.101.113a

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jns.2011.07.025

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.clineuro.2011.01.008

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PubMed

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat in the androgen receptor (AR) gene. The fundamental histopathological finding of this disease is an extensive loss of lower motor neurons in the spinal cord and brainstem. It is, however, difficult to evaluate clinically the degree of motor neuron degeneration, which stresses the need for biomarkers to detect the remaining neuronal function. METHODS: The authors performed motor unit number estimation (MUNE) in 52 patients with SBMA, to investigate whether this method could be a potential biomarker of SBMA, and re-evaluated MUNE 1 year later in a subgroup of the patients. RESULTS: The number of functioning motor units was remarkably reduced in patients with SBMA compared with controls, and was correlated with both ipsilateral grip power and disease duration. A longitudinal analysis demonstrated a further reduction in motor units within 1 year. CONCLUSIONS: The results suggest that MUNE is an electrophysiological parameter that reflects the severity and progression of motor neuron degeneration in patients with SBMA.

DOI： 10.1136/jnnp.2009.190462

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(一社)日本神経学会  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J02615&link_issn=&doc_id=20221216430054&doc_link_id=10.15082%2Fjsnt.39.3_306&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.39.3_306&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J02615&link_issn=&doc_id=20211126190045&doc_link_id=10.15082%2Fjsnt.38.6_S132&url=https%3A%2F%2Fdoi.org%2F10.15082%2Fjsnt.38.6_S132&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(株)中外医学社  

Language：English   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

J-GLOBAL

J-GLOBAL

J-GLOBAL

J-GLOBAL

Language：Japanese   Publisher：日本末梢神経学会  

Language：Japanese   Publisher：(一社)日本神経免疫学会  

Language：Japanese   Publisher：(一社)日本臨床神経生理学会  

Language：Japanese   Publisher：(一社)日本臨床薬理学会  

Language：Japanese   Publisher：(株)メディカルドゥ  

球脊髄性筋萎縮症(spinal and bulbar muscular atrophy:SBMA)は,アンドロゲン受容体遺伝子上のCAG繰り返し配列の異常延長を特徴とするポリグルタミン病である。異常アンドロゲン受容体タンパク質が運動ニューロンの細胞核へ蓄積することで,緩徐な運動ニューロンの神経変性を生じる。テストステロン依存性の変異タンパク質の核内移行がSBMAの病態の本幹であると考えられており,テストステロンの抑制をすることがSBMAの治療につながることが動物モデルに対する基礎的研究で明らかになった。これらの基礎研究結果に基づき医師主導型の医薬品開発臨床試験を実施した結果,2017年8月にLH-RHアナログであるリュープロレリン酢酸塩の効能に「球脊髄性筋萎縮症の進行抑制」が追加された。現在は,真のエンドポイント(死亡や死亡関連イベント)に関する十分なエビデンスを構築するため,疾患登録システム(患者レジストリ)にデータの蓄積を開始している。また,さらなる基礎的検討の結果,核内に集積した変異ARがDNMT1の発現を誘導し,Hes5などの遺伝子のDNAメチル化を亢進させることでニューロン変性を惹起すること,変異ARがSrcの活性化を介して神経・筋システム変性を惹起すること,など新たな知見も集積されつつあり,新規治療開発も期待されている。(著者抄録)

Language：Japanese   Publisher：(一社)日本神経学会  

J-GLOBAL

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞Summary ▼球脊髄性筋萎縮症(SBMA)は,アンドロゲン受容体遺伝子上のCAG繰り返し配列の異常延長を特徴とするポリグルタミン病である.▼異常アンドロゲン受容体蛋白質が運動ニューロンの細胞核に蓄積することで,緩徐な運動ニューロンの神経変性を生じる.▼テストステロン依存性の変異蛋白質の核内移行がSBMAの病態の本幹であり,テストステロンを抑制することはSBMAの治療につながるということが,動物モデルに対する基礎的研究で明らかになった.▼医師主導治験の結果,2017年8月にLH-RHアナログであるleuprorelin acetateの効能に「球脊髄性筋萎縮症の進行抑制」が追加された.▼真のエンドポイント(死亡や死亡関連イベント)に関する十分なエビデンスを構築するため,疾患登録システム(患者レジストリ)にデータの蓄積を開始している.

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00974&link_issn=&doc_id=20190611090009&doc_link_id=issn%3D0022-1961%26volume%3D123%26issue%3D6%26spage%3D1259&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D123%26issue%3D6%26spage%3D1259&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：(公社)日本医師会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(株)医学出版  

＜Point1＞運動ニューロンの疾患概念を説明できる。＜Point2＞運動ニューロンの特徴や症候を知り、鑑別診断を進めていくことができる。＜Point3＞運動ニューロンにおける新しい治療法を知り、治療可能な疾病に対応できる。(著者抄録)

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本内科学会  

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01159&link_issn=&doc_id=20180816080004&doc_link_id=10.2169%2Fnaika.107.1477&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.107.1477&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)北隆館  

特定のニューロンが選択的に変性・脱落し、神経症状が進行性に悪化する神経変性疾患には、希少疾患(orphan disease)も数多く存在する。近年の分子生物学の進歩に伴い、神経変性疾患の分子病態が明らかになりつつあり、神経変性の分子メカニズムそのものを阻止しようとする疾患修飾療法(disease-modifying therapy)をコンセプトとした医薬品開発が盛んになりつつある。上市後の市場規模の問題や、患者の希少性によって、診療経験のある医師や医療機関の確保が困難であるという問題から、製薬企業が開発に着手しにくい分野でもあり、アカデミアが主体となって医薬品開発を進めることが求められる分野でもある。特に、ドラッグリポジショニングによる医薬品開発の場合、臨床薬理試験や、初期の安全性および忍容性の確認にあたる試験を省略できる可能性もあることから、アカデミアが開発に着手しやすい分野でもある。本稿では、アカデミアにおいて、モデル動物を使った基礎的実験から臨床試験までを一貫して行い、最終的に、効能追加の薬事承認を得ることが出来た、球脊髄性筋萎縮症(Spinal and Bulbar Muscular Atrophy:SBMA)に対するリュープロレリン酢酸塩の開発について概説する。(著者抄録)

Language：Japanese   Publisher：(一社)日本神経治療学会  

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J02615&link_issn=&doc_id=20190514380013&doc_link_id=%2Fcq3neuro%2F2018%2F003504%2F013%2F0427-0431%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq3neuro%2F2018%2F003504%2F013%2F0427-0431%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)ライフメディコム  

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1016/j.jns.2017.08.3058

Web of Science

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1016/j.jns.2017.08.606

Web of Science

Language：Japanese   Publisher：(株)新興医学出版社  

Language：Japanese   Publisher：(一社)日本臨床薬理学会  

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01568&link_issn=&doc_id=20170817330003&doc_link_id=10.3999%2Fjscpt.48.141&url=https%3A%2F%2Fdoi.org%2F10.3999%2Fjscpt.48.141&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(株)日本プランニングセンター  

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Language：Japanese   Publisher：(有)科学評論社  

Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：TAYLOR & FRANCIS LTD  

Introduction: With greater longevity, the prevalence of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis is increasing, but these diseases remain intractable. This is also the case for a hereditary motor neuron disease, spinal and bulbar muscular atrophy or SBMA.Areas covered: SBMA typically affects adult males, eliciting motor deficits due to progressive loss of lower motor neurons, while females do not manifest neurological signs. It results from a CAG-trinucleotide repeat expansion in the androgen receptor or AR gene which is translated into an expanded polyglutamine tract within the encoded protein. Ligand-dependent nuclear accumulation of the mutant AR is implicated to lead to transcriptional dysregulation and subsequent defects in pivotal cellular functions, causing motor neuron death.Expert opinion: Even though the pathogenesis has not been fully understood, recent advances especially in the dissection of pathomechanisms associated with the pathogenic AR protein and aggregates accelerate the development of potential targeted therapeutics such as administration of leuprorelin acetate, a potent luteinizing hormone-releasing hormone analog, which has been successfully tested in clinical trials. Combination therapies antagonizing causative mutant AR and its downstream targets hold promise to further open a therapeutic avenue for the establishment of disease modifying drugs for SBMA.

DOI： 10.1080/21678707.2017.1329088

Web of Science

Scopus

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本臨床薬理学会  

Language：Japanese   Publisher：(有)科学評論社  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：大道学館出版部  

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2015274860

Language：Japanese   Publisher：(一社)日本神経学会  

球脊髄性筋萎縮症(SBMA)はアンドロゲン受容体(AR)遺伝子におけるCAGくりかえし塩基配列の異常延長を原因とする運動ニューロン疾患であり,伸長ポリグルタミン鎖を有する異常AR蛋白質がテストステロンと結合することによってニューロンの核内に蓄積することが病態の本質と考えられている.テストステロンの分泌を抑制するリュープロレリン酢酸塩のSBMAに対する第III相臨床試験では,主要評価項目である咽頭部バリウム残留率について,被験者全体の解析では統計学的有意差はみとめられなかったが,罹病期間が10年以内の被験者のみを対象としたサブ解析では残留率が酢酸リュープロレリン群で有意に低下したことから,発症からの期間が薬効に影響をおよぼすことが示唆された.早期の治療介入や鋭敏なエンドポイントの開発が今後のトランスレーショナルリサーチに重要であると考えられる.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01550&link_issn=&doc_id=20121213290135&doc_link_id=10.5692%2Fclinicalneurol.52.1207&url=https%3A%2F%2Fdoi.org%2F10.5692%2Fclinicalneurol.52.1207&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)北隆館  

我々は神経変性疾患の一つである球脊髄性筋萎縮症(SBMA)に対し、動物モデルの作製・病態解析から医師主導治験へと研究を進めてきた。SBMAの病因タンパク質である変異アンドロゲン受容体の細胞内局在は、リガンドである男性ホルモンの濃度に大きく影響されることから、テストステロン分泌を抑制するリュープロレリン酢酸塩をSBMA患者に投与したところ、嚥下機能が改善する可能性が示唆された。今後、神経変性疾患の分子標的治療開発を推進するためには、客観的指標を用いて自然歴を明らかにし、薬効評価に有用なバイオマーカーを確立することが重要である。(著者抄録)

Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(一社)日本神経治療学会  

Language：Japanese   Publisher：(一社)日本神経学会  

Language：Japanese   Publisher：(一社)日本内科学会  

Language：Japanese  

CiNii Books

Other Link： http://id.nii.ac.jp/1724/00001387/

Language：Japanese   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

Language：Japanese   Publisher：(一社)日本神経学会