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Neurol Neuroimmunol Neuroinflamm
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Neurology® Neuroimmunology & Neuroinflammation
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Lippincott Williams & Wilkins Hagerstown, MD

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NXI-2024-100160
10.1212/NXI.0000000000200293
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Clinical/Scientific Note
Different Complement Activation Patterns Following C5 Cleavage in MOGAD and AQP4-IgG+NMOSD
Kaneko Kimihiko MD, PhD
Kuroda Hiroshi MD, PhD
Matsumoto Yuki MD, PhD
Sakamoto Naohiro MD
https://orcid.org/0000-0002-9158-5686
Yamazaki Naoya MD
Yamamoto Naoki MD
Umezawa Shu MD
Namatame Chihiro MD, PhD
Ono Hirohiko MD, PhD
Takai Yoshiki MD, PhD
Takahashi Toshiyuki MD, PhD
https://orcid.org/0000-0001-7170-7853
Fujimori Juichi MD, PhD
https://orcid.org/0000-0002-2612-8948
Nakashima Ichiro MD, PhD
Harigaya Yasuo MD, PhD
Lassmann Hans MD, PhD
Fujihara Kazuo MD, PhD
https://orcid.org/0000-0002-7311-2578
Misu Tatsuro MD, PhD
Aoki Masashi MD, PhD
From the Department of Neurology (K.K., H.K., Y.M., N.S., N. Yamazaki, N. Yamamoto, S.U., C.N., H.O., Y.T., T.T., K.F., T.M., M.A.), Tohoku University Graduate School of Medicine, Sendai, Japan; Multiple Sclerosis and Neuromyelitis Optica Center (H.K., K.F.), Southern TOHOKU Research Institute for Neuroscience, Koriyama; Department of Multiple Sclerosis Therapeutics (H.K., K.F.), Fukushima Medical University, Fukushima, Japan; Department of Neurology (T.T.), NHO Yonezawa National Hospital, Yamagata, Japan; Division of Neurology (J.F., I.N.), Tohoku Medical and Pharmaceutical University, Sendai, Japan; Department of Neurology (Y.H.), Japanese Redcross Maebashi Hospital; Department of Neurology (Y.H.), Mihara Memorial Hospital, Isesaki, Japan; and Center for Brain Research (H.L.), Medical University of Vienna, Austria.
Correspondence Dr. Misu misu@med.tohoku.ac.jp
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

The Article Processing Charge was funded by the authors.

Submitted and externally peer reviewed. The handling editor was Deputy Editor Scott S. Zamvil, MD, PhD, FAAN.

9 2024
12 8 2024
12 8 2024
11 5 e20029306 3 2024
17 6 2024
Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.
2024
American Academy of Neurology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Objectives

In myelin oligodendrocyte glycoprotein IgG–associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD), the autoantibodies are mainly composed of IgG1, and complement-dependent cytotoxicity is a primary pathomechanism in AQP4+NMOSD. We aimed to evaluate the CSF complement activation in MOGAD.

Methods

CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase before treatment in patients with MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (MS) (n = 5), and noninflammatory neurologic disease (n = 2) were measured.

Results

CSF-C3a and CSF-C5a levels were significantly higher in MOGAD (mean ± SD, 5,629 ± 1,079 pg/mL and 2,930 ± 435.8 pg/mL) and AQP4+NMOSD (6,017 ± 3,937 pg/mL and 2,544 ± 1,231 pg/mL) than in MS (1,507 ± 1,286 pg/mL and 193.8 ± 0.53 pg/mL). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD while CSF-C5b-9 (membrane attack complex, MAC) levels were significantly lower in MOGAD (17.4 ± 27.9 ng/mL) than in AQP4+NMOSD (62.5 ± 45.1 ng/mL, p = 0.0019). Patients with MOGAD with severer attacks (Expanded Disability Status Scale [EDSS] ≥ 3.5) had higher C5b-9 levels (34.0 ± 38.4 ng/m) than those with milder attacks (EDSS ≤3.0, 0.9 ± 0.7 ng/mL, p = 0.044).

Discussion

The complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation is lower in MOGAD, particularly in those with mild attacks, than in AQP4+NMOSD. These findings may have pathogenetic and therapeutic implications in MOGAD.

OPEN-ACCESSTRUE
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pmcIntroduction

Myelin oligodendrocyte glycoprotein IgG–associated disease (MOGAD) and aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) are inflammatory diseases of the CNS. In these diseases, Th17-related cytokines/chemokines are remarkably upregulated in acute exacerbations1 and clinical phenotypes such as optic neuritis (ON) or longitudinally extensive myelitis may occur. Both MOG-IgG and AQP4-IgG are mainly composed of IgG1,2 which can efficiently activate complements. Complement-dependent cytotoxicity (CDC) is a key pathomechanism in AQP4+NMOSD,3 and anti-complement C5 monoclonals are highly effective in preventing relapse of AQP4+NMOSD. However, the pathogenetic role of complement activation in MOGAD remains unclear.

This study aimed to investigate complement activation in the CSF of patients with MOGAD relative to AQP4+NMOSD.4

Methods

CSF samples were collected from adults with MOGAD, AQP4+NMOSD, multiple sclerosis (MS), and noninflammatory neurologic disease (NIND) between 2018 and 2023. All samples from patients with MOGAD, AQP4+NMOSD, and MS were obtained before acute-phase treatments. Their clinical and laboratory data were also collected.

CSF samples were stored at −80°C until use. C3a, C4a, and C5a were measured using a bead-based assay (Human Anaphylatoxin Kit, BD, San Jose, CA) and C5b-9 by an ELISA (Human C5b-9 ELISA Set, BD, San Jose, CA) according to the manufacturers' protocol. MOG-IgG and AQP4-IgG were measured with in-house cell-based assays as previously reported.5

All parameters were compared among MOGAD, AQP4+NMOSD, MS, and NIND groups using the Kruskal-Wallis test. Statistical analyses were performed using PRISM 8.0 (GraphPad Software, Boston, MA). Data are available to qualified researchers based on reasonable request.

Ethics approval was granted by the Ethics Committee of Tohoku University Graduate School of Medicine, Sendai, Japan (#2022-1-1103). All the patients gave informed consent for their participation.

Results

Clinical Profiles of the Patients

In total, 30 patients with MOGAD (n = 12), AQP4-IgG+NMOSD (n = 11), MS (n = 5), or NIND (n = 2) were studied (Table 1). The mean age was significantly lower in the MOGAD group (median 32 years; range, 17–68 years) than in the AQP4+NMOSD group (59, 34–76 years) (p = 0.010). Approximately two-thirds of patients with MOGAD and AQP4+NMOSD were female. The most frequent clinical phenotype in patients with MOGAD (33.3%) and AQP4+NMOSD (63.6%) was myelitis. Among patients with MOGAD, AQP4+NMOSD, and MS, there were no significant differences in the percentage of the first attack at sample collection, interval from onset to sample collection, and Expanded Disability Status Scale (EDSS) scores at the acute phase and last follow-up. 3 patients with MOGAD had CSF-restricted MOG-IgG. All patients met respective diagnostic criteria.6,7

Table 1 Clinical, Laboratory Profiles and Complement Levels of Patients With MOGAD, AQP4-IgG+NMOSD, MS, and NIND

	MOGAD (n = 12)	AQP4-IgG+NMOSD (n = 11)	MS (n = 5)	NIND (n = 2)	
Clinical, laboratory profiles					
 Median age at sampling (years old)	32	59	32	42.5	
 Female sex (%)	66.6	63.6	100	100	
 Clinical phenotype	Myelitis (n = 4)	Myelitis (n = 7)	Relapsing-remitting (n = 5)	Idiopathic NPH (n = 1)	
ADEM (n = 3)	Optic neuritis (n = 2)	Psychogenic functional neurologic disorder (n = 1)	
Encephalitis (n = 3)	Area postrema syndrome (n = 1)		
Optic neuritis (n = 2)	Diencephalic syndrome (n = 1)		
 First attack (%)	66.7	54.5	N/A	N/A	
 Interval from onset to sampling (d)	17.5	12	22	N/A	
 EDSS at sampling	3.5 (1–7.5)	3 (2–7.5)	2 (1–5.5)	N/A	
 CSF cell count (/mm3)	6.5 (0–256)	10 (0–93)	1 (1–4)	0	
 CSF protein (mg/dL)	38.5 (19–123)	32 (19–210)	28 (20–41)	27 (26–28)	
 IgG index	0.54 (0.45–2.06)	0.57 (0.43–0.84)	0.71 (0.52–1.99)	N/A	
 OCB positivity (%)	33.3	27.2	100	N/A	
Complement levels					
 C3a (pg/mL)	5,624 ± 1,079	6,017 ± 3,937	1,507 ± 1,286	1947 ± 2,620	
 C4a (pg/mL)	115.2 ± 190.2	74.86 ± 144.8	1.756 ± 3.927	15.77 ± 22.31	
 C5a (pg/mL)	2,930 ± 435.8	2,544 ± 1,231	193.8 ± 0.53	777.5 ± 880.8	
 C5b-9 (ng/mL)	17.42 ± 27.92	62.48 ± 45.11	22.35 ± 4.239	22.46 ± 0.444	
Abbreviations: ADEM = acute disseminated encephalomyelitis, AQP4-IgG+NMOSD = aquaporin 4-IgG-positive neuromyelitis optica spectrum disorder, EDSS = Expanded Disability Status Scale, MOGAD = myelin oligodendrocyte glycoprotein IgG–associated disease, MS = multiple sclerosis, NIND = noninflammatory neurologic disease, NPH = normal pressure hydrocephalus, OCB = oligoclonal IgG band.

Values are presented as mean ± SD.

CSF Complement Levels

CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels are shown in Figure 1, A–D and the Table 1. C3a and C5a were significantly higher in MOGAD and AQP4+NMOSD than in MS, and C5a was significantly higher in MOGAD than in NIND. There were no differences in C3a, C4a, and C5a between MOGAD and AQP4+NMOSD. However, C5b-9 (membrane attack complex, MAC) was significantly lower in MOGAD than in AQP4+NMOSD (p = 0.002).

Figure 1 CSF Complement Components in MOGAD, AQP4+NMOSD, MS, and NIND

(A–E) Concentrations of activated complement components (C3a, C4a, C5a, C5b-9) and C5b-9/C5a in the CSF of patients with MOGAD, AQP4+NMOSD, MS, and NIND and (F) comparison of CSF-C5b-9 levels between patients with MOGAD with EDSS scores ≦3 and those with scores ≧3.5. AQP4+NMOSD = aquaporin-4 IgG+ neuromyelitis optica spectrum disorder, MOGAD = myelin oligodendrocyte glycoprotein IgG–associated disease, MS = multiple sclerosis, NIND = noninflammatory neurologic disease. ∗p < 0.05. Horizontal lines indicate mean values, and error bars indicate SD.

Terminal Complement Pathway Activation Patterns Differ Between MOGAD and AQP4+NMOSD

C5 is cleaved into C5a and C5b, which is followed by C5b-9 assembly. Therefore, we calculated the C5b-9/C5a ratios to assess terminal complement pathway activation after C5 cleavage. The CSF-C5b-9/C5a was significantly lower in MOGAD (mean ± SD, 17.4 ± 27.9) than in AQP4+NMOSD (62.5 ± 45.1, p = 0.0019) (Figure 1E).

Patients with higher EDSS scores (EDSS during attacks ≥3.5) had significantly higher CSF-C5b-9 than those with low EDSS scores (EDSS≤ 3.0) (p = 0.030) (Figure 1F). Furthermore, patients with high EDSS scores at the last follow-up (≥3.5, n = 3) tended to have higher CSF-C5b-9 (34.0 ± 38.4 ng/mL) than those with low EDSS scores (≤3.0, n = 8, 0.90 ± 0.72 ng/mL, p = 0.064).

There was no significant difference among data related to clinical phenotypes and MOG-IgG status in sera and CSF (Figure 2 and eTable 1). C5b-9 values were not different in relation to MOG-IgG status in sera and CSF. However, especially for clinical phenotypes, in both myelitis and others, the mean C5b-9 values tended to be lower in MOGAD than in AQP4+NMOSD.

Figure 2 CSF-C5b-9 Levels in Relation to Clinical Phenotypes and MOG-IgG Status

AQP4+NMOSD = aquaporin-4 IgG+ neuromyelitis optica spectrum disorder, MOGAD = myelin oligodendrocyte glycoprotein IgG–associated disease.

Discussion

We demonstrated that CSF-C3a and CSF-C5a levels during the acute phase in MOGAD were comparable with those in AQP4+NMOSD and higher than those in MS and NIND. We previously reported CSF complement activation in AQP4+NMOSD compared with NIND.4 Anaphylatoxin effects of C3a and C5a may contribute to CSF pleocytosis in MOGAD and AQP4+NMOSD and be part of MOGAD pathology even if downstream MAC formation is not present in all patients. Meanwhile, CSF-C5b-9 levels, indicative of MAC formation, were significantly lower in MOGAD than those in AQP4+NMOSD.

It was reported that increased levels of proteins indicative of systemic classical and alternative complement activation in the plasma of adult and pediatric patients with MOGAD (n = 71) compared with relapsing MS, AQP4+NMOSD, and healthy controls.8 More recently, Cho et al. reported complement activation in sera of MOGAD,9 but C5b-9 was not elevated compared with AQP4+NMOSD, which is similar to our result. Nevertheless, the studies analyzed only blood samples, which may not necessarily reflect complement activation in the CNS.

In vitro studies performed by Yandamuri et al. and Kohyama et al. demonstrated that MOG-IgG can induce CDC in MOG-transfected cells, depending on the amount of complement proteins or MOG-IgG titer.10,11 Furthermore, Macrini et al.12 reported that MOG-IgG requires bivalent binding to MOG monomers and C1q, an initiator of the classical complement pathway, poorly binds to MOG-IgG-MOG complexes, suggesting that CDC may not be a major pathomechanism in MOGAD. Lerch et al. showed that MOG-IgG can induce CDC in MOG-transfected HEK293A cells; however, CDC and MAC formation levels were significantly lower than those induced in AQP4-transfected HEK293A cells by AQP4-IgG.13 In line herewith, our histopathologic study in MOGAD and AQP4+NMOSD clearly demonstrated that C9neo was deposited at substantially lower levels in acute MOGAD lesions than in AQP4-NMOSD.14 By contrast, Höftberger et al. reported that activated complement deposition in lesions was more or less observed in all cases with MOGAD.15 The reason is unclear, but difference in detection methods and patient backgrounds might have contributed.

An interesting but perplexing finding in our study was that CSF-C5b-9 levels were significantly lower in MOGAD than those in AQP4+NMOSD, although the complement cascade leading to C5 in CSF was equally activated in MOGAD and AQP4+NMOSD. CD59 is the only complement-regulatory protein on the surface of human cells that inhibits MAC formation.16 In the CNS, CD59 is abundantly expressed on the outer layer of myelin, whereas it is weakly expressed on astrocyte foot process.17,18 Considering that MOG is mainly expressed on the outer layer of myelin and AQP4 is richly expressed on astrocyte foot processes, CD59 on myelin might inhibit MAC formation more efficiently in MOGAD than in AQP4+NMOSD. However, myelin vs astrocyte may not per se explain the significantly lower CSF-C5b-9 levels in MOGAD than in AQP4-NMOSD as observed in our study because, in the study by Lerch et al., both CDC and MAC were induced in HEK293A cells by MOG-IgG and AQP4-IgG,10 suggesting that other factors are involved in the distinct MAC formations in the 2 diseases.

From a therapeutic viewpoint, our results suggest that currently available anti-C5 monoclonal antibodies may not be as effective in MOGAD as in AQP4+NMOSD, although it might be beneficial for patients with severe attacks and high CSF-C5b-9 values.

The main limitations of this study were small sample size, especially ON, the lack of comparison with remission phase, and the insufficient involvement of pediatric cases. Larger scale clinical studies to address these issues are needed.

In summary, the complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation seems to be lower in MOGAD, particularly in cases with mild attacks, than in AQP4+NMOSD. Our findings may have pathogenetic and therapeutic implications in MOGAD.

Acknowledgment

The authors thank Izumi Nakamura, Yoko Suzuki (Tohoku University), and Yuri Atobe (Tohoku Medical and Pharmaceutical University) for technical assistance.

Study Funding

This study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) KAKENHI (19K07953 and 17H04192), the Ministry of Education, Culture, Sports, Science and Technology/JSPS WISE Programme and the Ministry of Health, Labour and Welfare of Japan.

Disclosure

K. Kaneko received speaker honoraria from Novartis and Biogen Japan. H. Kuroda received speaker honoraria from Alexion, Chugai, Novartis, and Otsuka. Y. Matsumoto received speaker honoraria from Novartis. N. Sakamoto has nothing to disclose. N. Yamazaki has nothing to disclose. N. Yamamoto has nothing to disclose. S. Umezawa has nothing to disclose. C. Namatame has nothing to disclose. H. Ono has nothing to disclose. Y. Takai received speaker honoraria from Alexion, Biogen, Novartis, Mitsubishi Tanabe, Chugai, and Takeda. T. Takahashi received research support from Cosmic Corporation. J. Fujimori has nothing to disclose. I. Nakashima received advisory fee from Mitsubishi Tanabe, Chugai, Alexion; honoraria for lectures from Biogen, Novartis, Mitsubishi Tanabe, Chugai, Alexion; support for attending meetings from Biogen, Novartis, Mitsubishi Tanabe, Chugai, Alexion; grants for commissioned/joint research from LSI Medience Corporation. Y. Harigaya has nothing to disclose. H. Lassman received honoraria for lectures from Novartis, Sanofi, Merck, Genzyme, Roche Biogen and Bristol-Myers Squibb. K. Fujihara received fees for consulting, speaking and serving on steering committees of AbbVie, Alexion, Asahi Kasei Medical, Biogen, Chugai/Roche, Eisai, Japan Tobacco, MedImmune/Viela Bio, Merck, Merck Biopharma, Mitsubishi-Tanabe, Novartis, Takeda, Teijin and UCB, and a Grant-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan. T. Misu received speaker honoraria from Tanabe Mitsubishi, Novartis, Alexion, Viela Bio, Teijin, Chugai, Sanofi, GE Health Care Japan, CSL Behring and Biogen Japan, and research support from Cosmic Corporation and Medical Biological Laboratories received a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Masashi Aoki received research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health, Labour and Welfare of Japan. Go to Neurology.org/NN for full disclosures.

Appendix Authors

Name	Location	Contribution	
Kimihiko Kaneko, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Hiroshi Kuroda, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama; Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Yuki Matsumoto, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data; additional contributions (in addition to one or more of the above criteria)	
Naohiro Sakamoto, MD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Naoya Yamazaki, MD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Naoki Yamamoto, MD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Shu Umezawa, MD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Chihiro Namatame, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Hirohiko Ono, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Yoshiki Takai, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	
Toshiyuki Takahashi, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai; Department of Neurology, NHO Yonezawa National Hospital, Japan	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data; additional contributions (in addition to one or more of the above criteria)	
Juichi Fujimori, MD, PhD	Division of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Ichiro Nakashima, MD, PhD	Division of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Yasuo Harigaya, MD, PhD	Department of Neurology, Japanese Redcross Maebashi Hospital; Department of Neurology, Mihara Memorial Hospital, Isesaki, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data	
Hans Lassmann, MD, PhD	Center for Brain Research, Medical University of Vienna, Austria	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	
Kazuo Fujihara, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama; Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Tatsuro Misu, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Masashi Aoki, MD, PhD	Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data	

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