Establishment of ultra-early diagnostic methods for familial amyloid polyneuropathy

• Project/Area Number: 18K15455
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kumamoto University
• Principal Investigator: Masuda Teruaki 熊本大学, 病院, 助教 (50464459)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: トランスサイレチン / アミロイドーシス / 小径線維ニューロパチー / 自律神経 / 皮膚生検 / 皮神経 / 家族性アミロイドポリニューロパチー / アミロイド / 小径線維

Outline of Final Research Achievements

In this study, we focused on small fiber neuropathy, which presents earliest in patients with transthyretin-type familial amyloid polyneuropathy (TTR-FAP), to develop a suitable biomarker for the disease. Histopathological analysis revealed early denervation of intraepidermal rather than sweat gland nerves. Additionally, we found that sensory deficits in the anterior trunk of patients with early stage TTR-FAP were caused by small fiber neuropathy. Furthermore, MR-neurography and pupillometry methods established in this study, were found to reflect the disease state of patients. By combining these methods, we devised an evaluation algorithm for ultra-early diagnosis and evaluation of the disease state.

Academic Significance and Societal Importance of the Research Achievements

様々な疾患修飾療法が開発され、根治療法が望める時代になったTTR-FAPにおいて、本研究で考案した検査法を用いて小径線維の異常を検出し、早期診断および早期治療に導くことで、TTR-FAP患者のQOLおよび生命予後の改善が期待できる。さらに、本研究の評価法は、糖尿病や他のアミロイドニューロパチーをはじめ様々な小径線維ニューロパチーを来す疾患の評価法としても応用可能であり、臨床試験のバイオマーカーとしても期待される。

Research Products

• [Journal Article] Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy (2020)
  • Author(s): Ogata H, Isobe N, Zhang X, Yamasaki R, Fujii T, Machida A, Morimoto N, Kaida K, Masuda T, Ando Y, Kuwahara M, Kusunoki S, Nakamura Y, Matsushita T, Kira J.
  • Journal Title: Journal of Neuroimmunology Volume: 339 Pages: 577139-577139
  • DOI: 10.1016/j.jneuroim.2019.577139
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hereditary ATTR Amyloidosis with Cardiomyopathy Caused by the Novel Variant Transthyretin Y114S (p.Y134S) (2019)
  • Author(s): Nakase Taku、Yamashita Taro、Matsuo Yoshimasa、Nomura Toshiya、Sasada Keiko、Masuda Teruaki、Misumi Yohei、Takamatsu Kotaro、Oda Seitaro、Furukawa Yutaro、Obayashi Konen、Matsui Hirotaka、Ando Yukio、Ueda Mitsuharu
  • Journal Title: Internal Medicine Volume: 58 Issue: 18 Pages: 2695-2698
  • DOI: 10.2169/internalmedicine.2456-18
  • NAID: 130007706923
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-09-15
  • Peer Reviewed / Open Access
• [Journal Article] Is ¹²³I-MIBG Scintigraphy Beneficial or Excessive for the Diagnosis of Parkinson’s Disease in the Early Phase? (2019)
  • Author(s): Ikeda Tokunori、Ikenoshita Susumu、Sakamoto Fumi、Shiraishi Shinya、Nakahara Keiichi、Masuda Teruaki、Yamashita Satoshi
  • Journal Title: Neurodegenerative Diseases Volume: 19 Issue: 2 Pages: 88-95
  • DOI: 10.1159/000504006
  • Peer Reviewed
• [Journal Article] Intrathecal cytokine profile in neuropathy with anti‐neurofascin 155 antibody (2019)
  • Author(s): Ogata H, Zhang X, Yamasaki R, Fujii T, Machida A, Morimoto N, Kaida K, Masuda T, Ando Y, Kuwahara M, Kusunoki S, Nakamura Y, Matsushita T, Isobe N, Kira J.
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 6 Issue: 11 Pages: 2304-2316
  • DOI: 10.1002/acn3.50931
  • Peer Reviewed / Open Access
• [Journal Article] Natural history and long-term effects of variant protein reduction in non-V30M ATTR amyloidosis. (2019)
  • Author(s): Yamashita T, Ueda M, Nomura T, Okazaki T, Okada M, Tsuda Y, Inoue Y, Masuda T, Misumi Y, Takamatsu K, Obayashi K, Inomata Y, Hibi T, Ando Y.
  • Journal Title: Neurology Volume: 93 Issue: 16 Pages: 714-716
  • DOI: 10.1212/wnl.0000000000008320
  • Peer Reviewed
• [Journal Article] Characteristics of acquired transthyretin amyloidosis (2019)
  • Author(s): Misumi Yohei、Ueda Mitsuharu、Masuda Teruaki、Tsuda Yukimoto、Nomura Toshiya、Okada Masamitsu、Inoue Yasuteru、Tasaki Masayoshi、Obayashi Konen、Yamashita Taro、Ando Yukio
  • Journal Title: Neurology Volume: － Issue: 17 Pages: 1587-1596
  • DOI: 10.1212/wnl.0000000000008360
  • Peer Reviewed
• [Journal Article] Reader response: Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy (2019)
  • Author(s): Ueda Mitsuharu、Yamashita Taro、Misumi Yohei、Masuda Teruaki、Ando Yukio
  • Journal Title: Neurology Volume: 93 Issue: 5 Pages: 228-229
  • DOI: 10.1212/wnl.0000000000007870
  • Peer Reviewed
• [Journal Article] Serum diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) in patients with ATTR-PN. (2019)
  • Author(s): Obayashi K, Masuda T, Tasaki M, Ando Y, Ueda M.
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 65-65
  • DOI: 10.1080/13506129.2019.1583183
  • Peer Reviewed
• [Journal Article] Evaluation of myoelectrical activities of descending colon by electrointestinogram in patients with ATTRm amyloidosis. (2019)
  • Author(s): Obayashi K, Masuda T, Tasaki M, Ando Y, Ueda M.
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 66-66
  • DOI: 10.1080/13506129.2019.1583184
  • Peer Reviewed
• [Journal Article] Histopathological and biochemical analyses of prostate corpora amylacea (2019)
  • Author(s): Kanenawa K., Ueda M., Isoguchi A., Nomura T., Tsuda Y., Masuda T., Misumi Y., Yamashita T., Ando Y.
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 160-161
  • DOI: 10.1080/13506129.2019.1583189
  • Peer Reviewed
• [Journal Article] Changes in nerve excitability indices in hereditary transthyretin amyloidosis (2019)
  • Author(s): Yamashita Taro、Ueda Mitsuharu、Misawa Sonoko、Inoue Yasuteru、Masuda Teruaki、Misumi Yohei、Takamatsu Kotaro、Obayashi Konen、Kuwabara Satoshi、Ando Yukio
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 9-10
  • DOI: 10.1080/13506129.2019.1582480
  • Peer Reviewed
• [Journal Article] Transthyretin amyloid-related cerebral angiitis after liver transplantation (2019)
  • Author(s): Yamashita Taro、Ohnishi Koji、Ueda Mitsuharu、Masuda Teruaki、Inoue Yasuteru、Misumi Yohei、Ueda Akihiko、Obayashi Konen、Takeya Motohiro、Ando Yukio
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 11-12
  • DOI: 10.1080/13506129.2019.1583179
  • Peer Reviewed
• [Journal Article] Reduced intraepidermal nerve fibre density in patients with hereditary transthyretin amyloidosis (2019)
  • Author(s): Masuda T., Ueda M., Misumi Y., Nomura T., Inoue Y., Isoguchi A., Kanenawa K., Tasaki M., Yamashita T., Sonoda Y., Obayashi K., Ando Y.
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 79-80
  • DOI: 10.1080/13506129.2019.1583198
  • Peer Reviewed
• [Journal Article] A novel transgenic mouse model expressing mutant TTR gene causing oculoleptomeningeal type of ATTRm amyloidosis (2019)
  • Author(s): Isoguchi A., Ueda M., Kanenawa K., Masuda T., Misumi Y., Yamashita T., Obayashi K., Ando Y.
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 69-69
  • DOI: 10.1080/13506129.2019.1583190
  • Peer Reviewed
• [Journal Article] Comparison of clinical features in transient focal neurological episodes between hereditary transthyretin type and Aβ type cerebral amyloid angiopathy (2019)
  • Author(s): Nakajima Makoto、Takeuchi Yosuke、Nagao Yoichiro、Masuda Teruaki、Yamashita Taro、Yonehara Toshiro、Terasaki Tadashi、Ando Yukio
  • Journal Title: Amyloid Volume: 26 Issue: sup1 Pages: 81-82
  • DOI: 10.1080/13506129.2019.1583199
  • Peer Reviewed
• [Journal Article] Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, attenuates cerebral amyloid angiopathy by increasing insulin-degrading enzyme expression. (2019)
  • Author(s): Inoue Y, Ueda M, Masuda M, Misumi Y, Yamashita T, Ando Y.
  • Journal Title: Mol Neurobiol Volume: 56 Issue: 12 Pages: 8573-8573
  • DOI: 10.1007/s12035-019-01678-7
  • Peer Reviewed
• [Journal Article] A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH (2019)
  • Author(s): Ueda Mitsuharu、Okada Masamitsu、Mizuguchi Mineyuki、et al.
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 29 Pages: 11259-11275
  • DOI: 10.1074/jbc.ra119.007851
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New simple and quick method to analyze serum variant transthyretins: direct MALDI method for the screening of hereditary transthyretin amyloidosis (2019)
  • Author(s): Nomura Toshiya、Ueda Mitsuharu、Tasaki Masayoshi、Misumi Yohei、Masuda Teruaki、Inoue Yasuteru、Tsuda Yukimoto、Okada Masamitsu、Okazaki Takahiro、Kanenawa Kyosuke、Isoguchi Aito、Nakamura Makoto、Obayashi Konen、Shinriki Satoru、Matsui Hirotaka、Yamashita Taro、Ando Yukio
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 14 Issue: 1 Pages: 116-116
  • DOI: 10.1186/s13023-019-1100-y
  • Peer Reviewed / Open Access
• [Journal Article] 遺伝性トランスサイレチンアミロイドーシスの早期診断に有用な皮神経脱落の解析 (2019)
  • Author(s): 増田 曜章, 植田 光晴, 大林 光念, 安東 由喜雄
  • Journal Title: 自律神経 Volume: 56 Pages: 264-268
  • NAID: 130007776372
  • Peer Reviewed
• [Journal Article] Reduced intraepidermal nerve fiber density in patients with hereditary transthyretin amyloidosis (2019)
  • Author(s): Masuda T, Ueda M, Misumi Y, Nomura T, Inoue Y, Isoguchi A, Kanenawa K, Tasaki M, Yamashita T, Sonoda Y, Obayashi K, Ando Y.
  • Journal Title: Amyloid Volume: in press
  • Peer Reviewed
• [Journal Article] A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1 (2019)
  • Author(s): Tasaki M, Ueda M, Hoshii Y, Mizukami M, Matsumoto S, Nakamura M, Yamashita T, Ueda A, Misumi Y, Masuda T, Inoue Y, Torikai T, Nomura T, Tsuda Y, Kanenawa K, Isoguchi A, Okada M, Matsui H, Obayashi K, Ando Y.
  • Journal Title: The Journal of Pathology Volume: 247 Issue: 4 Pages: 444-455
  • DOI: 10.1002/path.5203
  • Peer Reviewed
• [Journal Article] Development of transgenic Caenorhabditis elegans expressing human transthyretin as a model for drug screening (2018)
  • Author(s): Tsuda Yukimoto、Yamanaka Kunitoshi、Toyoshima Risa、Ueda Mitsuharu、Masuda Teruaki、Misumi Yohei、Ogura Teru、Ando Yukio
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 17884-17884
  • DOI: 10.1038/s41598-018-36357-5
  • Peer Reviewed / Open Access
• [Journal Article] Extreme Adhesion Activity of Amyloid Fibrils Induces Subcutaneous Insulin Resistance (2018)
  • Author(s): Nakamura M, Misumi Y, Nomura T, Oka W, Isoguchi A, Kanenawa K, Masuda T, Yamashita T, Inoue Y, Ando Y, Ueda M.
  • Journal Title: Diabetes Volume: 68 Issue: 3 Pages: 609-616
  • DOI: 10.2337/db18-0846
  • Peer Reviewed
• [Journal Article] rigin of sporadic late-onset hereditary ATTR Val30Met amyloidosis in Japan. (2018)
  • Author(s): Ueda M, Yamashita T, Misumi Y, Masuda T, Ando Y.
  • Journal Title: Amyloid Volume: 25 Pages: 143-147
  • Peer Reviewed
• [Journal Article] Teaching NeuroImages: Morphology of lumbosacral dorsal root ganglia and plexus in hereditary transthyretin amyloidosis (2018)
  • Author(s): Masuda T, Ueda M, Kitajima M, Morita K, Misumi Y, Yamashita T, Obayashi K, Yamashita Y, Ando Y
  • Journal Title: Neurology Volume: 91 Issue: 19
  • DOI: 10.1212/wnl.0000000000006474
  • Peer Reviewed / Open Access
• [Journal Article] The first Japanese case of biopsy-confirmed small-fiber neuropathy related to celiac disease (2018)
  • Author(s): Mitsutake A, Sato T, Katsumata J, Seki T, Maekawa R, Hideyama T, Kishida Y, Masuda T, Ando Y, Shiio Y.
  • Journal Title: Neurology and Clinical Neuroscience Volume: 7 Issue: 1 Pages: 31-33
  • DOI: 10.1111/ncn3.12236
  • Peer Reviewed
• [Journal Article] 神経アミロイドーシスのすべて 2017年診療ガイドライン (2018)
  • Author(s): 増田曜章、植田光晴、安東由喜雄
  • Journal Title: 神経治療学 Volume: 35 Pages: 174-178
  • NAID: 130007550041
  • Peer Reviewed
• [Journal Article] 家族性アミロイドポリニューロパチーと自律神経障害 (2018)
  • Author(s): 増田曜章、安東由喜雄
  • Journal Title: 自律神経 Volume: 5 Pages: 81-84
  • Peer Reviewed
• [Presentation] 遺伝性トランスサイレチンアミロイドーシスにおける体幹部皮神経脱落の検討 (2019)
  • Author(s): 増田曜章、植田光晴、三隅洋平、野村隼也、岡田匡充、磯口藍斗、井上泰輝、田崎雅義、山下太郎、大林光念、安東由喜雄
  • Organizer: 第7回日本アミロイドーシス学会学術集会
• [Presentation] 遺伝性トランスサイレチンアミロイドーシスにおける体幹部小径線維障害の解析 (2019)
  • Author(s): 増田曜章、植田光晴、三隅洋平、野村隼也、山下太郎、大林光念、安東由喜雄
  • Organizer: 第72回日本自律神経学会総会
• [Presentation] 遺伝性トランスサイレチンアミロイドーシスにおける体幹部神経障害の病態解析 (2019)
  • Author(s): 増田曜章、植田光晴、三隅洋平、野村隼也、磯口藍斗、井上泰輝、田崎雅義、山下太郎、大林光念、安東由喜雄
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] MR neurographyによる遺伝性ATTRアミロイドーシスの末梢神経障害の解析 (2018)
  • Author(s): 増田曜章、植田光晴、森田康祐、北島美香、三隅洋平、井上泰輝、田崎雅義、山下太郎、大林光念、山下康行、安東由喜雄
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] 末梢神経疾患 update: 診断と治療のピットフォール (アミロイドニューロパチーの診療のピットフォール) (2018)
  • Author(s): 増田曜章、植田光晴、安東由喜雄
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] 医原性トランスサイレチンアミロイドニューロパチーの臨床病態解析 (2018)
  • Author(s): 増田曜章、植田光晴、三隅洋平、野村隼也、山下太郎、大林光念、安東由喜雄
  • Organizer: 第6回日本アミロイドーシス研究会学術集会
• [Presentation] 医原性トランスサイレチンアミロイドニューロパチーにおける末梢神経障害の病態解析 (2018)
  • Author(s): 増田曜章、植田光晴、三隅洋平、野村隼也、園田優衣、山下太郎、大林光念、安東由喜雄
  • Organizer: 第29回日本末梢神経学会学術集会
• [Presentation] トランスサイレチン型家族性アミロイドポリニューロパチーの早期診断における瞳孔機能解析の有用性 (2018)
  • Author(s): 増田曜章、植田光晴、永利知佳子、三隅洋平、井上泰輝、野村隼也、山下太郎、大林光念、安東由喜雄
  • Organizer: 第71回日本自律神経学会総会
• [Presentation] 遺伝性ATTR型脳アミロイド血管症/眼軟膜アミロイドーシスの臨床像 (2018)
  • Author(s): 増田曜章、植田光晴、牧美充、三隅洋平、井上泰輝、杉村勇輔、中島誠、山下太郎、田崎雅義、大林光念、安東由喜雄
  • Organizer: 第44回日本脳卒中学会学術集会
• [Book] 検査からみる神経疾患 SUDOSCAN. Clinical Neuroscience 37 (2019)
  • Author(s): 増田 曜章, 植田 光晴, 安東 由喜雄
  • Total Pages: 2
  • Publisher: 中外医学社
• [Book] 希少疾患用医薬品の適応拡大と事業性評価: トランスサイレチン型家族性アミロイドポリニューロパチー (2018)
  • Author(s): 増田曜章、植田光晴、安東由喜雄
  • Total Pages: 538
  • Publisher: 技術情報協会
  • ISBN: 9784861047268
• [Remarks] 熊本大学病院脳神経内科 ホームページ
  • URL: http://kumadai-neurology.com/