Heterogeneity of TDP-43 pathology and clinicopathologic correlations in sporadic amyotrophic lateral sclerosis

• Project/Area Number: 26640029
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Niigata University
• Principal Investigator: TAKAHASHI Hitoshi 新潟大学, 脳研究所, 教授 (90206839)
• Co-Investigator(Kenkyū-buntansha): TOYOSHIMA Yasuko 新潟大学, 脳研究所, 准教授 (20334675) ; TADA Mari 新潟大学, 脳研究所, 助教 (30646394)
• Co-Investigator(Renkei-kenkyūsha): ONODERA Osamu 新潟大学, 脳研究所, 教授 (20303167)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 神経変性疾患 / 筋萎縮性側索硬化症 / TDP-43 / 病型分類 / 免疫組織化学

Outline of Final Research Achievements

A nuclear protein,TDP-43, is the major pathological protein in ALS. We attempted to clarify the corticalpathology in cases of sporadic amyotrophic lateral sclerosis (ALS: n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (classical ALS: ALS-C, n = 63), and those with such inclusions (ALS with temporal lesions: ALS-T, n = 33). Furthermore, the ALS-T cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: ALS-T/few DNs (n = 22) and ALS-T/many DNs (n = 11). Considering the patient survival time and severity of motor neuron loss in each group, transition from ALS-C to ALS-T, or from ALS-T/few DNs to ALS-T/many DNs during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.

Research Products

• [Journal Article] Pathological and Clinical Spectrum of Progressive Supranuclear Palsy: With Special Reference to Astrocytic Tau Pathology. (2016)
  • Author(s): Yokoyama Y, Toyoshima Y, Shiga A, Tada M, Kitamura H, Hasegawa K, Onodera O, Ikeuchi T, Someya T, Nishizawa M, Kakita A, Takahashi H.
  • Journal Title: Brain Pathol. Volume: 26 Issue: 2 Pages: 155-166
  • DOI: 10.1111/bpa.12265
  • Peer Reviewed
• [Journal Article] Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis (2015)
  • Author(s): Kaneko M, Noguchi T, Ikegami S, Sakurai T, Kakita A, Toyoshima Y, Kambe T, Yamada M, Inden M, Hara H, Oyanagi K, Inuzuka T, Takahashi H, Hozumi I.
  • Journal Title: J Neurosci Res Volume: 93(2) Issue: 2 Pages: 370-9
  • DOI: 10.1002/jnr.23491
  • NAID: 120007100194
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sortilin-related receptor CNS expressed 2 (SorCS2) is localized to Bunina bodies in amyotrophic lateral sclerosis (2015)
  • Author(s): Mori F, Miki Y, Tanji K, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 608 Pages: 6-11
  • DOI: 10.1016/j.neulet.2015.09.030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia. (2015)
  • Author(s): Takeuchi R, Toyoshima Y, Tada M, Tanaka H, Shimizu H, Shiga A, Miura T, Aoki K, Aikawa A, Ishizawa S, Ikeuchi T, Nishizawa M, Kakita A, Takahashi H.
  • Journal Title: Brain Pathology Volume: in press Issue: 1 Pages: 82-94
  • DOI: 10.1111/bpa.12262
  • Peer Reviewed
• [Presentation] Neuropathology of amyotrophic lateral sclerosis: discovery of TDP-43 and subsequent development. (2015)
  • Author(s): Takahashi H
  • Organizer: First Annual Conference of Neuropathology Society of India
  • Place of Presentation: Hyderabad, India
  • Year and Date: 2015-12-19
  • Invited
• [Presentation] Globular glial mixed four repeat tau and TDP-43 proteinopathy with motor neuron disease and frontotemporal dementia. (2015)
  • Author(s): Takeuchi R, Toyoshima Y, Tada M, Shiga A, Miura T, Aoki K, Ikeuchi T, Nishizawa M, Kakita A, Takahashi H
  • Organizer: 26th International Symposium on ALS/MND
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] Distinct patterns of neuronal and glial TDP-43 inclusions in motor cortex. (2015)
  • Author(s): Takeuchi R, Tada M, Toyoshima Y, Shiga A, Sato T, Horie M, Takebayashi H, Onodera O, Nishizawa M, Takahashi H, Kakita A
  • Organizer: 第56回日本神経学会
  • Place of Presentation: 朱鷺メッセ（新潟県・新潟市）
  • Year and Date: 2015-05-20
• [Presentation] Amyotrophic lateral sclerosis: discovery of TDP-43 and subsequent development (2014)
  • Author(s): Takahashi H
  • Organizer: The 3rd Congress of Asian Society of Neuropathology
  • Place of Presentation: Convention Plaza of Seoul University, Seoul, Korea
  • Year and Date: 2014-11-06 – 2014-11-08
  • Invited
• [Presentation] 筋萎縮性側索硬化症のTDP-43皮質組織像の多様性：臨床病理および生化学的解析 (2014)
  • Author(s): 竹内亮子, 他田真理, 志賀 篤, 今野卓哉, 豊島靖子, 小野寺理, 西澤正豊, 柿田明美, 高橋 均
  • Organizer: 日本神経病理学会
  • Place of Presentation: 学術総合センター、東京
  • Year and Date: 2014-06-05 – 2014-06-07
• [Presentation] Clinicopathologic analysis of TDP-43 expression in the cerebral cortex in ALS (2014)
  • Author(s): Takeuchi R, Tada M, Shiga A, Konno T, Toyoshima Y, Onodera O, Nishizawa M, Kakita A, Takahashi H.
  • Organizer: The 66th Annual Meeting of American Academy of Neurology
  • Place of Presentation: Pennsylvania Convention Center, Philadelphia, USA
  • Year and Date: 2014-04-27 – 2014-04-29