title: Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  TAR DNA-binding protein of 43 kDa (TDP-43) plays a major role in the pathogenesis of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Although a pathological continuity between FTLD and ALS has been suggested, the neuropathological changes of the lower motor neuron (LMN) systems have not been assessed in TDP-43-associated FTLD (FTLD-TDP), to our knowledge.
  
  
  OBJECTIVE
  To investigate a pathological continuity between FTLD-TDP and ALS by comparing their respective neuropathological changes in the motor neuron system.
  
  
  METHODS
  A retrospective clinical medical record review and a semiquantitative neuropathological evaluation of the cranial motor nerve nuclei and spinal cord were conducted at autopsy. We included 43 patients with sporadic FTLD-TDP, type A, B, or C, from 269 consecutively autopsied patients with TDP-43 proteinopathy. Patients were categorized as having FTLD without ALS, FTLD-ALS (onset of FTLD symptoms/signs preceded those of ALS), or ALS-FTLD (onset of ALS symptoms/signs preceded those of FTLD).
  
  
  METHODS
  Neuronal TDP-43 pathological changes and neuronal loss.
  
  
  RESULTS
  Forty-three patients were included in the clinical analysis, and 29 from whom spinal cords were obtained were included in the neuropathological analysis. Survival time was significantly shorter in the FTLD-ALS and ALS-FTLD groups than in the FTLD without ALS group (P < .001). At neuropathological examination, 89% of patients in the FTLD without ALS group showed aggregations of TDP-43 in the spinal motor neurons. The LMN loss was most severe in ALS-FTLD, followed by FTLD-ALS and FTLD without ALS. All the patients with type A or C FTLD-TDP were included in the FTLD without ALS group, and all those with type B pathological changes were in the FTLD-ALS or the ALS-FTLD group. Lower motor neuron loss and TDP-43-positive skeinlike inclusions were observed in all pathological subtypes.
  
  
  CONCLUSIONS
  The LMN systems of FTLD-TDP frequently exhibit neuropathological changes corresponding to ALS. Thus, a pathological continuity between FTLD-TDP and ALS is supported at the level of the LMN system.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Riku
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
authors.forename: Shinsui
authors.initials: S
authors.lastname: Tatsumi
authors.affiliation: Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Mimuro
authors.affiliation: Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Iguchi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Michihito
authors.initials: M
authors.lastname: Masuda
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Jo
authors.initials: J
authors.lastname: Senda
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Udagawa
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology*; D012189:Retrospective Studies
chemical_list: D004268:DNA-Binding Proteins