Clinical Significance of TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis

Matthew D. Cykowski, Suzanne Z Powell, Leif E Peterson, Joan W Appel, Andreana L. Rivera, Hidehiro Takei, Ellen Chang, Stanley H Appel

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0.07), though no association with disease duration or progression rate was seen. Shorter disease duration (p = 0.0016), more severe striatal pathology (p = 0.0029), and a trend toward greater whole brain TDP-43 pathology (p = 0.059) were found in c9ALS. Cluster analysis identified "TDP43-limited," "TDP43-moderate," and "TDP43-severe" subgroups. The TDP43-limited group contained more cognitively intact (p = 0.005) and lower extremity onset site (p = 0.019) patients, while other subgroups contained more cognitively impaired patients. We conclude that TDP-43 pathologic burden in ALS is associated with cognitive impairment and c9ALS, but not duration of disease or rate of progression. Further, we demonstrate a subgroup of patients with low TDP-43 burden, lower extremity onset, and intact cognition, which requires further investigation.

Original languageEnglish (US)
Pages (from-to)402-413
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Issue number5
StatePublished - May 1 2017


  • Amyotrophic lateral sclerosis
  • Frontotemporal dementia
  • Motor neuron disease
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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