Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis

Background: Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described. Objective: To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS. Design: Performance of an immunohistochemical whole central nervous system scan for evidence of pathological TDP-43 in ALS patients. Setting: An academic medical center. Participants: We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants. Main Outcome Measures: Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology. Results: In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls. Conclusions: These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.