Lower Motor Neuron Involvement in TAR DNA-Binding Protein of 43 kDa–Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Importance  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.

Design and Setting  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).

Main Outcomes and Measures  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 and Relevance  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.

JAMA Neurology 2014