Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Abstract

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.

• Authors: Yuichi Riku, Hirohisa Watanabe, Mari Yoshida, Shinsui Tatsumi, Maya Mimuro, Yasushi Iwasaki, Masahisa Katsuno, Yohei Iguchi, Michihito Masuda, Jo Senda, Shinsuke Ishigaki, Tsuyoshi Udagawa, Gen Sobue
• Journal: JAMA neurology (JAMA Neurol) Vol. 71 Issue 2 Pg. 172-9 (Feb 2014) ISSN: 2168-6157 [Electronic] United States
• PMID: 24378564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins

Topics

• Aged
• Amyotrophic Lateral Sclerosis (genetics, pathology)
• DNA-Binding Proteins (analysis, genetics)
• Female
• Frontotemporal Lobar Degeneration (genetics, pathology)
• Humans
• Inclusion Bodies (chemistry, pathology)
• Male
• Middle Aged
• Motor Neuron Disease (genetics, pathology)
• Retrospective Studies