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Original Investigation |

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

Yuichi Riku, MD1; Hirohisa Watanabe, MD1; Mari Yoshida, MD2; Shinsui Tatsumi, MD2; Maya Mimuro, MD2; Yasushi Iwasaki, MD2; Masahisa Katsuno, MD1; Yohei Iguchi, MD1; Michihito Masuda, MD1; Jo Senda, MD1; Shinsuke Ishigaki, MD1; Tsuyoshi Udagawa, PhD1; Gen Sobue, MD1
[+] Author Affiliations
1Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
2Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan
JAMA Neurol. 2014;71(2):172-179. doi:10.1001/jamaneurol.2013.5489.
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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.

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Figure 1.
Survival by Clinical Group

Kaplan-Meier plot showing the survival rates of patients with frontotemporal lobar degeneration (FTLD) without amyotrophic lateral sclerosis (ALS) (solid line; n = 11), those in whom the onset of FTLD symptoms/signs preceded those of ALS (FTLD-ALS) (dashed line; n = 9), and those in whom the onset of ALS symptoms/signs preceded those of FTLD (ALS-FTLD) (dotted line; n = 23). Survival times were significantly shorter in patients with FTLD without ALS than in those with FTLD-ALS or ALS-FTLD (P < .001).

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Figure 2.
Semiquantitative Evaluations of Pathological Changes by Clinical Group

Findings shown include the severity of neuronal loss, gliosis, phosphorylated TAR DNA-binding protein of 43 kDa (pTDP-43) pathological changes, and aggregations of macrophages and the presence of Bunina bodies in the lower motor neuron systems. The severity of each pathological change was graded as 0 (none [−, not colored]), 1 (mild [+, green]), 2 (moderate [++, yellow]), or 3 (severe [+++, red]). Neuropathological changes became increasingly severe in those in whom amyotrophic lateral sclerosis (ALS) symptoms/signs preceded those of frontotemporal lobar degeneration (FTLD; ALS-FTLD), as well as the FTLD-ALS (FTLD symptoms/signs preceding those of ALS) and FTLD without ALS groups (Spearman rank order). Cx indicates cervical cord; Lx, lumbar cord; NA, not assessed; Sx, sacral cord; TDP-43, TAR DNA-binding protein of 43 kDa; and Tx, thoracic cord.

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Figure 3.
Semimacroscopic Appearances and Brain Pathological Findings in Patients With Type A, B, and C Pathological Changes

Findings in patients with type A (A-D) , B (E-H), and C (I-L) pathological changes. In a patient with type A pathological change, cerebral coronal sections showed cortical atrophy of the parasylvian region (A). Transverse section of the cervical cord showed marked myelin pallor in the corticospinal tract (B). Microscopically, the frontal cortices showed marked neuronal loss (C) and phosphorylated TAR DNA-binding protein of 43 kDa (pTDP-43)–positive neuronal inclusions and short dystrophic neurites (D). In a patient with type B pathological change, the cerebral cortex showed severe temporal atrophy (E), neuronal loss (G), and pTDP-43–positive neuronal inclusions (H). The corticospinal tract showed mild myelin pallor (F). In a patient with type C patholgoical change, the frontal and temporal cortices showed severe atrophy (I), marked neuronal loss (K), and pTDP-43–positive long dystrophic neurites (L). The corticospinal tract showed marked myelin pallor (J). Klüver-Barrera staining (A, B, E, F, I, and J), hematoxylin-eosin staining (C, G, and K), and pTDP-43 immunohistochemistry (D, H, and L) were performed. Scale bars represent 1 cm (A, E, and I), 3 mm (B, F, and J), 100 μm (C, G, and K), and 20 μm (D, H, and L). Original magnifications are ×1 (A, B, E, F, I, and J), ×200 (C, G, and K), and ×400 (D, H, and L).

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Figure 4.
Pathological Findings of Spinal Motor Neuron in Subtypes of TAR DNA-Binding Protein of 43 kDa (TDP-43) Pathological Changes

Patients with type A (A-H), type B (I-L), and type C (M-P) pathological changes. A patient with type A pathological change showed mild neuronal loss (A), phosphorylated TDP-43 (pTDP-43)–positive skeinlike cytoplasmic inclusions (B), nuclear inclusions (C), and glial inclusions (D), Bunina bodies (E [arrow] and F) in the spinal anterior horn, and dystrophic neurites (G). In a patient with type B pathological change, neuronal loss (I), pTDP-43–positive skeinlike cytoplasmic inclusions (J), and Bunina bodies (K) were markedly observed. In a patient with type C pathological change, the spinal anterior horn showed mild neuronal loss (M), pTDP-43–positive skeinlike cytoplasmic inclusions (N), and dystrophic neurites (O). Double immunohistochemistry for choline acetyltransferase (ChAT) and pTDP-43 revealed cytoplasmic inclusions (violet [arrows]) present within the cytoplasm of a ChAT-positive spinal motor neuron (brown [asterisks]) of patients with type A (H), B (L), or C (P) pathological change. Hematoxylin-eosin staining (A, E, I, K, and M), pTDP-43 immunohistochemistry (B, C, D, G, J, N, and O), cystatin-C (F), and double immunohistochemical analysis for pTDP-43 and ChAT (H, L, and P) were performed. Scale bars represent 100 (A, I, and M), 20 (G, L, and O), and 10 (B-F, H, J, K, N, and P) μm. Original magnifications are ×100 (A, I, and M), ×400 (G, L, and O), and ×1000 (B-F, H, J, K, N, and P).

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