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- Title
TDP-43 Accumulation Within Intramuscular Nerve Bundles of Patients With Amyotrophic Lateral Sclerosis.
- Authors
Kurashige, Takashi; Morino, Hiroyuki; Murao, Tomomi; Izumi, Yuishin; Sugiura, Tomohito; Kuraoka, Kazuya; Kawakami, Hideshi; Torii, Tsuyoshi; Maruyama, Hirofumi
- Abstract
This dual case-control and cohort study assesses for a characteristic pathological hallmark in the muscle tissues of patients with amyotrophic lateral sclerosis. Key Points: Question: Does a characteristic pathological hallmark exist in the muscle tissues of those with amyotrophic lateral sclerosis (ALS)? Findings: In this dual case-control study of 10 autopsied patients and cohort study of 114 consecutive patients, those with sporadic ALS (SALS) were confirmed to have phosphorylated transactive response DNA-binding protein 43 (pTDP-43)–positive axons in intramuscular nerve bundles. In 114 patients without a family history of ALS or other neuromuscular diseases for whom muscle biopsies were performed, all patients with axonal pTDP-43–positive nerve bundles were diagnosed with SALS after biopsy. Meaning: Results of this study suggest that axonal pTDP-43 accumulation in intramuscular nerve bundles may be characteristic for patients with ALS. Importance: Degeneration of neuromuscular junctions and axons is considered an important aspect of the pathomechanism of amyotrophic lateral sclerosis (ALS). However, a mechanism including the role of transactive response DNA-binding protein 43 (TDP-43) in axons has not been pathologically clarified. Objective: To identify and characterize the histopathology of peripheral axons in the skeletal muscle of patients with ALS. Design, Setting, and Participants: This study comprised 2 parts: a postmortem case-control study and a retrospective population-based cohort study with a minimum of 1 year of follow-up. Patients in the cohort study were enrolled from January 1, 2004, to September 30, 2019. The postmortem study included patients with sporadic ALS (SALS) with TDP-43 pathology and control patients with non-ALS disease. The cohort study enrolled patients without a family history of ALS or other neuromuscular disease and those not diagnosed with a muscle disease at biopsy. Patients were excluded if their clinical records were not screened after biopsy, if they were diagnosed with a muscular disease, and if they were harboring known causative genes of ALS. Data were collected between September 2019 and June 2021 and analyzed in June 2021. Exposures: Muscle biopsy or postmortem muscle tissue examination. Main Outcomes and Measures: Clinical information and muscle pathological characteristics. Results: A total of 10 patients with autopsy-confirmed SALS (mean [SD] age at death, 76.1 [8.5] years; 8 men [80%]) exhibited axonal phosphorylated TDP-43 (pTDP-43)–positive accumulations in intramuscular nerve bundles; the 12 control patients without ALS did not. Among the 114 patients in the cohort study (mean [SD] age, 62.3 [16.1] years; 76 men [67%]), 71 patients (62.3%) exhibited intramuscular nerve bundles; 43 (37.7%) did not. Among those who exhibited pTDP-43–positive intramuscular nerve bundles, 33 patients (22 men [66.7%]; mean [SD] age, 65.2 [15.6] years) were later diagnosed with ALS. The other 38 patients (26 men [68.4%]; mean [SD] age, 59.3 [18.0] years) showed no pTDP-43–positive bundles and did not develop ALS. Among those without evident nerve bundles (28 men [65.1%]; mean [SD] age, 61.3 [15.3] years), 3 were later diagnosed with ALS. Among patients with ALS in the biopsy cohort, 9 with pTDP-43–positive bundles showed only lower motor neuron symptoms at biopsy. Conclusions and Relevance: Results of this dual case-control and retrospective cohort study suggest that axonal pTDP-43 accumulations may be characteristic for patients with ALS. As such findings precede clinical fulfillment of the Gold Coast criteria, TDP-43 in nerve bundles may be a novel diagnostic biomarker for ALS.
- Publication
JAMA Neurology, 2022, Vol 79, Issue 7, p693
- ISSN
2168-6149
- Publication type
Article
- DOI
10.1001/jamaneurol.2022.1113