Kurashige T, Morino H, Murao T, Izumi Y, Sugiura T, Kuraoka K, Kawakami H, Torii T, Maruyama H. TDP-43 Accumulation Within Intramuscular Nerve Bundles of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022 Jul 1;79(7):693-701. PubMed.

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  1. In this recent paper, evaluation of intramuscular nerve bundles emerges as frequent site of TDP43 pathology. A postmortem case control study showed TDP43 accumulations in every specimen from ALS patients, and in no control cases. These accumulations appear more frequently in nerve bundles than in the CNS; whereas over 90 percent of motor neurons do not have accumulations in brain and spinal cord, about 50 percent of nerve muscle specimens show this pathology. The selectivity for ALS was confirmed in a retrospective analysis of open muscle biopsies.

    Based on this study, muscle biopsy may again emerge as important diagnostic tool for patients in whom the diagnosis of ALS is viable but not established.  These results also emphasize the potential importance of the nerve terminal and neuromuscular junction as targets for therapy.

    View all comments by Jeremy Shefner

  2. Kurashige et al. found pTDP-43 in intramuscular nerve bundles in 10 of 10 autopsy-confirmed ALS patients, and none in 12 control patients without ALS. In a cohort study, 33 of 33 patients subsequently diagnosed with ALS had pTDP-43 in intramuscular nerve bundles, while zero of 38 individuals with pTDP-43–negative nerve bundles were subsequently diagnosed with ALS. On this basis, the authors conclude that pTDP-43-positive nerve bundles are specific for ALS and might be considered as a “novel diagnostic biomarker for ALS."

    However, a paper published in Brain earlier this year (Riva et al., 2022) could not document such specificity, and would suggest that pTDP-43 positive intramuscular nerve biopsies would not be a reliable diagnostic biomarker for ALS. The data from Riva et al. was obtained from diagnostic motor nerve biopsies in 102 lower motor neuron syndrome patients. Axonal accumulation of pTDP43 was found in 98.2 percent of ALS cases, but was also found in 30.4 percent of non-ALS cases. Thus accumulation of TDP-43 is not specific for ALS and therefore would not be a meaningful diagnostic biomarker.

    A possible explanation of the difference in the two studies may be that Kurashige was examining “intramuscular nerve bundle” specimens while Riva was examining “diagnostic motor nerve biopsies.” However, a lack of specificity is a more likely finding given the fact that pTDP-43 is not specific for ALS and has been reported in a wide range of tissues and conditions. Furthermore, biopsies of muscle nerves or intramuscular nerves are sufficiently invasive that they are unlikely to become readily accepted diagnostic procedures.

    Nevertheless, both papers provide valuable documentation that TDP-43 is present long before a diagnosis of ALS can be made; the presence of pTDP-43 axonal aggregates may well be an early event in the pathogenesis of ALS, occurring well before axonal degeneration.

    References:

    Riva N, Gentile F, Cerri F, Gallia F, Podini P, Dina G, Falzone YM, Fazio R, Lunetta C, Calvo A, Logroscino G, Lauria G, Corbo M, Iannaccone S, Chiò A, Lazzerini A, Nobile-Orazio E, Filippi M, Quattrini A. Phosphorylated TDP-43 aggregates in peripheral motor nerves of patients with amyotrophic lateral sclerosis. Brain. 2022 Mar 29;145(1):276-284. PubMed.

    View all comments by Stanley Appel

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  1. Aggregates of TDP-43 in Muscle—Potential ALS Marker?