Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates also occur in the skeletal muscles in a certain proportion of ALS patients.AimThe aim of this study was to clarify the distribution and incidence of pTDP-43 aggregates in the skeletal and cardiac muscles of patients with ALS, and also those of patients with neuromuscular diseases (NMDs) and non-NMDs.Material and methodsFive regions of muscle (tongue, cervical muscle, diaphragm, iliopsoas muscle and heart) were examined histologically and immunohistochemically in patients with ALS (n = 30), NMDs (n = 13) and non-NMDs (n = 7).ResultsTwo types of pTDP-43 aggregates were distinguishable morphologically: dense filamentous and short linear inclusions. These inclusions were found in at least one of the five muscle regions in all 30 cases of ALS; skeletal muscles in 28 cases and myocardium in 12. pTDP-43 aggregates were also found in 9 of 13 patients with NMDs, including myositis, muscular dystrophy and mitochondrial myopathy, as well as in 3 of 7 patients with non-NMDs. In ALS, pTDP-43 aggregates were most frequent in the diaphragm (19 cases). The mean density of pTDP-43 aggregates in ALS was significantly higher than that in NMDs and non-NMDs. In contiguous sections stained with hematoxylin and eosin and anti-pTDP-43, muscle fibers with dense filamentous inclusions demonstrated single-fiber atrophy with vacuolar degeneration.ConclusionThe present findings indicate that pTDP-43 aggregates in skeletal and cardiac muscle are a myogenic pathological marker in multiple diseases including ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is characterized pathologically by loss of upper and lower motor neurons with consistent occurrence of phosphorylated TDP-43-immunoreactive neuronal and glial inclusions in the central nervous system [2, 15]
In each of the 50 cases in Group B, 5 regions were examined (Table 2). phosphorylated TDP-43 (pTDP-43) aggregates were found in at least one of these 5 regions in all 30 cases of ALS (100%); pTDP-43 aggregates were present in the skeletal muscles of 28 cases and in the myocardium in (Table 2). pTDP-43 aggregates were found in 9 of the patients with neuromuscular diseases (NMDs) (69.2%) and in 3 of the 7 patients with non-NMDs (42.9%) (Table 2)
In the patients with NMDs, pTDP-43 aggregates were found in the diaphragm (6 cases), myocardium (4 cases), cervical muscle (3 cases), tongue (1 case) and iliopsoas muscle (1 case)
Summary
Amyotrophic lateral sclerosis (ALS) is characterized pathologically by loss of upper and lower motor neurons with consistent occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system [2, 15]. TDP-43 aggregates have been described in the skeletal muscles from patients with various diseases, including sporadic inclusion body myositis (IBM) [7, 26], ALS with TARDBP mutation [8], IBM with Paget’s disease of the bone and fronto-temporal dementia [3, 25], polymyositis with mitochondrial pathology [22], non-IBM myopathies with rimmed vacuoles (limb girdle muscular dystrophy and myotonic dystrophy type 2) [9], distal hereditary motor neuropathy and myofibrillary. Amyotrophic lateral sclerosis (ALS) is characterized pathologically by the occurrence of phosphorylated TDP-43 (pTDP-43)-immunoreactive neuronal and glial inclusions in the central nervous system. Recent studies have shown that pTDP-43 aggregates occur in the skeletal muscles in a certain proportion of ALS patients
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