Amyotrophic lateral sclerosis with speech apraxia, predominant upper motor neuron signs, and prominent iron accumulation in the frontal operculum and precentral gyrus

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease; transactivation response DNA-binding protein of 43 kDa (TDP-43) and iron accumulation are supposed to play a crucial role in the pathomechanism of the disease. Here, we report an unusual case of a patient with ALS who presented with speech apraxia as an initial symptom and upper motor neuron deficiencies. In the early clinical stages, singlephoton emission computed tomography visualized focal hypoperfusion of the right frontal operculum, and magnetic resonance imaging identified a hypointense area along the frontal lobe on T2-weighted images. Neuropathological examination revealed that neuronophagia of Betz cells, gliosis, appearance of phosphorylated TDP-43 (p-TDP-43)-positive glial and neuronal inclusions, and prominent iron accumulation were frequently visible in the precentral gyrus. TDP-43 pathology and focal iron accumulation were also visible in the frontal operculum, but only a mild neuronal loss and a few p-TDP-43-positive neuronal and glial inclusions were found in the hypoglossal nucleus of the medulla oblongata and anterior horn of the spinal cord. Immunoblot analysis revealed an atypical band pattern for ALS. In our case, abnormal TDP-43 and iron accumulation might possibly have caused neurodegeneration of the frontal operculum, in tandem or independently; it might then have spread into the primary motor area. Our results suggest a causative association between TDP-43 and iron accumulation in the pathomechanisms of ALS presenting with upper motor neuron signs.

Atypical TDP‐43 proteinopathy clinically presenting with progressive nonfluent aphasia: A case report

“…Mitani et al . reported a case of ALS that showed a similar band pattern to our case 14 . Our case had no Bunina bodies, but p‐TDP‐43‐positive NCIs were in lower motor neurons.…”

“…7 In many reported cases, dysphagia presents within 2 years of disease onset. [12][13][14][15] However, our patient exhibited dysphagia within a year. We attributed his swallowing dysfunction to bilateral cortical spongiform changes and gliosis and to lower motor neuron involvement.…”

“…Predominantly left‐sided atrophy of the temporal and frontal lobes is known to be responsible for apraxia of speech 7 . In many reported cases, dysphagia presents within 2 years of disease onset 12–15 . However, our patient exhibited dysphagia within a year.…”

Metals in ALS TDP-43 Pathology

“…Of these metals, Pb, MeHg [42] and Zn [62,128] have been reported to induce the aggregation of TDP-43 in vitro, whereas similar experiments with Fe, Cu [62] and Mn [42] have failed to show any effect on TDP-43 aggregation. Focal Fe accumulation has been linked to TDP-43 aggregation in atypical ALS [134], while Cu-containing compounds have rather been reported to prevent TDP-43 accumulation [133]. MeHg has been observed to induce TDP-43 aggregation also in vivo [42], while inorganic Hg has been shown not to [124].…”

“…In a recent case report study, Mitani et al [134] described a Japanese male ALS patient presenting with speech apraxia and upper motor neuron symptoms, combined with postmortem histopathology of TDP-43 aggregation and Fe accumulation in the prefrontal gyrus and the frontal operculum. While these atypical symptoms corresponded with the pathological changes in relevant brain regions, it remained unclear to what extent the TDP-43 aggregation and the Fe accumulation were causatively associated [134].…”