Anterior Cingulate Cortex TDP-43 Pathology in Sporadic Amyotrophic Lateral Sclerosis

Neuronal constituents of the human anterior cingulate cortex displayed morphological changes related to the 43-kDa transactive response DNA-binding protein (TDP-43) in advanced pathological stages of sporadic amyotrophic lateral sclerosis (sALS). By using nonphosphorylation-dependent TDP-43 immunocytochemistry, it was seen that the changes in susceptible pyramidal cells of the superficial cellular layers II-IIIab differed from those in the deep layers IIIc-Vb: A complete loss of nuclear TDP-43 expression (i.e. nuclear clearing) in the small projection neurons of layers II-IIIab was consistently accompanied by the development of somatic skein-like TDP-43-immunopositive inclusions. In contrast, in the large pyramidal cells of layers IIIc-Vb and von Economo neurons of layer Vb, skein-like inclusions were lacking or, when aggregated TDP-43 was present, the aggregates presented as dash-like TDP-43-immunopositive particles in the vicinity of the cell nucleus. The cytoskeleton of projection neurons in layers II-IIIab is neurofilament-sparse in contrast to that of the large neurons in layers IIIc-Vb, which are rich in neurofilaments and also heat shock proteins that function as their molecular chaperones. The disparities between the two neuronal populations may contribute to the two differing immunocytochemical profiles reported here. Some implications of the findings for the pathogenesis and progression of TDP-43 pathology in sALS are discussed.