Stages of pTDP‐43 pathology in amyotrophic lateral sclerosis

Abstract

Objective To see if the distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages. Methods pTDP-43 immunohistochemistry was performed on 70 μm sections from ALS autopsy cases (N=76) classified by clinical phenotype and genetic background. Results ALS cases with the lowest burden of pTDP-43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves XII-X, VII, V, and spinal cord α-motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP-43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP-43 lesions showed pTDP-43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP-43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as non-expansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP-43 pathology. Interpretation pTDP-43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of four neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways. Moreover, the fact that pTDP-43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS.

TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia

“…Family history for ALS was more prevalent in pure bvFTD cases with TDP-43 in the hypoglossal nucleus, but this did not reach significance compared to other bvFTD cohorts (p = 0.06). The recent topographical staging of TDP-43 pathology in bvFTD and ALS [6,7] demonstrated that TDP-43 initiated in the motor system network in ALS is also seen in the majority of bvFTD cases, despite the absence of ALS in over 50% of these [6,21]. In a recent analysis [21], we identified the hypoglossal nucleus as a key brain region in discriminating between cases with and without ALS and the present study corroborates this finding in bvFTD cases.…”

C9orf72 promoter hypermethylation is neuroprotective

“…30 Also, a neuropathologic staging study of TDP-43 in ALS suggests that there is early pathology in motor cortex (stage 1) that spreads to prefrontal cortex (stage 3) and does not reach hippocampus until later in the disease course Table 2 Linear (stage 4). 31 One source of discrepancy of hippocampus decline between the prior imaging study and the current study is that group averages may obscure heterogeneous rates of decline across individuals who are hypomethylated or hypermethylated. Future studies with larger samples are warranted to better understand the association between longitudinal decline and C9orf72 methylation in each individual GM region.…”

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

“…In addition to SOD1, 6 TAR DNA-binding protein of 43 kDa (TDP-43) aggregate propagation has been compared with a prion-like seeding mechanism, with evidence of regional spreading of pathology occurring in a sequential pattern through the neuroaxis. 7 Initially, evidence from HEK293 cells suggested that recombinantly produced TDP-43 could trigger aggregation of cell produced TDP-43 after its translocation into the cell, 8 consistent with a seeding reaction. It has also been observed that insoluble TDP-43 from human ALS brain could seed further TDP-43 aggregation in SH-SY5Y cells after its artificial translocation into cells, and that these aggregates could transfer to na€ ıve cells.…”