Stages of pTDP-43 pathology in amyotrophic lateral sclerosis

Johannes Brettschneider, Kelly Del Tredici, Jon B. Toledo, John L. Robinson, David J. Irwin, Murray Grossman, Eunran Suh, Vivianna M. Van Deerlin, Elisabeth M. Wood, Young Baek, Linda Kwong, Edward B. Lee, Lauren Elman, Leo McCluskey, Lubin Fang, Simone Feldengut, Albert C. Ludolph, Virginia M.Y. Lee, Heiko Braak, John Q. Trojanowski

Research output: Contribution to journalArticlepeer-review

623 Scopus citations

Abstract

Objective To see whether the distribution patterns of phosphorylated 43kDa 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 70μm 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 V, VII, and X-XII, 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 nonexpansion 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 4 neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways. Moreover, the finding 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.

Original languageEnglish (US)
Pages (from-to)20-38
Number of pages19
JournalAnnals of Neurology
Volume74
Issue number1
DOIs
StatePublished - Jul 2013

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint

Dive into the research topics of 'Stages of pTDP-43 pathology in amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this