Stages of pTDP-43 pathology in amyotrophic lateral sclerosis

Ann Neurol. 2013 Jul;74(1):20-38. doi: 10.1002/ana.23937. Epub 2013 Jun 19.

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 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / complications*
  • Amyotrophic Lateral Sclerosis / genetics
  • Brain / metabolism*
  • Brain / pathology
  • C9orf72 Protein
  • Cell Cycle Proteins / genetics
  • Cross-Sectional Studies
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Female
  • Genetic Testing
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Proteins / genetics
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology*
  • TDP-43 Proteinopathies / genetics
  • TDP-43 Proteinopathies / pathology*
  • Ubiquitins / genetics

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proteins
  • UBQLN2 protein, human
  • Ubiquitins