Stages of pTDP-43 pathology in amyotrophic lateral sclerosis
Article first published online: 19 JUN 2013
© 2013 American Neurological Association
Annals of Neurology
Volume 74, Issue 1, pages 20–38, July 2013
How to Cite
Brettschneider, J., Del Tredici, K., Toledo, J. B., Robinson, J. L., Irwin, D. J., Grossman, M., Suh, E., Van Deerlin, V. M., Wood, E. M., Baek, Y., Kwong, L., Lee, E. B., Elman, L., McCluskey, L., Fang, L., Feldengut, S., Ludolph, A. C., Lee, V. M.-Y., Braak, H. and Trojanowski, J. Q. (2013), Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol., 74: 20–38. doi: 10.1002/ana.23937
- Issue published online: 27 AUG 2013
- Article first published online: 19 JUN 2013
- Accepted manuscript online: 20 MAY 2013 02:54AM EST
- Manuscript Accepted: 10 MAY 2013
- Manuscript Revised: 15 APR 2013
- Manuscript Received: 25 FEB 2013
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.
pTDP-43 immunohistochemistry was performed on 70μm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background.
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.
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. Ann Neurol 2013;74:20–38