An Emerging Model of Disease Propagation in ALS

Summary and Comment |
December 24, 2013

An Emerging Model of Disease Propagation in ALS

  1. Michael Benatar, MD, MS, PhD

An autopsy study suggests a sequential pattern of disease progression whereby TDP-43 pathology propagates along axonal pathways.

  1. Michael Benatar, MD, MS, PhD

In amyotrophic lateral sclerosis (ALS), symptoms typically progress in a relatively orderly fashion from an initially focal site of origin, to more widespread symptomatology as the disease advances. The neuropathological underpinning of this clinical observation has been unknown but, akin to other neurodegenerative diseases, is speculated to reflect the progressive spread of pathology across specific brain regions. Because phosphorylated TAR DNA-binding protein (pTDP-43) is the major component of ubiquitinated neuronal inclusions in ALS, investigators carefully examined pTDP-43 pathology in 22 regions of the central nervous system using autopsy tissue from 76 patients with ALS.

The investigators identified four pathological stages based on the distribution and extent of pTDP-43 pathology. Stage 1 is characterized by pTDP-43 pathology in the agranular motor cortex, α-motor neurons of the spinal cord, and brainstem motor nuclei of cranial nerves V, VII, and X–XII. In stage 2, pTDP-43 pathology extends to the prefontal neocortex, the reticular formation, precerebellar nuclei of the brainstem, and the red nucleus. Stage 3 pathology includes the postcentral neocortex and the striatum. Involvement of the anteromedial temporal lobe, including the hippocampus, characterizes stage 4. The authors hypothesize that this neuroanatomical gradient of pTDP-43 pathology in ALS implies dissemination of TDP-43 pathology in a sequential pattern.


These investigators' compelling conclusion is consistent with the observation that progressive accumulation of protein aggregates is characteristic of other neurodegenerative diseases such as Alzheimer disease (Tau) and Parkinson disease (α-synuclein). However, this study was cross-sectional and based on autopsy tissue from patients with relatively advanced disease. Stages based on an increasingly widespread distribution of pathology do not necessarily imply stages of temporal progression. Moreover, the authors did not find a correlation between clinical measures of disease severity/duration and the burden of neuropathology. Nevertheless, this is a landmark publication. The findings are consistent with the idea that pTDP-43 pathology is sequentially disseminated via anterograde propagation along axonal pathways. This idea is particularly important given the substantial evidence that prionlike mechanisms underlie ALS and other neurodegenerative diseases and that prionlike propagation of misfolded and aggregated proteins, such as TDP-43, is the cellular mechanism of such spread. Such insights are critical to ongoing efforts to develop effective treatments for ALS and related neurodegenerative disorders such as frontotemporal lobar degeneration.

Editor Disclosures at Time of Publication

  • Disclosures for Michael Benatar, MD, MS, PhD at time of publication Royalties Parker-Waichman LLC Editorial boards Cochrane Collaboration; Muscle & Nerve


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