Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Richard A. Armstrong*, Nigel J. Cairns, Peter L. Lantos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration ('reaction' hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.

Original languageEnglish
Pages (from-to)133-146
Number of pages14
Issue number3
Publication statusPublished - Sept 2002


  • disease pathogenesis
  • extracellular protein deposits
  • intracellular inclusions
  • neurodegenerative disorders
  • pathological lesions


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