Mixed pathology as a rule, not exception: Time to reconsider disease nosology

Yaping Chu, Warren D. Hirst, Jeffrey H. Kordower

Research output: Chapter in Book/Report/Conference proceedingChapter


Parkinson's disease is a progressive neurodegenerative disorder that is associated with motor and nonmotor symptoms. Accumulation of misfolded α-synuclein is considered a key pathological feature during disease initiation and progression. While clearly deemed a synucleinopathy, the development of amyloid-β plaques, tau-containing neurofibrillary tangles, and even TDP-43 protein inclusions occur within the nigrostriatal system and in other brain regions. In addition, inflammatory responses, manifested by glial reactivity, T-cell infiltration, and increased expression of inflammatory cytokines, plus other toxic mediators derived from activated glial cells, are currently recognized as prominent drivers of Parkinson's disease pathology. However, copathologies have increasingly been recognized as the rule (> 90%) and not the exception, with Parkinson's disease cases on average exhibiting three different copathologies. While microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy may have an impact on disease progression, α-synuclein, amyloid-β, and TDP-43 pathology do not seem to contribute to progression.

Original languageEnglish (US)
Title of host publicationHandbook of Clinical Neurology
PublisherElsevier B.V.
Number of pages15
StatePublished - Jan 2023
Externally publishedYes

Publication series

NameHandbook of Clinical Neurology
ISSN (Print)0072-9752
ISSN (Electronic)2212-4152


  • Alpha-synuclein
  • Amyloid
  • Inflammation
  • Parkinson disease
  • Proteinopathy
  • Tau

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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