TY - CHAP
T1 - Mixed pathology as a rule, not exception
T2 - Time to reconsider disease nosology
AU - Chu, Yaping
AU - Hirst, Warren D.
AU - Kordower, Jeffrey H.
N1 - Funding Information:
This manuscript is supported by Aligning Science Against Parkinson's (ASAP).
Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Alpha-synuclein
KW - Amyloid
KW - Inflammation
KW - Parkinson disease
KW - Proteinopathy
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=85148260858&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85148260858&partnerID=8YFLogxK
U2 - 10.1016/B978-0-323-85538-9.00012-2
DO - 10.1016/B978-0-323-85538-9.00012-2
M3 - Chapter
C2 - 36796948
AN - SCOPUS:85148260858
T3 - Handbook of Clinical Neurology
SP - 57
EP - 71
BT - Handbook of Clinical Neurology
PB - Elsevier B.V.
ER -