title: Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series.
abstract: Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis (p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others (p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change (p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients.
authors.affiliation: Institute of Neurology, Medical University Vienna, AKH 4J, Währinger Gürtel 18-20, 1097, Vienna, Austria. gabor.kovacs@meduniwien.ac.at
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.forename: Ivan
authors.initials: I
authors.lastname: Milenkovic
authors.forename: Adelheid
authors.initials: A
authors.lastname: Wöhrer
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.forename: Christine
authors.initials: C
authors.lastname: Haberler
authors.forename: Selma
authors.initials: S
authors.lastname: Hönigschnabl
authors.forename: Angelika
authors.initials: A
authors.lastname: Reiner-Concin
authors.forename: Harald
authors.initials: H
authors.lastname: Heinzl
authors.forename: Susanne
authors.initials: S
authors.lastname: Jungwirth
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Krampla
authors.forename: Peter
authors.initials: P
authors.lastname: Fischer
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D001344:Autopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051844:alpha-Synuclein; D016875:tau Proteins