TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort.
J Alzheimers Dis
; 75(1): 337-350, 2020.
Article
em En
| MEDLINE
| ID: mdl-32280087
ABSTRACT
Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Demência
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Proteinopatias TDP-43
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Hipocampo
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Degeneração Neural
Tipo de estudo:
Risk_factors_studies
Limite:
Aged80
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article