Affiliations: [a] Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK
| [b] Cognitive Ageing and Impairment Neurosciences, School of Psychology, Social Work and Social Policy, University of South Australia, Adelaide, Australia
| [c] Department of Radiology, University of Cambridge, Cambridge, UK
| [d] Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| [e] Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Correspondence:
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Correspondence to: Sally Hunter, Department of Public Health and Primary Care, Institute of Public Health, Forvie Site, University of Cambridge School of Clinical Medicine, Box 113 Cambridge Biomedical Campus, Cambridge CB2 0SP, UK. Tel.: +44 0 1223330321; E-mail: [email protected].
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.
Keywords: Aging, dementia, hippocampus, phosphorylation, population study, TAR-DNA binding protein of 43 kDa
