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Relationship between tau, neuroinflammation and atrophy in Alzheimer's disease: The NIMROD study

Accepted version
Peer-reviewed

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Authors

Su, L 
Surendranathan, A 
Huang, Y 
Bevan-Jones, WR 

Abstract

© 2020 Elsevier B.V. In addition to beta-amyloid accumulation, misfolded tau and activated microglia are also present in Alzheimer's disease (AD). It is important to study the relationship amongst these pathologies in vivo and their effects on the cognitive deficits for developing effective trails and future therapeutic or preventive strategies for AD. To investigate the relationships amongst different pathologies in AD, in particular how they interact resulting in cognitive impairments, we conducted a study of sixty-six subjects (15 AD, 24 Mild Cognitive Impairment (MCI) and 27 similarly aged healthy controls), who underwent standardised clinical and neuropsychological assessments followed by dynamic PET using [18F]AV1451 (tau) and [11C]PK11195 (activated microglia) and multimodal 3T MRI. MCI patients also underwent [11C]PIB (beta-amyloid) PET. We compared regional PET binding and grey matter atrophy amongst AD, amyloid positive MCI and controls, as well as their spatial distribution across different brain areas. We also applied a mediation analysis to infer the direct and indirect effects of tau, neuroinflammation and grey matter atrophy on cognitive functioning. We found increased [18F]AV1451 and [11C]PK11195 binding as well as grey matter atrophy in AD, with a strong spatial overlap amongst these AD related biomarkers suggesting them interacting with each other. We demonstrated that both tau ([18F]AV1451) and neuroinflammation ([11C]PK11195) have significant effects on cognition however their effects were fully mediated by grey matter atrophy. No mediation effect between tau and neuroinflammation were found with respect to cognition. In conclusion, grey matter atrophy not only spatially overlapped with tau and microglia activity in AD, but also mediate them in affecting cognitive impairments. The mediation analysis enabled data fusion across multiple imaging modalities (PET and MRI) and multiple PET tracers. Our results have significant implications for trials targeting tau and inflammation, and future therapeutic or preventive strategies for AD.

Description

Keywords

AD, MCI, Tau, Neuroinflammation, Mediation analysis, MRI, PET, Data fusion

Journal Title

Information Fusion

Conference Name

Journal ISSN

1566-2535
1872-6305

Volume Title

67

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (103838/Z/14/Z)
Alzheimer's Society (443 (AS-JF-18-017))
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/M009041/1)
Medical Research Council (MC_U105597119)
Medical Research Council (MC_UU_00005/12)
Medical Research Council (MR/K02308X/1)