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Neuroinflammation is independently associated with brain network dysfunction in Alzheimer’s disease

Leng, Fangda, Hinz, Rainer, Gentleman, Steve, Hampshire, Adam, Dani, Melanie, Brooks, David J. and Edison, Paul 2022. Neuroinflammation is independently associated with brain network dysfunction in Alzheimer’s disease. Molecular Psychiatry 28 (3) , pp. 1303-1311. 10.1038/s41380-022-01878-z

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Abstract

Brain network dysfunction is increasingly recognised in Alzheimer’s disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. 42 participants (12 Aβ-positive MCI, 14 Aβ-positive AD and 16 Aβ-negative healthy controls) were recruited. Participants had 11C-PBR28 and 18F-flutemetamol PET to quantify Aβ deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aβ-positive patients. Increased 11C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11C-PBR28 uptake correlated negatively with structural integrity (standardised β = −0.375, p = 0.037) and network local efficiency (standardised β = −0.468, p < 0.001), independent of cortical thickness and Aβ deposition, while Aβ was not. Network structural integrity, small-worldness and local efficiency, and cortical thickness were positively associated with cognition. Our findings suggest cortical neuroinflammation coincide with structural and functional network disruption independent of Aβ and cortical atrophy. These findings link the brain connectivity change and pathological process in Alzheimer’s disease, and suggest a pathway from neuroinflammation to systemic brain dysfunction.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher: Springer Nature [academic journals on nature.com]
ISSN: 1359-4184
Date of First Compliant Deposit: 13 March 2023
Date of Acceptance: 8 November 2022
Last Modified: 15 May 2023 15:51
URI: https://orca.cardiff.ac.uk/id/eprint/157694

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