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Lookup NU author(s): Professor David BrooksORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background: Abnormal neuronal activity, disrupted brain connectivity and neurovascular dysregulation are all observed in Alzheimer’s disease (AD) and considered to be factors that drive disease progression. Glial cells support normal functioning of neurons, neuronal circuits and neurovascular regulations in healthy brains, but become activated in AD causing neuroinflammation. It remains unclear how this neuroinflammation influences neuronal activity, brain connectivity and cerebral blood perfusion in AD. Methods: Twenty six MCI/AD patients whose 18F-flutemetamol PET scans were β-amyloid positive (Aβ+) and 17 healthy controls (HC) had 11C-PBR28 PET, diffusion tensor imaging (DTI), resting state fMRI (rs-fMRI), and arterial spin labelling (ASL) MRI scans. The amplitude of low-frequency fluctuations (ALFF, a proxy of neuronal activity) in rs-fMRI signals, functional connectivity and cerebral blood flow (CBF) were compared between Aβ+ participants and HC. The independent influence of 11C-PBR28 uptake on ALFF, CBF, functional and structural connectivity was tested using regression models adjusted for age, diagnosis and 18F-flutemetamol uptake. Results: Aβ+ subjects showed increased ALFF in the prefrontal, cingulate and occipital cortices, and decreased ALFF in temporal cortex. Functional connectivity between medial prefrontal (MPFC), posterior cingulate, and precuneus cortices was impaired in Aβ+ patients. 11C-PBR28 uptake in the MPFC had a positive influence on ALFF but a negative relationship with MPFC functional connectivity, fractional anisotropy of cingulum bundle and CBF in widespread brain regions. This suggests that, while neuroinflammation is associated with locally increased neuronal activity, it is also associated with decreased structural and functional connectivity with anatomically remote regions, and a decreased blood supply, Conclusion: The association between neuroinflammation, ineffective local neuronal hyperactivity, reduced blood supply, and impairment in connectivity suggests that microglial activation has a deleterious influence on neuronal function in Alzheimer’s disease. The neuronal hyperactivity and reduced perfusion associated with neuroinflammation implies a mismatch between increased energy demand and reduced nutritional supply which could cause further disruption of brain connectivity. Therefore, neuroinflammation, insufficient perfusion and neuronal hyperactivity may form a vicious cycle that accelerates disease deterioration. Our finding suggests that strategies targeting neuroinflammation and neuronal hyperactivity would be rational in AD drug discovery.
Author(s): Leng F, Hinz R, Gentleman S, Dani M, Brooks DJ, Edison P
Publication type: Article
Publication status: Published
Journal: Molecular Psychiatry
Year: 2023
Volume: 28
Pages: 1303-1311
Print publication date: 01/03/2023
Online publication date: 06/12/2022
Acceptance date: 08/11/2022
Date deposited: 09/11/2022
ISSN (print): 1359-4184
ISSN (electronic): 1476-5578
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41380-022-01878-z
DOI: 10.1038/s41380-022-01878-z
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