@article{2a0e090e7e4e4dd7b24e15a5b6685648,
title = "Increased serum peripheral C-reactive protein is associated with reduced brain barriers permeability of TSPO radioligands in healthy volunteers and depressed patients: implications for inflammation and depression",
abstract = "The relationship between peripheral and central immunity and how these ultimately may cause depressed behaviour has been the focus of a number of imaging studies conducted with Positron Emission Tomography (PET). These studies aimed at testing the immune-mediated model of depression that proposes a direct effect of peripheral cytokines and immune cells on the brain to elicit a neuroinflammatory response via a leaky blood–brain barrier and ultimately depressive behaviour. However, studies conducted so far using PET radioligands targeting the neuroinflammatory marker 18 kDa translocator protein (TSPO) in patient cohorts with depression have demonstrated mild inflammatory brain status but no correlation between central and peripheral immunity. To gain a better insight into the relationship between heightened peripheral immunity and neuroinflammation, we estimated blood-to-brain and blood-to-CSF perfusion rates for two TSPO radiotracers collected in two separate studies, one large cross-sectional study of neuroinflammation in normal and depressed cohorts (N = 51 patients and N = 25 controls) and a second study where peripheral inflammation in N = 7 healthy controls was induced via subcutaneous injection of interferon (IFN)-α. In both studies we observed a consistent negative association between peripheral inflammation, measured with c-reactive protein P (CRP), and radiotracer perfusion into and from the brain parenchyma and CSF. Importantly, there was no association of this effect with the marker of BBB leakage S100β, that was unchanged. These results suggest a different model of peripheral-to-central immunity interaction whereas peripheral inflammation may cause a reduction in BBB permeability. This effect, on the long term, is likely to disrupt brain homeostasis and induce depressive behavioural symptoms.",
keywords = "BBB permeability, Choroid plexus, CSF, Depression, Inflammation, PET, Tracer percolation",
author = "Turkheimer, {Federico E.} and Noha Althubaity and Julia Schubert and Nettis, {Maria A.} and Oliver Cousins and Danai Dima and Valeria Mondelli and Bullmore, {Edward T.} and Carmine Pariante and Mattia Veronese",
note = "Funding Information: The BIODEP study (dataset 1) was sponsored by the Cambridgeshire and Peterborough NHS Foundation Trust and the University of Cambridge, and funded by a strategic award from the Wellcome Trust (104025) in partnership with Janssen, GlaxoSmithKline, Lundbeck and Pfizer. Recruitment of participants was supported by the National Institute of Health Research (NIHR) Clinical Research Network: Kent, Surrey and Sussex & Eastern. Additional funding was provided by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, and by the NIHR Cambridge Biomedical Research Centre (Mental Health). The FLAME study (dataset 2) was sponsored by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London in partnership whit Janssen Pharmaceutical Companies of Johnson&Johnson. We would like to gratefully thank all study participants, research teams and laboratory staff, without whom this research would not have been possible. Finally, we would like to thank the three anonymous reviewers for their very insightful and valuable comments that have substantially improved the paper. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the studies. The BIODEP study was approved by the NRES Committee East of England Cambridge Central (REC reference:15/EE/0092) and the UK Administration of Radioactive Substances Advisory Committee. The FLAME study was approved by the Queen Square London Ethical committee (REC reference. 16/LO/1520) Funding Information: The BIODEP study (dataset 1) was sponsored by the Cambridgeshire and Peterborough NHS Foundation Trust and the University of Cambridge, and funded by a strategic award from the Wellcome Trust (104025) in partnership with Janssen, GlaxoSmithKline, Lundbeck and Pfizer. Recruitment of participants was supported by the National Institute of Health Research (NIHR) Clinical Research Network: Kent, Surrey and Sussex & Eastern. Additional funding was provided by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London, and by the NIHR Cambridge Biomedical Research Centre (Mental Health). The FLAME study (dataset 2) was sponsored by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London in partnership whit Janssen Pharmaceutical Companies of Johnson&Johnson. We would like to gratefully thank all study participants, research teams and laboratory staff, without whom this research would not have been possible. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = jan,
doi = "10.1016/j.bbi.2020.10.025",
language = "English",
volume = "91",
pages = "487--497",
journal = "Brain, Behavior, and Immunity",
issn = "0889-1591",
publisher = "ACADEMIC PRESS INC",
}