Journal
SCHIZOPHRENIA BULLETIN
Volume 47, Issue 2, Pages 542-551Publisher
OXFORD UNIV PRESS
DOI: 10.1093/schbul/sbaa134
Keywords
diffusion-weighted imaging; magnetic resonance imaging; DWI; MRI; cytokines
Categories
Funding
- National Health and Medical Research Council (NHMRC) [1175754, 1177370]
- NHMRC [1136649, 1105825, 1117079]
- National Institute of Mental Health [R01MH108574]
- NSW Ministry of Health, Office of Health and Medical Research
- National Health and Medical Research Council of Australia [1175754, 1177370, 1117079, 1136649] Funding Source: NHMRC
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This study found widespread cytokine deregulation in schizophrenia patients and identified inflammation as a potential mechanism underlying increases in brain FW levels.
Introduction: Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter. Methods: All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-ianti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls. Results: Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = -3.56, P = .0004) and IL-12(p70) (t = -2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNF alpha (t = 4.30, P < .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNF alpha (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA. Conclusions: We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.
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