Large-Scale Evidence for an Association between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals

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-/anti-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 TNFα (t = 4.30, P <. 0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P =. 0007) and TNFα (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.