Maria A Di Biase1,2, Andrew Zalesky1,3, Suheyla Cetin-Karayumak2, Yogesh Rathi2,4, Jinglei Lv5, Danny Boerrigter6,7, Hayley North6,7, Paul Tooney8, Christos Pantelis1,3, Ofer Pasternak2,4, Cynthia Shannon Weickert6,7,9, Vanessa L Cropley1,10. 1. Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia. 2. Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 3. Melbourne School of Engineering, The University of Melbourne, Parkville, VIC, Australia. 4. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 5. School of Biomedical Engineering, The University of Sydney, Camperdown, NSW, Australia. 6. Neuroscience Research Australia, Randwick, NSW, Australia. 7. School of Psychiatry, University of New South Wales, Sydney, NSW, Australia. 8. School of Biomedical Sciences & Pharmacy, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia. 9. Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY. 10. Centre for Mental Health, Faculty of Health, Arts and Design, Swinburne University, Melbourne, VIC, Australia.
Abstract
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.
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.
Authors: S G Fillman; N Cloonan; V S Catts; L C Miller; J Wong; T McCrossin; M Cairns; C S Weickert Journal: Mol Psychiatry Date: 2012-08-07 Impact factor: 15.992
Authors: Brian J Miller; Peter Buckley; Wesley Seabolt; Andrew Mellor; Brian Kirkpatrick Journal: Biol Psychiatry Date: 2011-06-08 Impact factor: 13.382
Authors: S G Fillman; T W Weickert; R K Lenroot; S V Catts; J M Bruggemann; V S Catts; C S Weickert Journal: Mol Psychiatry Date: 2015-07-21 Impact factor: 15.992
Authors: Yunting Zhu; Maree J Webster; Caitlin E Murphy; Frank A Middleton; Paul T Massa; Chunyu Liu; Rujia Dai; Cyndi Shannon Weickert Journal: Front Neurosci Date: 2022-06-30 Impact factor: 5.152
Authors: Maria Paula Maziero; Johanna Seitz-Holland; Kang Ik K Cho; Joshua E Goldenberg; Taís W Tanamatis; Juliana B Diniz; Carolina Cappi; Maria Alice de Mathis; Maria C G Otaduy; Maria da Graça Morais Martin; Renata de Melo Felipe da Silva; Roseli G Shavitt; Marcelo C Batistuzzo; Antonio C Lopes; Eurípedes C Miguel; Ofer Pasternak; Marcelo Q Hoexter Journal: Biol Psychiatry Cogn Neurosci Neuroimaging Date: 2021-04-17
Authors: Johanna Seitz-Holland; Monica Lyons; Leila Kushan; Amy Lin; Julio E Villalon-Reina; Kang Ik Kevin Cho; Fan Zhang; Tashrif Billah; Sylvain Bouix; Marek Kubicki; Carrie E Bearden; Ofer Pasternak Journal: Transl Psychiatry Date: 2021-11-10 Impact factor: 6.222