Ellen Ji1, Danny Boerrigter2, Helen Q Cai3, David Lloyd3, Jason Bruggemann4, Maryanne O'Donnell5, Cherrie Galletly6, Andrew Lloyd7, Dennis Liu8, Rhoshel Lenroot3, Thomas W Weickert9, Cynthia Shannon Weickert10. 1. Psychiatric University Hospital Zurich, Zurich, Switzerland; Neuroscience Research Australia, Sydney, NSW, Australia. 2. Neuroscience Research Australia, Sydney, NSW, Australia. 3. Neuroscience Research Australia, Sydney, NSW, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. 4. Neuroscience Research Australia, Sydney, NSW, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Edith Collins Centre (Translational Research in Alcohol Drugs & Toxicology), Sydney Local Health District, Australia; Speciality of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Australia. 5. School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. 6. Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia; Northern Adelaide Local Health Network, Adelaide, South Australia, Australia; Ramsay Health Care (SA) Mental Health Services, Adelaide, South Australia, Australia. 7. Inflammation and Infection Research Centre, University of New South Wales, Sydney, Australia. 8. Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia; Northern Adelaide Local Health Network, Adelaide, South Australia, Australia. 9. Neuroscience Research Australia, Sydney, NSW, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA. 10. Neuroscience Research Australia, Sydney, NSW, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA. Electronic address: c.weickert@neura.edu.au.
Abstract
BACKGROUND: There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. METHOD: Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. RESULTS: There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. CONCLUSIONS: Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in healthy controls. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.
BACKGROUND: There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. METHOD: Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. RESULTS: There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. CONCLUSIONS: Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in healthy controls. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.
Authors: Federica Klaus; Tanya T Nguyen; Michael L Thomas; Sharon C Liou; Benchawanna Soontornniyomkij; Kyle Mitchell; Rebecca Daly; Ashley N Sutherland; Dilip V Jeste; Lisa T Eyler Journal: Front Psychiatry Date: 2022-08-12 Impact factor: 5.435