Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity

Paris Alexandros Lalousis; Lianne Schmaal; Stephen J Wood; Renate L E P Reniers; Vanessa L Cropley; Andrew Watson; Christos Pantelis; John Suckling; Nicholas M Barnes; Carmine Pariante; Peter B Jones; Eileen Joyce; Thomas R E Barnes; Stephen M Lawrie; Nusrat Husain; Paola Dazzan; Bill Deakin; Cynthia Shannon Weickert; Rachel Upthegrove

doi:10.1016/j.bbi.2023.06.023

Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity

Brain Behav Immun. 2023 Oct:113:166-175. doi: 10.1016/j.bbi.2023.06.023. Epub 2023 Jul 7.

Authors

Paris Alexandros Lalousis¹, Lianne Schmaal², Stephen J Wood³, Renate L E P Reniers⁴, Vanessa L Cropley⁵, Andrew Watson⁶, Christos Pantelis⁷, John Suckling⁸, Nicholas M Barnes⁹, Carmine Pariante¹⁰, Peter B Jones⁸, Eileen Joyce⁶, Thomas R E Barnes¹¹, Stephen M Lawrie¹², Nusrat Husain¹³, Paola Dazzan¹⁴, Bill Deakin¹⁵, Cynthia Shannon Weickert¹⁶, Rachel Upthegrove¹⁷

Affiliations

¹ Institute for Mental Health, University of Birmingham, Birmingham, United Kingdom; Centre for Human Brain Health, University of Birmingham, Birmingham, United Kingdom; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. Electronic address: paris.lalousis@kcl.ac.uk.
² Orygen, Parkville, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Australia.
³ Institute for Mental Health, University of Birmingham, Birmingham, United Kingdom; Orygen, Parkville, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Australia.
⁴ Institute for Mental Health, University of Birmingham, Birmingham, United Kingdom; Centre for Human Brain Health, University of Birmingham, Birmingham, United Kingdom; Institute of Clinical Sciences, University of Birmingham, United Kingdom.
⁵ Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, Australia.
⁶ The Department of Clinical and Motor Neuroscience, UCL Queen Square Institute of Neurology, London, United Kingdom.
⁷ Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, Australia; NorthWestern Mental Health, Western Hospital Sunshine, St. Albans, Vicroria, Australia.
⁸ Brain Mapping Unit, Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, University of Cambridge, United Kingdom; Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, United Kingdom.
⁹ Institute for Clinical Sciences, University of Birmingham, Birmingham, United Kingdom.
¹⁰ Stress, Psychiatry and Immunology Lab & Perinatal Psychiatry, The Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom.
¹¹ Division of Psychiatry, Imperial College London, London United Kingdom.
¹² Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
¹³ Division of Psychology and Mental Health, University of Manchester & Mersey Care NHS Foundation Trust.
¹⁴ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
¹⁵ Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, United Kingdom.
¹⁶ Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA; Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
¹⁷ Institute for Mental Health, University of Birmingham, Birmingham, United Kingdom; Centre for Human Brain Health, University of Birmingham, Birmingham, United Kingdom; Birmingham Early Interventions Service, Birmingham Women's and Children's NHS Foundation Trust, United Kingdom.

PMID: 37423513
DOI: 10.1016/j.bbi.2023.06.023

Abstract

Objective: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles.

Methods: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups.

Results: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset.

Conclusions: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.

Keywords: Inflammation; MRI; Machine learning; Schizophrenia.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Brain / diagnostic imaging
Gray Matter
Humans
Interleukin-6
Interleukin-8
Magnetic Resonance Imaging
Schizophrenia*
Supervised Machine Learning

Substances

Interleukin-6
Interleukin-8

Abstract

Publication types

MeSH terms

Substances

Grants and funding