Brain aging in bipolar disorder using a neuroimaging and machine learning-derived metric: Findings from the ENIGMA BD Working Group.
Authors
Affiliations (56)
Affiliations (56)
- Department of Cognitive Science, University of California San Diego, USA; Department of Psychiatry, Jena University Hospital/Friedrich-Schiller-University Jena, Jena, Germany; Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Sweden; Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany; German Center for Mental Health (DZPG), Site Jena-Magdeburg-Halle, Germany; Quantify Research, Stockholm, Sweden; Department of Psychiatry, University of São Paulo Medical School, Brazil.
- Department of Clinical Neuroscience, Karolinska Institutet, Sweden.
- Department of Psychiatry, Dalhousie University, Canada.
- FIDMAG Germanes Hospitalàries Research Foundation, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain.
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain; Bipolar and Depressive Disorders Unit, Institute of Neurosciences, Hospital Clinic, Barcelona, Spain; University of Barcelona, Spain.
- University of Münster, Department of Clinical Radiology, Germany.
- University of Münster, Institute for Translational Psychiatry, Germany.
- Department of Psychiatry and Psychotherapy, University of Marburg, Germany; Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
- Laboratory of Psychiatric Neuroimaging (LIM-21), Departamento e Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil.
- Psychosomatic and CL Psychiatry, Clinic for Mental Health and Addiction, Oslo University Hospital, Norway.
- FIDMAG Germanes Hospitalàries Research Foundation, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain; Signal Processing Laboratory (LTS5), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
- Clinical Neuroimaging Laboratory, Center for Neuroimaging, Cognition & Genomics (NICOG), Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, University of Galway, Galway, Ireland.
- Centre for Medical Image Computing, Department of Computer Science, University College London, United Kingdom of Great Britain and Northern Ireland; Dementia Research Centre, Queen Square Institute of Neurology, University College London, United Kingdom of Great Britain and Northern Ireland.
- Department of Psychology, San Diego State University, USA.
- Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University Hospital, Germany.
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Norway; Department of Neurology, Oslo University Hospital, Norway; Department of Behavioural Medicine, Institute of Basic Medical Sciences, University of Oslo, Norway.
- CEA, UNIACT, Psychiatry Team, Neurospin, France.
- CUBRIC, Cardiff University, United Kingdom of Great Britain and Northern Ireland.
- Neuroscience Research Australia, Sydney, NSW, Australia; School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
- Department of Psychiatry, University Medical Center Groningen, University of Groningen, the Netherlands.
- Department of Psychiatry, Dalhousie University, Canada; National Institute of Mental Health Klecany, Czechia.
- Orygen, Parkville, VIC, Australia; Department of Psychiatry, Amsterdam University Medical Centers, Vrije Universiteit and GGZ inGeest, Amsterdam Neuroscience, Amsterdam, the Netherlands; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
- Université de Paris, Service Hospitalo-Universitaire, GHU Paris Psychiatrie & Neuroscience, France.
- CEA, UNIACT, Psychiatry Team, Neurospin, France; APHP, Mondor University Hospitals, INSERM U955 Translational Psychiatry Team, IMRB, France.
- Neuroscience Institute, University of Cape Town, South Africa; Department of Psychiatry and Mental Health, University of Cape Town, South Africa.
- Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
- Department of Psychiatry and Psychotherapy, University of Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), University of Marburg, Germany.
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden.
- Department of Psychiatry and Psychotherapy, University of Marburg, Germany; Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.
- Laureate Institute for Brain Research, USA.
- Department of Psychiatry, University of São Paulo Medical School, Brazil.
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- UTHealth Bipolar Disorder Program, Department of Psychiatry and Behavioral Sciences, University of Texas, Houston, TX, USA; Department of Psychiatry, University of Sao Paulo, Brazil.
- Department of Behavioural Medicine, Institute of Basic Medical Sciences, University of Oslo, Norway.
- University of Münster, Institute for Translational Psychiatry, Germany; University of Münster, Institute for Translational Neuroscience, Germany.
- Discipline of Psychiatry & Mental Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
- Center Of Excellence On Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, USA.
- University of Münster, Institute for Translational Psychiatry, Germany; Department of Psychiatry, Jena University Hospital/Friedrich-Schiller-University Jena, Jena, Germany.
- LIM44, Departamento e Instituto de Radiologia, Faculdade de Medicina, Universidade de São Paulo, Brazil.
- Neuroscience Research Australia, Sydney, NSW, Australia.
- Psychiatry Department, University Hospital of Grenoble, 38000, Grenoble, France; INSERM U1216, Grenoble Institut des Neurosciences, 38000, Grenoble, France; Univ. Grenoble Alpes, France.
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain; University of Barcelona, Spain; Early Psychosis: Interventions and Clinical-detection (EPIC) lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, United Kingdom of Great Britain and Northern Ireland.
- University of Münster, Institute for Translational Psychiatry, Germany; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt - Goethe University, Frankfurt am Main, Germany.
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, USA.
- Laureate Institute for Brain Research, USA; Oxley College of Health Sciences, The University of Tulsa, USA.
- Orygen, Parkville, VIC, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
- West Region, Institute of Mental Health, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
- Neuroscience Institute, University of Cape Town, South Africa; Department of Psychiatry and Mental Health, University of Cape Town, South Africa; SAMRC Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry & Neuroscience Institute, University of Cape Town, South Africa.
- Department of Psychiatry, University of California San Diego, USA.
- Department of Psychiatry and Mental Health, University of Cape Town, South Africa; Therapeutic and Intermediate Service, Valkenberg Hospital, South Africa.
- Department of Psychiatry and Mental Health, University of Cape Town, South Africa; Department of Child and Adolescent Psychiatry and Psychotherapy, TU Dresden, Germany.
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain; University of Barcelona, Spain.
- Laboratory of Psychiatric Neuroimaging (LIM-21), Departamento e Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Brazil; Hospital Sírio-Libanês, São Paulo, Brazil.
- Department of Psychiatry, Amsterdam University Medical Centers, the Netherlands.
- NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Norway.
- Department of Psychiatry, University of California San Diego, USA; Desert-Pacific Mental Illness Research, Education, and Clinical Center, VA San Diego Healthcare System, USA. Electronic address: [email protected].
Abstract
Bipolar disorder (BD) is associated with clinical and biological markers of premature aging. In this largest study of brain age in BD to date, with 2919 participants, we compared brain-predicted age difference (brain-PAD) in individuals with BD and healthy comparison (HC) participants. Brain-PAD is a machine learning-estimated metric that quantifies the difference between an individual's predicted brain age and their chronological age, a potential clinical bio-signature of premature brain aging. Within individuals with BD, we also examined how medication and clinical characteristics were related to brain-PAD. Age was predicted from 77 MRI measures of regional subcortical and lateral ventricle volumes, cortical thickness, and surface area for 1342 BD and 1577 HC adult participants, aged 18-75 yrs. old (μ = 37.2; SD = 12.3), from the curated ENIGMA Bipolar Disorder working group (ENIGMA-BD) and leveraging an ENIGMA machine learning model previously trained and validated using independent samples. Chronological age was subtracted from predicted age to produce an individual-level estimate known as brain-PAD. Linear mixed models (adjusting for sex and age as fixed effects and site as a random effect) were used to examine group differences and clinical associations. BD was associated with higher brain-PAD, compared to HC, primarily among older patients, as demonstrated by a significant age by diagnosis interaction (+0.05 [SE: 0.02] years). Individuals with BD on antiepileptic (AED) medications only (+3.20 [SE: 0.78] years) or on both AED and second-generation antipsychotics (SGA) (+3.74 [SE: 0.89] years) demonstrated greater brain-PAD compared to individuals who were not on any of the examined medications. Those taking lithium, whether alone or with AED and SGA independently, showed no difference in brain-PAD compared to individuals not taking any of the examined medications. However, individuals who were taking lithium showed lower brain-PAD compared to those on AED (-4.48 [SE: 0.84] years) or AED and SGA (-5.01 [SE:0.92] years). Individuals with a BD I subtype diagnosis had a higher brain-PAD (+1.50 [SE:0.55] years) compared to those with BDII or subtypes that are not otherwise specified (NOS). Results from this study suggest compounding effects of BD diagnosis and older age on brain-PAD, an ML-derived summary metric of structural alterations. Within BD, brain-PAD was differentially related to medication use, consistent with prior findings from ENIGMA-BD. Notably, AED use was generally related to more advanced brain age. Lithium use, alone or in combination with other medications, was not associated with advanced brain age, suggesting a possible neuroprotective effect of lithium. Brain-PAD as an ML-derived summary metric of structural alterations of the brain may provide clinical utility in assessing long-term holistic brain health to monitor the effectiveness of lifestyle modifications or treatments over time. The cross-sectional nature of the study design and the limited granularity of the clinical data limit interpretation. Longitudinal studies with detailed chronicity data, medications and clinical measures overtime will improve brain-PAD modeling in BD.