Age-dependent structural brain aging in medication-free major depressive disorder: A multi-site analysis from COORDINATE-MDD consortium.
Authors
Affiliations (37)
Affiliations (37)
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada; Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Imaging Research Centre, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada; Child Health & Exercise Medicine Program, McMaster University, Hamilton, ON, Canada.
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada; Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
- Department of Psychology, University of East London, London, UK; School of Childhood and Social Care, University of East London, London, UK.
- Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Centre for Affective Disorders, Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 8AF, UK; College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, United Arab Emirates; Division of Psychiatry, Department of Brain Sciences, Imperial College London, Burlington Danes, The Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
- Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada.
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institute of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, Sichuan, China; Xiamen Key Laboratory of Psychoradiology and Neuromodulation, Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian, China.
- Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Centre for Depression & Suicide Studies, St. Michael's Hospital, Unity Health Toronto; Department of Psychiatry, University of Toronto.
- Department of Psychiatry, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Psychology, University of East London, London, UK.
- Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
- Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, Alberta, Canada; Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Department of Psychiatry, University Health Network, Toronto, Ontario, Canada.
- Division of Psychiatry, Centre for Clinical Brain Sciences, Royal Infirmary Edinburgh, UK.
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institute of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, Sichuan, China; Xiamen Key Laboratory of Psychoradiology and Neuromodulation, Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian, China; Department of Radiology, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
- Department of Psychiatry, University Health Network, Toronto, Ontario, Canada; Centre for Depression and Suicide Studies, Unity Health Toronto, Toronto, Ontario, Canada.
- Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Laureate Institute for Brain Research, Tulsa, OK, USA.
- Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Statistics in Imaging and Visualization Endeavor (PennSIVE) Center, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA.
- Neurobiology Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Psychiatry, Psychiatric Centre Copenhagen, Copenhagen, Denmark.
- Neurobiology Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Computer Science, University of Copenhagen, Copenhagen, Denmark.
- Department of Psychiatry, University of California San Francisco, San Francisco, USA.
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
- School of Psychology, Southwest University, Chongqing, China.
- Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK.
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; Department of Psychology, Emory University, Atlanta, GA, USA.
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
- Department of Psychology, Stanford University, Stanford, CA, USA.
- Department of Psychiatry, University of Oxford, Oxford, UK.
- Division of Psychiatry, Centre for Clinical Brain Sciences, Royal Infirmary Edinburgh, UK; Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Neurobiology Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Division of Psychiatry, Centre for Clinical Brain Sciences, Royal Infirmary Edinburgh, UK; Generation Scotland, Centre for Medical Informatics, University of Edinburgh, UK.
- Department of Psychological and Cognitive Sciences, Tsinghua University, Beijing, China.
- Department of Psychiatry, Imperial College London, London, UK.
- Department of Psychology, University of East London, London, UK; Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; National Institute for Health and Care Research (NIHR), Maudsley Biomedical Research Centre (BRC), London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada; Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada. Electronic address: [email protected].
Abstract
Major depressive disorder (MDD) is associated with altered brain structure and accelerated brain aging. However, previous studies have been limited by clinical samples with mixed medication status and multiple mood states, modest sample sizes, underrepresentation of older adults with MDD, and/or reliance on summary-level data. Harmonized T1-weighted MRI from MDD (n = 645), all medication-free and in a current depressive episode, and matched healthy controls (n = 645), segmented into 145 regional volumes, from 11 sites in COORDINATE-MDD consortium. Brain age gap (BAG) was estimated cross-sectionally using gradient boosting regression with nested cross-validation. Group differences in BAG (and age-corrected BAG [cBAG]) were examined across age strata. Regional contributions were evaluated using SHAP values. MDD was associated with significantly elevated cBAG compared with healthy controls (mean difference + 2.0 years [95% CI 1.251, 2.774], Cohen's d -0.289 [95% CI -0.399, -0.179]). Age-stratified analyses showed no differences before mid-30s, with progressively larger gaps thereafter, reaching +6.8 years in MDD aged 55 and older in unadjusted analyses (4.3 years after accounting for site). cBAG differed across neuroanatomical phenotypes previously identified using COORDINATE-MDD data. Key contributing regions included lateral and medial prefrontal regions, middle temporal gyrus, putamen, supplementary motor cortex, central operculum, and cerebellum. Structural brain aging in MDD is age-dependent and most pronounced in a neuroanatomical phenotype associated with poorer key clinical outcomes. The findings are consistent with, but do not establish, neuroprogression models of MDD and demonstrate that cBAG is not a uniform feature of MDD, being more strongly expressed in a specifically clinically vulnerable disease phenotype.