Abstract
Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I 2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.
| Original language | English |
|---|---|
| Pages (from-to) | 1201-1209 |
| Number of pages | 9 |
| Journal | Molecular Psychiatry |
| Volume | 28 |
| Issue number | 3 |
| Early online date | 9 Dec 2022 |
| DOIs | |
| Publication status | Published - 31 Mar 2023 |
Bibliographical note
Funding Information:The ENIGMA Schizophrenia Working Group acknowledges the National Institutes of Health (NIH) Big Data to Knowledge (BD2K) award for foundational support and consortium development (Grant No. U54 EB020403 to PMT). For a complete list of ENIGMA-related grant support please see here: http://enigma.ini.usc.edu/about-2/funding/. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of NIH. CC was supported by grant MR/N0137941/1 for the GW4 BIOMED Doctoral Training Partnership awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/ UK Research & Innovation (UKRI). JHC was supported by a UKRI Innovation Fellowship (MR/R024790/2). LE was supported by Desert-Pacific Mental Illness Research Education and Clinical Center, US, NIH grant R01MH083968-05. TH was funded by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4 to TH). LH was supported by a Rubicon fellowship (grant number 452020227) provided by The Dutch Research Council (NWO). NJ and LS were supported by NIH grant R01 MH117601. NJ was also supported by NIH grants R01AG059874, R01MH11760. LS was also supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship (1140764) and a University of Melbourne Dame Kate Campbell fellowship. PMT was supported in part by NIH grant R01 MH116147. EW was supported by the European Union Horizon 2020 research and innovation programme (EarlyCause, grant number 848158). Acknowledgements for the various participating data contributors follow - ASRB: the Australian Schizophrenia Research Bank (ASRB) was supported by NHMRC (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief Investigators for ASRB were Carr, V., Schall, U., Scott, R., Jablensky, A., Mowry, B., Michie, P., Catts, S., Henskens, F., Pantelis, C. We thank Loughland, C., the ASRB Manager, and acknowledge the help of Jason Bridge for ASRB database queries. CP was also supported by a NHMRC Senior Principal Research Fellowship (1105825), an NHMRC L3 Investigator Grant (1196508). CSW was funded by the NSW Ministry of Health, Office of Health and Medical Research and a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). CAMH: the datasets were generated and shared with support from the CAMH Foundation and the Canadian Institutes of Health Research. CASSI: this study was supported by NHMRC grant 568807 (awarded to CSW and TW). CSW was funded by the NSW Ministry of Health, Office of Health and Medical Research and a recipient of a NHMRC (Australia) Principal Research Fellowship (PRF) (#1117079). COBRE: the study and investigators were supported by NIH grants R01MH118695, R01MH121101, as well as National Science Foundation (NSF) grant 2112455 (awarded to VC). JT (senior author) was supported by NIH grant R01MH121246. EONCKS: all processing of contributed neuroimaging data was conducted on the Centre for High Performance Computing, Cape Town, South Africa. ESO: the study and investigators (AC, FS, DT) was funded by the Ministry of Health, Czech Republic - Conceptual Development of Research Organization (Institute for Clinical and Experimental Medicine – IKEM, IN 00023001), and Ministry of Health of the Czech Republic, grants nr. NU20-04-00393 and NU21-08-00432. FBIRN: The study was supported by National Institutes of Health grant numbers: NIH 1 U24 RR021992 (Function Biomedical Informatics Research Network), NIH 1 U24 RR025736 (Biomedical Informatics Research Network Coordinating). FBIRN data was processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the NCRR and the National Center for Advancing Translational Sciences. JT (senior author) was also supported by NIH grant R01MH121246. FIDMAG: this study was supported by Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and the Catalonian Government, Generalitat de Catalunya (2017-SGR-1271 to EP-C from AGAUR). PFC was supported by a Sara Borrell contract (CD19/00149), funded by Instituto de Salud Carlos III, co-funded by the European Union (European Regional Development Fund/European Social Fund [ERDF/ESF], “Investing in your future”). FSLRome: the IRCCS Santa Lucia Foundation of Rome study (FSLRome) was partially supported by the Italian Ministry of Health (RC12-13-14-15A Grant) and by the European Commission ERA-Net NEURON joint transnational calI 2010 (European Research Projects on Mental Disorders: NEUCONNECT). GROUP: This work was supported by the Geestkracht program of the Dutch Health Research Council (ZON-MW, grant number: 10-000-1002), and the European Community’s Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). Huilong: this study was funded by the National Natural Science Foundation of China (81761128021;31671145;81401115;81401133), Beijing Municipal Science & Technology Commission grant (Z141107002514016) and Beijing Natural Science Foundation (7162087, Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding (XMLX201609; zylx201409). IGP: The Imaging Genetics in Psychosis (IGP) study was supported by NHMRC Project Grant APP630471, APP1051673, APP1081603 (awarded to MJG), and the Macquarie University’s ARC Centre of Excellence in Cognition and its Disorders (CE110001021). MJG was supported by an Australian Research Council Future Fellowship (FT0991511; 2009-13) and a R.D. Wright Biomedical Career Development Award from the NHMRC (1061875; 2014-17). IMH: this study was supported by the National Healthcare Group, Singapore (SIG/05004; SIG/05028) and the Singapore Bioimaging Consortium (RP C009/06) research grants (awarded to KS). iRELATE: this study was supported by grants to GD from the European Research Council (ERC-2015-STG-677467) and Science Foundation Ireland (SFI-16/ERCS/3787). JBNU: YC was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI18C2383). Madrid: this research was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (grants SAM16PE07CP1, PI16/02012, and PI19/01024 awarded to CAra; PI17/01249 awarded JJ; and PI17/00481, JR19/00024 and PI20/00721 awarded to CMD-C), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM; Madrid Regional Government (B2017/BMD-3740 AGES-CM-2 awarded to CAra), European Union Structural Funds; European Union Seventh Framework Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7- HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN) and FP7- HEALTH-2013-2.2.1-2-602478 (Project METSY) awarded to Cara; and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS awarded to CAra), Fundación Familia Alonso and Fundación Alicia Koplowitz. MCIC: this work was primarily supported by the Department of Energy (DE-FG02- 99ER62764) and the Mind Research Network. VC was also supported by NSF (grant no. 2112455) and NIH (grant no. R01MH118695, R01MH121101). MPRC: support was received from NIH grants R01MH123163, R01EB015611, R01NS114628 (awarded to PK). PAFIP: this study has been funded by Instituto de Salud Carlos III through the project PI17/01056 (co-funded by ERDF/ESF “A way to make Europe”/“Investing in your future”). RSCZ: the study was supported by National Institutes of Health grant number: NIMH R21MH097196 to TGMvE. SCORE: this study was supported in part by grant 3232BO_119382 from the Swiss National Science Foundation. We thank the FePsy (Frueherkennung von Psychosen; early detection of psychosis) Study Group from the University of Basel, Department of Psychiatry, Switzerland, for the recruitment of the study participants. The FePsy study was supported in part by grant No. SNF 3200-057216/1, ext./2, ext./3. SNUH: this research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and by the KBRI Basic Research Program through the Korea Brain Research Institute, funded by the Ministry of Science & ICT, funded by the Ministry of Science & ICT (Grant no. 2020M3E5D9079910 and 21-BR-03-01 awarded to JSK; 2019R1C1C1002457 and 21-BR-03-01 awarded to MK). UNIBA: this study was supported by grant funding from the Italian Ministry of Health (PE-2011-02347951). PS was supported by a PhD studentship jointly funded by the NIHR-BRC at SLaM and the Department of Neuroimaging, King’s College London. Zurich: this study was supported by the Swiss National Science Foundation (SNSF; grant no. 105314_140351 and 10001CL_169783 to SK). MK acknowledges funding from SNSF (grant no. P2SKP3_178175).
