Metabolic inflammation, brain age and cognitive functioning in short- and long-term clinical weight loss trials.
Authors
Affiliations (8)
Affiliations (8)
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, European Reference Network on Rare Endocrine Diseases (ENDO-ERN), 10117, Berlin, Germany; Pituitary Tumor Center of Excellence at Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany. Electronic address: [email protected].
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, European Reference Network on Rare Endocrine Diseases (ENDO-ERN), 10117, Berlin, Germany; Pituitary Tumor Center of Excellence at Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, European Reference Network on Rare Endocrine Diseases (ENDO-ERN), 10117, Berlin, Germany; Pituitary Tumor Center of Excellence at Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany; Cambridge Endocrine Molecular Imaging Group, Institute of Metabolic Science, University of Cambridge, National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
- Department of Neurology, University Medicine Greifswald, Greifswald, 17475, Germany.
- Experimental and Clinical Research Center, A Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Lindenberger Weg 80, 13125, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Cluster of Excellence NeuroCure, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center, 10117, Berlin, Germany; Bernstein Center for Computational Neuroscience and Berlin Center for Advanced Neuroimaging and Clinic for Neurology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Philippstraße 13, Haus 6, 10115, Germany.
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, European Reference Network on Rare Endocrine Diseases (ENDO-ERN), 10117, Berlin, Germany.
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, European Reference Network on Rare Endocrine Diseases (ENDO-ERN), 10117, Berlin, Germany; Department of Human Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.
- Experimental and Clinical Research Center, A Cooperation between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin Berlin, Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental and Clinical Research Center, Lindenberger Weg 80, 13125, Berlin, Germany; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Electronic address: [email protected].
Abstract
Observational studies suggest that metabolic inflammation in obesity can impair brain health, but studies on beneficial effects of weight loss-induced improvements in such markers on brain health and their consequences for clinical outcomes are scarce. Consequently, we investigated 53 obese participants in a short-term dietary weight loss trial (up to 4 months, 137 samples; "Muscle Metabolism Study" or "MMS") and 30 in an independent long-term trial (up to 39 months, 100 samples; "Maintain"). For each participant and visit, brain health was characterised in terms of the "brain-predicted age difference" ("brain-PAD"; the difference of the age of a person predicted with machine learning from structural brain MRI minus their chronological age). Increasingly positive brain-PAD scores indicate increasingly poorer brain health. Further, we determined the HOMA index, leptin, fetuin B and CRP levels as markers collectively reflecting low-grade inflammation and impaired metabolic signalling. Finally, we evaluated the relevance of these parameters for brain-PAD and the association of brain-PAD alterations for cognition, which was measured in the MMS with neuropsychological tests. Weight loss led to improved brain-PAD scores (MMS: t = -2.02, p = 0.023, effect size partial η<sup>2</sup> (η<sup>2</sup><sub>p</sub>) = 0.03; Maintain: t = -7.37, p = 4.2·10<sup>-11</sup>, η<sup>2</sup><sub>p</sub> = 0.38). According to a False Discovery Rate (FDR) method-corrected threshold (α<sub>FDR</sub> = 0.05), HOMA index (MMS: t = 2.28, p<sub>FDR</sub> = 0.024, η<sup>2</sup><sub>p</sub> = 0.04; Maintain: t = 2.33, p<sub>FDR</sub> = 0.023, η<sup>2</sup><sub>p</sub> = 0.08), and leptin (MMS: t = 4.43, p<sub>FDR</sub> = 4.3·10<sup>-5</sup>, η<sup>2</sup><sub>p</sub> = 0.14; Maintain: t = 1.91, p<sub>FDR</sub> = 0.041, η<sup>2</sup><sub>p</sub> = 0.06), showed significant positive links to brain-PAD in both trials, fetuin B did so in Maintain (t = 2.57, p<sub>FDR</sub> = 0.023, η<sup>2</sup><sub>p</sub> = 0.11). Brain-PAD variations were associated with a neuropsychological test of psychomotor speed and visual attention (t = 2.32, p<sub>FDR</sub> = 0.022, η<sup>2</sup><sub>p</sub> = 0.05). Application of explainable artificial intelligence methods showed that this link was parallelled by widespread brain age-related tissue alterations in white and grey matter involved in these functions. Analyses of two independent weight loss trials suggest that weight loss-induced improvements in metabolic-inflammatory markers have beneficial effects on brain-PAD and the latter were associated with enhancements in cognitive functioning, underscoring the potential clinical relevance of metabolic brain age regulation. German Research Foundation; German Ministry for Education and Research, Berlin Institute of Health; German Centre for Cardiovascular Research; German Center for Diabetes Research.