PMID- 38508346 OWN - NLM STAT- MEDLINE DCOM- 20240410 LR - 20240410 IS - 1090-2139 (Electronic) IS - 0889-1591 (Linking) VI - 118 DP - 2024 May TI - A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives. PG - 449-458 LID - S0889-1591(24)00310-6 [pii] LID - 10.1016/j.bbi.2024.03.029 [doi] AB - AIMS: Substantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. METHODS: In a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. RESULTS: Compared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12-1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09-1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04-1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02-1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC. Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75-0.77) CONCLUSIONS: Higher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD. CI - Copyright (c) 2024. Published by Elsevier Inc. FAU - Coello, Klara AU - Coello K AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark. Electronic address: klara.coello@regionh.dk. FAU - Holstad Pedersen, Helle AU - Holstad Pedersen H AD - Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark. FAU - Munkholm, Klaus AU - Munkholm K AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. FAU - Lie Kjaerstad, Hanne AU - Lie Kjaerstad H AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark. FAU - Stanislaus, Sharleny AU - Stanislaus S AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark. FAU - Rye Ostrowski, Sisse AU - Rye Ostrowski S AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Faurholt-Jepsen, Maria AU - Faurholt-Jepsen M AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. FAU - Miskowiak, Kamilla Woznica AU - Miskowiak KW AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. FAU - Frikke-Schmidt, Ruth AU - Frikke-Schmidt R AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Vinberg, Maj AU - Vinberg M AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; The Early Multimodular Prevention and Intervention Research Institution (EMPIRI), Mental Health Centre, Northern Zealand, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark. FAU - Thorn Ekstrom, Claus AU - Thorn Ekstrom C AD - Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark. FAU - Lyng Forman, Julie AU - Lyng Forman J AD - Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark. FAU - Vedel Kessing, Lars AU - Vedel Kessing L AD - Copenhagen University Hospital Frederiksberg, Frederiksberg, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. LA - eng PT - Journal Article DEP - 20240319 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 RN - 130068-27-8 (Interleukin-10) RN - 0 (Interleukin-6) RN - 0 (Anti-Inflammatory Agents) SB - IM MH - Humans MH - *Bipolar Disorder MH - Interleukin-10 MH - Interleukin-6 MH - Case-Control Studies MH - Anti-Inflammatory Agents OTO - NOTNLM OT - Bipolar Disorder OT - Immune dysregulation OT - Immune markers OT - Inflammation OT - Newly Diagnosed OT - Unaffected Relatives OT - Vascular stress COIS- Declaration of Competing Interest KC, HHP, JLF, KM, SS, MFJ, HLK, RFS, CTE, SRO and KMW declare no conflicts of interest. MV discloses within the last three years consultancy fees from Lundbeck and Janssen Cilag. LVK has within the preceding three years been a consultant for Lundbeck and Teva. EDAT- 2024/03/21 00:43 MHDA- 2024/04/10 06:43 CRDT- 2024/03/20 20:26 PHST- 2023/10/24 00:00 [received] PHST- 2024/02/15 00:00 [revised] PHST- 2024/03/17 00:00 [accepted] PHST- 2024/04/10 06:43 [medline] PHST- 2024/03/21 00:43 [pubmed] PHST- 2024/03/20 20:26 [entrez] AID - S0889-1591(24)00310-6 [pii] AID - 10.1016/j.bbi.2024.03.029 [doi] PST - ppublish SO - Brain Behav Immun. 2024 May;118:449-458. doi: 10.1016/j.bbi.2024.03.029. Epub 2024 Mar 19.