TY - JOUR
T1 - Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin
AU - Mansur, Rodrigo B.
AU - Delgado-Peraza, Francheska
AU - Subramaniapillai, Mehala
AU - Lee, Yena
AU - Iacobucci, Michelle
AU - Nasri, Flora
AU - Rodrigues, Nelson
AU - Rosenblat, Joshua D.
AU - Brietzke, Elisa
AU - Cosgrove, Victoria E.
AU - Kramer, Nicole E.
AU - Suppes, Trisha
AU - Raison, Charles L.
AU - Fagiolini, Andrea
AU - Rasgon, Natalie
AU - Chawla, Sahil
AU - Nogueras-Ortiz, Carlos
AU - Kapogiannis, Dimitrios
AU - McIntyre, Roger S.
N1 - Funding Information:
Dr Mansur reported receiving funding from the Academic Scholar Awards, Department of Psychiatry, University of Toronto , outside the submitted work. Dr McIntyre reported receiving grants from Stanley Medical Research Institute during the conduct of the study; receiving grants from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation outside the submitted work; and receiving speaking/consultation fees from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, and Minerva outside the submitted work. Ms Subramaniapillai reported receiving grants from Stanley Medical Research Institute during the conduct of the study. Dr Brietzke reported receiving personal fees from Daiichi Sankyo and Lundbeck and receiving grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, São Paulo Research Foundation, Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES), Southeastern Ontario Academic Medical Organization, Queen’s University School of Medicine and L’Oreal forWomen in Science Award outside the submitted work. Dr Suppes reported in the last 36 months receiving grants from Stanley Medical Research Institute during the conduct of the study and from the National Institute on Drug Abuse, the National Institutes of Health, National Institute of Mental Health, Palo Alto Health Sciences, Pathway Genomics, and VA Cooperative Studies Program; receiving personal and nonfinancial support from CMEology, Global Medical Education, and Sunovion Pharmaceuticals Inc; and receiving personal fees from Allergan Inc, Hogrefe Publishing, Jones and Bartlett, Medscape Education, and UpToDate. Dr. Raison is director of Clinical and Translational Research for Usona Institute and serves as a consultant to Usona Institute, Emory Healthcare, Alkermes and Novartis, outside the submitted work. Dr. Fagiolini is /has been a consultant and/or a speaker and/or has received research grants from Allergan, Angelini, Apsen, Boheringer Ingelheim, Daiichi Sankyo Brasil Farmacêutica, Doc Generici, FB-Health, Italfarmaco, Janssen, Lundbeck, Mylan, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, Vifor, outside the submitted work. The remaining authors declare no conflicts of interest.
Funding Information:
This study was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health .
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.
AB - Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.
KW - Bipolar disorders
KW - Cognition
KW - Extracellular vesicles
KW - Inflammation
KW - Insulin
KW - TNF-α
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U2 - 10.1016/j.jpsychires.2020.12.007
DO - 10.1016/j.jpsychires.2020.12.007
M3 - Article
C2 - 33316649
AN - SCOPUS:85097452724
VL - 133
SP - 82
EP - 92
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
SN - 0022-3956
ER -