Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin

Rodrigo B Mansur; Francheska Delgado-Peraza; Mehala Subramaniapillai; Yena Lee; Michelle Iacobucci; Flora Nasri; Nelson Rodrigues; Joshua D Rosenblat; Elisa Brietzke; Victoria E Cosgrove; Nicole E Kramer; Trisha Suppes; Charles L Raison; Andrea Fagiolini; Natalie Rasgon; Sahil Chawla; Carlos Nogueras-Ortiz; Dimitrios Kapogiannis; Roger S McIntyre

doi:10.1016/j.jpsychires.2020.12.007

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin

J Psychiatr Res. 2021 Jan:133:82-92. doi: 10.1016/j.jpsychires.2020.12.007. Epub 2020 Dec 4.

Authors

Rodrigo B Mansur¹, Francheska Delgado-Peraza², Mehala Subramaniapillai³, Yena Lee⁴, Michelle Iacobucci³, Flora Nasri³, Nelson Rodrigues³, Joshua D Rosenblat¹, Elisa Brietzke⁵, Victoria E Cosgrove⁶, Nicole E Kramer⁶, Trisha Suppes⁶, Charles L Raison⁷, Andrea Fagiolini⁸, Natalie Rasgon⁹, Sahil Chawla², Carlos Nogueras-Ortiz², Dimitrios Kapogiannis¹⁰, Roger S McIntyre¹¹

Affiliations

¹ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
² Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD, USA.
³ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
⁴ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁵ Kingston General Hospital, Providence Care Hospital, Department of Psychiatry, Queen's University School of Medicine, Kingston, ON, Canada.
⁶ Department of Psychiatry & Behavioral Sciences, Stanford University, School of Medicine, and Veterans Affairs Health Care System, Palo Alto, CA, USA.
⁷ School of Human Ecology, University of Wisconsin-Madison, Madison, WI, USA; Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁸ Department of Molecular Medicine, University of Siena, Italy.
⁹ Center for Neuroscience in Women's Health, Stanford University, Palo Alto, USA.
¹⁰ Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD, USA. Electronic address: kapogiannisd@mail.nih.gov.
¹¹ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Abstract

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.

Keywords: Bipolar disorders; Cognition; Extracellular vesicles; Inflammation; Insulin; TNF-α.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Intramural

MeSH terms

Adult
Bipolar Disorder* / diagnostic imaging
Bipolar Disorder* / drug therapy
Bipolar Disorder* / metabolism
Brain / diagnostic imaging
Brain / metabolism
Extracellular Vesicles* / metabolism
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Insulin / metabolism
Insulin Resistance*
Phosphorylation

Substances

Insulin
Glycogen Synthase Kinase 3 beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding