Monocyte and microglial activation in patients with mood-stabilized bipolar disorder

Monocyte and microglial activation in patients with mood-stabilized bipolar disorder

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J Psychiatry Neurosci 2015;40(4):250-258

Joel Jakobsson, PhD; Maria Bjerke, PhD; Sara Sahebi; Anniella Isgren, MD; Carl Johan Ekman, MD; Carl Sellgren, MD, PhD; Bob Olsson, PhD; Henrik Zetterberg, MD, PhD; Kaj Blennow, MD, PhD; Erik Pålsson, PhD; Mikael Landén, MD, PhD

Abstract

Background: Bipolar disorder is associated with medical comorbidities that have been linked to systemic inflammatory mechanisms. There is, however, limited evidence supporting a role of neuroinflammation in bipolar disorder. Here we tested whether microglial activation and associated tissue remodelling processes are related to bipolar disorder by analyzing markers in cerebrospinal fluid (CSF) and serum from patients and healthy controls.

Methods: Serum was sampled from euthymic patients with bipolar disorder and healthy controls, and CSF was sampled from a large subset of these individuals. The levels of monocyte chemoattractant protein-1 (MCP-1), YKL-40, soluble cluster of differentiation 14 (sCD14), tissue inhibitor of metalloproteinases-1 (TIMP-1) and tissue inhibitor of metalloproteinases-2 (TIMP-2), were measured, and we adjusted comparisons between patients and controls for confounding factors.

Results: We obtained serum samples from 221 patients and 112 controls and CSF samples from 125 patients and 87 controls. We found increased CSF levels of MCP-1 and YKL-40 and increased serum levels of sCD14 and YKL-40 in patients compared with controls; these differences remained after controlling for confounding factors, such as age, sex, smoking, blood–CSF barrier function, acute-phase proteins and body mass index. The CSF levels of MCP-1 and YKL-40 correlated with the serum levels, whereas the differences between patients and controls in CSF levels of MCP-1 and YKL-40 were independent of serum levels.

Limitations: The cross-sectional study design precludes conclusions about causality.

Conclusion: Our results suggest that both neuroinflammatory and systemic inflammatory processes are involved in the pathophysiology of bipolar disorder. Importantly, markers of immunological processes in the brain were independent of peripheral immunological activity.


Submitted July 8, 2014; Revised Oct. 8, 2014; Accepted Dec. 1, 2014; Early-released Mar. 17, 2015.

Acknowledgements: This research was supported by grants from the Swedish foundation for Strategic Research, the Swedish Medical Research Council (K2014-62X-14647-12-51 and K2010-61P-21568-01-4), the Swedish Brain foundation, the Swedish Federal Government under the LUA/ALF agreement (ALF 20130032, ALFGBG-142041), Märta Lundqvists stiftelse, Demensfonden, Tore Nilssons stiftelse, and Gun och Bertil Stohnes stiftelse. We thank Åsa Källén, Monica Christiansson, Lobna Almasalmeh, Sara Hullberg, and Dzemila Secic for excellent technical assistance, the St. Göran bipolar affective disorder unit, including coordinator Martina Wennberg, study nurses Agneta Carlswärd-Kjellin, Lena Lundberg, and Benita Gezelius, and data managers Haydeh Olofsson and Mathias Kardell. Yngve Hallström is acknowledged for performing lumbar punctures. Kristoffer Bäckman and Erik Joas are acknowledged for statistical support. We are also thankful to the patients and controls participating in this study.

Affiliations: From the Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (Jakobsson, Bjerke, Sahebi, Isgren, Olsson, Zetterberg, Blennow, Pålsson, Landén); Departments of Clinical Neuroscience (Ekman, Landén) and Medical Epidemiology and Biostatistics (Sellgren, Landén), Karolinska Institutet, Stockholm, Sweden; UCL Institute of Neurology, Queen Square, London, UK (Zetterberg).

Competing interests: C.-J. Ekman declares receiving lecture honoraria from Medivir AB outside the scope of the submitted work. K. Blennow has received personal fees and research support from Roche Diagnostics outside the scope of the submitted work. M. Landén declares personal fees received from Biophausia, Servier Sweden, AstraZeneca and Lundbeck outside the scope of the submitted work. No other competing interests declared.

Contributors: J. Jakobsson, M. Bjerke and M. Landén designed the study. J. Jakobsson, M. Bjerke, C.-J. Ekman, C. Sellgren, B. Olsson, H. Zetterberg, K. Blennow and M. Landén acquired the data, which J. Jakobsson, M. Bjerke, S. Sahebi, A. Isgren, B. Olsson, E. Pålsson, H. Zetterberg, K. Blennow and M. Landén analyzed. J. Jakobsson wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.140183

Correspondence to: Joel Jakobsson, Sahlgrenska University hospital, Blå Stråket 15, floor 3, SE-413 45 Gothenburg, Sweden; joel.jakobsson@neuro.gu.se