Full-length ArticleMarkers of neuroinflammation and neuronal injury in bipolar disorder: Relation to prospective clinical outcomes
Introduction
Bipolar disorder is a mood disorder characterized by recurrent episodes of elevated (mania or hypomania), depressed, or mixed mood (Belmaker, 2004). Several lines of evidence indicate that the neuroimmune system and neuroinflammation play a role in the pathophysiology of bipolar disorder (Rosenblat et al., 2014). Neuroinflammation is a wide concept involving central nervous system (CNS) innate immunological responses (O'Callaghan et al., 2008). Microglia, the resident innate immune cells of the CNS, are essential cellular mediators of neuroinflammation. Activated microglia produce cytokines and chemokines that impact synaptic plasticity, neurotransmitter metabolism, and neurocircuits relevant to mood regulation (McAfoose and Baune, 2009, Beumer et al., 2012, Haroon et al., 2012, Kraneveld et al., 2014). Another important cell type in the neuroimmune system is astrocytes, which are considered being regulators of neuroinflammatory processes and may promote or inhibit neuronal damage and inflammation depending on the kind of stimuli present in the inflamed milieu (Cekanaviciute and Buckwalter, 2016, Colombo and Farina, 2016).
Interestingly, cross-sectional studies have found associations of peripheral markers of neuroinflammation or neuronal injury with brain imaging findings and clinical features. Thus, a recent bipolar disorder study found that the serum concentrations of TNF-α, IL-8, IFN-γ, and IL-10 were associated with structural connectivity in cortico-limbic networks (Benedetti et al., 2016). Another study reported a possible relationship between pro-inflammatory gene expression and manic symptoms (Haarman et al., 2014).
But even though many studies have demonstrated peripheral inflammation in psychiatric disorders, this is not tantamount to neuroinflammation or microglial activation in the CNS (Bhattacharya et al., 2016). This is because the serum or plasma concentrations of cytokines and other proteins differ from the respective CSF (cerebrospinal fluid) concentrations due to the relative impermeability of the blood–CSF barrier (Maier et al., 2005, Bromander et al., 2012, Isgren et al., 2015). Thus, altered concentrations of CSF proteins might be more sensitive and specific to CNS processes than equivalent blood alterations. We have in previous studies found higher CSF concentrations of some markers of neuroinflammation, glial activation and neuronal injury in patients with bipolar disorder compared with control subjects. In one of these studies we found higher CSF concentrations of interleukin-8 (IL-8) in euthymic patients with bipolar disorder compared with controls, with a strong association to lithium- and antipsychotic treatment (Isgren et al., 2015). In a second study, we found increased CSF concentrations of two markers of monocyte and glial activation in patients with bipolar disorder: monocyte chemoattractant protein 1 (MCP-1; also known as CCL-2) and chitinase-3-like protein 1 (CHI3L1; also known as YKL-40) (Jakobsson et al., 2015). Finally, we have investigated CSF markers reflecting damages in brain cells and subcellular structures in patients with bipolar disorder compared with controls. We found higher levels of neurofilament light chain (NF-L; a marker of axonal damage) in patients, as well as a positive association to treatment with atypical antipsychotic drugs (Jakobsson et al., 2014).
The implications of our previous findings are, however, not yet clear. The question remains open if neuroinflammation is associated with disease progression, since prospective studies of neuroinflammation and clinical outcomes are lacking (Barbosa et al., 2014). The aim of this study was thus to investigate if CSF markers of neuroinflammation and neuronal injury in patients with bipolar disorder predict important clinical outcomes during a 6–7 year follow-up period.
Section snippets
Study population
Patients with bipolar disorder who had underwent clinical characterization and lumbar puncture at baseline, as well as completed a clinical 6–7 year follow-up were eligible for this study (N = 77). The baseline work-up procedures have been described in detail previously (Ryden et al., 2009). Patients were included in the St. Göran Bipolar Project, enrolling patients from the Northern Stockholm psychiatric clinic, Stockholm, Sweden, between October 2005 and April 2008. Inclusion criteria were age
Demographics
Demographic and clinical characteristics of the study population are presented in Table 1. The clinical data from the follow-up refers to clinical events that had occurred between baseline and the 6–7 year follow-up. At baseline, all patients undergoing lumbar puncture were euthymic as judged by a physician. The results from the MADRS and YMRS assessments at the time of lumbar puncture showed that 80% of the patients had MADRS scores below 12 and that 100% of the patients had YMRS scores below
Discussion
This is the first prospective study investigating if CSF markers of neuroinflammation and neuronal injury predict clinical outcomes in a long-term follow-up of patients with bipolar disorder. We found that YKL-40 was negatively associated with manic/hypomanic relapse during a 6–7-year follow-up period. This finding survived correction for multiple testing, but should nevertheless be interpreted with caution as we noticed a possible problem with collinearity when including the highly correlated
Disclosure
K.B. and H.Z. are co-founders of Brain Biomarker Solutions in Gothenburg AB, a Venture-based platform company at the University of Gothenburg. The other authors declare no other conflicts of interest.
Acknowledgments
We thank the patients participating in this study. We also thank the staff at the St. Göran Bipolar Affective Disorder unit for the diagnostic assessments and enrolling patients for this study, including study coordinators Martina Wennberg and Haydeh Olofsson, study nurses Lena Lundberg and Agneta Carlswärd-Kjellin. Yngve Hallström is acknowledged for performing lumbar punctures. We thank Åsa Källén, Monica Christiansson, Sara Hullberg, and Dzemila Secic for technical assistance. Mathias
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