ReviewInflammatory mediators of cognitive impairment in bipolar disorder
Introduction
The mood symptoms of bipolar disorder (BD) are more often than not accompanied by verbal and working memory deficits (Bearden et al., 2006, Diwadkar et al., 2011), poor sustained attention (Glahn et al., 2007) and reduced executive functioning (Quraishi and Frangou, 2002, Najt et al., 2007, Ancin et al., 2010). Cognitive deficits persist during the euthymic phase of BD (Robinson et al., 2006, Malhi et al., 2007) which suggests that cognitive dysfunction may not be attributable to mood disturbance. In the last decade an increasing number of papers have emphasized the roles of inflammation, oxidative stress and related cellular degeneration in the pathophysiology of mood disorders (Miller et al., 2011, Carey et al., 2013, Turner, 2013). It is however still unclear whether these mechanisms are associated with the risk of developing cognitive impairment in patients diagnosed with BD.
BD is characterized by high peripheral levels of pro-inflammatory agents, such as interleukins (in particular IL-6, IL-2R, IL-1beta), tumour necrosis factor (TNF-α) and cellular TNF-α receptors (TNFR1) (Barbosa et al., 2011), and elevated pro-oxidative C-reactive protein (CRP) concentrations (Kapczinski et al., 2011, Kunz et al., 2011, Gimeno et al., 2009, Myint et al., 2009). This increase in the peripheral inflammation is likely to be associated with elevated neuroinflammation. Indeed cytokines penetrate the brain via leaky regions (e.g. choroid plexus) and are associated with the increased expression of pro-inflammatory eicosanoids (prostaglandin 2 – PGE2), nitric oxide (NO) (Capuron and Dantzer, 2003), TNF-α, IL-1β, reactive oxygen species as well as monocytes and macrophages in the brain (Capuron and Dantzer, 2003, Minagar and Alexander, 2005, Blank and Prinz, 2013) (Fig. 1). Alongside the increase in peripheral inflammation, BD has been associated with a decrease in brain-derived neurotrophic factor (BDNF) levels (Cunha et al., 2006, Bourne et al., 2013). Neurotrophins, such as BDNF, are a group of secreted proteins that are essential for neuron survival and synaptic functioning (Ichim et al., 2012, Huang and Reichardt, 2001, Buckley et al., 2007, Jiang et al., 2009).
Clinical and preclinical evidence suggest that multiple mood episodes disrupt the homeostasis between inflammatory mechanisms, oxidative processes, and neuroprotective mechanisms, such as BDNF, and lead to neuronal death (apoptosis) (Fries et al., 2012, Berk et al., 2011). This cycle of events is defined as “neuroprogression” and has been linked to an increase in the individual's vulnerability to psychological stress, brain atrophy and ultimately cognitive impairment (Berk et al., 2010, Kapczinski et al., 2008). The concept of “staging” has been applied to the pathophysiology of BD to explain the progressive decline in mental health, psychosocial functioning and cognitive performance over the course of the disease (Gama et al., 2013, Frodl and Amico, 2013, Kapczinski et al., 2009).
Accordingly, neuroimaging studies show that individuals diagnosed with BD exhibit a significant loss of gray matter volume and white matter integrity, which is likely related to inflammatory processes such as apoptosis, cellular shrinkage, alterations in neurogenesis and reduced gliogenesis (Czéh and Lucassen, 2007). Recent neuroimaging studies have also identified a significant cortical atrophy and enlargement of the ventricles in individuals who experienced multiple mood episodes as compared to gender and age-matched healthy individuals (Pfaffenseller et al., 2012, Strakowski et al., 2012). Furthermore, an inverse relationship between gray matter volumes and length of illness has also been reported (Brambilla et al., 2001, Frey et al., 2008).
In summary, chronic inflammation may lead to structural brain abnormalities and cognitive deficits in individuals diagnosed with BD. However, to date, this hypothesis has not been systematically reviewed. Thus, the purpose of this review is to assess the potential association between cognitive impairment and biomarkers of inflammation, oxidative stress and neurotrophic activity in individuals diagnosed with BD.
Section snippets
Literature search
Scopus (all databases), Pubmed and Ovid Medline were systematically searched with no language or year restrictions, up to November 2013, for research articles addressing the relationship between bipolar disorder, inflammation and cognition. Selected search terms were ‘bipolar disorder’, ‘depression’, ‘mania’, ‘psychosis’, ‘inflammatory’, ‘cognitive’ and ‘neurotrophic’ as occurring either anywhere in the article (for Pubmed and Ovid Medline) or in the case of PUBMED, in the title, abstract or
Quality evaluation
Since there is no official instrument for the evaluation of observational studies in psychiatry and inflammation we conducted a quality evaluation based on the Centre for Reviews and Dissemination (CRD) Hierarchy of evidence (Cochrane, 2003) and a revised version of Ibrahim and colleague's quality evaluation scale (Ibrahim et al., 2012). The CRD Hierarchy of evidence ranks study designs in descending order of strength: 1. Experimental studies, 2. Quasi experimental studies, 3. Controlled
Study characteristics
We identified ten published clinical studies exploring the association between peripheral pro-inflammatory cytokines, oxidative markers, neurotrophins and cognitive performance in individuals diagnosed with BD. Two studies collected peripheral measures of oxidative stress (CRP, RBANS) and peripheral pro-inflammatory cytokine measurements (IL-18, TNF). Eight studies examined the relationship between BDNF levels or polymorphism and cognitive functioning (see Table 1). All studies were
Pro-inflammatory cytokines, markers of oxidative stress and cognitive functioning
Peripheral serum CRP expression was negatively correlated with performance scores of immediate memory, language, and attention, on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in a study involving 107 individuals diagnosed with BD. The authors interpreted these results as indicating that oxidative damage negatively affects cognitive functioning in BD patients. However, as this study did not include a control population it is unknown whether the relationship
Quality evaluation: findings
The quality and reliability of the 10 studies included in this review are shown in Table 2. The CDR hierarchy of evidence was estimated to be 3–4, as the current studies are not randomized cross-sectional studies with and without a control group. Given the observational nature of the studies, the current findings provide little information on trends over time and do not investigate possible causality link between inflammation and cognitive impairment in bipolar disorder. Further, investigators
Discussion
This review aimed to examine the literature exploring the relationship between the cognitive deficits seen among individuals diagnosed with bipolar disorder, and markers of inflammation, neurotrophins and oxidative damage. Thus, we conducted a systematic search of the human literature on inflammation and cognition in BD. It is important to emphasize that this is a novel approach as previous reviews have linked inflammation with mood symptoms, but have not explored the relationship between
Role of funding source
This work was partly supported by the Stanley Medical Research Institute, National Institutes of Health grant 1R01MH085667 (JCS), and by the Pat Rutherford Jr. Chair in Psychiatry (UTHealth).
Contributors
IB managed and searched the literature and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
Dr Bauer, Dr Pascoe and Dr Wollenhaupt-Aguiar have no conflicts of interest.
Professor Kapczinski has received grants/research support from AstraZeneca,Eli Lilly, Janssen-Cilag, Servier, CNPq, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, NARSAD and Stanley Medical Research Institute; has been a member of the board of speakers for Astra-Zeneca, Eli Lilly, Janssen and Servier; and has served as a consultant for Servier.
Professor J. C. Soares has received grants/research support
Acknowledgements
N/A.
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