The Link between High-Sensitivity C-Reactive Protein and Orbitofrontal Cortex in Euthymic Bipolar Disorder

Chung, Kuo Hsuan; Huang, Shou-Hung; Wu, Jui-Yu; Chen, Pao‐Huan; Hsu, Jung-Lung; Tsai, Shang‐Ying

doi:10.1159/000353613

Cited by 34 publications

(22 citation statements)

References 33 publications

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“…As for bipolar disorder, we found a nominal effect of a 1.21-fold increase in risk for bipolar disorder with a 10-s% increase in CRP level. Though this nominal predisposing effect needs to be confirmed, our finding corroborates epidemiological observations suggesting that elevated CRP is associated with the disease and supports a potential causal influence of general inflammation in bipolar disorder [ 86 ]. We note that, though it may be biologically sensible, this result failed to pass multiple testing correction.…”

Section: Discussionsupporting

confidence: 88%

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

et al. 2016

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BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and FindingsWe performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed.The strengths (F-statistics) of the IVs were 31.92–3,761.29 and 82.32–9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79–0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94–0.98]; p < 1.72 × 10−6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10−4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10−4) showed a statistically significant (p < 2.45 × 10−4) protective effect with an OR of 0.97 (95% CI 0.95–0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84–0.94]; p < 2.4 × 10−5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74–0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70–0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00–1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01–1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05–1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11–1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06–0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003–0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004–0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008–0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes...

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Section: Discussionsupporting

confidence: 88%

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

et al. 2016

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“…Preliminary evidence of persistent CNS‐driven inflammation is also provided by a [ 11 C]‐(R)‐PK11195 positron emission tomography (PET) study that identified increased microglial activation in the right hippocampus of euthymic individuals with BD . Extending from these observations, peripheral and central markers of inflammation have been associated with cognitive dysfunction in euthymic and symptomatic individuals with BD (for reviews of cognitive deficits and underlying neurobiological models, the reader is referred to the Mood Disorders – Neurocognition special issue of Bipolar Disorders ). Taken together, the available evidence provides a rationale for testing the hypothesis that concurrently mitigating both peripheral and central inflammation may alleviate depressive and cognitive symptoms of BD.…”

Section: Introductionmentioning

confidence: 98%

A pilot, open‐label, 8‐week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression

et al. 2017

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“…Direct evidence of neuroinflammation has been scarcer, but has supported the hypothesis of inflammatory dysregulation [3][4][5]. In addition, inflammatory mediators have been consistently associated with neurostructural abnormalities in individuals with BD [6][7][8][9][10]. As a result, anti-inflammatory agents have been recently tested as therapies for mood disorders, including bipolar depression [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…Abbreviations: TNFR1: Tumour necrosis factor-alpha receptor-1; NF-κB: nuclear factor-kappa B; PA: with clinically significant history of physical abuse; No PA: without clinically significant history of physical abuse. Cells 2020,9, 895…”

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confidence: 99%

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

Mansur

Delgado-Peraza

Subramaniapillai

et al. 2020

Cells

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Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-α) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab’s effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-α receptors (TNFRs) and nuclear factor-kappa B (NF-κB) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab’s effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (χ2 = 9.275, p = 0.026), NF-κB (χ2 = 13.825, p = 0.003), and inhibitor of NF-κB (IκBα)α (χ2 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (χ2 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = −0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-κB neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

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The Link between High-Sensitivity C-Reactive Protein and Orbitofrontal Cortex in Euthymic Bipolar Disorder

Cited by 34 publications

References 33 publications

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

A pilot, open‐label, 8‐week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

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