Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Green, Claire; Shen, Xueyi; Stevenson, Anna J.; Conole, Eleanor L.S.; Harris, Mathew A.; Barbu, Miruna C.; Hawkins, Emma L.; Adams, Mark; Hillary, Robert F.; Lawrie, Stephen M.; Evans, Kathryn; Walker, Rosie M.; Morris, Stewart W.; Porteous, David J.; Wardlaw, Joanna M.; Steele, J. Douglas; Waiter, Gordon D.; Sandu, Anca-Larisa; Campbell, Archie; Marioni, Riccardo E.; Cox, Simon R.; Cavanagh, Jonathan; McIntosh, Andrew M.; Whalley, Heather C.

doi:10.1016/j.bbi.2020.11.024

Cited by 63 publications

(70 citation statements)

References 78 publications

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“…A large number of literature reports indicated that there was a deterministic relation between higher CRP level, change in brain structure, and depression (D'Mello & Swain, 2017; Felger et al., 2020; Kelly et al., 2019; Ng et al., 2018; Vulser et al., 2015), still the relationship between peripheral inflammation, brain structure, and depression remains unclear. A recent work showed that DNA methylation of CRP was significantly associated with reduced global gray matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts, the methylation‐based measures showed stronger associations with imaging metrics than serum‐based CRP measures, and these findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression (Green et al., 2020). A review demonstrated that the early life adversity–perinatal depressive risk model, as we have proposed, invokes epigenetic embedding as a key pathway that promotes a pro‐inflammatory phenotype (higher levels of pro‐inflammatory cytokines and lower levels of oxytocin), which, in turn, shapes maternal stress reactivity, mood, and behavior (Garfield et al., 2015).…”

Section: Discussionmentioning

confidence: 92%

Prenatal stress induced depressive‐like behavior and region dependently high CRP level in offspring rats

Zhang

Gao

et al. 2021

Brain and Behavior

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Introduction To explore the changes in C‐reactive protein (CRP) level in different regions of one old offspring rats exposed to prenatal stress (PS). Methods The rat model was constructed with prenatal restraint stress on pregnant dams on days 14–20 of gestation. Offspring rats were randomly divided into PS susceptibility (PS‐S) group and control (CON) group. Behavioral experiments including sucrose preference test (SPT), open‐field test (OFT), and forced swimming test (FST) were used to measure depressive‐like behaviors. Immunohistochemistry, qRT‐PCR, and Western blotting were applied to detect the changes in CRP level. Results The results showed that PS could cause depressive‐like behaviors in all SPT, OFT, and FST. Concomitantly, CRP mRNA and protein expression significantly increased in hippocampus, prefrontal cortex, and hypothalamus in the PS‐S group when compared that in the CON group, while no significantly changes in liver, heart, olfactory bulb, striatum, and cerebellum in the PS‐S group when compared that in the CON group. Conclusion Increasing of CRP expression in hippocampus, prefrontal cortex, and hypothalamus may play a critical role in the mechanism under depressive‐like behavior in offspring rats exposed to PS.

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Section: Discussionmentioning

confidence: 92%

Prenatal stress induced depressive‐like behavior and region dependently high CRP level in offspring rats

Zhang

Gao

et al. 2021

Brain and Behavior

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“…Third, there are potential factors such as a genetic predisposition or the gut microbiome mediating or moderating the relationship between inflammation and neural-circuit dysfunction in depression. 124 125 For example, a recent study by Green et al 126 found that the DNA methylation score of the CRP gene was associated with a reduction in global gray matter/cortical volumes and damaged integrity of the white matter in widespread tracts in patients with MDD, whereas no significant association was found between the serum CRP level and structural changes in the brain. Future studies should take these factors into consideration.…”

Section: Discussionmentioning

confidence: 99%

How Inflammation Affects the Brain in Depression: A Review of Functional and Structural MRI Studies

Han

Ham

2021

J Clin Neurol

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This narrative review discusses how peripheral and central inflammation processes affect brain function and structure in depression, and reports on recent peripheral inflammatory marker-based functional and structural magnetic resonance imaging (MRI) studies from the perspective of neural-circuit dysfunction in depression. Chronic stress stimulates the activity of microglial cells, which increases the production of pro-inflammatory cytokines in the brain. In addition, microglial activation promotes a shift from the synthesis of serotonin to the synthesis of neurotoxic metabolites of the kynurenine pathway, which induces glutamate-mediated excitotoxicity in neurons. Furthermore, the region specificity of microglial activation is hypothesized to contribute to the vulnerability of specific brain regions in the depression-related neural circuits to inflammation-mediated brain injury. MRI studies are increasingly investigating how the blood levels of inflammatory markers such as C-reactive protein, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α are associated with functional and structural neuroimaging markers in depression. Functional MRI studies have found that peripheral inflammatory markers are associated with aberrant activation patterns and altered functional connectivity in neural circuits involved in emotion regulation, reward processing, and cognitive control in depression. Structural MRI studies have suggested that peripheral inflammatory markers are related to reduced cortical gray matter and subcortical volumes, cortical thinning, and decreased integrity of white matter tracts within depression-related neural circuits. These neuroimaging findings may improve our understanding of the relationships between neuroinflammatory processes at the molecular level and macroscale in vivo neuralcircuit dysfunction in depression.

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“…Additionally, changes in brain structure [11,12], gastrointestinal factors [13,14], oxidative stress [15], and endocannabinoid system components [16] have also been implicated in depression [17]. In addition, correlation studies for the aforementioned biomarkers such as inflammatory factors and brain structural changes also have been conducted in depression [18,19]. Family, twin, and adoption studies suggest that genetic factors account for 30-40% of the variance in depression risk [20], but early genome-wide association studies (GWASs) failed to identify genetic variants strongly associated with depression, suggesting that genetic susceptibility is mediated by heterogeneous combinations of risk alleles [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression

Park

Kim

Ahn

et al. 2021

IJMS

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Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors.

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Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Cited by 63 publications

References 78 publications

Prenatal stress induced depressive‐like behavior and region dependently high CRP level in offspring rats

Prenatal stress induced depressive‐like behavior and region dependently high CRP level in offspring rats

How Inflammation Affects the Brain in Depression: A Review of Functional and Structural MRI Studies

Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression

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