Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression

Goldsmith, David R.; Bekhbat, Mandakh; Le, Ngoc‐Anh; Chen, Xiangchuan; Woolwine, Bobbi J.; Li, Zhihao; Haroon, Ebrahim; Felger, Jennifer C.

doi:10.1016/j.bbi.2020.05.013

Cited by 25 publications

(22 citation statements)

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“…We also observed that both inflammatory (e.g., TNF, NF-kB signaling) and metabolic (e.g. insulin, AKT) gene expression signatures in peripheral blood immune cells correlated with low functional connectivity in corticostriatal circuitry in MD, including circuits involving dorsal striatum, which have been associated with psychomotor processing speed 32 .…”

Section: Introductionmentioning

confidence: 63%

Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming

et al. 2021

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Inflammation impacts basal ganglia motor circuitry in association with psychomotor retardation, a key symptom of major depression (MD). We previously reported associations between circulating protein inflammatory biomarkers and psychomotor slowing as measured by neuropsychological tests probing psychomotor speed in patients with MD. To discover novel transcriptional signatures in peripheral blood immune cells related to psychomotor slowing, microarray data were analyzed in a primary cohort of 88 medically-stable, unmedicated, ambulatory MD patients. Results were confirmed and extended in a second cohort of 57 patients with treatment resistant depression (TRD) before and after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab versus placebo. Composite scores reflecting pure motor and cognitive-motor processing speed were linearly associated with 403 and 266 gene transcripts in each cohort, respectively (| R| >0.30, p <0.01), that were enriched for cytokine signaling and glycolysis-related pathways ( p <0.05). Unsupervised clustering in the primary cohort revealed two psychomotor slowing-associated gene co-expression modules that were enriched for interferon, interleukin-6, aerobic glycolysis, and oxidative phosphorylation pathways ( p <0.05, q <0.1). Transcripts were predominantly derived from monocytes, plasmacytoid dendritic cells, and natural killer cells ( p ’s<0.05). In infliximab-treated TRD patients with high plasma C-reactive protein concentrations (>5mg/L), two differential co-expression modules enriched for oxidative stress and mitochondrial degradation were associated with improvements in psychomotor reaction time ( p <0.05). These results indicate that inflammatory signaling and associated metabolic reprogramming in peripheral blood immune cells are associated with systemic inflammation in depression and may affect relevant brain circuits to promote psychomotor slowing.

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Section: Introductionmentioning

confidence: 63%

Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming

et al. 2021

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“…There is increased focus on the interaction of inflammatory and metabolic pathways in psychiatric disorders [1][2][3][4] . Individuals with schizophrenia consistently show disruptions of several metabolic parameters, including lipid and glucose homeostasis, which may be associated with underlying genetic risk for the disorder 5,6 .…”

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confidence: 99%

The interaction of lipids and inflammatory markers predict negative symptom severity in patients with schizophrenia

et al. 2021

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Finding biological predictors and novel mechanisms underlying negative symptoms of schizophrenia is of significant importance given the lack of effective treatments. Increasing data support a role for metabolic dysfunction and inflammation in reward processing deficits in psychiatric illness. Herein, we found an interaction between lipids and inflammation as a predictor of worse negative symptom severity in individuals with schizophrenia. Future studies may seek to further elucidate this relationship and thereby reveal novel treatment targets for negative symptoms.

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“…Following Lamers et al (2020), an inflammation index was calculated from plasma levels of CRP and IL-6. Plasma high sensitivity (hs)-CRP concentrations were assayed using the Ultra WR CRP immunoturbidimetric assay from Sekisui Diagnostics (Exton, PA) implemented on the AU480 chemistry analyzer (Beckman Coulter, Brea, CA; detection limit 0.01 mg/L) (Le, Innis-Whitehouse et al 2000, Mehta, Raison et al 2013, Raison, Rutherford et al 2013, Felger, Li et al 2016, Bekhbat, Chu et al 2018, Goldsmith, Bekhbat et al 2020). Concentrations of plasma IL-6 were assessed using high-sensitivity Quantikine enzyme-linked immunosorbent assay (ELISA) kits from R&D systems (Minneapolis, MN; detection limit 0.04 pg/ml) (Raison, Borisov et al 2009, Raison, Borisov et al 2010, Musselman, Royster et al 2013, Smith, Conneely et al 2014).…”

Section: Methodsmentioning

confidence: 99%

Metabolomic and Inflammatory Signatures of Symptom Dimensions in Major Depression

Brydges¹,

Bhattacharyya

Dehkordi

et al. 2021

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Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. Methods: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. Results: The IMD clinical dimension and the inflammatory index were positively correlated (r=0.19, p=.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. Conclusion: The IMD dimension of depression is reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.

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Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression

Cited by 25 publications

References 100 publications

Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming

Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming

The interaction of lipids and inflammatory markers predict negative symptom severity in patients with schizophrenia

Metabolomic and Inflammatory Signatures of Symptom Dimensions in Major Depression

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