The association between inflammatory markers in blood and cerebrospinal fluid: a systematic review and meta-analysis

Gigase, Frederieke; Smith, Emma; Moore, Kendall; Snijders, Gijsje; Katz, Daniel; Perez‐Rodriguez, M. Mercedes; Witte, Lot de

doi:10.1038/s41380-023-01976-6

Cited by 20 publications

(8 citation statements)

References 81 publications

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“…In fact, we were able to demonstrate increased levels of IL-6 in serum and brain of animals treated with ACTH compared to controls, suggesting its role as a periphery-brain signalling molecule in this context. Although serum and central levels of IL-6 were not directly correlated in our study, it corroborates with a recent meta-analysis study demonstrating the lack of general blood-CSF correlation for interleukins [50], suggesting indirect mechanisms of communication and/or the involvement of other mediators in this process.…”

Section: Discussionsupporting

confidence: 90%

“…A clinical study has demonstrated a correlation between IL-6 levels and increase in phenylalanine concentration (a precursor of tyrosine) in cancer patients [49]. IL-6 treatment in animals was also shown to decrease tetrahydrobiopterin (BH4) in presynaptic neurons, a TH enzyme cofactor [50]. Corroborating with these observations, the present study demonstrates a negative correlation between serum IL-6 levels and TH levels in the ILC.…”

Section: Discussionsupporting

confidence: 81%

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The role of IL-6 in dopamine dysregulation underlying anhedonia phenotype in rats

Varela,

Macpherson,

Houghton

et al. 2023

Preprint

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AimsTo investigate the role of peripheral metabolic change and chronic low-grade inflammation on striatal dopamine dynamics and anhedonia-like behaviour induced by hypothalamic–pituitary–adrenal (HPA) axis disruption.MethodsWistar rats were trained in a progressive-ratio/concurrent effort-related choice paradigm to assess effort-related decision making. After reaching a stable baseline, animals received daily injections of adrenocorticotrophic hormone (ACTH) or saline for 24 days. On the 23rdand 24thday, animals received a bupropion challenge (10mg/kg and 20mg/kg respectively) 30 minutes prior to the behavioural testing session. On the 25thday, animals received a single injection of bupropion (20mg/kg) 30 minutes prior to euthanasia. Peripheral and central inflammatory markers were assessed through ELISA and In-Cell Western assay; glucose transport activity was assessed in peripheral blood mononuclear cells though a commercial assay kit; brain levels of dopaminergic and inflammatory markers were assessed in the nucleus accumbens (NAc) and prefrontal cortex (PFC) through immunohistochemistry; and serum central carbon metabolism metabolites were assessed through a metabolomics approach.ResultsACTH induced an anhedonia-like phenotype, decreased tyrosine hydroxylase (TH) levels in the NAc, increased peripheral IL-6 levels, and decreased glucose transport activity and glucose metabolites when compared to control group. Bupropion treatment was not able to reverse the anhedonic phenotype. Glucose uptake was positively correlated to behaviour; TH levels were correlated to microglia volume; metabolites were correlated to TH levels; and IL6 was correlated to TH levels and metabolites.ConclusionChronic ACTH treatment can induce treatment-resistant anhedonia in rats, and the interaction between peripheral immunometabolic state and central dopamine synthesis is a potential mechanism underlying this phenotype.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 81%

The role of IL-6 in dopamine dysregulation underlying anhedonia phenotype in rats

Varela,

Macpherson,

Houghton

et al. 2023

Preprint

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“…However, the direction of the change across the meta-analyzed studies was not consistent across all studies: while immune pathways were strongly upregulated in resistant samples in the two studies profiling gene expression in blood (one derived from human patients), these pathways were weakly upregulated in responding samples in studies profiling brain tissues. A recent systematic review has noted that inflammatory markers are only weakly correlated between peripheral and cerebrospinal fluid (66).…”

Section: Discussionmentioning

confidence: 99%

Gene expression signatures of response to fluoxetine treatment: systematic review and meta-analyses

Cooper,

Cowden,

Stanley

et al. 2024

Preprint

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BackgroundSelecting the best antidepressant for a patient with major depressive disorder (MDD) remains a challenge, and some have turned to genomic (and other ‘omic) data to identify an optimal therapy. In this work, we synthesized gene expression data for fluoxetine treatment in both human patients and rodent models, to better understand biological pathways affected by treatment, as well as those that may distinguish clinical or behavioral response.MethodsFollowing the PRISMA guidelines, we searched the Gene Expression Omnibus (GEO) for studies profiling humans or rodent models with treatment of the antidepressant fluoxetine, excluding those not done in the context of depression or anxiety, in an irrelevant tissue type, or with fewer than three samples per group. Included studies were systematically reanalyzed by differential expression analysis and Gene Set Enrichment Analysis (GSEA). Individual pathway and gene statistics were synthesized across studies by three p-value combination methods, and then corrected for multiple testing.ResultsOf the 74 data series that were screened, 20 were included: 18 in rodents, and two in tissue from human patients. Studies were highly heterogeneous in the comparisons of both treated vs. control samples and responders vs. non-responders, with 737 and 356 pathways, respectively, identified as significantly different between groups in at least one study. 19 pathways were identified as consistently different in responders vs. non-responders, including Toll Like Receptor (TLR) and other immune pathways. Signal transduction pathways were identified as consistently affected by fluoxetine treatment in depressed patients and rodent models.DiscussionThese meta-analyses confirm known pathways and provide new hints toward antidepressant resistance, but more work is needed. Most included studies involved rodent models, and both patient studies had small cohorts. Additional large-cohort studies applying additional ‘omics technologies are necessary to understand the intricacies and heterogeneity of antidepressant response.

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“…Additionally, it is well known there is little to no correlation between inflammatory markers in blood compared to cerebrospinal fluid [ 52 ], indicating there are likely different inflammatory mechanisms underlying central and peripheral inflammation. Unfortunately, it is impossible to tease apart contributions from neural sources due to breakdown in the blood-brain barrier (loss of blood brain barrier integrity), activation of immune cells in the glymphatic system, and inflammatory responses arising from peripheral sources for the inflammatory response observed here.…”

Section: Discussionmentioning

confidence: 99%

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI

Clarke,

Follestad,

Skandsen

et al. 2024

J Neuroinflammation

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Background Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. Methods Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI – i.e., presence of any traumatic intracranial injury on neuroimaging – was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. Results The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1β and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). Conclusions The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

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The association between inflammatory markers in blood and cerebrospinal fluid: a systematic review and meta-analysis

Cited by 20 publications

References 81 publications

The role of IL-6 in dopamine dysregulation underlying anhedonia phenotype in rats

The role of IL-6 in dopamine dysregulation underlying anhedonia phenotype in rats

Gene expression signatures of response to fluoxetine treatment: systematic review and meta-analyses

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI

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