Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study

Bromander, Sara; Anckarsäter, Rolf; Kristiansson, Marianne; Blennow, Kaj; Zetterberg, Henrik; Anckarsäter, Henrik; Wass, Caroline

doi:10.1186/1742-2094-9-242

Cited by 82 publications

(81 citation statements)

References 55 publications

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“…Bromander et al, found no correlation between serum and cerebrospinal fluid TNF-α in neurosurgical patients. 37 Similarly, dissociation between central and peripheral cytokines in preclinical data have been reported following peripheral 38, 39 or central inflammatory stimuli. 40 It has been proposed that peripheral cytokines cross the blood brain barrier in severe medical illness to induce neuroinflammation and symptoms of depression.…”

Section: Discussionmentioning

confidence: 92%

Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes

et al. 2015

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Section: Discussionmentioning

confidence: 92%

Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes

et al. 2015

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“…[9][10][11][12] In patients, inflammatory molecules such as TNF-a and interleukins appear in CSF within 12 hours after major surgery. 4,[13][14][15] Although such clinical observations are in line with a series of experimental studies, 2,3,8 the time course pattern beyond the immediate postsurgery phase of immune activation within the human CNS is unknown, and how the systemic pro-and anti-inflammatory response [16][17][18] is associated with cognitive performance is largely unexplored.…”

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confidence: 76%

The immune response of the human brain to abdominal surgery

Forsberg

Červenka

Fagerlund

et al. 2017

Annals of Neurology

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Objective: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short-and longterm impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. Methods: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [ 11 C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed. Results: Patients showed a global downregulation of gray matter [ 11 C]PBR28 binding of 26 6 26% (mean 6 standard deviation) at 3 to 4 days postoperatively compared to baseline (p 5 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-a in blood displayed a reduction (41 6 39%) on the 3rd to 4th postoperative day, corresponding to changes in [ 11 C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [ 11 C]PBR28 binding (p 5 0.027). Interpretation: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function. ANN NEUROL 2017;81:572-582 A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that ultimately reaches and activates the intrinsic immune system of the brain. [1][2][3][4] Triggered by surgery-induced damage-associated molecular patterns (DAMPs), an array of proinflammatory mediators and activated blood-borne immune cells orchestrate a rapid spread of this systemic response to the central nervous system (CNS), with inflammatory markers detectable in human cerebrospinal fluid (CSF) within 12 hours. [4][5][6][7] In surgical rodent models, this periphery-to-brain pathway seems critically dependent on NF-jB and proinflammatory cytokine signaling (eg, tumor necrosis factor-a [TNF-a]) associated with a shortlasting disruption of blood-brain barrier integrity, 2,3,8 migration of peripheral macrophages into the CNS, and subsequent hippocampal neuronal dysfunction and cognitive impairment. 8 In addition to an acute and transient response, often referred to as a syndrome of sickness behavior including fatigue, anorexia, and fever, surgery-induced immune activation may be associated with prolonged impairments in learning,...

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“…In a study where patients with major depressive episodes had higher TSPO V T compared with healthy controls, no correlations were found between serum cytokines and brain TSPO binding, even after controlling for genotype and body mass index (27). Another study showed no correlations between cytokines in the serum and cerebrospinal fluid in patients before and after knee surgery, where cytokine levels were higher in the CNS than in the periphery after surgery (43). The authors surmise that although peripheral inflammation presumably induces the central inflammatory response, the CNS might regulate inflammation independently.…”

Section: Discussionmentioning

confidence: 99%

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

Sandiego

Gallezot

Pittman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the brain. We measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer [ 11 C]PBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min [ 11 C]PBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second [ 11 C]PBR28 scan. LPS administration significantly increased [ 11 C]PBR28 binding 30-60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with [ 11 C]PBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.neuroinflammation | PBR28 | endotoxin | microglia | cytokines

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Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study

Cited by 82 publications

References 55 publications

Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes

Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes

The immune response of the human brain to abdominal surgery

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

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