Open‐heart surgery increases cerebrospinal fluid levels of <scp>A</scp>lzheimer‐associated amyloid β

Reinsfelt, Björn; Westerlind, A.; Blennow, Kaj; Zetterberg, Henrik; Ricksten, Sven‐Erik

doi:10.1111/j.1399-6576.2012.02769.x

Cited by 50 publications

(42 citation statements)

References 35 publications

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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: 73%

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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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confidence: 73%

“…Arterial blood was sampled using an automated system for the first 5 minutes. Manual samples were drawn at 2, 4,6,8,10,15,20,25,30,45, and 60 minutes. All patients were genotyped for the genetic polymorphism of rs6971, which affects binding of TSPO radioligands, including [ 11 C]PBR28, both in vitro and in vivo.…”

Section: Pet Imagingmentioning

confidence: 99%

The immune response of the human brain to abdominal surgery

Forsberg

Červenka

Fagerlund

et al. 2017

Annals of Neurology

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“…Indeed, surgery is associated with a central neuroinflammatory response in humans (92–96). It remains unclear, though, whether this central neuroinflammatory response is associated with POCD.…”

Section: What Causes Pocd?mentioning

confidence: 99%

Postoperative Cognitive Dysfunction

Berger

Nadler

Browndyke

et al. 2015

Anesthesiology Clinics

227

119

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Ever since Bedford’s seminal Lancet case series in 1955, we have known that perioperative care is sometimes followed by significant cognitive dysfunction (1). Although the safety of perioperative care has improved dramatically since 1955, the descriptions of cognitive dysfunction in that case series are eerily similar to the complaints of current patients suffering from post-operative cognitive dysfunction (POCD). POCD remains a common post-operative complication associated with significant morbidity and even mortality, especially among elderly patients. There has been a great deal of interest in and controversy about POCD, from how it is measured, to how long it lasts, to its precise implications for patients. This interest and controversy is reflected partly in the increasing number of papers published on this subject recently (shown in Figure 1). Recent work has also suggested surgery may be associated with cognitive improvement in some patients (2–4), termed Post-Operative Cognitive Improvement (POCI). As the number of surgeries performed worldwide approaches 250 million per year (5) (with an increasing number elderly patients), optimizing postoperative cognitive function and preventing/treating POCD are major public health issues. In this article we review the literature on POCD and POCI, and discuss current research challenges in this area.

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“…Inflammatory markers have been found in the cerebrospinal fluid of patients at 24 hours postsurgery, 29 but also at up to a week after CABG surgery, 42 and, intriguingly, an increase in brain inflammatory markers after aortic valve surgery was noted to occur in tandem with an increase in biomarkers associated with Alzheimer disease (amyloid β peptide). 37 These findings should be interpreted in the knowledge that such biomarkers may also be increased in patients with more general cardiovascular disease. In general, the functional consequences of neuroinflammation are currently unclear, 43 particularly in relation to CABG surgery and POCD.…”

Section: Hogan Et Al Fixing Hearts and Protecting Minds 163mentioning

confidence: 99%

“…34 Specifically, cytokines have been implicated in neuropathology, particularly that involving the hippocampi and hippocampally dependent memory dysfunction in mice models of noncardiac interventions. 35,36 Such changes might affect the brain irrespective of microembolic load, 29,37 and perhaps provide a better explanation for early postoperative POCD 38 than evolving structural brain lesions per se. However, it should be borne in mind that there is no evidence of a specific deficit in hippocampally dependent memory in humans following CABG surgery, suggesting that functionally relevant pathology extends beyond this structure and involves other mechanisms.…”

Section: Hogan Et Al Fixing Hearts and Protecting Minds 163mentioning

confidence: 99%