The immune response of the human brain to abdominal surgery

Abstract

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 long-term 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 ± 26% (mean ± standard deviation) at 3 to 4 days postoperatively compared to baseline (p = 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-α in blood displayed a reduction (41 ± 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 = 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.

FIGURE 1:. Parametric images of [¹¹C]PBR28 binding at 3 occasions preoperatively, days 3 to 4 postoperatively (Post-op), and after 3 months in 2 patients (Subjects 1 and 4) undergoing major abdominal surgery.

FIGURE 2:. Changes in [¹¹C]PBR28 binding. (A) Changes in distribution volume (V_T) across brain regions preoperatively, that is, before abdominal surgery (white), days 3 to 4 postoperatively (gray), and after 3 months (black) by positron emission tomography (PET). Paired t test, *p < 0.05, **p < 0.01. GM = gray matter; HIP = hippocampus; LFC = lateral frontal cortex; LPC = lateral parietal cortex; PUT = putamen. (B) Individual changes of V_T across brain regions by PET in gray matter at 3 time points: before abdominal surgery (Preop), 3 to 4 days postoperatively (Postop), and after 3 months.

FIGURE 3:. Ex vivo and plasma cytokines. (A) Ex vivo cytokine production in abdominal surgery patients. The cytokine responses were measured by tumor necrosis factor (TNF)-α and interleukin (IL)-1β protein levels after lipopolysaccharide (LPS) + adenosine triphosphate (ATP) stimulation of whole blood preoperatively (Preop), postoperatively (Postop) at days 3 to 4, and after 3 months. Protein levels were normalized to number of leukocytes (LPK; TNF-α or IL-1β/leucocyte particle count; top panels). The TNF-α response is dampened 4 days postsurgery despite an increase in leukocytes, but has returned to normal 3 months after surgery. Although similar trends were present for TNF-α and IL-1β in unstimulated blood samples (bottom panels), the differences did not reach statistical significance. Protein levels measured Preop were compared to levels at Postop days 3 to 4 and 3 months Postop using paired t test; significant differences are indicated by asterisks. Bars indicate median value, and boxes indicate second and third quartiles. (B, C) Plasma cytokine, high-mobility group box 1 protein (HMGB1), C-reactive protein (CRP), serum amyloid A (SAA), neurofilament light chain (NFL), and tau concentrations following major abdominal surgery in 8 male surgical patients. Data are presented as Preop, Postop days 3 to 4, and after 3 months. Statistical significance is indicated by asterisks (paired t test). Bars indicate median value. and boxes indicate second and third quartiles. *p < 0.05, **p < 0.01, ***p < 0.001.