Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study

Abstract

Background: Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation.

Methods: We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). The integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine the correlation between biofluids.

Results: Mean Qalb did not change between baseline and PO1MO. Mean plasma and CSF levels of CRP and plasma levels of YKL-40 and IL-6 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CRP CSF levels relative to plasma levels (CRP tripled in CSF vs. increased 10% in plasma). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline.

Conclusions: In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, plasma-CSF correlations were observed for CRP and IL-6, plasma levels of all three markers (CRP, IL-6, and YKL-40) increased from PREOP to PO1MO, and CSF levels of only CRP increased between the two time points. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

Keywords: Blood-brain barrier; Cerebrospinal fluid; Inflammation; Neuroinflammation; Plasma.

Fig. 1

Box and whisker plots of interleukin-6 (IL-6) cerebrospinal fluid (CSF) levels at baseline and postoperative 1 month* (PO1MO). *Highest value for PO1MO (130.0 pg/ml) not plotted to facilitate visualization of the distributions. The height of the box represents the interquartile range (the distance between the 25th and 75th percentiles). The horizontal line in the box interior represents the group median. The vertical lines (whiskers) extending from the box indicate the group minimum value and maximum value within the “upper fence” (i.e., 1.5*IQR + Quartile 3). The diamond symbol represents the group mean, and the circle symbols represent outlying values that extend beyond the upper fence

Fig. 2

Summary of findings related to the posited hypotheses. Abbreviations: CSF cerebrospinal fluid, IL-6 interleukin-6, Qalb CSF albumin-plasma albumin ratio, PREOP preoperative, PO1MO postoperative 1 month, YKL-40 chitinase 3-like protein 1. *p < .01. Each hypothesis and its associated empirical result are shown in blue for hypothesis 1, green for hypothesis 2a, orange for hypothesis 2b, purple for hypothesis 3a, and red for hypothesis 3b