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.

Cytokine changes in cerebrospinal fluid and plasma after emergency orthopaedic surgery

“…Cytokine activation is only part of the neuroinflammatory process after surgery 1 . Other studies in this field have looked at the CSF to serum albumin ratio before and after surgery as a marker of BBB integrity, which was not investigated here 33 , 11 , 28 . A more detailed analysis of the CSF including cell count levels and the immunoglobulin subtypes IgM, IgG and IgA could be performed in future studies, as these would also have relevance in understanding the role neuroinflammation plays in PND 34 .…”

Putative Involvement of Cytokine Modulation in the Development of Perioperative Neurocognitive Disorders

“… 32 One recent large-scale study found that in 29 patients undergoing either a total knee or total hip replacement, IL-6 levels were increased in plasma, but not in CSF, after an LP was performed at 1 month following the operation. 68 Levels of CRP were found to be increased in both CSF and plasma at 1 month. This may indicate that the cytokine-driven neuroinflammatory process had already resolved by 1 month after the operation.…”

“… Renner et al 2011 76 11 Hip arthroplasty Spinal Elective RCT with etoricoxib 0, 1.5, 2, 4, 8, 12, 24, 26, 32 and 48 hours after surgery IL-6, PGE2 Preoperative administration of etoricoxib lead to a reduction in serum IL-6 and pain levels, but no reduction was seen in CSF IL-6. Vasunilashorn et al 2021 68 29 Knee or hip total arthroplasty Spinal Elective Nil Before surgery and 1-month after surgery IL-6, CHI3L1, CRP In serum samples there was a significant increase in IL-6 at 1 month. Wang et al 2013 91 36 Aortic aneurysm surgery ± cardiopulmonary bypass Spinal Elective Nil Pre-incision, wound closure and every 4 hours for up to 5 days after surgery IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IFN-γ and TNF-α Plasma IL-6 levels were higher in the patient group which underwent cardiopulmonary bypass.…”

Cytokine Changes in Cerebrospinal Fluid and Plasma Post-Emergency Orthopaedic Surgery

“…Cytokine activation is only part of the neuroin ammatory process after surgery [1]. Other studies in this eld have looked at the CSF to serum albumin ratio before and after surgery as a marker of BBB integrity [6,7,23]. We did not investigate markers of neuronal injury, such as S-100B, t-tau, neuronal speci c enolase (NSE) and neuro lament light chain protein (NFL), which other studies have investigated [24].…”

“…Some cytokines tend to have a pro-in ammatory role; IL-1β, IL-6 and IL-8, while others, such as IL-4, IL-10 and IL-13, tend to be anti-in ammatory [4]. Studies on elective surgical patients have shown that there are greater post-operative cytokine increases in the cerebral spinal uid (CSF) than in plasma [5,6,7]. There is also some evidence to suggest that CSF cytokine changes may be associated with PND.…”