Human Alzheimer and Inflammation Biomarkers after Anesthesia and Surgery

Abstract

Background The prevalence of post-operative cognitive disturbance, coupled with growing in vitro, cell and animal evidence suggesting anesthetic effects on neurodegeneration, calls for further study of the interaction between surgical care and Alzheimer neuropathology. Here, we study human cerebral spinal fluid (CSF) biomarkers perioperatively. Methods Eleven patients undergoing idiopathic nasal CSF leak correction joined this Institutional Review Board approved study. Lumbar subarachnoid catheters were placed prior to the procedure. Anesthesia was total intravenous anesthesia (propofol/remifentanil) or inhalational (sevoflurane), depending on provider choice. CSF samples were taken after catheter placement (base), at procedure end (0h), and then at 6, 24 and 48h. CSF was analyzed using xMAP Luminex immunoassay (Luminex, Austin, TX). Results Patients: 53±6 yrs old; 8 women; 4 received intravenous anesthesia, 6 sevoflurane, 1 mixed. Procedures lasted 6.4 ± 2h. Mean CSF amyloid-β1-42 remained unchanged, but total-tau and phosphorylated-tau181P increased progressively until at least 48h. Total-tau, phosphorylated-tau or amyloid-β1-42 levels were not different between anesthetic groups. CSF interleukin-10, S100B and tumor necrosis factor alpha were increased similarly in both anesthetic groups at 24h, but interleukin-6 was increased more in the inhalational group. Conclusion These data indicate a robust neuroinflammatory response, including not only the usual markers (interleukin-6, tumor necrosis factor α, interleukin-10), but also S100B and tau, markers of injury. The total-tau/amyloid-β1-42 ratio increased in a pattern consistent with Alzheimer disease, largely due to an increase in total-tau rather than a decline in amyloid-β1-42. The differences in CSF interleukin-6 levels, suggest that anesthetic management may make a difference in neuroinflammatory response.

The immune response of the human brain to abdominal surgery

“…This observation is in line with results from earlier animal models 2-4 and supports the hypothesis that the postoperative cognitive dysfunction syndrome is related to surgery-induced activation of the brain immune system. [2][3][4] This was further supported by an association between acute changes in systemic IL-6 and long-term cognitive performance at follow-up.…”

“…This observation is in line with results from earlier animal models 2-4 and supports the hypothesis that the postoperative cognitive dysfunction syndrome is related to surgery-induced activation of the brain immune system. [2][3][4] This was further supported by an association between acute changes in systemic IL-6 and long-term cognitive performance at follow-up.The lack of relationship between simultaneous changes in systemic cytokines and brain [ 11 C]PBR28 binding are in agreement with a recent human study showing no correlation between changes in TSPO and systemic cytokine levels after LPS infusion. 28 It may be argued that measured plasma levels of inflammatory mediators reflect the net balance of production and degradation during a prolonged timespan, which is the combined production from multiple cell types, including stromal cells, for example, endothelial cells and hepatocytes, as well as blood-borne immune cells.…”

“…[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.…”

“…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.…”

“…[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, memory, and concentration termed postoperative cognitive dysfunction.…”