The study, conducted at Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, focused on complement component C1q, the molecule that fires the opening shot of the classical complement cascade. C1q is an elaborate glycoprotein built from 18 polypeptide chains, with a collagen-like tail that orchestrates immune signaling and a globular head that recognizes a wide range of molecular targets on pathogens, damaged cells, and debris. Long known for its role in tagging microbes and cellular wreckage for destruction, C1q has increasingly been implicated in chronic inflammatory disease, vascular injury, and, intriguingly, in the brain itself. In the central nervous system, C1q helps prune synapses during development, but when reactivated in adulthood, it can drive microglial cells to eliminate synapses that are still needed, a mechanism linked to cognitive decline in several conditions.

The researchers drew on a prospective observational study of neurological complications after type A aortic dissection surgery, registered with the Chinese Clinical Trial Registry. Between January and December 2022, 265 patients scheduled for emergency aortic surgery were screened, and 67 met the strict inclusion criteria: adults with confirmed acute type A dissection undergoing open thoracotomy, free of prior neurological or psychiatric disease, severe cerebral infarction, pregnancy, malignancy, or terminal illness. Blood samples were collected at three time points: immediately upon admission before surgery, on the first morning after the operation, and, for patients who developed delirium, on the morning after they were assessed as awake. Serum C1q concentrations were quantified with a human C1q-specific enzyme-linked immunosorbent assay, while delirium was diagnosed using the Confusion Assessment Method and its ICU variant, administered twice daily for the first three postoperative days and then daily for four more days by trained investigators.

The results were striking. Roughly 55 percent of the enrolled patients developed postoperative delirium, a rate consistent with previous reports for this operation. Those who did had markedly higher serum C1q before surgery: a median of 12.72 nanograms per milliliter, compared with 9.31 nanograms per milliliter in patients who remained clear-headed. The difference persisted after surgery and even after delirious patients regained full awareness, suggesting that elevated C1q is not simply a fleeting response to the trauma of the operation. In univariate logistic analysis, both preoperative and postoperative C1q levels significantly predicted delirium, with preoperative values showing the stronger performance. When the team built a multivariable model refined with LASSO regression and cross-validation, preoperative C1q remained an independent predictor alongside the type of cerebral perfusion used during surgery, with patients receiving retrograde cerebral perfusion facing substantially higher odds of delirium.

The predictive power of the biomarker was quantified with receiver operating characteristic analysis. Preoperative serum C1q achieved an area under the curve of 0.788, with a sensitivity of 65.4 percent and a specificity of 78.4 percent, a level of discrimination that compares favorably with existing candidates such as neuron-specific enolase and S100β, both of which have shown limitations in this clinical setting. Perhaps most compelling was the dose-response relationship. When patients were divided into quartiles by preoperative C1q concentration, the risk of delirium climbed steeply across the gradient: compared with the lowest quartile, the adjusted odds of delirium were 6.72-fold higher in the third quartile and 21.02-fold higher in the fourth, with a statistically significant trend across quartiles. This graded relationship strengthens the case that C1q is not merely correlated with delirium by chance but tracks a genuine biological gradient of susceptibility.

Why would a complement protein measured in the blood, before any surgical insult, foreshadow a delirium that emerges days later? The authors propose that C1q reflects a pre-existing state of immune-inflammatory activation that primes the brain for injury. Delirium is thought to arise when systemic inflammatory mediators cross the blood-brain barrier and activate microglia, the resident immune cells of the brain, triggering neuroinflammation that disrupts synaptic function. Notably, in this study, preoperative C-reactive protein showed only a trend toward elevation in the delirium group without reaching statistical significance, hinting that the relevant process may be neuroinflammatory rather than a blunt systemic inflammatory response. C1q, with its established role in tagging synapses for microglial elimination, fits this picture neatly. In sepsis-associated encephalopathy, recent work has shown that microglia mediate cognitive deficits by engulfing C1q-tagged synapses, and that pharmacologically reducing C1q levels with the oral blocker PLX5622 can prevent neuronal damage and improve neurocognitive outcomes.

C1q also has documented effects on the vasculature that may be relevant to aortic dissection patients specifically. The protein induces proliferation of vascular smooth muscle cells, and elevated circulating levels have been identified as a risk factor for atherosclerosis and arteriolar vasculopathy. In the context of dissection surgery, where cerebral perfusion is deliberately interrupted and restored, and where deep hypothermic circulatory arrest imposes ischemia-reperfusion stress on the brain, a vasculature already primed by complement-driven remodeling may be less resilient. The study found that delirium patients spent longer on mechanical ventilation, stayed in the intensive care unit substantially longer, and suffered pulmonary infections far more often than their non-delirious counterparts, underscoring the clinical weight of this complication even when it appears transient.

The findings do not stand alone. The same group recently reported that serum NPTX2, a marker of synaptic plasticity and neuronal integrity, also predicts postoperative delirium in acute type A dissection patients, with an area under the curve of 0.895 for postoperative measurements. The two biomarkers appear to capture complementary dimensions of the disease: NPTX2 reflects the vulnerability of neurons and synapses, while C1q signals activation of the immune-inflammatory cascade that can exploit that vulnerability. Together, they sketch a two-hit model in which a brain with weakened synaptic reserves meets an immune system primed for complement-mediated attack. The authors suggest that integrating both measurements into preoperative assessment could enable multidimensional risk stratification, allowing clinicians to identify high-risk patients before surgery and to intensify postoperative surveillance, for example by administering cognitive assessments multiple times daily in the ICU.

The research carries clear caveats. The cohort of 67 patients is small, and the authors acknowledge that the findings may not generalize to broader populations. The original study’s blood collection protocol excluded many patients whose samples were inaccessible or hemolyzed, raising the possibility of selection bias, and ethical constraints prevented the comparison of serum C1q with cerebrospinal fluid levels, leaving the link between blood measurements and brain biology indirect. Height, which appeared significant in univariate analysis, was excluded from the final model as biologically implausible and likely a proxy for frailty or nutritional reserve. Even so, the study is the first to demonstrate that preoperative C1q is elevated in patients who go on to develop delirium after aortic dissection, establishing complement pathway activation as a candidate susceptibility marker rather than a mere acute-phase echo of surgical stress. If larger trials confirm the result, complement profiling could become a routine part of preoperative evaluation for one of cardiac surgery’s most feared complications, and drugs that temper the complement cascade, already in development for other conditions, could open a genuine therapeutic frontier for protecting the surgical brain.

Subject of Research: Serum complement C1q as a predictive biomarker for postoperative delirium after acute type A aortic dissection surgery

Article Title: Serum C1q as a Novel Predictive Biomarker for Postoperative Delirium After Acute Type A Aortic Dissection

Article References: Serum C1q as a Novel Predictive Biomarker for Postoperative Delirium After Acute Type A Aortic Dissection. (n.d.). https://doi.org/10.1002/iid3.70500

Image Credits: AI Generated

DOI: 10.1002/iid3.70500

Keywords: C1q, complement system, postoperative delirium, aortic dissection, biomarker, neuroinflammation, cardiac surgery, microglia, NPTX2, risk prediction, cerebral perfusion, ICU