Chronic and Acute Systemic Inflammation and Long-Term Cognitive Decline

Abstract

Chronic inflammation is commonly proposed to contribute to brain dysfunction in various medical conditions and ageing processes. Additionally, acute inflammation has also been frequently proposed to threaten brain integrity in patients requiring critical care for infections, including, most recently, Sars-Cov-2 infection. <br /> Both chronic and acute inflammation occur among cardiac surgery patients. These processes may, individually or combined, contribute to cognitive impairment. Examination of inflammatory levels both before and after surgical intervention among heart surgery patients requiring critical care enabled examining both inflammatory processes on long-term cognition in three separate study cohorts. Importantly, this kind of direct investigation of two important aspects of inflammation and cognition in the same cohort has not been done before. Cardiac surgery patients offer the chance to investigate the non-septic effects of chronic and acute inflammation on long-term cognition. <br /> Study one examined a cohort of 125 transcatheter aortic valve implantation (TAVI) patients (mean age 80.5 years) monitored at the intensive care unit. All patients had comparatively low cognitive performance prior to surgery based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Strong main effects of elevated pre-surgery levels of C-Reactive Protein (CRP) and Interleukin-6 (IL-6) and a higher propensity to develop post-operative systemic inflammatory response syndrome (SIRS) on cognitive performance over 12 months were revealed, i.e., associations with poorer cognition were shown to begin prior to surgery, and it continued throughout the follow-up period. The actual cognitive trajectory over time was modified by Interleukin-8 peak level after surgery, with a more significant decline in cognition. The opposite was true for presurgery Leukocyte counts, with a more rapid improvement in cognition over time. The cognitive trajectory was not modified by the event of SIRS or by either chronic or acute levels of CRP, Procalcitonin, or IL-6. <br /> Study two examined a younger sample of 215 cardiac surgery patients (mean age 69.7 years) over six months who underwent one of two types of heart valve implant (mitral or aortic) or a coronary artery bypass graft using a narrow panel of three inflammatory markers. This population was altogether cognitively healthier compared to that of study one. The primary measure used was the Mini-Mental Status Examination. The acute rise and absolute peak levels of the inflammatory marker CRP were negatively associated with a global cognitive screening score six months later, after controlling for presurgery cognition, although the effects were small. The clinical syndrome of SIRS did not associate with cognitive performance over time. A subset of patients in this study was given more in-depth cognitive examinations, which yielded similar results. <br /> Study three used a broader panel of inflammatory biomarkers and an in-depth neuropsychological examination in a small sample of 31 major surgery patients aged an average of 64 years. Almost all underwent cardiac surgery and were kept in the intensive care unit for monitoring. SIRS diagnosis was negatively correlated with working memory (digit span backward) and positively with presurgery IL-6. S100 post-surgery at Visit 2 negatively correlated with delayed verbal recall (VLMT Trial 7). Different relationships for individual cytokines, notably procalcitonin, and Interleukin-6, explain variance in global cognition or verbal delayed recall. Hence, there appears to be an association, albeit different, depending on the particular inflammatory measure between acute systemic inflammation and long-term cognitive performance. Several pre-operative inflammatory levels did correlate with long-term cognitive performance. <br /> Together these three studies show no simple, straightforward relationship between chronic or acute inflammatory states and cognition while controlling for age as an essentialbiological factor. Hence, worse cognitive performance occurs in those experiencing higher degrees of inflammation, both chronic (i.e., sampled prior to operation) and acute (highest level after operation). What was not shown was a modification of the trajectory of cognitive performance itself, i.e., an overall strong association with inflammatory biomarkers on the general level of cognitive performance. Interaction effects between chronic and acute systemic inflammation were, on the whole, not supported by the data.