Cognitive Function, Sarcopenia, and Inflammation Are Strongly Associated with Frailty: A Framingham Cohort Study

Background: Frailty is an important contributor to morbidity and mortality in chronic liver disease. Understanding the contributors to frailty has the potential to identify individuals at risk for frailty and may potentially provide targets for frailty-modifying interventions. We evaluated the relationship among cognitive function, inflammation, and sarcopenia and frailty. Methods: Using cohorts from the Framingham Heart Study (2011-2014), we evaluated for factors associated with frailty. Exposures included cognitive tests (combined Trails A/B test, Animal Naming Test, and combined Digit Span Forward/Backward test), inflammation (interleukin-6 and tumor necrosis factor receptor II), and sarcopenia (creatinine-to-cystatin C ratio). We performed linear and logistic regression to identify the relationship between these exposures and the Liver Frailty Index (LFI). Results: The study population (N = 1208) had a median age of 70 years, was 56% female, and 48.5% had evidence of liver disease. The combined Trails A/B test (β 0.05, P <.001), creatinine-to-cystatin C (β -0.17, P =.006), and both inflammatory markers, interleukin-6 levels (β 0.16, P =.002) and tumor necrosis factor receptor II (β 0.21, P =.04), were independently associated with the LFI. Using an LFI cutoff of ≥4.5 to define frailty, Trails A/B (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07-1.37), Animal Naming Test (OR 0.64, 95% CI 0.42-0.97), sarcopenia (OR 0.10, 95% CI 0.01-0.73), and interleukin-6 (OR 4.99, 95% CI 1.03-15.53) were all associated with frailty. Although liver disease did not modify the relationship between the LFI and the Trails A/B test, interleukin-6 was significantly associated with the LFI only in the presence of liver disease. Conclusions: Cognitive performance, inflammation, and sarcopenia, each highly prevalent in cirrhosis, are associated with the LFI in this population-based study of persons without cirrhosis. Further research is warranted for interventions aiming to prevent frailty by tailoring their approach to the patient's underlying risk factors.