Effects of metabolic syndrome on cognitive outcomes in long-term survivors of childhood cancer.
Authors: Alexander Tyler , Liu Wei , Dixon Stephanie B , Williams AnnaLynn M. , Chemaitilly Wassim , Mulrooney Daniel A. , Ness Kirsten K. , Brinkman Tara M. , Banerjee Pia , Srivastava Deokumar , Robison Leslie L. , Hudson Melissa M. , Krull Kevin R. 
Published: June 2021

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Background: Childhood cancer therapy increases risk for cognitive impairment and other chronic conditions, which also may impact cognition. We assessed the unique impact of metabolic syndrome (MetS) on cognition in survivors participating in the St. Jude Lifetime Cohort Study. Methods: Participants included 4058 survivors of childhood cancer (53.9% female; mean [SD] age 30.1 [10.5] years at evaluation; 22.6 [10.1] years from diagnosis) who completed clinical evaluation and cognitive testing. MetS criteria followed Adult Treatment Panel III guidelines (at least 3 of: hypertension, high triglycerides, abdominal obesity, low high-density lipoprotein [HDL], high fasting glucose). Multivariable log-binomial regression models assessed risk of cognitive impairment associated with MetS stratified by survivors who did (n = 2301) or did not (n = 1757) receive central nervous system (CNS)-directed therapy. Mediation analysis assessed effects of MetS and physical activity in cranial radiotherapy (CRT)-associated cognitive impairment. Models were adjusted for age, sex, follow-up time and treatment exposures. Results: MetS was associated with increased risk of impaired attention (relative risk [RR] 1.34 95% confidence interval [CI] 1.07-1.66), processing speed (RR 1.25 CI 1.11-1.41) and executive function (RR 1.18 CI 1.01-1.37) in survivors with CNS-directed therapy and academic achievement (RR 1.84 CI 1.18-2.89), attention (RR 1.43 CI 1.10-1.87), and processing speed (RR 1.46 CI 1.21-1.75) in those without CNS-directed therapy. MetS components associated with cognitive impairment included abdominal obesity (memory RR 1.34 CI 1.13-1.59; processing speed RR 1.41 CI 1.24-1.59; executive function RR 1.21 CI 1.05-1.39) and low HDL (intelligence RR 1.26 CI 1.06-1.49; attention RR 1.27 CI 1.03-1.57; processing speed RR 1.17 CI 1.01-1.35; executive function RR 1.20 CI 1.05-1.37) in survivors with CNS-directed therapy. In survivors treated without CNS-directed therapy hypertension (academic achievement RR 1.49 CI 1.18-1.88; intelligence RR 1.34 CI 1.02-1.76; attention RR 1.42 CI 1.12-1.79; memory RR 1.45 CI 1.14-1.84; processing speed RR 1.30 CI 1.08-1.55; executive function RR 1.32 CI 1.08-1.62) and abdominal obesity (academic achievement RR 1.71 CI 1.07-2.72; processing speed RR 1.23 CI 1.02-1.49; executive function RR 1.38 CI 1.09-1.75) were associated with impairment. In mediation analyses, direct effects of CRT were identified, as were indirect effects through physical activity (processing speed β = 0.035 p < 0.01; attention β = 0.03 p < 0.01; executive function β = 0.172 p < 0.01). Conclusions: MetS increases risk of cognitive impairment in survivors, particularly abdominal obesity, hypertension and low HDL. Physical activity appears to partially mediate impact of CRT on cognitive outcomes and is an important target for interventions to lower impairment risk.