Impact of sleep, fatigue, and systemic inflammation on neurocognitive and behavioral outcomes in long-term survivors of childhood acute lymphoblastic leukemia

Abstract

Background: Long-term survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive impairment, which may be associated with fatigue, sleep problems, systemic inflammation, and oxidative stress. We examined these associations among survivors of childhood ALL treated with chemotherapy only.

Methods: Survivors of childhood ALL (male, n = 35 and female, n = 35; mean age, 14.3 years [standard deviation, 4.7 years] and mean years from diagnosis, 7.4 years [standard deviation, 1.9 years]) completed neurocognitive testing, behavioral ratings, and reported sleep quality and fatigue symptoms 5 years after diagnosis. Serum was collected concurrently and assayed for interleukin (IL)-1β and IL-6, tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hsCRP), malondialdehyde, myeloperoxidase, and oxidized low-density lipoprotein. General linear modeling was used to assess associations among biomarkers and functional outcomes, adjusting for age and stratified by sex.

Results: Survivors performed worse than population norms on executive function and processing speed and reported more behavioral problems (P < .05 adjusted for multiple comparison). In female survivors, fatigue was associated with poor executive function (r = 0.41; P = .02), processing speed (r = 0.56; P < .001), and attention (r = 0.36-0.55; P < .05). Female survivors with frequent nighttime awakening displayed more inattention (P = .01), hyperactivity (P = .03), and aggression (P = .01). Worse executive function, processing speed, and behavioral symptoms were observed in female survivors with higher levels of IL-6, IL-1β, and hsCRP (P < .05). Male survivors with high levels of TNF-α demonstrated worse organization (P = .03), but no significant associations between neurocognitive outcomes and sleep/fatigue measures were observed.

Conclusion: Neurocognitive function in female survivors of childhood ALL appears more susceptible to the effects of sleep disturbance and fatigue. Systemic inflammation may play a role in neurocognitive impairment and behavioral symptoms. Cancer 2017;123:3410-9. © 2017 American Cancer Society.

Keywords: behavioral; childhood acute lymphoblastic leukemia; fatigue; inflammation; neurocognitive; oxidative stress; sleep; survivorship.

Figure 1. Association between Sleep Duration and Executive Function

Longer duration of sleep was associated with worse executive function in female survivors but less consistently in male survivors. Associations between sleep duration and other neurocognitive/behavioral measures are presented in Supplementary Material 4. A: Cognitive flexibility (Males: r=−0.47, P=0.01; Females: r=0.68, P<0.0001); B: Verbal fluency (Males: r=0.08, P=0.68; Females: r=−0.50, P=0.004). C: Organization (Males: r=−0.04, P=0.83; Females: r=−0.47, P=0.01).

Figure 2. Association between Frequent Nighttime Awakening and Behavior in Female Survivors

Female survivors who reported frequent nighttime awakening displayed more behavioral symptoms than those who did not, in (A) inattention, P=0.01; (B) hyperactivity/impulsivity, P=0.03; (C) learning problems, P=0.01; (D) defiance/aggression, P=0.04. Such associations were not observed in male survivors; associations between sleep variables and other neurocognitive/behavioral measures are presented in Supplementary Material 4.

Figure 3. Association between Inflammatory Biomarkers and Executive Function/Processing Speed in Female Survivors

Comparison of each executive function/processing speed measure was conducted between female survivors within the top tertile, versus those within other tertiles, for IL-6 (A), IL-1β (B) and CRP (C). Female survivors within the top tertile demonstrated worse performance on multiple measures of executive function and processing speed, as compared to those within other tertiles. Associations between inflammatory biomarkers and other neurocognitive/behavioral measures are presented in Supplementary Material 7.