Inflammation Linked to Cognitive Difficulties in Childhood ALL Survivors

Female survivors of childhood acute lymphoblastic leukemia (ALL) were at risk for neurocognitive impairment and were more susceptible to the effects of sleep disturbance and fatigue compared with their male counterparts, according to the results of a study published in Cancer.

“Our results support the contribution of poor sleep and fatigue to neurocognitive impairment and behavioral symptoms in adolescent survivors of childhood ALL, and suggest that systemic inflammation may be one of the critical pathophysiological basis linking these functions,” wrote Yin Ting Cheung, PhD, of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital in Memphis, and colleagues. “Female survivors appear particularly sensitive to the adverse effects of sleep, fatigue, and systemic inflammation.”

Survivors of ALL are at risk for a variety of late effects including neurocognitive impairment and significant fatigue and sleep disturbances. One possible explanation for the impaired sleep and fatigue is systemic inflammation. In this study, Cheung and colleagues evaluated the effect of sleep and fatigue on neurocognitive function of survivors of ALL and the associations of biomarkers of inflammation and oxidative stress with neurocognitive outcomes.

The study included 70 adolescent survivors of ALL. Participants completed neurocognitive testing, behavioral ratings, and reported sleep quality and fatigue symptoms 5 years after diagnosis. In addition, blood was collected and tested for a variety of inflammation biomarkers.

Overall, about two-thirds of participants reported delayed sleep onset, and 30% to 40% had frequent nighttime and premature awakenings.

In female survivors of ALL, a higher level of general fatigue was associated with poorer performance on cognitive flexibility, processing, and multiple measures of attention (P < .05). Higher cognitive fatigue among female survivors was linked with more parent-reported neurobehavioral symptoms, and more self-reported inattention, hyperactivity, learning problems, and aggression (P < .05). In contrast, among the male survivors, higher fatigue was only associated with more self-reported inattention problems (P < .05).

Female participants with frequent nighttime awakening also had more self-reported behavioral symptoms and lower performance on cognitive flexibility and processing speed.

“Sex differences for fatigue, sleep duration, and neurocognitive measures were somewhat surprising and might be attributed to more prevalent self-reported symptoms of fatigue in female survivors,” the researchers wrote.

The analysis of inflammatory biomarkers showed worse executive function, processing speed and behavioral symptoms in female survivors with high levels of interleukin-6, interleukin-1beta, and high-sensitivity C-reactive protein (P < .05). No significant association between neurocognitive outcomes and sleep/fatigue measured were observed among the male survivors.

“There is mounting evidence in the literature that supports inflammatory mediators and immune cells as principle regulators of brain sexual differentiation, other than just neurotransmitters and sex hormones,” the researchers wrote. “Because the levels of biomarkers were similar between male survivors and female survivors in our sample, it is plausible that female survivors of ALL may be more sensitive, with a lower physiologic threshold for the effects of chronic inflammation.”