Sickle cell disease (SCD) is an inherited hemoglobin disorder that affects approximately 100,000 Americans and causes progressive organ damage, acute and chronic pain, and ischemic brain lesions ¹. As patients age, medical complications and neurocognitive deficits intensify ^2,3.

The neurocognitive effects of SCD emerge in the early developmental period and persist into adulthood ^4,5. In addition to reduced global intellectual functioning (i.e., full scale intellectual quotient [FSIQ]), adults with SCD also exhibit specific deficits in processing speed, working memory, and executive functioning skills ⁶. Executive functioning skills describe a range of complex mental activities required for goal-directed behavior, including focused attention, cognitive flexibility, strategic planning, and inhibitory control. Although neurocognitive difficulties are exacerbated by cerebrovascular events in SCD, weaknesses also exist in the absence of overt stroke or silent infarct ⁷.

Engagement in daily living activities relies on various skills that increase in complexity and are supported by neurocognitive processing ⁸. Adaptive daily living (ADL) skills describe basic tasks, such as ability to independently eat, dress, and ambulate, whereas instrumental activities of daily living (IADL) include complex skills that support independent living within the community ⁹. Examples of IADL skills include money management, responsibility for medications, domestic life activities, learning, self-care, interpersonal interactions and relationships, and community, civil, and social life ^8,10. IADL skills require more complex neuropsychological abilities than ADL skills and are most susceptible to cognitive changes ¹¹. Executive dysfunction has emerged as the best predictor of decline in IADL skills, even when accounting for health status, age, and education in the general population ¹².

Adolescents and young adults with SCD report weaknesses in IADL skills that limit independence and impact participation in societal activities, including money management, vocational skills, living arrangements, health care knowledge, and emergency preparedness ¹³. In a robust international sample, more than a third of individuals with SCD reported that the disease impacted their participation in daily household chores and social activities ¹⁴. Medication adherence, another aspect of IADL skills, is often poor among youth and adults with SCD ¹⁵.

Workforce and educational engagement represent another marker of IADL skills. The rate of employment for individuals with SCD in the U.S. is below the general population and estimates of workforce participation span 15–56% ^5,16. Emerging evidence has suggested that reduced intellectual functioning, lower educational attainment, female gender, reduced assertiveness, and perceived impact of disease are all predictors of unemployment in individuals with SCD ^5,17. In several studies, the rate of disabled participants has exceeded the rate of unemployed individuals, with prevalence rates of disability status spanning 28–37% ^18,19.

Patient reported outcome (PRO) measures allow patients to directly communicate information regarding disease-related symptoms, as well as symptoms specific to cognitive, psychological, adaptive, and social concerns. PROs facilitate patient-centered care and can be used as primary or secondary outcome measures with patients who have SCD ²⁰. Incorporation of PROs into clinical care can facilitate patient engagement, support individualized care through shared decision-making, and improve patient outcomes by identifying areas of healthcare and psychosocial needs ²¹.

The relation of PRO measures of cognitive difficulties and IADL skills in SCD is not well understood. In the present study, we examined PRO measures of cognitive difficulties in areas of attention, executive functioning, processing speed, learning, and comprehension. We report the prevalence of self-reported cognitive difficulties in a large sample of adolescents and adults with SCD and tested the hypothesis that patients who reported daily difficulties across neurocognitive domains had lower IADL skills, including employment, school enrollment, independence, engagement in leisure activities, and medication adherence.

In the largest PRO study of individuals with SCD in the United States, more than half of adolescent and adult participants reported contending with cognitive difficulties on a regular basis, including inattention, poor executive functioning, reduced processing speed, and difficulty with comprehension. Difficulty with executive functioning skills, comprehension, and learning emerged as significant predictors of IADL skills (i.e., workforce engagement, independence, and leisure). Poor IADL skills were also associated with aging, chronic pain, and history of hydroxyurea use, and collectively, these variables appear to represent markers of disease impact and severity. Female gender was associated with worse IADL skills. Attentional difficulties were the only significant cognitive symptom associated with IADL skills when excluding participants who were disabled from analysis, suggesting that the influence of cognitive symptoms on IADL skills was more circumscribed for this subset of participants. These results are among the first to demonstrate that PRO measures of cognitive symptoms in SCD are associated with limited engagement in IADLs.

In the current study, a large proportion (40%) of participants reported missing at least one dose of hydroxyurea within the past week. Executive functioning difficulties, age (25–34 years old), severe genotype (Hb SS/Sβ⁰-thalassemia/SD/SO/SE), and hemoglobin concentration were significantly associated with medication non-adherence in multivariable modeling. Recent research has identified unintentional forgetting as a leading factor in hydroxyurea non-adherence and poor executive functioning skills may underlie forgetfulness ²⁶. Our results indicate that medication non-adherence is a significant challenge for adults with SCD and that symptoms of executive dysfunction play a primary role in predicting non-adherence. Hydroxyurea adherence varied by SCDIC site and our findings suggest differences in behaviors that impact medication adherence may be associated with location.

Cognitive difficulties described on PRO measures in the current study are consistent with normative weaknesses that have been identified on standardized performance-based measures. Reported problems with executive functioning skills were particularly impactful, which was expected given that executive functioning skills rely on attention and support some of our most complex IADL skills. Executive functioning skills undergo rapid development between adolescence and young adulthood when myelination increases in the frontal cortex ²⁷. Adults with SCD may be especially vulnerable to executive functioning deficits due to delayed or interrupted myelination as a result of chronic, sub-clinical hypoxic-ischemic events, or focal vascular injuries in the frontal lobe. Interestingly, patient-reported history of stroke was not associated with IADL skills or medication non-adherence, suggesting that cognitive symptoms, as opposed to formal neurovascular insult, may be more predictive of functional limitations with societal engagement and medication adherence.

Consistent with previous studies, we found that rates of unemployment in SCD (17%) are nearly three times greater than that of the general population and the prevalence of disability status (24%) is more than twice as high as rates in other racial and ethnic groups ²⁸. Individuals with severe sickle genotype, history of stroke, and no college degree had greater rates of workforce disengagement (i.e., unemployed, disabled and not working, and retired). Contrary to previous studies, we did not find a significant relationship between gender and specific cognitive symptoms or employment, which we believe is a reflection of our sample size and methodology ^17,23. Our findings indicate that the rate of African American or Black participants with a college degree (21% combined for undergraduate and graduate) is less than national estimates for this group (33.4%), hence suggesting that SCD complications have detrimental effects on post-secondary educational achievement and earning potential ²⁹.

There are several limitations to the current study. History of stroke was patient-reported and not verified with imaging studies, therefore, the rate of stroke in our study (22.2%) is likely inflated and may be reflecting the participants’ other cerebrovascular events (e.g., transient ischemic attacks or silent cerebral infarcts). Although PRO of neurocognitive symptoms was correlated with demographic and medical variables, symptoms could not be validated via performance-based measurement tools. Future studies should examine the concordance between patient-reported symptoms and deficits identified on formal evaluation using standardized measures. Further research is needed to examine additional markers of IADL skills including managing appointments and finances, navigating complex systems (e.g., healthcare and insurance), and community, civil, and social life to further elucidate the effect of SCD on independence and societal engagement. In our study, exploration of medication adherence was limited to hydroxyurea and a brief recall period (i.e., past seven days). Subjective data on medication adherence, as used in our study, is vulnerable to influence from social desirability and may over-estimate adherence ³⁰, thus our findings may not fully capture the extent of non-adherence. Our results suggest medication adherence varied by SCDIC site and future research is needed to elucidate factors that may contribute to these differences. Additional research is also needed to understand how cognitive symptoms and attitudes about medication efficacy impact adherence.

In conclusion, we found that self-reported neurocognitive symptoms predicted reduced IADL skills, including employment and post-secondary education, independence with daily tasks, and ability to engage in leisure activities, as well as poor medication adherence. The neurocognitive burden of SCD is high and IADL skills are particularly vulnerable to symptoms of cognitive dysfunction. Targeted interventions to improve executive functioning skills (e.g., mobile applications that deliver cognitive remediation training) that are cost- and time-sensitive should be prioritized within this population, as this will support societal engagement and medication adherence. Mobile health (mHealth) apps to improve medication adherence and self-efficacy among individuals with SCD are currently being investigated through the SCDIC ^31,32. Further, programming should be developed to support employment and educational pursuits among individuals with risk factors for disengagement. Self-report of neurocognitive difficulties could be considered as an adjunct clinical tool in monitoring patient functional skills that impact engagement in societal activities and medication adherence. When collected prior to transition to adult care, PRO of executive functioning difficulties can be used to proactively guide future interventions to enhance employment and medication adherence.