Background: Increasingly studied are the neurocognitive complications in adults with SCD. The most common presentation of such is a decline in executive function, described mainly in the pediatric SCD population which occurs independent of MRI changes on brain imaging. The NIH toolbox is a battery of cognitive tests that have been shown to correlate with cognitive decline in various populations.

Methods: This was a prospective observational study conducted at MedStar Washington Hospital Center in between 2022-2025, with IRB approval. We recruited SCD patients presenting with VOC to our ED, and then after written informed consent, assessed them cognitively at baseline, and at 6 month-increments with planned followed up for 18 months. During each cognitive assessment we applied the Cognitive NIH Toolbox to assess their cognitive function in six domains (executive function, attention, episodic memory, language, processing speed, and working memory) which is a simple test that can be perfomed in clinic. Scores were compared to national average cognition scores and adjusted for age.

Results: 44 patients with SCD were analyzed: 43/44 were Black and 1/44 was Hispanic. 63% were HbSS (28/44), followed by 20% of HbSC (9/44) and 11% of HbS/β Thalassemia (5/44), there was minimal representation of HbSS with alpha thalassemia trait (1/44), and HbSC with alpha thalassemia trait (1/44). Average age was 31 years old (range 21-45). The average number of VOC was 1.5 during the first period of 6 month follow up. Strikingly, compared to the national average, 100% of SCD patients scored below than the age matched controls on 5 out of 7 batteries of tests (p <0.001) (List Sorting Working Memory, Pattern Comparison, Picture Sequence Memory, Flanker Inhibitory Control, Dimensional Change Card Sort). The remaining 2 tests, both calculated through raw scores, required age group sub-analysis. In the Raw Score Oral Symbol Digit Test from age 18-29, SCD patients had statistically significant lower scores than the national average (p<0.001). In older age groups a similar association could not be established due to small sample size.

We collected data to characterize their baseline risk factors. We did not observe a correlation between the number of recent VOC in the past six months and neurocognitive scores, nor with a self-reported history of stroke (although number was small). Interestingly, using the Pattern Comparison test, we noted that individuals without a recent diagnosis of acute chest syndrome (ACS) scored 11.5 points higher than those recently managed for ACS (n=27 vs. n=17; 95% CI: [0.59, 22.41], p=0.039). We also evaluated hemoglobin levels and found that participants with a baseline hemoglobin level below 7 mg/dL exhibited significantly worse scores on the Auditory Verbal Learning Test (95% CI: [1.48, 7.13], p=0.004). There were no observed differences in neurocognitive scores when comparing degrees of hemolysis (LDH> 300 vs. LDH <300). Similarly, no differences were noted in scores between participants taking Hydroxyurea or Crizanlizumab and those who were not. Compliance was not assessed.

Six-month and 12-month follow-up was completed for 54% (24/44) of participants. Changes in neurocognitive scores were noticed using the Pattern Comparison test and the Picture Sequence Memory test. [(Age-correlated Standard Score Pattern Comparison at 6 month was 7.9 higher than at baseline (95% CI: [1.6, 14.3], p=0.017, Age-correlated Standard Score Picture Sequence Memory at 6 month was 9.4 higher than at baseline (95% CI: [1.06, 17.8], p=0.030)]. We then looked at whether the changes in the mean scores were correlated with the number of VOC (< 2 vs. ≥ 2 episodes). There was a trend to lower neurocognitive scores in patients with higher number of VOC with a change in mean score more apparent at 12 months, although there was no statistically significant correlation. All other five domain scores of the test battery remained unchanged during follow up evaluations.

Conclusion: AdultSCD patients have lower neurocognition scores in all domains using the NIH toolbox cognitive battery of tests when compared to the age-matched normal controls. To our knowledge, we are the first to report serial neurocognition testing in non-pediatric SCD patients that suggests that disease severity, assessed by degree of anemia and ACS, lowers neurocognition. We believe that this testing approach can be incorporated into clinical practice.

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2025
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