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Background. Brain dysfunction may be the most important and least studied problem afflicting the aging SCD population. 25% of neurologically intact pediatric SCD patients have NP dysfunction and silent CNS infarction. In children, age is associated with progressive decline in NP scores suggesting adults are at risk for progressive brain injury and NP decline. Objective. To determine the extent of NP impairment, the prevalence of MRI abnormalities, and their relationship in neurologically asymptomatic adult SCD patients compared to national norms and matched controls. Methods. Patients (21–55 yrs) with HbSS, normal neurologic exams and no history of stroke or abnormal neuroimaging, were recruited from 11 centers and screened for mental status and depression. The patient to control ratio goal was 3:1. After consenting, participants completed NP tests that assessed verbal and nonverbal intelligence, academic achievement, executive functioning, processing speed (PS), attention, and memory. Tests included the Wechsler Adult Intelligence Scale (WAIS-III), the Wechsler Memory Scales (WMS-III), the Woodcock-Johnson Tests of Achievement (WJ III), the Test of Everyday Attention (TEA), and others. Participants underwent standardized brain MRI read for atrophy and lesions. Volumetric analysis (vMRI) quantitated white and grey matter. Results. This is a report of 138 of the 150 planned SCD subjects and 37 controls: 62% female, 21–29 yrs, with mean hemoglobin (Hb) 8.2g/dl. 32% and 39% of patients scored one standard deviation (below 86) on the WAIS-III Performance IQ (PIQ) and PS index (PSI) scores compared to 16% in national norms. 26% and 22% of patients scored below 86 on the WMS-III visual immediate and immediate memory scales compared to 16% in national norms. Controlling for age, gender, and education, patients and controls differed significantly on the WAIS-III PSI Score, −14.1 (95% CI of −19.2 to −9.0) and the WJ-III including reading, math and following directions. Subtests of attention and flexibility of thought of the TEA significantly decreased with age in patients but not controls. In 82 patients with MRIs, 63% had an abnormal MRI or NP dysfunction, 38% had atrophy and/or ischemic lesions, and 18% had ischemic lesions only. Low PIQ and PSI were significantly associated with ischemic lesions. In vMRI, adjusting for age and gender, hippocampal volume in patients was 541.1 μL < controls (95% CI of 212.0, 870.3) and CSF volume in patients was 16 mL > controls (95% CI of 1.7, 31.5). These dfferences were significant. Patient Hb was a significant independent predictor of verbal IQ, PIQ, PSI, math, and executive function (Pearson r = .20 –.28). Conclusion. NP dysfunction and/or undetected brain injury affect the majority of neurologically intact adults with SCD, especially in areas of executive functioning, reading and math fluency. Patients with lower Hb have lower IQ scores. Ischemic lesions, alone, do not account for the extent of the NP impairment observed. Hb, age, and hippocampal volume were predictive of NP dysfunction, suggesting a link between reduced oxygenation, neuronal loss, and cognitive impairment. This supports the importance of a transfusion trial to improve NP function.

The proportion of some a chain variants in the peripheral blood of heterozygotes has been a most useful marker for the number and activity of the a chain genes of human hemoglobin. Among these, Hb G-Philadelphia(or α2 68Lys β2) has been found in association with a heterozygous or a homozygous α-thal-2, a β-thal trait (AGAβTH) or a Hb S heterozygosity (ASAG) and a Hb S homozygosity (SSG). Hb G-Philadelphia heterozygotes differ in the proporticn of Hb G, MCV and MCH values and Σα/non-α biosynthetic ratios. Two categories have been noted in our laboratories among adult heterozygotes., peer-reviewed