Kari Struemph

Neurofibromatosis type 1 (NF1) is a genetic syndrome affecting about 1 in 3500 individuals; many of those affected have plexiform neurofibroma (pNF) tumors and associated symptoms and complications. Furthermore, learning and attention problems, as well as deficits in adaptive functioning, are common, often beginning in early childhood. This study aimed to describe adaptive functioning and to examine relationships between adaptive functioning and cognitive and academic variables and level of independence among adolescents and young adults (AYA) with NF1 and pNF tumors. Fifty‐five AYA aged 16–31 years participated in a series of neuropsychological evaluations while parents completed the Vineland Adaptive Behavior Scales (VABS‐II) as part of a larger natural history study. Over one‐third (35%) of AYA were neither in school nor employed. Mean VABS‐II daily living and socialization scores were low average while mean Verbal and Performance IQ scores were average. VABS‐II scores were positively correlated with processing speed, executive functioning, and working memory scores. Verbal IQ was the only significant predictor of work/school status. Identification of the correlates and predictors of adaptive functioning and life achievement can help guide healthcare providers with the early identification of risk factors and possible areas for intervention.

Background and Objectives Neurofibromatosis type 1 (NF1)-associated cognitive impairments carry significant lifelong morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of mitogen-activated protein kinase inhibitor (MEKi) treatment. Methods Fifty-nine patients with NF1 aged 5–27 years on an MEKi clinical trial treating plexiform neurofibroma underwent pretreatment and follow-up cognitive assessments over 48 weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were the primary outcomes. Group-level (paired t tests) and individual-level analyses (Reliable Change Index, RCI) were used. Results Analysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: t₍₅₈₎ = 3.03, p = 0.004, d = 0.24; 48-week Metacognition Index: t₍₃₉₎ = 2.70, p = 0.01, d = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ² = 11.95, p = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate (p > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ² = 8.36, p = 0.004, OR = 4.6, and 48-week χ² = 9.34, p = 0.004, OR = 5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than nonimpaired patients (24 weeks 46% vs 8%; χ² = 9.54, p = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ² = 7.50, p = 0.02, OR = 9.0). Discussion Our data show no evidence of neurotoxicity in 48 weeks of treatment with an MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.

Objective: NF1-associated cognitive impairments carry significant life-long morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of MEK inhibitor (MEKi) treatment. Methods: 59 NF1 patients ages 5-27 on a MEKi clinical trial treating plexiform neurofibroma underwent pre-treatment and follow-up cognitive assessments over 48-weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were primary outcomes. Group-level (paired t -tests) and individual-level analyses (reliable change index; RCI) were used. Results: Analysis showed statistically significant improvements on BRIEF compared to baseline (24-week BRI: t ₍₅₈₎ =3.03, p =.004, d =0.24; 48-week MCI: t ₍₃₉₎ =2.70, p =.01, d =0.27). RCI indicated more patients had clinically significant improvement at 48-weeks than expected by chance ( Chi Square =11.95, p =.001, OR=6.3). Group-level analyses indicated stable performance on Cogstate ( p >.05). RCI statistics showed high proportions of improved working memory (24-weeks Chi Square =8.36, p =.004, OR=4.6 and 48-weeks Chi Square =9.34, p =.004, OR=5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than non-impaired patients (24-weeks 46% v. 8%; Chi Square =9.54, p =.008, OR=9.22; 48-weeks 63% v. 16%; Chi Square =7.50, p =.02, OR=9.0). Interpretation: Our data shows no evidence of neurotoxicity in 48-weeks of treatment with a MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.