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.

Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) have a higher risk for socioemotional problems. The current study aims to identify the socioemotional developmental pattern and its predictors across childhood and adolescence in individuals with NF1 and PNs. Participants included 88 children with NF1 and PNs (aged 6–18 years old, M = 12.05, SD = 3.62, 57% male) in a natural history study. Neuropsychological assessments were administered three times over six years. There are large variabilities in socioemotional development in the study participants. Developmental patterns varied across socioemotional domains, respondent type (parent-report [PR] vs. child-report [CR]), demographic factors, and NF1 disease-related factors. For instance, lower parental education was associated with a greater decline in internalizing problems (PR) but a greater increase in school disconnectedness (CR) over time. Non-White (vs. White) children were more likely to experience increased adaptive skills (PR) but decreased personal adjustment (CR). Children with more visible tumors experienced a greater decrease in school disconnectedness (CR). Children with more NF1 complications experienced a greater decrease in externalizing problems (PR). These findings indicate the necessity of using multi-informants and investigating subdomains of socioemotional functions. They also highlight the importance of developing individualized approaches to patient care and interventions.

Background: Oral therapeutic options for plexiform neurofibromas (PNs) in individuals with neurofibromatosis type 1 (NF1) are receiving attention in clinical research. The MEK inhibitor (MEKi) Selumetinib is FDA-approved in children ages 2+ years with inoperable PNs, and shows activity in adults. Prolonged therapy with selumetinib is necessary to maintain tumor reduction. Therefore, investigating long-term adherence is vital to understand patterns of adherence over time and its impact on clinical outcomes. Mixed methods research offers rich information about adherence that can inform future intervention trials, and can assist practitioners in addressing medication adherence concerns. Methods: This mixed-method pilot study is the first examination of the feasibility of a technology-based adherence assessment method, the medication events monitoring system (MEMS^TM), among individuals with NF1-PN. Adherence was monitored in a small sample of patients (N = 12; mean age = 34.36 years; 58% male) with NF1 and PN across eighteen 28-day treatment cycles. Qualitative data were obtained from individual interviews using inductive and deductive techniques for thematic analysis. Results: The predetermined criterion was met, suggesting that using MEMS^TM is feasible despite some challenges with the caps. Depression and overall stress were significantly related to reduced adherence, although these results should be considered hypothesis-generating. Barriers to medication adherence included forgetting and the timing of doses related to eating. Facilitators included consistency, reminders, and social support. Conclusions: This study highlights patient characteristics that may be related to increased risk for nonadherence, as well as challenges with electronic pill caps that should be considered in future clinical trials for NF1-related PN. Results can inform future adherence interventions for adults with NF1 and PNs. Future research with larger samples is needed to fully explore factors related to long-term medication adherence among individuals with NF1.

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.