Abstract
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.
Glossary
- ANOVA=
- analysis of variance;
- BRI=
- Behavioral Regulation Index;
- BRIEF=
- Behavior Rating Inventory of Executive Function;
- CI=
- confidence interval;
- MCI=
- Metacognition Index;
- MEKi=
- mitogen-activated protein kinase inhibitor;
- NF1=
- neurofibromatosis type 1;
- OCL=
- one-card learning task;
- ONB=
- one-back task;
- OR=
- odds ratio;
- PN=
- plexiform neurofibroma;
- RCI=
- Reliable Change Index
Footnotes
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
- Received February 17, 2021.
- Accepted in final form July 6, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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