Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1
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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.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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