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. 2021 Aug 6;7(5):e616.
doi: 10.1212/NXG.0000000000000616. eCollection 2021 Oct.

Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1

Karin S Walsh  1 , Pamela L Wolters  1 , Brigitte C Widemann  1 , Allison Del Castillo  1 , Maegan D Sady  1 , Tess Inker  1 , Marie Claire Roderick  1 , Staci Martin  1 , Mary Anne Toledo-Tamula  1 , Kari Struemph  1 , Iris Paltin  1 , Victoria Collier  1 , Kathy Mullin  1 , Michael J Fisher  1 , Roger J Packer  1
Affiliations

Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1

Karin S Walsh et al. Neurol Genet. .

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.

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Figures

Figure 1
Figure 1. RCI-Based Outcomes on Observer-Rated Executive Functions Following 24 and 48 Weeks of Treatment
BRIEF BRI = Behavior Rating Inventory of Executive Functioning, Behavioral Regulation Index; BRIEF MCI = Behavior Rating Inventory of Executive Functioning, Metacognition Index; CI = confidence interval; MEK = received mitogen-activated protein kinase inhibitor; RCI = Reliable Change Index. *Significantly different from normative (expected) proportions using 2-tailed 90% CI.
Figure 2
Figure 2. RCI-Based Outcomes on Performance-Based Learning and Working Memory Following 24 and 48 Weeks of Treatment
CI = confidence interval; MEK = received mitogen-activated protein kinase inhibitor; OCL = one-card learning task; ONB = one-back task; RCI = Reliable Change Index. *Significantly different from normative (expected) proportions using 2-tailed 90% CI.
Figure 3
Figure 3. RCI-Based Change in Observer-Rated Executive Function Outcomes on the BRIEF MCI Associated With Baseline Performance Levels
BRIEF MCI = Behavior Rating Inventory of Executive Functioning, Metacognition Index; CI = confidence interval; MEK = received mitogen-activated protein kinase inhibitor; RCI = Reliable Change Index. *Significantly different from the corresponding nonimpaired group and normative (expected) proportions using 2-tailed 90% CI.
Figure 4
Figure 4. Performance-Based Working Memory Outcomes (ONB Speed) Associated With Baseline Performance Levels
CI = confidence interval; MEK = received mitogen-activated protein kinase inhibitor; ONB = one-back task; RCI = Reliable Change Index. *Significantly different from the corresponding nonimpaired group and normative (expected) proportions using 2-tailed 90% CI.
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References

    1. Krab LC, de Goede-Bolder A, Aarsen FK, et al. Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA. 2008;300(3):287-294. - PMC - PubMed
    1. Krab LC, Oostenbrink R, de Goede-Bolder A, Aarsen FK, Elgersma Y, Moll HA. Health-related quality of life in children with neurofibromatosis type 1: contribution of demographic factors, disease-related factors, and behavior. J Pediatr. 2009;154(3):420-425, 425.e1. - PubMed
    1. Martin S, Wolters P, Baldwin A, et al. Social-emotional functioning of children and adolescents with neurofibromatosis type 1 and plexiform neurofibromas: relationships with cognitive, disease, and environmental variables. J Pediatr Psychol. 2012;37(7):713-724. - PMC - PubMed
    1. Moore BD III, Ater JL, Needle MN, Slopis J, Copeland DR. Neuropsychological profile of children with neurofibromatosis, brain tumor, or both. J Child Neurol. 1994;9(4):368-377. - PubMed
    1. Payne JM, Hyman SL, Shores EA, North KN. Assessment of executive function and attention in children with neurofibromatosis type 1: relationships between cognitive measures and real-world behavior. Child Neuropsychol. 2011;17(4):313-329. - PubMed