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Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1
Neurology Genetics ( IF 3.1 ) Pub Date : 2021-10-01 , DOI: 10.1212/nxg.0000000000000616
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
Affiliation  

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 (2 = 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 2 = 8.36, p = 0.004, OR = 4.6, and 48-week 2 = 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%; 2 = 9.54, p = 0.008, OR = 9.22; 48 weeks 63% vs 16%; 2 = 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.



中文翻译:

MEK 抑制剂治疗对 NF1 神经认知功能的影响

背景和目标

1 型神经纤维瘤病 (NF1) 相关的认知障碍具有显着的终生发病率。缺乏有针对性的生物治疗仍然是一个重大的未满足需求。我们检查了 NF1 患者在有丝分裂原活化蛋白激酶抑制剂 (MEKi) 治疗的前 48 周内的认知变化。

方法

在一项治疗丛状神经纤维瘤的 MEKi 临床试验中,59 名 5-27 岁的 NF1 患者在 48 周的治疗中接受了预处理和随访认知评估。绩效任务(Cogstate)和观察者报告的功能(BRIEF)是主要结果。使用了组级(配对t检验)和个人级分析(可靠变化指数,RCI)。

结果

分析显示,与基线相比,BRIEF 有统计学意义的改善(24 周行为调节指数:t (58) = 3.03,p = 0.004,d = 0.24;48 周元认知指数:t (39) = 2.70,p = 0.01,d = 0.27)。RCI 表明,48 周时临床显着改善的患者数量比偶然预期的要多(2 = 11.95,p = 0.001,优势比 [OR] = 6.3)。组级分析表明 Cogstate 的性能稳定 ( p > 0.05)。RCI 统计数据显示,工作记忆改善的比例很高(24 周2 = 8.36,p= 0.004,OR = 4.6,48 周2 = 9.34,p = 0.004,OR = 5.3)但不是视觉学习/记忆。与非受损患者相比,BRIEF 有基线损伤的患者更有可能表现出显着改善(24 周 46% vs 8%;2 = 9.54,p = 0.008,OR = 9.22;48 周 63% vs 16%;2 = 7.50,p = 0.02,或 = 9.0)。

讨论

我们的数据显示,在使用 MEKi 治疗的 48 周内没有神经毒性的证据,以及支持未来将 MEKi 作为认知干预研究的潜在临床信号。

更新日期:2021-08-07
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