Walsh Karin S, Wolters Pamela L, Widemann Brigitte C, Del Castillo Allison, Sady Maegan D, Inker Tess, Roderick Marie Claire, Martin Staci, Toledo-Tamula Mary Anne, Struemph Kari, Paltin Iris, Collier Victoria, Mullin Kathy, Fisher Michael J, Packer Roger J
Children's National Medical Center (K.S.W., A.C., M.D.S., T.I., R.J.P.), Washington, DC; National Cancer Institute (P.L.W., B.C.W., M.C.R., S.M., K.S.), Bethesda, MD; Clinical Research Directorate (M.A.T.-T.), Frederick National Library for Cancer Research, MD; and Children's Hospital of Philadelphia (I.P., V.C., K.M., M.J.F.), Philadelphia.
Neurol Genet. 2021 Aug 6;7(5):e616. doi: 10.1212/NXG.0000000000000616. eCollection 2021 Oct.
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.
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 tests) and individual-level analyses (Reliable Change Index, RCI) were used.
Analysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: = 3.03, = 0.004, = 0.24; 48-week Metacognition Index: = 2.70, = 0.01, = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ = 11.95, = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate ( > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ = 8.36, = 0.004, OR = 4.6, and 48-week χ = 9.34, = 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%; χ = 9.54, = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ = 7.50, = 0.02, OR = 9.0).
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.
1型神经纤维瘤病（NF1）相关的认知障碍会导致严重的终身发病。缺乏针对性的生物治疗仍然是一个重大的未满足需求。我们研究了丝裂原活化蛋白激酶抑制剂（MEKi）治疗的前48周内NF1患者认知功能的变化。
59例年龄在5 - 27岁、正在接受MEKi治疗丛状神经纤维瘤的NF1患者在治疗的48周内接受了治疗前和随访认知评估。主要结局指标为执行任务（Cogstate）和观察者报告的功能（BRIEF）。采用组水平分析（配对检验）和个体水平分析（可靠变化指数，RCI）。
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 = 3.03，P = 0.004，效应量 = 0.24；48周元认知指数：t = 2.70，P = 0.01，效应量 = 0.27）。RCI表明，48周时临床上有显著改善的患者比偶然预期的更多（χ² = 11.95，P = 0.001，优势比[OR] = 6.3）。组水平分析表明Cogstate表现稳定（P > 0.05）。RCI统计显示，工作记忆改善的比例较高（24周χ² = 8.36，P = 0.004，OR = 4.6；48周χ² = 9.34，P = 0.004，OR = 5.3），但视觉学习/记忆无改善。BRIEF基线有损伤的患者比无损伤的患者更有可能表现出显著改善（24周时分别为46%和8%；χ² = 9.54，P = 0.008，OR = 9.22；48周时分别为63%和16%；χ² = 7.50，P = 0.02，OR = 9.0）。
我们的数据显示，MEKi治疗48周没有神经毒性的证据，并且有一个潜在的临床信号支持未来将MEKi作为一种认知干预措施进行研究。
