Neurobiology and Treatment of Reading Disability in NF1

项目摘要/摘要 神经纤维瘤病1型(NF1)，一种常染色体显性遗传性神经皮肤综合征，发病率为 1：3000是由神经纤维蛋白的突变引起的，神经纤维蛋白是一种通过改变RAS而对学习产生负面影响的蛋白质 长时程增强(LTP)中的信号传递。临床上，NF1显示的学习障碍率是普通人的四倍 (65%)与普通人群(15%)相比，包括阅读障碍(RD)，导致教育 减损。对学术的负面影响使这些学习障碍，包括阅读障碍， 患有NF1儿童的父母最关心的问题之一。在之前的研究(NS49096)中，我们 表明患有阅读困难(NF+RD)的儿童能够对标准反应做出反应 以语音为基础的阅读辅导，最初是为了治疗普通人群中的儿童而开发的 患有特发性阅读障碍(IRD)。对这一应用程序至关重要的是，在 神经营养不良的小鼠模型已经表明，药物治疗(洛伐他汀)可以逆转学习障碍(Li等人， 2005)。推测的机制是HMGCoA还原酶抑制剂洛伐他汀上调RAS 信号以抵消神经纤维蛋白缺陷的LTP负效应，从而允许更好的记忆 在学习中形成。这一发现刺激了翻译研究，以评估洛伐他汀，一种 美国儿科学会认可的儿童安全使用的药物可以逆转 患有NF1的人类的认知缺陷。在类似于老鼠的研究中发现了令人振奋的结果 研究、测量特定的认知领域或将洛伐他汀与缺乏技能的培训配对。鉴于(A) NF+RD受益于阅读辅导和(B)药物益处似乎与特定研究设计有关， 要更好地理解NF1中认知的行为和神经机制，还需要几个后续步骤。 具体地说，我们提出了一项临床试验，在这项试验中，我们用洛伐他汀对12名NF+RD儿童进行预治疗 在阅读辅导前几周，与接受阅读辅导或洛伐他汀的NF+RD组相比； 关键的是，就像动物研究一样，我们将针对那些在学习特定技能方面表现出学习障碍的人， 也就是说，Nf+RD将接受阅读辅导。提出了行为和神经生物学措施，并 功能和结构连通性的变化预计会随着认知的加强而发生。特别是， 行为干预和药物干预的结合被认为具有协同效应。 在认知和神经生物学方面产生比单独使用洛伐他汀或辅导更大的收获。总而言之， 在下一阶段的研究中，我们的首要目标是利用目前的发现来阐明 NF1认知障碍的机制及最佳治疗方法。这样的方法还可能有一个 更广泛的适用性，以更好地理解人类在发育障碍中的学习机制。

PROJECT SUMMARY/ABSTRACT Neurofibromatosis Type 1 (NF1), an autosomal dominant neurocutaneous syndrome with an incidence of 1:3000, is caused by a mutation in neurofibromin -- a protein that negatively impacts learning by altering RAS signaling in long term potentiation (LTP). Clinically, NF1 shows four times greater rate of learning disabilities (65%) compared to the general population (15%), including reading disability (RD), resulting in educational impairment. The negative impact on academics makes these learning disabilities, including reading disability, among the most common concerns of parents of children with NF1. In previous research (NS49096), we demonstrated that children with NF-1 with reading difficulty (NF+RD) are able to respond to standard phonologically-based reading tutoring that was originally developed to treat children in the general population with idiopathic reading disability (IRD). Of central importance to this application, another line of research in the mouse model of NF has shown that pharmacological treatment (Lovastatin) reverses learning deficits (Li et al., 2005). The assumed mechanism is that Lovastatin, an HMGCoA reductase inhibitor, upregulates RAS signaling to counteract the negative LTP effects of deficient neurofibromin, thus allowing for better memory formation during learning. This finding has stimulated translational research to assess whether Lovastatin, a medication that the American Academy of Pediatrics to endorses as safe to use in children, can reverse cognitive deficits in humans with NF1. Promising results have been found in studies that, similar to the mouse studies, measure specific cognitive domains or pair Lovastatin with training of the deficient skill. Given that (a) NF+RD benefit from reading tutoring and (b) pharmaceutical benefits appear linked to specific study designs, several next steps are needed to better understand the behavioral and neural mechanisms of cognition in NF1. Specifically, we propose a clinical trial in which we pre-treat the NF+RD children with Lovastatin for the 12 weeks prior to reading tutoring, as compared to NF+RD who receive either reading tutoring or Lovastatin; critically, like animal studies, we will target those who show impaired learning on the specific skill to be taught, i.e., NF+RD will receive reading tutoring. Both behavioral and neurobiological measures are proposed, and changes in functional and structural connectivity are expected to occur with enhanced cognition. In particular, the combination of behavioral and pharmacological intervention is hypothesized to have a synergistic effect producing greater gains in cognition and changes in neurobiology than Lovastatin or tutoring alone. In sum, our overarching goal in this next phase of our research is to capitalize on current findings to elucidate mechanisms of and best treatments for the cognitive deficits in NF1. Such approach could also have a broader applicability for better understanding human learning mechanisms in developmental disorders.