Neurobiology and Treatment of Reading Disability in NF1

1型神经纤维瘤病（NF 1）是一种常染色体显性遗传的神经皮肤综合征，发病率为1：3000，由神经纤维蛋白突变引起，神经纤维蛋白是一种通过改变长时程增强（LTP）中的RAS信号对学习产生负面影响的蛋白质。在临床上，NF 1表现出四倍于普通人群（15%）的学习障碍率（65%），包括阅读障碍（RD），导致教育障碍。对学业的负面影响使得这些学习障碍，包括阅读障碍，成为NF 1儿童父母最常见的担忧之一。在之前的研究（NS 49096）中，我们证明了NF-1伴阅读困难（NF+RD）的儿童能够对标准的基于语音的阅读辅导做出反应，该辅导最初是为治疗患有特发性阅读障碍（IRD）的一般人群中的儿童而开发的。对于该应用至关重要的是，在NF小鼠模型中的另一系列研究已经表明，药物治疗（洛伐他汀）逆转了学习缺陷（Li等人，2005年）。假设的机制是，洛伐他汀，HMGCoA还原酶抑制剂，上调RAS信号，以抵消缺乏神经纤维蛋白的负LTP效应，从而允许在学习过程中更好的记忆形成。这一发现刺激了转化研究，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，是否可以逆转NF 1患者的认知缺陷。与小鼠研究类似，在测量特定认知领域或将洛伐他汀与缺乏技能的训练配对的研究中发现了有希望的结果。鉴于（a）NF+RD受益于阅读辅导和（B）药物效益似乎与特定的研究设计，需要几个后续步骤，以更好地理解NF 1的认知行为和神经机制。具体来说，我们提出了一项临床试验，在该试验中，我们在阅读辅导之前用洛伐他汀预处理NF+RD儿童12周，与接受阅读辅导或洛伐他汀的NF+ RD儿童相比;关键的是，像动物研究一样，我们将针对那些在要教授的特定技能方面表现出学习障碍的儿童，即，NF+RD将接受阅读辅导。提出了行为和神经生物学措施，并预计将发生功能和结构连接的变化，增强认知。特别是，行为和药物干预的组合被假设为具有协同效应，产生更大的收益，在认知和神经生物学的变化比单独的洛伐他汀或辅导。总之，我们下一阶段研究的首要目标是利用目前的发现来阐明NF 1认知缺陷的机制和最佳治疗方法。这种方法也可以有更广泛的适用性，更好地了解人类的学习机制，在发育障碍。

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.