Neurobiology and Treatment of Reading Disability in NF1

1型神经纤维瘤病（NF1）是一种常染色体显性神经皮肤综合征，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期增强（LTP）中RAS信号传导对学习产生负面影响的蛋白质。在临床上，NF1的学习障碍率（65%）是普通人群（15%）的四倍，包括阅读障碍（RD），导致教育障碍。对学业的负面影响使这些学习障碍，包括阅读障碍，成为NF1儿童的父母最关心的问题。在之前的研究（NS49096）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，这种辅导最初是为了治疗普通人群中患有特发性阅读障碍（IRD）的儿童而开发的。对这一应用至关重要的是，另一项对NF小鼠模型的研究表明，药物治疗（洛伐他汀）可以逆转学习缺陷（Li et al., 2005）。假设的机制是洛伐他汀，一种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，以评估洛伐他汀是否可以逆转NF1患者的认知缺陷。洛伐他汀是美国儿科学会认可的安全用于儿童的药物。与小鼠研究类似，在测量特定认知领域或将洛伐他汀与缺陷技能训练相结合的研究中发现了有希望的结果。考虑到(a) NF+RD受益于阅读辅导和(b)药物益处似乎与特定的研究设计有关，接下来的几个步骤需要更好地理解NF1认知的行为和神经机制。具体来说，我们建议进行一项临床试验，在阅读辅导前用洛伐他汀对NF+RD儿童进行12周的预处理，与接受阅读辅导或洛伐他汀的NF+RD进行比较；关键的是，就像动物研究一样，我们将针对那些在被教授的特定技能上表现出学习障碍的人，即NF+RD将接受阅读辅导。研究人员提出了行为和神经生物学的测量方法，并预计功能和结构连接的变化会随着认知的增强而发生。特别是，行为和药物干预的结合被假设具有协同效应，在认知和神经生物学方面比单独的洛伐他汀或辅导产生更大的收益。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NF1认知缺陷的机制和最佳治疗方法。这种方法对于更好地理解发育障碍中的人类学习机制也有更广泛的适用性。

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.