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Neurobiology and Treatment of Reading Disability in NF1

神经生物学和 NF1 阅读障碍的治疗

基本信息

批准号：
10628742
负责人：
Laurie E Cutting
金额：
$ 25.51万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-01-31
项目状态：
已结题

项目摘要

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.

项目概要/摘要 1 型神经纤维瘤病 (NF1)，一种常染色体显性遗传性神经皮肤综合征，发病率 1:3000，是由神经纤维蛋白突变引起的，神经纤维蛋白是一种通过改变 RAS 对学习产生负面影响的蛋白质长时程增强 (LTP) 信号传导。临床上，NF1 表现出四倍的学习障碍发生率 (65%) 与一般人群 (15%) 相比，包括阅读障碍 (RD)，导致教育损害。对学业的负面影响使得这些学习障碍，包括阅读障碍，这是 NF1 儿童家长最普遍关心的问题之一。在之前的研究（NS49096）中，我们证明患有阅读困难 (NF+RD) 的 NF-1 儿童能够对标准做出反应基于语音的阅读辅导最初是为了治疗普通人群的儿童而开发的患有特发性阅读障碍（IRD）。对该应用至关重要的是另一项研究神经纤维瘤小鼠模型表明药物治疗（洛伐他汀）可逆转学习缺陷（Li 等人， 2005）。假设的机制是洛伐他汀（一种 HMGCoA 还原酶抑制剂）上调 RAS 信号传导抵消神经纤维蛋白缺陷的 LTP 负面影响，从而提高记忆力学习过程中的形成。这一发现刺激了转化研究，以评估洛伐他汀是否是一种美国儿科学会认可的儿童可安全使用的药物可以逆转患有 NF1 的人类存在认知缺陷。研究中发现了有希望的结果，类似于小鼠研究、测量特定的认知领域或将洛伐他汀与缺乏技能的训练结合起来。鉴于（一） 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相关，为了更好地理解 NF1 认知的行为和神经机制，接下来需要采取几个步骤。具体来说，我们提出了一项临床试验，其中我们用洛伐他汀预先治疗 NF+RD 儿童 12 个月。与接受阅读辅导或洛伐他汀的 NF+RD 相比，阅读辅导前几周；至关重要的是，就像动物研究一样，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人，即NF+RD将接受阅读辅导。提出了行为和神经生物学措施，并且随着认知的增强，功能和结构连接预计会发生变化。尤其，行为和药物干预的结合被认为具有协同效应与洛伐他汀或单独辅导相比，它在认知和神经生物学变化方面产生了更大的收益。总而言之，我们下一阶段研究的首要目标是利用当前的发现来阐明 NF1 认知缺陷的机制和最佳治疗方法。这种方法还可以有一个更广泛的适用性，可以更好地理解发育障碍中的人类学习机制。