Characterization and Treatment of CNS Abnormalities in Premutation Carriers (4 of

脆性X相关震颤/共济失调综合征（FXTAS）发生在大约40%的老年男性（和 较不常见，女性）脆性X智力突变前扩展（55-200个CGG重复）携带者 FMR 1基因。该项目的总体目标是制定和利用量化措施， 前突变携带者的CNS功能障碍作为FXTAS靶向治疗研究的结局指标。 60名前突变携带者，年龄30至79岁，受影响和未受影响， 在项目的前3年，每年将招募性别和教育程度匹配的对照组。后 医学评估，包括一个录像带的神经系统检查与定量标准化 受试者将参与几项CNS功能障碍的定量分析（目标1），包括 容积MRI研究、事件相关电位（ERP）、心理生理学研究（前脉冲抑制和 恐惧增强惊吓），定量运动测量（CATALYST），神经心理测量（执行 功能和记忆）和神经传导研究（NCS）。这些量化指标中的许多也将 在FXTAS的转基因小鼠模型中进行（项目2），然后将其用作动物 相关，以更好地衡量FXTAS的神经病理学及其作为模型的内在可逆性， 成功的治疗干预。这项研究的一个组成部分将与项目4一起开发一个综合的 研究前突变携带者寿命期间体积变化的MRI方法。 联合会项目1描述了锂在神经保护作用中的初步观察结果， FXTAS的神经细胞模型。本项目的目的2将研究碳酸锂在脑缺血再灌注损伤中的神经保护作用。 一项针对有FXTAS早期症状的老年前突变携带者的对照试验（目的2）。我们将使用 除了精神病学外，上述定量测量作为锂试验的结果测量 临床改善评估，包括神经精神量表、症状自评量表-90 （SCL-90）和临床总体不愉快量表-改善（CGI-I）。在目标3中，我们还将提供 开放试验，对不符合或不愿意参加锂试验的患者进行评估， NMDA拮抗剂美金刚。项目1和2中的研究，涉及谷氨酸毒性， FXTAS将更好地为该治疗试验提供信息。

Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in approximately 40% of aging male (and less commonly, female) carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The overall goal of this project is to develop and utilize quantitative measures of CNS dysfunction in premutation carriers as outcome measures for targeted treatment studies of FXTAS. Sixty premutation carriers, ages 30 to 79 yr, both affected and unaffected, and an equal number of age-, sex-, and education-matched controls will be recruited per year for the first 3 years of the project. Following a medical assessment that includes a videotaped neurological examination with quantitative standardized measures, subjects will participate in several quantitative analyses of CNS dysfunction (Aim 1), including volumetric MRI studies, event related potentials (ERPs), psychophysiological studies (prepulse inhibition and fear potentiated startle), quantitative motor measures (CATSYS), neuropsychological measures (executive function and memory), and nerve conduction studies (NCS). Many of these quantitative measures will also be carried out in transgenic mouse models of FXTAS (Project 2), which will then be used as animal correlates, to better gauge the neuropathology of FXTAS and its intrinsic reversibility as a model for successful therapeutic intervention. A component of this research will develop, with Project 4, an integrated MRI approach for studying volumetric changes across the lifespan of premutation carriers. Consortium Project 1 described preliminary observations for the neuroprotective effect of lithium in a neural cell model of FXTAS. Aim 2 of this project will study the neuroprotective effects of lithium carbonate in a controlled trial of aging premutation carriers who have early symptoms of FXTAS (Aim 2). We will use the quantitative measures outlined above as outcome measures for this lithium trial in addition to psychiatric assessments of clinical .improvement, including the Neuropsychiatric Inventory, the Symptom Checklist-90 (SCL-90), and the Clinical Global Impressions Scale- Improvement (CGI-I). In Aim 3, we will also offer an open trial, to patients who are ineligible or unwilling to participate in the lithium trial, to assess the benefit of the NMDA antagonist, memantine. Studies in Project 1 and 2, related to involvement of glutamate toxicity in FXTAS, will better inform this treatment trial.