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

前突变携带者中枢神经系统异常的特征和治疗（4

• 批准号: 7502187
• 负责人: RANDI J. HAGERMAN
• 金额: $ 115.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502187
• 关键词: Adult; Affect; Age; Aging; Alleles; Animals; Ataxia; Brain; CGG repeat; Cell model; Clinical; Clinical Trials; Clinical assessments; Condition; D-Aspartic Acid; Data; Dementia; Endocrine; Equipment and supply inventories; Event-Related Potentials; FMR1 Gene; FXTAS; Female; Fright; Functional disorder; Glutamates; Goals; Life; Lithium; Lithium Carbonate; Longevity; Magnetic Resonance Imaging; Measures; Medical; Memantine; Memory; Modeling; Motor; Mus; N-Methylaspartate; Nerve Degeneration; Neural Conduction; Neurologic; Neurologic Examination; Neurons; Neuropsychological Tests; Numbers; Outcome Measure; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Psychophysiology; RNA; Rate; Recruitment Activity; Research; Sex Education; Symptoms; Therapeutic Human Experimentation; Therapeutic Intervention; Toxic effect; Transgenic Organisms; Tremor; Videotape; White Matter Disease; double-blind placebo controlled trial; excitotoxicity; executive function; human study; impression; male; middle age; mouse model; neuropathology; neuroprotection; neuropsychiatry; neuropsychological; prepulse inhibition; prevent; response; sex; treatment trial; white matter

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.

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 不太常见的是，女性)精神脆性X基因前突变扩展(55-200个CGG重复)的携带者 迟滞1(FMR1)基因。该项目的总体目标是开发和利用 突变前携带者中枢神经系统功能障碍作为FXTAS靶向治疗研究的结果指标。 60名前突变携带者，年龄在30岁到79岁之间，既有受影响的，也有未受影响的，以及同等数量的年龄-- 在该项目的头3年，每年将招募性别、教育程度相匹配的控制组。在此之后 医学评估，包括录像的神经学检查和量化标准化 措施，受试者将参与对中枢神经系统功能障碍的几项量化分析(目标1)，包括 容量磁共振研究、事件相关电位(ERPs)、心理生理学研究(脉冲前抑制和 恐惧强化惊吓)、量化运动测量(CATsys)、神经心理测量(执行 功能和记忆)和神经传导研究(NCS)。其中许多量化措施也将 在FXTAS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的神经病理及其作为一种模型的内在可逆性 成功的治疗性干预。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 研究前突变携带者生命周期内体积变化的核磁共振方法。 联合体项目1描述了锂在高血压患者中的神经保护作用的初步观察 FXTAS的神经细胞模型。本项目的目标2将研究碳酸锂对大鼠的神经保护作用。 一项对有FXTAS早期症状的老年前突变携带者的对照试验(目标2)。我们将使用 上面概述的量化措施是这项锂试验的结果指标，除了精神病学 对临床改善的评估，包括神经精神病学问卷、症状自评量表 (SCL-90)和临床总体印象量表(CGI-I)。在AIM 3中，我们还将提供 开放试验，对不符合条件或不愿参加锂试验的患者，评估 NMDA的拮抗剂，美金汀。项目1和2中与谷氨酸毒性有关的研究 FXTAS将更好地通知这项治疗试验。