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: 8084150
• 负责人: RANDI J. HAGERMAN
• 金额: $ 118.5万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084150
• 关键词: Adult; Affect; Age; Aging; Alleles; Animals; Ataxia; Brain; CGG repeat; Cell model; Clinical; Clinical Trials; Clinical assessments; D-Aspartic Acid; Data; Dementia; Endocrine; Equipment and supply inventories; Event-Related Potentials; FMR1 Gene; FXTAS; Female; Fright; Functional disorder; Glutamates; Goals; Human; 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; Outcome Measure; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Psychophysiology; RNA; Recruitment Activity; Research; Sex Education; Symptoms; Therapeutic Human Experimentation; Therapeutic Intervention; Toxic effect; Transgenic Mice; Tremor; Videotape; White Matter Disease; control trial; double-blind placebo controlled trial; excitotoxicity; executive function; impression; male; middle age; mouse model; neuropathology; neuroprotection; neuropsychiatry; neuropsychological; prepulse inhibition; prevent; response; sex; standardize measure; 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.

大约 40% 的老年男性（以及 脆弱 X 心理的前突变扩展（55-200 CGG 重复）的携带者（不太常见，女性） 延迟 1 (FMR1) 基因。该项目的总体目标是开发和利用定量措施 前突变携带者的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 30 至 79 岁，受影响和未受影响，以及同等数量的年龄 在该项目的前 3 年，每年都会招募与性别和教育程度相匹配的对照。继 医学评估，包括定量标准化的录像神经学检查 措施，受试者将参与中枢神经系统功能障碍的多项定量分析（目标 1），包括 体积 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（CATSYS）、神经心理学测量（执行 功能和记忆）和神经传导研究（NCS）。其中许多定量措施也将 在 FXTAS 转基因小鼠模型（项目 2）中进行，然后将其用作动物 相关性，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 用于研究前突变携带者整个生命周期中体积变化的 MRI 方法。 联盟项目 1 描述了锂对神经保护作用的初步观察 FXTAS 的神经细胞模型。该项目的目标 2 将研究碳酸锂的神经保护作用 对具有 FXTAS 早期症状的老年前突变携带者进行的对照试验（目标 2）。我们将使用 除精神科之外，还采用上述定量措施作为本次锂试验的结果测量 临床改善评估，包括神经精神量表、症状检查表 90 (SCL-90) 和临床总体印象量表-改进 (CGI-I)。在目标 3 中，我们还将提供 公开试验，针对不符合或不愿意参加锂试验的患者，以评估其益处 NMDA 拮抗剂美金刚。项目 1 和 2 中的研究，涉及谷氨酸毒性 FXTAS 将为该治疗试验提供更好的信息。

项目成果

Clustered burst firing in FMR1 premutation hippocampal neurons: amelioration with allopregnanolone.

FMR1 突变前海马神经元中的簇状爆发放电：用四氢孕酮改善。

• DOI: 10.1093/hmg/dds118
• 发表时间: 2012-07-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Zhengyu Cao;S. Hulsizer;F. Tassone;Hiu;R. Hagerman;M. Rogawski;P. Hagerman;I. Pessah
• 通讯作者: I. Pessah