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: 7881684
• 负责人: RANDI J. HAGERMAN
• 金额: $ 120.86万
• 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/7881684
• 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.

脆性x相关震颤/共济失调综合征（FXTAS）发生在大约40%的老年男性中