Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers

FMR 1前突变携带者表现出轻度认知障碍， 精神疾病 关键的是，他们有患上神经退行性疾病的风险，脆性X相关性 震颤/共济失调综合征（FXTAS），其特征在于进行性步态共济失调、意向性 震颤，帕金森综合征，痴呆，自主神经功能障碍，周围神经病变和关键 神经病理学特征这种疾病有一个可变的和与年龄有关的发病率，影响75%的 男性前突变携带者在80岁之前。鉴于FMR的高流行率1 前突变在人口中（约1/468男性），这是一个重要的健康问题， 大量的个人。目前没有FXTAS的治疗方法，也没有经验评估 干预措施，以防止或减缓疾病的进展。重要的是，没有生物或行为 标记物可用于预测哪个前突变携带者将在FXTAS之前发展FXTAS。 出现临床症状。 在我们研究计划的最后一个资助期（“轨迹和 脆性X前突变携带者中的神经变性标志物”），我们已经成功地跟踪了FMR 1 突变前携带者和年龄匹配的对照至少有两个，在某些情况下3个纵向 时间点，获得神经影像学，神经心理学和分子测量，以及 医学和神经学检查。我们已经确定了神经成像，行为和分子 在临床症状出现之前，显示出预测前景的标记物， 携带者将转换为FXTAS，并在疾病的早期阶段跟踪变化。我们 仍然是唯一的前瞻性，纵向研究FMR 1前突变携带者正在进行， 了解FXTAS的前驱症状对于早期干预和预防仍然至关重要。 这种神经退行性疾病 对于目前的项目，我们将继续收集纵向 神经影像学，神经心理学和分子数据，从我们现有的队列和一个新的队列， 承运人和控制的首要目标是定义FXTAS的前驱，完善我们的 根据我们在过去五年中所学到的知识， 对生活方式因素进行临床敏感的测量和评估，以更好地解决假设 关于这个群体的风险和适应力。

FMR1 premutation carriers exhibit mild cognitive impairment and have an increased rate of psychiatric disorders. Critically, they are at risk for developing a neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), which is characterized by progressive gait ataxia, intention tremor, Parkinsonism, dementia, autonomic dysfunction, peripheral neuropathy and key neuropathological features. The disease has a variable and age-related penetrance, affecting 75% of male premutation carriers by the eighth decade of life. Given the high prevalence of the FMR1 premutation in the population (about 1/468 males) this is a significant health issue that affects a large number of individuals. There is currently no treatment for FXTAS and no empirically evaluated interventions to prevent or slow the disease progression. Importantly, no biological or behavioral markers are available for predicting which premutation carrier will develop FXTAS before the clinical symptoms appear. In the last funding period of our program of research (“Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers”) we have successfully followed FMR1 premutation carriers and age-matched controls for at least two, and in some cases 3 longitudinal time points, obtaining neuroimaging, neuropsychological, and molecular measurements as well as medical and neurological examinations. We have identified neuroimaging, behavioral and molecular markers that show promise for predicting, before the onset of clinical symptoms, which premutation carriers will convert to FXTAS, and for tracking changes during the early stages of disease. Ours remains the only prospective, longitudinal study of FMR1 premutation carriers being conducted, and understanding the prodrome of FXTAS remains critical for the early intervention and prevention of this neurodegenerative disease. For the current project, we will continue to collect longitudinal neuroimaging, neuropsychological and molecular data from our existing cohort and a new cohort of carriers and controls with an overarching goal to define the prodrome of FXTAS, refining our protocol in accordance with what we learned in the last five years, and adding biomarkers and clinically sensitive measures and assessments of lifestyle factors to better address hypotheses about risk and resilience in this population.