Trajectories and Markers of Neurodegeneration in Fragile X Premutation Carriers

FMR1前突变携带者表现出轻微的认知障碍，并有增加的几率 精神障碍。 至关重要的是，他们面临着患上一种神经退行性疾病的风险，这种疾病与脆性X相关 震颤/共济失调综合征(FXTAS)，以进行性步态共济失调为特征 震颤、帕金森综合征、痴呆、自主神经功能障碍、周围神经病和钥匙 神经病理特征。这种疾病有一种可变的和年龄相关的外显性，影响75%的 男性前突变携带者将活到第八个十年。鉴于FMR1的高流行率 人群中的前突变(约1/468男性)这是一个重大的健康问题，影响到 大量的个体。目前还没有治疗FXTAS的方法，也没有经验性评估 预防或减缓疾病进展的干预措施。重要的是，没有生理上或行为上的 有标记可用来预测哪个前突变携带者会在 临床症状出现。在我们研究计划的最后一个资助期(“轨迹和 脆性X基因前突变携带者神经退行性变的标志物研究 前突变携带者和年龄匹配的对照组至少有两人，在某些情况下有三人纵向 时间点，获得神经成像、神经心理学和分子测量以及 体检和神经学检查。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，有希望预测哪些前突变 携带者将改用FXTAS，并在疾病的早期阶段跟踪变化。我们的 仍然是对FMR1前突变携带者进行的唯一前瞻性、纵向研究，以及 了解FXTAS的前驱症状对早期干预和预防仍是至关重要的 这种神经退行性疾病。对于目前的项目，我们将继续纵向收集 来自我们现有队列和新队列的神经成像、神经心理学和分子数据 载体和控制，总体目标是定义FXTA的前奏，完善我们的 根据我们在过去五年中所学到的，并添加了生物标志物和 对生活方式因素的临床敏感测量和评估，以更好地解决假说 关于这一人群中的风险和韧性。

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.