Fragile X-associated tremor/ataxia syndrome (FXTAS) pathology and anatomy: imaging and clinical correlates

!项目主任/主要研究者（最后一名、第一名、中间名）：Martínez-Cerdeño，Verónica 摘要 脆性X相关性震颤/共济失调综合征（FXTAS）的病理学和解剖学：影像学和临床 相关 FXTAS是一种与前突变等位基因（55-200 CGG重复序列）相关的迟发性神经退行性疾病 FMR 1基因。较大的扩张引起脆性X综合征（FXS），这是最常见的遗传形式 认知障碍一般人群中前突变携带者的患病率（1：400男性; 1：200 女性），以及高达40%的携带者发展FXTAS的事实，强调了高个人和 社会的经济负担。尽管其重要性，FXTAS患者的病理报告数量 目前非常有限。特别是，全面的组织病理学研究与临床和成像 FXTAS患者的相关性不存在，据我们所知，我们是唯一的研究组 致力于研究FXTAS的病理学。使用我们独特的FXTAS大脑存储库，我们将执行一个 对约70例FXTAS病例进行全面的组织病理学分析，并将其病理学与放射学相关联， 临床和分子史。我们假设FXTAS是一种微出血性白色物质疾病， 除了目前认为的灰质神经退行性疾病之外。具体而言，我们建议， 白色物质中的内含物内皮细胞不能维持毛细血管的完整性，导致 红细胞在分解时释放铁。铁在毛细血管和白色物质组织中积累 诱导小胶质细胞和星形胶质细胞的活化、细胞因子和趋化因子的释放、高氧化状态和/或 线粒体功能障碍，所有这些都导致髓鞘损失和轴突变性。我们还假设 MRI中信号（T2高信号）区域对应于白色疾病，其特征在于 微出血，存在星形胶质细胞/小胶质细胞活化和铁沉积。另外我们 推测桥脑小脑系统的改变是FXTAS的主要解剖特征。 我们将通过建立病理学来确定FXTAS是否为微出血性白色物质疾病（目的1） 的FXTAS，氧化应激水平和MRI高信号的出血性质。我们还将 通过评价星形胶质细胞和小胶质细胞是否存在，确定FXTAS是否存在慢性炎症状态（目的2） 如果细胞因子和趋化因子的水平增加。我们将测试如果 少突胶质细胞和浦肯野细胞是FXTAS中受细胞死亡影响的主要细胞群， 针对特定神经类型的量化实验。我们还将调查是否更改 桥脑小脑系统是FXTAS的主要解剖学特征（目的3）。为此，我们将核实 核内包涵体，确定与脑桥小脑相关的脑区的萎缩水平 系统，PC丢失的解剖分布，以及小脑内侧脚中的纤维数量 和胼胝体。 从这个项目中获得的知识将是对FXTAS的理解的巨大进步， 可能会改变未来的治疗方法，以解决FXTAS中的微血管病变和炎症。

! Program Director/Principal Investigator (Last, First, Middle): Martínez-Cerdeño, Verónica Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) pathology and anatomy: imaging and clinical correlates FXTAS is a late-onset neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the FMR1 gene. Larger expansions give rise to fragile X syndrome (FXS), the most common inherited form of cognitive impairment. The prevalence of premutation carriers in the general population (1: 400 males; 1: 200 females), and the fact that up to 40% of carriers develop FXTAS, underscores the a high personal and economic burden for society. Despite its importance, the number of pathology reports on FXTAS patients is currently very limited. Particularly, comprehensive histopathological studies with clinical and imaging correlation of FXTAS patients do not exist and to the best of our knowledge we are the only research group dedicated to study the pathology of FXTAS. Using our unique FXTAS brain repository, we will perform a thorough histopathological analysis of ~70 FXTAS cases and correlate their pathology to their radiological, clinical and molecular history. We hypothesize that FXTAS is a microhemorrhage white matter disease - in addition to a grey matter neurodegenerative disease as currently thought. Specifically, we propose that inclusion-bearing endothelial cells in white matter fail to maintain capillary integrity, resulting in the release of erythrocytes that, upon breakdown, release iron. Iron accumulates in the capillaries and white matter tissue inducing activation of microglia and astrocytes, cytokine and chemokine release, high oxidative state and/or mitochondrial dysfunction, all leading to myelin loss and axonal degeneration. We also hypothesize high signal (T2 hyper-intensities) regions in MRI correspond to white matter disease characterized by microhemorrhage, the presence astrocyte/microglia activation and iron deposition. Additionally, we hypothesize that the alteration of the pontocerebellar system is the main anatomical trait of FXTAS. We will determine if FXTAS is a micro-hemorrhage white matter disease (aim 1) by establishing the pathology of FXTAS, the level of oxidative stress, and the hemorrhagic nature of MRI hyperintensities. We will also determine if FXTAS presents with a chronic inflammatory state (aim 2) by evaluating if astrocytes and microglia are activated and if there is an increase in the levels of cytokines and chemokines. We will test if oligodendrocytes and Purkinje cells are the main cell population affected by cell death in FXTAS by performing quantification experiments for specific neural types. We will also investigate if the alteration of the pontocerebellar system is the main anatomical trait of FXTAS (aim 3). To do so we will verify the presence of intranuclear inclusions, determine level of atrophy in the brain areas associated with the pontocerebellar system, the anatomical distribution of the PC loss, and the number of fibers in the medial cerebellar peduncle and corpus callosum. The knowledge gained from this project will be a tremendous advance in the understanding of FXTAS and could change future treatments to address microhemorrhages and inflammation in FXTAS.