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

好了！方案主任/首席调查员(最后、第一、中间)：Martínez-Cerdeño，Verónica 摘要 脆性X相关震颤/共济失调综合征(FXTAS)的病理和解剖：影像和临床 关联性 FXTAS是一种与前突变等位基因(55-200个CGG重复)相关的迟发性神经退行性疾病 FMR1基因。更大的扩张会导致脆性X综合征(FXS)，这是最常见的遗传性形式 认知障碍的症状。前突变携带者在一般人群中的流行率(1：400男性；1：200 女性)，以及高达40%的携带者患FXTA的事实，突显了个人和 社会的经济负担。尽管它很重要，但关于FXTAS患者的病理报告数量是 目前非常有限。尤其是全面的组织病理学研究，包括临床和影像 FXTAS患者的相关性并不存在，据我们所知，我们是唯一的研究小组 致力于FXTAS的病理学研究。使用我们独特的FXTAS Brain存储库，我们将执行 对70例FXTAS进行了全面的组织病理学分析，并将其病理与其放射学、CT、CT等进行对照分析。 临床和分子病史。我们假设FXTAS是一种微血性脑白质疾病 除了目前认为的灰质神经退行性疾病。具体来说，我们建议 白质内含包涵体的内皮细胞不能保持毛细血管的完整性，导致释放 红细胞在分解时会释放铁。铁在毛细血管和白质组织中积聚 诱导小胶质细胞和星形胶质细胞的激活，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，所有这些都会导致髓鞘丢失和轴突变性。我们还假设很高 MRI上的信号区(T2高信号)对应于脑白质疾病，特征是 微出血，星形胶质细胞/小胶质细胞活化，铁沉积。此外，我们 假设桥小脑系统的改变是FXTAS的主要解剖特征。 我们将通过建立病理学来确定FXTAS是否是一种微出血白质病(目标1) FXTAS、氧化应激水平和MRI高信号的出血性质。我们还将 通过评估星形胶质细胞和小胶质细胞，确定FXTAS是否存在慢性炎症状态(目标2) 如果细胞因子和趋化因子水平增加，就会被激活。我们将测试是否 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了 桥小脑系是FXTAS的主要解剖特征(目标3)。为此，我们将核实是否存在 核内包涵体，确定桥小脑相关脑区的萎缩程度 系统、PC丢失的解剖分布和小脑内侧脚的纤维数量 和结缔组织。 从这个项目中获得的知识将是对FXTAS和 可能会改变未来的治疗方法，以解决FXTAS中的微出血和炎症。

! 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.