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

脆性 X 相关震颤/共济失调综合征 (FXTAS) 病理学和解剖学：影像学和临床相关性

• 批准号: 10178127
• 负责人: Veronica Martinez-Cerdeno
• 金额: $ 45.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178127
• 关键词: Address; Affect; Age; Age of Onset; Alcohol abuse; Alleles; Anatomy; Anesthesia procedures; Architecture; Area; Astrocytes; Atrophic; Autopsy; Axon; Blood capillaries; Brain; Brain region; CGG repeat; Cell Death; Cells; Cerebellum; Cerebrum; Chronic; Clinical; Corpus Callosum; Deposition; Development; Drug abuse; Economic Burden; Endothelial Cells; Erythrocytes; FMR1; FXTAS; Female; Fiber; Fragile X Syndrome; Future; Gender; General Population; Heme Iron; Hemorrhage; Histologic; Image; Immunochemistry; Impaired cognition; Inflammation; Inflammatory; Inherited; Iron; Knowledge; Magnetic Resonance Imaging; Measures; Medial; Microglia; Microscopy; Mitochondria; Molecular; Morphology; Myelin; Nature; Neurodegenerative Disorders; Neurologic; Nuclear Inclusion; Oligodendroglia; Oxidative Stress; Pathologic; Pathology; Pathology Report; Patients; Population; Prevalence; Principal Investigator; Purkinje Cells; Radiology Specialty; Recording of previous events; Research; Signal Transduction; Signaling Molecule; Societies; Stains; Symptoms; System; Testing; Tissues; Veronica; White Matter Disease; axonal degeneration; cell type; chemokine; comorbidity; cytokine; experimental study; genetic analysis; gray matter; male; mitochondrial dysfunction; multiplex assay; programs; relating to nervous system; repository; response; risk variant; trait; white matter

! 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.

呢项目总监/首席调查员（最后，第一，中间）：Martínez-Cerdeño，Verónica 抽象的 脆弱的X相关震颤/共济失调综合征（FXTAS）病理学和解剖学：成像和临床 相关 FXTA是一种与预先享有等位基因相关的晚期神经退行性疾病（55-200 CGG重复） FMR1基因。较大的扩展产生脆弱的X综合征（FXS），这是最常见的遗传形式 认知障碍。普通人口中的首席携带者的流行率（1：400男性； 1：200 女性），以及多达40％的承运人发展FXTA的事实，强调了一个高个性的个人和 社会经济燃烧。尽管重要性，但有关FXTAS患者的病理报告的数量是 目前非常有限。特别是通过临床和成像的全面组织病理学研究 FXTAS患者的相关性不存在，据我们所知，我们是唯一的研究小组 致力于研究FXTA的病理。使用我们独特的FXTA脑存储库，我们将执行 对〜70例FXTA病例的彻底组织病理学分析，并将其病理与放射学相关联， 临床和分子病史。我们假设FXTA是一种微型遗物白质疾病 - 如目前认为，除了灰质神经退行性疾病外。具体来说，我们建议 白质中包含的内皮细胞无法维持毛细血管完整性，从而释放 细胞释放铁后的红细胞。铁在毛细血管和白质组织中积聚 诱导的小胶质细胞和星形胶质细胞，细胞因子和趋化因子释放，高氧化态和/或 线粒体功能障碍，全部导致髓磷脂损失和轴突变性。我们还假设高 MRI中的信号（T2高强度）区域对应于白质疾病，其特征是 微毛发，存在星形胶质细胞/小胶质细胞活化和铁沉积。另外，我们 假设pontocerebellar系统的改变是FXTA的主要解剖特征。 我们将通过确定病理学来确定FXTA是否是微渗透性白质疾病（AIM 1） FXTA，氧化应激水平以及MRI高强度的出血性质。我们也会 确定FXTA是否通过评估星形胶质细胞和小胶质细胞来表现出慢性炎症状态（AIM 2） 被激活，如果细胞因子和趋化因子的水平增加。我们将测试是否 少突胶质细胞和purkinje细胞是通过进行FXTA细胞死亡影响的主要细胞群 特定神经类型的数量实验。我们还将调查是否改变 pontocerebellar系统是FXTA的主要解剖特征（AIM 3）。为此，我们将验证 插图夹杂物，确定与pontocerebellar相关的大脑区域的萎缩水平 系统，PC损耗的解剖分布以及内侧小脑梗的纤维数量 和call体。 从该项目中获得的知识将是对FXTA和 可能会改变未来的治疗方法，以解决FXTA中的微生物患者和炎症。