Deep gray matter iron and disease progression in multiple sclerosis

项目总结 丘脑组织丢失是多发性硬化症最早的影像特征之一。然而，目前 无法在细胞和分子水平上非侵入性地研究不同亚区的组织变化 深部灰质，履行不同的功能角色，是理解和 靶向可能先于神经变性或与神经变性相互作用的生物机制。磁共振 磁性组织磁化率的成像代表了一个独特的窗口，通过该窗口，组织铁可以 经临床评估。铁是各种生化途径中必不可少的辅助因子。它从神经胶质细胞中被剥夺 外观正常的白质中的细胞是多发性硬化症的病理标志 与神经元损伤有关。最近观察到多发性硬化症患者的丘脑 显示出磁化率的逐渐下降。其他研究表明，一个类似的现象 可能存在于其他深部灰质区。迫切需要确认和确认这一观察结果-- 原因深部灰质损伤与残疾的进展密切相关。《公约》的总体目标 建议的研究是确定疾病进展是否与铁相关的少突胶质细胞有关 深部灰质功能障碍。中心假设是少突胶质细胞铁的可利用性下降，如 在磁共振成像上显示，是疾病进展的独立生物关联 发生在整个大脑中。这项拟议的研究的基本原理是，随着时间的推移，铁损失之间的联系 疾病的进展将导致我们对铁在神经退行性变中的作用的理解的典型性转变- 消除过量铁的毒性，避免关键生化所需的铁不足 小路。该项目将追求以下具体目标以实现这一目标：1)确定关联-- 脑铁稳态磁共振成像标记物与疾病进展之间的关系。2) 鉴定脑铁磁共振成像标志物的细胞和分子底物。在COM之后- 这些目标的完成，预期的结果是已经确定了少突胶质细胞铁在 慢性病阶段，发展到这一状态与残疾的恶化有关。特别是， 这项研究有望确定一种可推广的成像标志物进化模型 患者相对于对照组的时间；成像标志物的细胞和分子基础；以及IM如何。 铁的老化标记与白质中的神经退化和损伤有关。这些贡献是 预期意义重大，因为临床残疾和少突胶质细胞缺失之间存在联系的证据 灰质中的铁以及用于评估这一现象的成像标记的可用性将会进步 这是一个垂直的领域，并支持开发新的治疗策略。这项拟议的研究是徒劳的- 因为铁丢失的新假说，对深部灰质亚区的关注，以及一种独特的模式-- 对铁浓度变化采取的方法代表着与现状的实质性偏离。

PROJECT SUMMARY Tissue loss in the thalamus is one of the earliest imaging hallmarks of multiple sclerosis. However, the current inability to study tissue alterations non-invasively on the cellular and molecular level in the different sub-regions of the deep gray matter, which fulfill distinct functional roles, represents a critical barrier for understanding and targeting biological mechanisms that may precede or interact with neurodegeneration. Magnetic resonance imaging of magnetic tissue susceptibility represents a unique window through which tissue iron can be assessed clinically. Iron is an essential co-factor in various biochemical pathways. Its deprivation from glial cells in the normal-appearing white matter is a pathological hallmark of multiple sclerosis that has been implicated in neuronal injury. It was recently observed that the thalamus of patients with multiple sclerosis shows a progressive decline in magnetic susceptibility. Other research suggests that a similar phenomenon may exist in other deep gray matter regions. A critical need exists to confirm and validate this observation be- cause deep gray matter injury is strongly linked to the progression of disability. The overall objective of the proposed research is to determine whether disease progression is linked to iron-related oligodendroglia dysfunction in the deep gray matter. The central hypothesis is that declining oligodendroglial iron availability, as manifested on magnetic resonance imaging, is an independent biological correlate of disease progression that occurs throughout the brain. The rationale for the proposed research is that a link between iron loss over time and disease progression will cause a paradigmatic shift in our understanding of the role of iron for neurodegen- eration away from the toxicity of excess iron toward an insufficient availability of iron for critical biochemical pathways. The project will pursue the following specific aims to achieve the objective: 1) Determine the associ- ation between disease progression and magnetic resonance imaging markers of brain iron homeostasis. 2) Identify the cellular and molecular substrate of magnetic resonance imaging markers of brain iron. Upon com- pletion of these aims, the expected outcome is to have determined that oligodendroglia iron is reduced in the chronic disease phase and that the progression to this state is linked to a worsening in disability. In particular, the research is expected to have determined a generalizable model of the evolution of imaging markers over time in patients relative to controls; cellular and molecular underpinnings of the imaging markers; and how im- aging markers of iron are linked to neurodegeneration and injury in the white matter. These contributions are expected to be significant because the evidence of a link between clinical disability and loss of oligodendroglial iron in the gray matter as well as the availability of an imaging marker to assess this phenomenon will advance the field vertically and support the development of new therapeutic strategies. The proposed research is inno- vative because the new hypothesis of iron loss, the focus on deep gray matter sub-regions, and a unique mod- eling approach for changes in iron concentration represent substantive departures from the status quo.