Deep Gray Matter Iron and Disease Progression in Multiple Sclerosis

项目摘要 丘脑的组织丢失是多发性硬化症最早的影像学标志之一。但目前 无法在不同亚区域的细胞和分子水平上非侵入性地研究组织变化 深层灰质，履行不同的功能作用，代表了理解和理解的关键障碍， 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 磁组织磁化率的成像代表了一个独特的窗口， 临床评估。铁是各种生化途径中的重要辅助因子。它的神经胶质细胞被剥夺 正常外观的白色物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 显示了磁化率的逐渐下降。其他研究表明，类似的现象 可能存在于其他深层灰质区域。迫切需要确认和验证这一观察结果， 因为深部灰质损伤与残疾的进展密切相关。的总体目标 拟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 深层灰质功能障碍核心假设是，少突胶质细胞铁的可用性下降， 在磁共振成像上表现出来的，是疾病进展的独立生物学相关物， 发生在整个大脑中。这项研究的基本原理是，随着时间的推移， 和疾病进展将导致我们对铁在神经变性中作用的理解发生范式转变- 从过量铁的毒性转向铁的可用性不足， 途径。为实现这一目标，本项目将遵循以下具体目标：1）确定协会， 疾病进展与脑铁稳态的磁共振成像标记物之间的关系。（二） 确定脑铁磁共振成像标记物的细胞和分子底物。在com- 作为这些目标的一部分，预期的结果是已经确定少突胶质细胞铁在细胞中减少。 慢性疾病阶段，进展到这种状态与残疾恶化有关。特别是， 这项研究预计已经确定了一个普遍适用的模型， 患者相对于对照组的时间;成像标记物的细胞和分子基础;以及 铁的老化标记与白色物质中的神经变性和损伤有关。这些捐款 由于临床残疾和少突胶质细胞丢失之间存在联系的证据， 灰质中的铁以及评估这种现象的成像标记物的可用性将提高 该领域的垂直和支持新的治疗策略的发展。这项研究是创新的- 由于铁损失的新假设，对深灰质子区域的关注，以及独特的模型， 铁浓度变化的eling方法代表了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.