Assessment of Brain Iron and Neuronal Integrity Using Novel T1r and T2r MRI

描述（由申请人提供）：帕金森病（PD）是一种神经退行性疾病，其特征为缓慢、僵硬和经常震颤。超过100万美国人患有PD，预计到2030年全球将有900万人患有PD。迄今为止，还没有公认的客观生物学指标，即生物标志物，反映疾病的发病机制或对治疗的药理学反应。缺乏可靠的生物标志物严重限制了早期诊断、神经保护疗法的研究和疾病发病机制的评价。目前的放射性示踪成像技术，如正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）缺乏确定多巴胺神经元计数以及密度的能力。 同样，磁共振成像（MRI）在其目前的状态是没有用作为PD的生物标志物。 因此，仍然需要一种PD神经成像技术，其提供测量神经元活力和密度以及解决目前成像技术无法解决的其他问题的手段。一种可以确定神经元状态以及可能的致病因素如铁的方法将是潜在有用的。最近，我们开发了用于人类研究的新型MRI技术，这些技术非常有助于为神经系统疾病（特别是PD）的分子过程提供新的见解。这些方法利用所谓的“绝热”脉冲（基于脉冲期间射频（RF）的扫描），并利用基于旋转框架纵向和横向弛豫T？而T？分别在绝热脉冲期间。T2？是敏感的扩散的水质子在不同的地方磁化率的环境，并可能反映铁含量; whileT 1？主要反映水-蛋白质相互作用，因此可能提供可用于评估PD黑质变性的神经元损失的指示。我们已经证明了T？-加权脉冲序列提供了一种直接评估4.7特斯拉下人脑中非血红素铁负荷的方法。所获得的弛豫速率常数值和区域非血红素铁浓度之间的强相关性表明实用的T？脉冲序列在高磁场下定量体内脑铁。然而，T？ MRI技术仍需适当的验证，以建立作为神经元计数的定量方法。在这项研究中，我们的目的是确定T？？测量以充分反映大脑中的神经元密度。因此，T？神经元密度的测量在此进行进一步的研究。我们将探讨弛豫时间常数T？？而T？从而潜在地揭示了神经元密度和非血红素铁之间的联系。公共卫生相关性在这个项目中，我们的目标是建立新的高分辨率磁共振成像（MRI）技术，T？作为定量方法敏感的神经元损失和T？作为对大脑中铁负荷敏感的方法。我们将调查的预测/歧视能力的T？使用单侧6-羟基多巴胺（6-OHDA）PD小鼠模型（纹状体内注射2？g 6-OHDA/？L）。我们将研究T？神经元密度和T？在无晶状体小鼠（其中黑质中多巴胺能神经元的缺陷和神经元存活的途径被很好地研究）中用铁负载。一旦得到验证，T？这项技术可以作为一个有价值的工具，以调查是否以及如何在黑质神经元的损失与帕金森病的进展。我们将探讨弛豫时间常数T？？而T？从而潜在的神经元密度和非血红素铁之间的关联。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disorder characterized by slowness, stiffness and often tremor. Over 1 million Americans have PD and globally 9 million people are projected to have PD by the year 2030. To date, there is no accepted objective biological measure, i.e, biomarker, that is reflective of disease pathogenesis or of pharmacological responses to treatment. Absence of a reliable biomarker severely limits early diagnosis, research on neuroprotective therapies and appreciation of disease pathogenesis. Current radiotracing imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) lack the ability to ascertain dopamine neuronal counts as well as density. Likewise, magnetic resonance imaging (MRI) in its present state is not useful as a biomarker for PD. Therefore, there remains a need for a PD neuroimaging technique that provides a means to measure neuronal viability and density as well as address other issues of which present imaging techniques are unable to do. A method which could ascertain neuronal status as well as possible pathogenic factors such as iron would be potentially useful. Recently we developed novel MRI techniques for human studies that can be extremely helpful in providing new insights into the molecular processes characterizing neurological diseases, in particular PD. These methods utilize the so called "adiabatic" pulses (based on the sweep of the radiofrequency (RF) during the pulses) and exploit a novel MRI contrast based on the rotating frame longitudinal and transverse relaxations, T???and T???respectively, during the adiabatic pulses. T2? is sensitive to diffusion of water protons in environments with different local magnetic susceptibilities and likely reflects iron content; whileT1? reflects predominantly water-protein interactions, and, therefore might provide an indication of neuronal loss that could be used to assess PD nigral degeneration. We have demonstrated that T???- weighted pulse sequences provide a method to directly assess non-heme iron loads in the human brain at 4.7 Tesla. The strong correlation between the obtained relaxation rate constant values and the regional non-heme iron concentrations suggests utility for the T???pulse sequences in quantifying in vivo brain iron at high magnetic fields. However, T?? MRI technique still needs proper validation in order to be established as quantitative method for neuronal count. In this study we aim to determine the validity of T?? measurements to adequately reflect neuronal density in the brain. Therefore, the specificity and sensitivity of T???measurements to neuronal density are subjected here to further investigation. We will investigate functional relationship between relaxation time constants T???and T???and thus potentially the association between neuronal density and non-heme iron. PUBLIC HEALTH RELEVANCE In this project we aim to establish novel high-resolution magnetic resonance imaging (MRI) techniques, T???as quantitative method sensitive to neuronal loss and T???as method sensitive to iron loading in the brain. We will investigate the predictive/discriminatory ability of the T???using a unilateral 6-hydroxydopamine (6-OHDA) PD mouse model (intrastriatal injection of 2 ?g 6-OHDA/?L). We will study the functional relationship between T???with neuronal density and T???with iron loading in aphakia mice (where the deficit of dopaminergic neurons in substantia nigra and the pathways for survival of neurons are well investigated). Once validated, the T???technique can be used as a valuable tool to investigate if and how neuronal loss in substantia nigra is correlated with the progression of Parkinson's disease. We will investigate functional relationship between relaxation time constants T????and T???and thus potentially the association between neuronal density and nonheme iron.