Structural MRI marker(s) of Parkinson's Disease's Progression

描述（由申请人提供）：帕金森病（PD）的临床特征为运动功能障碍的不对称表现，病理特征为基底神经节（BG）中的黑质纹状体多巴胺（DA）神经元丢失，并且通常伴有黑质、非多巴胺能、非运动症状。大多数PD的发病机制尚未得到证实，并且没有证明可以减缓，阻止或逆转细胞死亡和疾病进展的疗法。此外，由于缺乏与PD进展相关的细胞丢失的可靠、客观的体内标记物，对PD相关细胞丢失的理解和对潜在神经保护疗法的评价都受到阻碍。最好的体内技术是功能性放射成像（PET和SPECT），评估DA转运蛋白密度或神经元活性。虽然有价值，但这些终点间接反映了DA细胞损失，受PD对症治疗的调节，无法评估非多巴胺能系统，并且无法广泛获得。或者，结构体积成像可以反映体内宏观萎缩（由细胞丢失引起），不太可能受到纯粹对症治疗的影响，可以评估神经元/非多巴胺能系统，并且广泛可用。然而，这种方法还没有被彻底探讨，因为在一个特定的机制或功能的萎缩性变化的困难，因为不一致的结果，在以前的结构成像研究PD。后者可能是横截面设计、小样本量和/或可靠性低的成像分析方法的结果。我们的目标是在PD中进行结构成像研究，从而提供对PD相关细胞丢失的更复杂的理解，并确定MRI是否可以成为疾病进展的有用和非侵入性标记物。在强有力的初步数据的支持下，我们的中心假设是PD患者发生局灶性显著的脑萎缩变化（例如，在BG结构中）和全球相对于标准年龄匹配样本。这些变化不仅可以使用高分辨率MRI结合复杂的分析技术可靠地量化，而且它们可能具有与临床和启发式水平的PD相关的功能性影响。我们建议对80名临床诊断10年内的PD受试者和54名对照（年龄，性别，利手和教育程度匹配3：2）进行纵向研究。我们的目标是：1）确定与对照相比PD患者中侧脑室扩大和选择BG区域萎缩的年龄趋势; 2）表征PD进展过程中侧脑室和选择BG区域的纵向体积变化的偏侧化和时间过程，与PD运动不对称性和持续时间相关; 3）探索不同感兴趣结构的体积测量作为疾病进展期间PD运动和非运动功能障碍的个体方面的标记的潜力;（4）探讨不同脑区变化的相互关系及PD相关的功能改变。公共卫生相关性：帕金森病（PD）是一种与年龄相关的神经系统疾病，尽管患者正在接受最好的治疗，但仍会通过引起运动和其他功能障碍影响约100万美国人的生活质量。了解确切的原因，并评估治疗以减缓或停止疾病的进展，由于缺乏广泛可用但可靠的标志物，因此阻碍了PD患者的进展。这项资助的目的是建立MRI测量作为这样一个标志物，从而导致更好地了解PD的原因和改善对PD潜在神经保护剂的评估。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is marked clinically by asymmetrical presentation of motor dysfunction, pathologically by the nigrostriatal dopamine (DA) neuronal loss in the basal ganglia (BG), and often is accompanied by extranigral, non-dopaminergic, non-motor symptoms. The pathogenesis of most PD is unproven, and there are no therapies proven to slow, arrest, or reverse cell death and disease progression. Moreover, both the understanding of PD-associated cell loss and evaluation of potential neuroprotective therapies have been hindered by the lack of a reliable, objective, in vivo marker for cell loss associated with PD progression. The best available in vivo techniques are functional radioimaging (PET & SPECT), assessing either DA transporter density or neuronal activity. While valuable, these endpoints reflect DA cell loss indirectly, are modulated by the symptomatic treatments in PD, are not able to assess non-dopaminergic systems, and are not widely available. Alternatively, structural volumetric imaging can reflect in vivo macroscopic atrophy (caused by cell loss), is less likely to be influenced by purely symptomatic treatments, can assess extranigral/nondopaminergic systems, and is widely available. Yet this approach has not been as exhaustively explored because of the difficulty in relating atrophic changes to a specific mechanism or function; and because of inconsistent findings in prior structural imaging studies in PD. The latter may be a result of cross-sectional designs, small sample sizes, and/or imaging analysis methods with low reliability. Our goal is to pursue structural imaging studies in PD, thus providing a more sophisticated understanding of PD-related cell loss, and a determination of whether MRI can be a useful and non-invasive marker of disease progression. Supported by strong preliminary data, our central hypothesis is that PD patients undergo significant brain atrophic changes focally (e.g., in BG structures) and globally relative to a normative age-matched sample. Not only can these changes be quantified reliably using high resolution MRI coupled with sophisticated analysis techniques, but they may have functional implications that are relevant to PD at both the clinical and heuristic levels. We propose to do longitudinal studies of a cohort of 80 PD subjects within 10 years of clinical diagnosis, and 54 Controls (matched 3:2 in age, gender, handedness, & education). Our aims are to: 1) Establish the age trend of lateral ventricle enlargement and select BG regional atrophy in PD patients compared to Controls; 2) Characterize the lateralization and time-course of longitudinal volumetric changes of lateral ventricles and select BG regions during the course of PD progression in relation to PD motor asymmetry and duration; 3) Explore the potential of the volumetric measures of different structures of interest as a marker(s) of individual aspects of PD motor and non-motor dysfunction during the disease progression; and 4) Explore the interrelationships of changes among different brain regions and PD-related functional changes. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is an age-related neurological disorder that affects about one million Americans' quality of life by causing motor and other dysfunctions, despite patients being on the best treatments available. Understanding the exact cause, and assessing a treatment to slow, or stop, the progression of the disease are hindered by the lack of a widely available, yet reliable, marker for its progression as it unfolds in PD patients. The goal of this grant is to establish MRI measurements as such a marker, thereby leading to a better understanding of the cause of PD and improved assessment of potential neuroprotective agents in PD.