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

描述(申请人提供)：帕金森病(PD)临床上以运动功能障碍的不对称性表现为特征，病理上以基底节(BG)的黑质纹状体多巴胺(DA)神经元丢失为特征，常伴有黑质外、非多巴胺能、非运动症状。大多数帕金森病的发病机制尚未得到证实，也没有被证明可以减缓、阻止或逆转细胞死亡和疾病进展的治疗方法。此外，由于缺乏与帕金森病进展相关的可靠的、客观的体内细胞丢失标记物，对帕金森病相关细胞丢失的理解和潜在神经保护治疗的评估都受到了阻碍。最好的体内技术是功能放射成像(PET和SPECT)，评估DA转运体密度或神经元活动。虽然有价值，但这些终点间接反映DA细胞的丢失，受帕金森病症状治疗的调节，不能评估非多巴胺能系统，也不能广泛获得。或者，结构体积成像可以反映体内的宏观萎缩(由细胞丢失引起)，不太可能受到纯粹的对症治疗的影响，可以评估黑质外/非多巴胺能系统，并且可以广泛使用。然而，由于难以将萎缩改变与特定的机制或功能联系起来，以及先前在帕金森病的结构成像研究中不一致的发现，这种方法还没有得到详尽的探索。后者可能是横断面设计、小样本量和/或可靠性较低的成像分析方法的结果。我们的目标是在帕金森病中进行结构成像研究，从而提供对帕金森病相关细胞丢失的更复杂的了解，并确定MRI是否可以作为疾病进展的有用和非侵入性标记。在强大的初步数据的支持下，我们的中心假设是，相对于标准的年龄匹配样本，PD患者经历了局灶性(例如，在BG结构中)和全局的显著脑萎缩变化。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，而且它们可能在临床和启发式水平上具有与帕金森病相关的功能暗示。我们建议对临床诊断10年内的80名帕金森病患者和54名对照组(年龄、性别、利手和教育程度3：2匹配)进行纵向研究。我们的目标是：1)建立PD患者侧脑室扩大的年龄趋势，并选择与对照组相比的BG区域萎缩；2)表征侧脑室纵向体积变化的定侧化和时程，并选择PD进展过程中与PD运动不对称和持续时间相关的BG区域；3)探索不同感兴趣结构的体积测量作为PD运动和非运动功能障碍在疾病进展过程中个别方面的标志物(S)的可能性；以及4)探索不同脑区之间的变化与PD相关功能变化的相互关系。公共卫生相关性：帕金森氏病(PD)是一种与年龄相关的神经疾病，尽管患者正在接受最好的治疗，但它仍会导致运动和其他功能障碍，从而影响约100万美国人的生活质量。在帕金森病患者中，由于缺乏广泛可用的但可靠的疾病进展标志物，理解确切的原因，并评估减缓或阻止疾病进展的治疗方法是受阻的。这笔赠款的目的是建立MRI测量作为这样的标记，从而导致更好地了解帕金森病的原因，并改进对帕金森病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.