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

描述（申请人提供）：帕金森病（PD）临床表现为运动功能障碍的不对称表现，病理表现为基底神经节（BG）黑质纹状体多巴胺（DA）神经元丢失，常伴有神经节外、非多巴胺能、非运动症状。大多数帕金森病的发病机制尚未证实，也没有治疗方法被证明可以减缓、阻止或逆转细胞死亡和疾病进展。此外，由于缺乏与PD进展相关的细胞损失的可靠、客观的体内标志物，对PD相关细胞损失的理解和潜在神经保护疗法的评估都受到了阻碍。最好的活体技术是功能放射成像（PET和SPECT），可以评估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了DA细胞的损失，由PD的对症治疗调节，不能评估非多巴胺能系统，并且不能广泛使用。另外，结构体积成像可以反映体内宏观萎缩（由细胞损失引起），不太可能受到纯粹对症治疗的影响，可以评估神经节外/非多巴胺能系统，并且广泛可用。然而，由于很难将萎缩变化与特定的机制或功能联系起来，这种方法尚未得到详尽的探索；也因为PD之前的结构成像研究结果不一致。后者可能是由于横断面设计、小样本量和/或可靠性较低的成像分析方法。我们的目标是进行PD的结构成像研究，从而提供对PD相关细胞丢失的更复杂的理解，并确定MRI是否可以作为疾病进展的有用且非侵入性标志物。在强有力的初步数据的支持下，我们的中心假设是，相对于规范的年龄匹配样本，PD患者在局部（例如BG结构）和整体上经历了显著的脑萎缩变化。这些变化不仅可以通过高分辨率MRI和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PD相关的功能含义。我们建议对临床诊断10年内的80名PD患者和54名对照组（年龄、性别、利手性和教育程度为3:2）进行纵向研究。我们的目的是：1)建立侧脑室增大的年龄趋势，选择PD患者与对照组相比BG区域萎缩；2)表征PD进展过程中侧脑室纵向体积变化的偏侧性和时间过程，选择与PD运动不对称性和持续时间相关的BG区域；3)探索不同感兴趣结构的体积测量作为PD疾病进展过程中运动和非运动功能障碍个体方面的标志物的潜力；4)探索不同脑区变化与pd相关功能变化的相互关系。

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.