Phenotypic Spectrum of LRRK2 Mutations

描述（由申请人提供）：制定策略以识别帕金森病（PD）风险个体和干预措施以预防其发作，可能是减轻疾病负担的最大希望。PD发病率相对较低，难以确定表型转化高风险样本，以及缺乏预防治疗的分子靶点，限制了预防性研究。富亮氨酸重复激酶（LRRK2）基因突变是帕金森病（PD）最常见的单基因病因，这一发现为解决这些挑战提供了机会。G2019S突变占德系犹太人PD的20%，LRRK2被认为是一个可药物靶点，使LRRK2 PD本身成为一种重要的疾病。LRRK2 PD在临床特征、生物标志物、病理和对治疗的反应方面也与特发性PD （IPD）相似，使其成为一种很有希望的模型。为了实现这一承诺，我们必须首先更好地表征突变携带者的表型表达范围。对表型异质性的进一步了解包括非运动和早期运动特征。非运动异常，如嗅觉功能障碍、黑质高回声性和自主神经异常，可能发生在明显的运动体征和PD的临床诊断之前。这些特征，以及非皮肤癌，已经在LRRK2 PD中报道过，然而，它们的患病率和对PD表现的预测有效性尚不清楚。对大量LRRK2突变PD受试者和非PD携带者的评估将有助于确定非运动异常和非皮肤癌是独立于PD发展的突变效应（风险标记），还是在可能处于运动恶化轨迹或已诊断为PD的个体中表现出来（进展标记）。此外，量化非运动和早期运动PD特征的存在和特征将阐明人类LRRK2的病理生理，并有助于建立疾病负担的领域。该建议为确定LRRK2 G2019在非显性携带者（NMC）以及LRKK2 PD （MC）患者中的表型迈出了重要的一步，并将有助于为LRRK2 NMC的纵向研究铺平道路。本研究以我在K23期间进行的研究为基础，并利用Fox基金会资助的两项当前研究，德系犹太人PD研究联盟（该联盟，Beth Israel, Columbia, Tel Aviv），以及LRRK2 PD联盟受试者一级亲属子集的DaTSCAN研究（神经退行性疾病研究所，IND研究）。它将通过在纽约和以色列两个地点（Aim 1）增加测量，包括癌症评估（Aim 3），并将联盟标记数据与多巴胺能功能障碍的替代标记（Aim 2）相结合，从而极大地扩展这两项研究。这项研究，加上遗传学、流行病学和经颅超声检查方面的结构化培训计划，将帮助我成为一名帕金森病（PD）研究人员，通过更好地表征疾病，了解帕金森病的标志物，促进帕金森疗法的开发、测试和早期应用。我在运动障碍和流行病学方面接受了广泛的培训，并发表了关于LRRK2 PD， Gaucher相关性PD和PD相关生物标志物的文章，特别是螺旋分析和经颅超声检查。K02提出的教育计划将使我在遗传学、表观遗传学、经颅超声成像、流行病学等领域通过课程学习、实践培训和研究学习，加深自己的知识和专业技能。如前所述，这项研究将通过增加测量和新的分析，扩展对德系犹太人PD，家庭成员和对照组的独特队列的大型财团研究。在Aim 1候选非运动中，将比较突变携带者、无LRRK2 G2019S突变的PD和对照组不同亚组之间的定量运动和影像学指标。在Aim 3中，将测试非皮肤癌与LRRK2 PD之间的关系。最后，在Aim 2中，由于不能直接在横断面上研究进展，DAT扫描将用作PD发展的替代结果标记物。作为本研究的直接成果，对计划R01中非运动特征进展的纵向分析将允许确定a)预测表型转化的标记算法，B)相对于PD发病的标记进展斜率，以及确定在表现PD之前存在的中间状态。

DESCRIPTION (provided by applicant): Developing strategies to identify individuals at risk for Parkinson disease (PD) and interventions to prevent its onset may be the best hope for reducing the disease burden. Preventative research has been limited by the relatively low incidence of PD, difficulties in defining samples at high risk for phenoconversion, and the lack of molecular targets for preventive treatments. The discovery that mutations in the leucine rich repeat kinase kinase (LRRK2) gene comprise the most common monogenic etiology of Parkinson disease (PD) provides an opportunity to address many of these challenges. The G2019S mutation accounts for up to 20% of PD in Ashkenazi Jews, and LRRK2 is considered a druggable target, making LRRK2 PD an important disease in its own right. LRRK2 PD also resembles idiopathic PD (IPD) in terms of clinical features, biomarkers, pathology and response to treatment, making it overall a model of great promise. To deliver on this promise, we must first better characterize the range of phenotypic expression in mutation carriers. Greater understanding of the phenotypic heterogeneity includes non-motor and early motor features. Non-motor abnormalities such as olfactory dysfunction, hyperechogenicity of the substantia nigra, and dysautonomia may occur before overt motor signs and clinical diagnosis of PD. These features, as well as non-skin cancer, have been reported in LRRK2 PD, however, their prevalence and predictive validity for manifesting PD is not known. Evaluation of a larger number of LRRK2 mutation PD subjects and carriers without PD will help determine whether non-motor abnormalities and non-skin cancer are mutation effects independent of development of PD (risk markers), or manifest in individuals who may be on the trajectory to motor worsening or have diagnosed PD (progression markers). Further, quantifying the presence and characteristics of non-motor and early motor PD features will illuminate human LRRK2 pathophysiology and help establish domains of disease burden. This proposal takes important steps towards defining the phenotype of LRRK2 G2019 in nonmanifesting carriers (NMC), as well as and in persons with established LRKK2 PD (MC), and will help pave the way for longitudinal study of LRRK2 NMC. This research builds on studies conducted during my K23 and capitalizes on two current studies funded by the Fox Foundation, the Consortium study of PD in Ashkenazi Jews (the Consortium, Beth Israel, Columbia, Tel Aviv), and a DaTSCAN study in a subset of first degree relatives of LRRK2 PD Consortium subjects (the Institute for Neurodegenerative Disease, IND study). It will critically expand both studies by adding measures to both New York and Israeli sites (Aim 1), including cancer assessment (Aim 3), and combining Consortium marker data with a surrogate marker for dopaminergic dysfunction (Aim 2). This research, together with a program of structured training in genetics, epidemiology and transcranial sonography will help me develop as a Parkinson disease (PD) researcher who will facilitate the development, testing and early application of Parkinson therapeutics through better characterization of the disease, and understanding markers of parkinsonism. I have extensive training in movement disorders and epidemiology, and have published on LRRK2 PD, Gaucher associated PD, and biomarkers associated with PD, particularly spiral analysis and transcranial sonography. The proposed educational plan in the K02 would allow me to deepen my knowledge and expertise in the areas of genetics, epigenetics, and imaging with transcranial sonography, and epidemiology through coursework, practical training and the research study. As noted, this study will expand on a large Consortium study of a unique cohort of Ashkenazi Jews with PD, family members and controls, by adding measures and new analyses. In Aim 1 candidate non-motor, quantitative motor and imaging measures will be compared between different subgroups of mutation carriers, PD without LRRK2 G2019S mutation, and controls. In Aim 3, the association between non-skin cancer and LRRK2 PD will be tested. Finally in Aim 2, DAT scan will be used as a surrogate outcome marker for development of PD, as progression cannot be directly studied in cross-section. Longitudinal analysis of progression of non-motor features in the planned R01 as a direct outgrowth of this study will allow determination of A) an algorithm of markers which predicts phenoconversion, and B) the slopes of marker progression relative to the onset of PD, and the determination of an intermediary state which is present prior to manifesting PD. PUBLIC HEALTH RELEVANCE: Mutations in the LRRK2 gene constitute the leading genetic model for Parkinson's disease. However, much is not yet known about the clinical course of Parkinson's disease in mutation carriers, whether non-motor features are present prior to the development of PD, and whether these correlate with pathologic brain changes. This study capitalizes on an existing precious cohort of LRRK2 PD, other PD and family members in order to better learn about these features.