Phenotypic Spectrum of LRRK2 Mutations

描述（由申请人提供）：制定识别帕金森病（PD）风险个体的策略和预防其发作的干预措施可能是减少疾病负担的最佳希望。PD的发病率相对较低，难以确定表型转化高风险样本，以及缺乏预防性治疗的分子靶点，限制了预防性研究。富含亮氨酸的重复序列激酶激酶（LRRK2）基因的突变构成了帕金森病（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。在德系犹太人中，G2019S突变占PD的20%，LRRK2被认为是一个可药用的靶点，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、病理学和对治疗的反应方面也类似于特发性PD（IPD），使其总体上成为一个很有前途的模型。为了实现这一承诺，我们必须首先更好地描述突变携带者的表型表达范围。对表型异质性的更多理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，黑质的强回声，和自主神经功能障碍可能发生在明显的运动体征和PD的临床诊断。在LRRK2 PD中报告了这些特征以及非皮肤癌，然而，其患病率和表现PD的预测有效性尚不清楚。对大量LRRK2突变PD受试者和无PD的携带者进行评估将有助于确定非运动异常和非皮肤癌是否是独立于PD发展的突变效应（风险标志物），或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（进展标志物）。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病理生理学并帮助建立疾病负担的领域。该提案为在非显性携带者（NMC）以及已确诊的LRRK2 PD（MC）患者中定义LRRK2 G2019表型迈出了重要一步，并将有助于为LRRK2 NMC的纵向研究铺平道路。这项研究建立在我K23期间进行的研究基础上，并利用了福克斯基金会资助的两项当前研究，即德系犹太人PD的联盟研究（联盟，Beth Israel，哥伦比亚，特拉维夫），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研究中心（目标1）增加测量，包括癌症评估（目标3），并将联盟标志物数据与多巴胺能功能障碍的替代标志物（目标2）相结合，来对这两项研究进行重大扩展。这项研究，再加上遗传学，流行病学和经颅超声检查的结构化培训计划将帮助我发展成为帕金森病（PD）研究人员，通过更好地表征疾病，并了解帕金森症的标志物，促进帕金森治疗的开发，测试和早期应用。我在运动障碍和流行病学方面接受过广泛的培训，并发表了LRRK2 PD，戈谢病相关PD和与PD相关的生物标志物，特别是螺旋分析和经颅超声检查。在K02拟议的教育计划将使我能够加深我的知识和专业知识在遗传学，表观遗传学和经颅超声成像领域，并通过课程，实践培训和研究性学习流行病学。如前所述，这项研究将通过增加测量和新的分析，扩展一项针对患有PD的德系犹太人、家庭成员和对照的独特队列的大型联盟研究。在目标1中，将在突变携带者、无LRRK2 G2019S突变的PD和对照的不同亚组之间比较候选非运动、定量运动和成像测量。在目标3中，将测试非皮肤癌与LRRK2 PD之间的关联。最后，在目标2中，DAT扫描将用作PD发展的替代结局标志物，因为不能直接在横断面中研究进展。作为本研究的直接结果，对计划的R01中非运动功能进展进行纵向分析，将允许确定A）预测表型转化的标志物算法，和B）标志物进展相对于PD发作的斜率，并确定在表现PD之前存在的中间状态。 公共卫生相关性：LRRK2基因的突变构成了帕金森病的主要遗传模型。然而，关于突变携带者的帕金森病的临床过程，在PD发展之前是否存在非运动特征，以及这些特征是否与病理性脑变化相关，目前还不清楚。这项研究利用了现有的LRRK2 PD，其他PD和家族成员的宝贵队列，以便更好地了解这些特征。

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.