Brain Drivers, Cognition, and Parkinson's Disease: A Psychometric Approach

项目摘要/摘要 帕金森病(PD)是美国增长最快的神经退行性疾病之一， 认知衰退是其最令人衰弱的非运动症状之一。随着疾病的发展，大多数 个人最终会患上痴呆症。然而，认知能力下降的轨迹不同于 个人--导致对即将到来的下跌的风险因素的搜索。2019年，瑞安和同事们提出了一项 精确衰老模型，并认为典型的年龄相关性认知下降受三个方面的影响 “脑驱动因素”的类别：神经病理(例如，α-突触核蛋白，tau)、神经炎症(例如，细胞因子)、 和脑血管功能障碍(如脑白质高信号)。过去的研究一直在测量 这些大脑驱动因素是孤立的，尽管这些因素都属于相互关联的、神经生物学的 系统。因此，本研究的目的是确定是否能更好地解释帕金森病患者的认知差异 通过这些神经生物学风险因素的组合，相对于单独的因素。中心假设是 每一类大脑驱动因素(即神经病理、神经炎症、脑血管功能障碍)将 独特地与认知表现(特别是执行功能和记忆)有关，因此将每个 类别将更好地解释每个认知领域的变化。这项拟议的研究将审查来自 现有的、特征良好的特发性帕金森病患者队列(N=112)，以确定 大脑驱动因素与认知表现之间的横向和纵向关联(在2- 一年的随访)。要做到这一点，大脑驱动与认知的关系将被孤立地评估(使用相关性) 以及组合(使用分层线性回归，添加来自每个大脑驱动程序类别的因素 顺序)。总体而言，这种方法将重点转移到精准医学方法上--即检查 多个大脑驱动因素可能有助于更好地了解个体认知能力下降的个体化风险 和警察在一起。改善认知风险评估可以为帕金森病患者的临床预后和 允许更有针对性地选择参与者参加旨在减缓即将到来的认知能力的实验试验 拒绝。拟议的培训计划将为申请人提供除以下培训以外的其他培训经验 她的博士课程。具体的培训目标包括：(1)获得衡量方法方面的专门知识 神经炎性和神经病理生物标记物及其解释，(2)熟练掌握结构 测量白质的磁共振成像(采集、处理和解释) 高信号(脑血管功能障碍的衡量标准)，(3)先进的统计能力和 实验严谨，以及(4)专业和职业技能发展。拟议的项目和培训目标 将在强大的研究环境的资源和支持下完成，包括富有成效的 在建议的研究领域拥有特定专业知识的指导团队。综上所述，拟议的研究 而其他活动将帮助申请者在过渡到独立调查人员的职业生涯时做好准备。

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is one of the fastest-growing neurodegenerative disorders in the United States, with cognitive decline being among its most debilitating non-motor symptoms. With disease progression, most individuals eventually develop dementia. However, the trajectory of cognitive decline varies between individuals—leading to a search for risk factors of impending decline. In 2019, Ryan and colleagues proposed a precision aging model and suggested that typical age-related cognitive decline was influenced by three broad categories of “brain drivers”: neuropathology (e.g., alpha-synuclein, tau), neuroinflammation (e.g., cytokines), and cerebrovascular dysfunction (e.g., white matter hyperintensities). Past research has consistently measured these brain driver factors in isolation, despite these factors all belonging to an interconnected, neurobiological system. Thus, the goal of the proposed study is to determine whether cognitive variation in PD is better explained by a combination of these neurobiological risk factors, relative to isolated factors. The central hypothesis is that each category of brain drivers (i.e., neuropathology, neuroinflammation, cerebrovascular dysfunction) will uniquely relate to cognitive performance (specifically executive function and memory), such that adding in each category will better explain changes in each cognitive domain. The proposed study will examine data from an existing, well-characterized cohort of individuals with idiopathic PD without dementia (N=112) to determine the association between brain driver factors and cognitive performance cross-sectionally and longitudinally (at a 2- year follow-up). To do so, brain driver relationships with cognition will be assessed in isolation (using correlations) and in combination (using hierarchical linear regressions, adding in factors from each brain driver category sequentially). Overall, this method shifts the focus towards a precision medicine approach—whereby examining multiple brain drivers may allow for greater understanding of individualized risk of cognitive decline in individuals with PD. Improving the assessment of cognitive risk could inform both clinical prognosis for patients with PD and allow for a more targeted selection of participants into experimental trials aiming to slow impending cognitive decline. The proposed training plan will provide the applicant with additional training experiences beyond that of her Ph.D. program. Specific training goals include (1) gaining expertise in the methodologies measuring neuroinflammatory and neuropathology biomarkers and their interpretation, (2) gaining proficiency with structural magnetic resonance imaging (acquisition, processing, and interpretation) to measure white matter hyperintensities (a metric of cerebrovascular dysfunction), (3) advancing statistical competencies and experimental rigor, and (4) professional and career skills development. The proposed project and training goals will be completed with the resources and support of a strong research environment, including a productive mentoring team with specific expertise in the proposed area of study. Taken together, the proposed research and other activities will help prepare the applicant as she transitions into a career as an independent investigator.