Cerebrovascular contributions to cognitive impairment in Lewy body dementias

项目摘要/摘要 路易体痴呆[帕金森氏病痴呆(PDD)和路易氏痴呆 身体(DLB)]会导致严重的功能障碍，对现有的治疗方法反应不佳。 也许开发这些疾病的有效治疗方法的最大挑战是缺乏目标性 根据PDD/DLB患者的位置和程度早期识别和分层的生物标志物 神经病理过程。脑血管损伤可能是早期发病的一个重要因素。 疾病病程，因为有许多干预的机会。但是，有几个限制 前人的研究包括：1)脑血管功能的客观测量；2)对脑血管功能的评价 受试者特定脑血管异常的频率和一致性，3)检查 脑血管功能障碍的临床表现与4)检查之间的关系 脑血管功能障碍与阿尔茨海默病血浆生物标志物目前的研究解决了这些差距， 文献和利用创新的磁共振成像方法，包括：脑血管反应性 (CVR)，微动脉和毛细血管对血管扩张挑战的反应能力，以及动脉 传输时间(ATT)-标记血液到达成像组织的传播时间。这项研究既有临床意义，也有 在方法上创新，因为我们使用最先进的多模式成像来量化以下几个方面 脑血管功能和综合生物谱学分析，以回答关键的临床问题。具体地说，PDD 将招募年龄和性别匹配的健康对照组(n=20)、DLB组(n=20)和健康对照组(HC，N=20)进行评估 新的相对于已建立的MRI脑血管生物标志物的敏感性和特异性以及 患者组的脑血管功能异常(目标1)。然后我们将评估两国之间的关系 脑血管异常、阿尔茨海默病血浆生物标志物和认知症状(目标2)。在……结束时 这一成功的应用，我们将确定哪些脑血管功能在PDD/DLB中发生了改变， PDD/DLB型脑血管异常的发生率及其与脑血管的关系 异常，阿尔茨海默病血浆生物标志物，和认知结果。这些信息对于开发 对这些疾病的干预措施，因为潜在的脑血管功能障碍可能发生在早期，并提供充足的 干预的机会。此外，根据PAS-19-392中概述的目标，该项目将 建立一个可以通过竞争性R01扩大的路易体痴呆患者的初始队列 应用于评估路易体病患者脑血管功能的纵向变化 认知谱(如PD-MCI、前驱DLB型)。作为当前项目的一部分，国际和平研究所将参与 通过几个当地NIH中心的专业发展努力，增加联网机会， 协作，以及在现场的保留。

Project Summary / Abstract Cognitive decline in Lewy body dementias [Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB)] causes significant functional impairment and does not respond well to existing treatments. Perhaps the largest challenge for developing efficacious treatments in these diseases is the lack of objective biomarkers for early identification and stratification of PDD/DLB patients based on the location and extent of neuropathological processes. Cerebrovascular impairment may be an important factor to capture early in the disease course as there are numerous opportunities for intervention. However, there are several limitations of the prior research, including: 1) objective measurement of cerebrovascular functions, 2) evaluation of the frequency and consistency in subject specific cerebrovascular abnormalities, 3) examination of the impact of cerebrovascular dysfunction on clinical presentation, and 4) examination of the relationship between cerebrovascular dysfunction and AD plasma biomarkers. The current study addresses these gaps in the literature and leverages innovative magnetic resonance imaging measures, including: cerebrovascular reactivity (CVR), the ability of the arterioles and capillaries to dilate in response to a vasodilatory challenge, and arterial transfer time (ATT) - the travel time of labeled blood to the imaged tissue. This study is both clinically and methodologically innovative as we use state of the art multimodal imaging to quantify several aspects of cerebrovascular function and integrate biospecimen analyses to answer key clinical questions. Specifically, PDD (N = 20), DLB (N = 20), and healthy controls (HC, N = 20) matched on age and sex will be recruited to evaluate the sensitivity and specificity of novel relative to established MRI cerebrovascular biomarkers and frequency of abnormal cerebrovascular functions in patient groups (Aim 1). We will then evaluate the relationships between cerebrovascular abnormalities, AD plasma biomarkers, and cognitive symptoms (Aim 2). At the conclusion of this successful application, we will identify which cerebrovascular functions are altered in PDD/DLB, the frequency of cerebrovascular abnormalities in PDD/DLB, and the relationship between cerebrovascular abnormalities, AD plasma biomarkers, and cognitive outcomes. This information is crucial to developing interventions for these disorders as potentially cerebrovascular dysfunction may occur early and provide ample opportunity for intervention. Additionally, in line with the objectives outlined in PAS-19-392, this project will establish an initial cohort of Lewy body dementia patients that can be expanded through a competitive R01 application to evaluate longitudinal change in cerebrovascular functioning in Lewy body disease across the cognitive spectrum (e.g. in PD-MCI, prodromal DLB). As part of the current project, the PI will engage in professional development efforts through several local NIH Centers, enhancing opportunities for networking, collaboration, and retention in the field.