Cerebrovascular contributions to cognitive impairment in Lewy body dementias

脑血管对路易体痴呆认知障碍的影响

• 批准号: 10355030
• 负责人: Sephira Ryman
• 金额: $ 18.1万
• 依托单位: LOVELACE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355030
• 关键词: Accounting; Address; Age; Amyloid beta-42; Amyloid beta-Protein; Biological Markers; Blood; Blood Vessels; Blood capillaries; Cerebrovascular Disorders; Clinic; Clinical; Cognitive; Collaborations; Dementia; Dementia with Lewy Bodies; Deposition; Development; Disease; Early Diagnosis; Early identification; Etiology; Evaluation; Exhibits; Foundations; Frequencies; Functional disorder; Goals; Health; Imaging Techniques; Impaired cognition; Impairment; Intervention; Label; Lewy Body Dementia; Lewy Body Disease; Literature; Location; Magnetic Resonance Imaging; Measurement; Measures; Methodology; Monitor; Multimodal Imaging; Nerve Degeneration; Neurobehavioral Manifestations; Outcome; Parkinson' s Dementia; Patients; Perfusion; Plasma; Process; Research; Sensitivity and Specificity; Severities; Stratification; Threonine; Time; Tissue imaging; Translations; Travel; United States National Institutes of Health; White Matter Hyperintensity; Work; alpha synuclein; arteriole; base; cardiovascular risk factor; cerebrovascular; cognitive impairment in Parkinson' s; cohort; disability; early detection biomarkers; efficacious treatment; functional disability; innovation; magnetic resonance imaging biomarker; neurovascular; novel; protein aggregation; recruit; response; sex; tau Proteins; tau-1; Accounting; Address; Age; Amyloid beta-42; Amyloid beta-Protein; Biological Markers; Blood; Blood Vessels; Blood capillaries; Cerebrovascular Disorders; Clinic; Clinical; Cognitive; Collaborations; Dementia; Dementia with Lewy Bodies; Deposition; Development; Disease; Early Diagnosis; Early identification; Etiology; Evaluation; Exhibits; Foundations; Frequencies; Functional disorder; Goals; Health; Imaging Techniques; Impaired cognition; Impairment; Intervention; Label; Lewy Body Dementia; Lewy Body Disease; Literature; Location; Magnetic Resonance Imaging; Measurement; Measures; Methodology; Monitor; Multimodal Imaging; Nerve Degeneration; Neurobehavioral Manifestations; Outcome; Parkinson' s Dementia; Patients; Perfusion; Plasma; Process; Research; Sensitivity and Specificity; Severities; Stratification; Threonine; Time; Tissue imaging; Translations; Travel; United States National Institutes of Health; White Matter Hyperintensity; Work; alpha synuclein; arteriole; base; cardiovascular risk factor; cerebrovascular; cognitive impairment in Parkinson' s; cohort; disability; early detection biomarkers; efficacious treatment; functional disability; innovation; magnetic resonance imaging biomarker; neurovascular; novel; protein aggregation; recruit; response; sex; tau Proteins; tau-1

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.

项目摘要 /摘要 Lewy身体痴呆症的认知能力下降[帕金森氏病痴呆症（PDD）和痴呆症与Lewy 身体（DLB）]引起严重的功能障碍，对现有治疗方法的反应不佳。 在这些疾病中开发有效治疗的最大挑战也许是缺乏客观 根据位置和范围 神经病理学过程。脑血管损伤可能是捕获早期的重要因素 疾病课程由于有很多干预机会。但是，有几个限制 先前的研究，包括：1）客观测量脑血管功能，2）评估 特定受试者脑血管异常的频率和一致性，3）检查的影响 临床表现的脑血管功能障碍，以及4）检查 脑血管功能障碍和AD血浆生物标志物。当前的研究解决了这些差距 文献和利用创新的磁共振成像措施，包括：脑血管反应性 （CVR），Artiolles和毛细血管应响应血管舒张挑战和动脉的能力 转移时间（ATT） - 标记的血液的旅行时间到成像的组织。这项研究既是临床，又是 当我们使用艺术状态多模式成像来量化的几个方面时，从方法上创新了 脑血管功能和综合生物循环分析，以回答关键的临床问题。具体来说，PDD （n = 20），DLB（n = 20）和健康对照（HC，n = 20）在年龄和性别上匹配以评估 相对于已建立的MRI脑血管生物标志物的敏感性和特异性和 患者组的脑血管功能异常（AIM 1）。然后，我们将评估 脑血管异常，AD血浆生物标志物和认知症状（AIM 2）。结束 这项成功的应用程序，我们将确定在PDD/DLB中改变了哪些脑血管功能 PDD/DLB中脑血管异常的频率以及脑血管之间的关系 异常，AD血浆生物标志物和认知结果。此信息对于发展至关重要 这些疾病的干预措施可能会较早发生，并提供充足的脑血管功能障碍 干预的机会。此外，根据PAS-19-392中概述的对象，该项目将 建立可以通过竞争性R01扩展的Lewy身体痴呆症患者的最初队列 应用于评估路易疾病中脑血管功能的纵向变化 认知频谱（例如，在PD-MCI中，Promal DLB）。作为当前项目的一部分，PI将参与 通过几个当地NIH中心的专业发展努力，增强了网络的机会， 合作，并保留该领域。