Biomarkers for White Matter Injury in Mixed and Vascular Cognitive Impairment

描述（由申请人提供）：血管性认知障碍（VCI）是一种异质性疾病，是老年人智力丧失的主要原因。病理研究表明，由高血压、糖尿病和淀粉样血管病引起的皮质下缺血性血管病（SIVD）是VCI的主要亚群。2002年和2011年卒中进展审查小组报告都将VCI确定为研究和治疗的主要目标。由于SIVD的进展过程，它被认为是临床试验的最佳类型，MRI上的白质高强度（WMHs）被建议作为替代标记。然而，SIVD发病隐匿，难以与其他形式的痴呆区分开来，尤其是阿尔茨海默病（AD），其病理上与VCI重叠。因此，寻求能够帮助区分各种类型VCI的生物标志物，并在可能的早期治疗阶段分离出重叠或混合综合征。在先前的资助期间，PI使用MRI和CSF研究确定了几种新的VCI生物标志物，并表明它们可以帮助诊断。目前的拨款是使用这些机械性生物标志物前瞻性地诊断SIVD。核心假设是深部白质的进行性损伤是由MMPs表达的炎症、血脑屏障的破坏、血管源性水肿和少突胶质细胞死亡引起的。动物实验表明，缺氧驱动分子级联损伤，但蛋白酶是血管损伤和髓磷脂分解的最终共同途径。由于很大一部分痴呆患者同时具有VCI和AD病理过程，因此使用多模式诊断方法可能是识别纯形式并将其与混合形式区分开来的唯一方法。目的1：目的是确定一组生物标志物，可用于在病程早期诊断SIVD型VCI患者的算法。本研究的总体目标是从临床、神经心理学、影像学和脑脊液研究中确定一组最佳的生物标志物，以准确地分离患者进行治疗试验。目的2：该目的是确定血管疾病和阿尔茨海默病的生物标志物，这将有助于选择混合患者。目的是确定SIVD患者脑脊液中淀粉样蛋白和tau蛋白的含义。对AD、VCI患者和非痴呆正常受试者进行的大型尸检研究表明，单纯形式的AD或SIVD比两者都存在的情况要少，并且这两种类型的病理证据通常存在于正常受试者中，识别AD和VCI生物标志物将提高诊断。目的3：确定炎症在WMHs生长和认知能力下降中的作用，并检验SIVD量表的预测能力。具体目标1和2中收集的数据将用于目标3，即确定一组生物标志物，用于区分患者，并可根据最终诊断进行测试，并可用于指示自然史。总体目标是从临床检查、神经心理测试、MRI和CSF中确定一组最小的生物标志物，这些生物标志物可以在初步评估中获得，并且可以最好地预测自然病史

DESCRIPTION (provided by applicant): Vascular cognitive impairment (VCI) is a heterogeneous disease that is a major cause of intellectual loss in the elderly. Pathological studies indicate that subcortical ischemic vascular disease (SIVD) due to hypertension, diabetes, and amyloid angiopathy is the major subgroup of VCI. Both the 2002 and 2011 Stroke Progress Review Group Reports identified VCI as a major target for research and treatment. Because of the progressive course of SIVD, it is considered the optimal type for clinical trials, and white matter hyperintensities (WMHs) on MRI are suggested as a surrogate marker. However, SIVD has an insidious onset, making it difficult to separate from other forms of dementia, particularly Alzheimer's disease (AD), which overlaps pathologically with VCI. Therefore, biomarkers are sought that could aid the differentiation of the various types of VCI and separate out the overlap or mixed syndromes at an early stage when treatment is possible. During the prior grant, the PI used MRI and CSF studies to identify several novel biomarkers for VCI, and showed that they can aid in diagnosis. The current grant is to use these mechanistic biomarkers prospectively to diagnose the SIVD. The central hypothesis is that progressive injury to the deep white matter is due to inflammation with expression of MMPs, disruption of the BBB, vasogenic edema, and oligodendrocyte death. Studies in animals indicate that hypoxia drives the molecular injury cascade, but that proteases are the final common pathway of blood vessel damage and break down of myelin. Since a large proportion of patients with dementia have both VCI and AD pathological processes, using a multi-modal approach to diagnosis may be the only way to identify the pure forms and separate them from the mixed forms. Aim 1: This aim is to determine a set of biomarkers that can be used in an algorithm to diagnose patients with the SIVD form of VCI early in the disease course. The overall goal of this study is to identif the optimal set of biomarkers from clinical, neuropsychological, imaging and CSF studies to accurately separate patients for treatment trials..Aim 2: This aim is to identify biomarkers for vascular disease and Alzheimer's disease that will aid in selection of mixed patients. This aim is focused on determining the implications of amyloid and tau proteins in the CSF of SIVD patients. Large autopsy studies of patients with AD, VCI and non-demented normal subjects show that pure forms of either AD or SIVD are less common than finding both present, and that evidence of both types of pathology is often present in normal subjects and identifying both AD and VCI biomarkers will improve diagnosis. Aim 3: To determine the role of inflammation in the growth of WMHs and cognitive decline and to test the predictive ability of a SIVD Scale. Data collected in Specific Aims 1 and 2 will be used in Aim 3, which is to determine a set of biomarkers that separate patients and that can be tested against the final diagnoses, and which can be used to indicate the natural history. The overall goal is to identify a minimal set of biomarkers from clinical examination, neuropsychological testing, MRI and CSF that could be obtained at an initial evaluation, and which will best predict the natural history and which can be used to select a more homogeneous group of clinical trials. PUBLIC HEALTH RELEVANCE: Vascular cognitive impairment (VCI) is an important cause of dementia in the elderly and accelerates the most common form, Alzheimer's disease (AD). Both the 2002 and 2011 Stroke Progress Review Group Reports identified lack of understanding of the pathophysiology and treatment of VCI as a major target for research. We have proposed that the small vessel form of VCI is an inflammatory disease due to hypoxia- driven white matter injury. This proposal will use a unique set of biomarkers for VCI and AD to test the hypothesis. The importance is that early identification of VCI patients will facilitate treatment trials.