Biomarkers for White Matter Injury in Mixed and Vascular Cognitive Impairment

描述(申请人提供)：血管认知障碍(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变引起的皮质下缺血性血管病(SIVD)是VCI的主要亚型。2002年和2011年卒中进展审查小组的报告都将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上的白质高信号(WMHs)可作为替代标记物。然而，SIVD的发病具有潜伏性，这使得它很难与其他形式的痴呆症区分开来，特别是阿尔茨海默病(AD)，它在病理学上与VCI重叠。因此，寻找生物标志物可以帮助区分不同类型的VCI，并在治疗可能的早期阶段分离出重叠或混合的综合征。在之前的拨款中，PI使用核磁共振和脑脊液研究来确定VCI的几个新的生物标记物，并表明它们可以帮助诊断。目前的拨款是前瞻性地使用这些机械性生物标记物来诊断SIVD。中心假设是深部白质的进行性损伤是由于炎症和MMPs的表达，血脑屏障的破坏，血管源性水肿和少突胶质细胞的死亡。在动物身上的研究表明，低氧驱动分子损伤级联反应，但蛋白酶是血管损伤和髓鞘分解的最终共同途径。由于很大比例的痴呆患者同时存在VCI和AD的病理过程，使用多模式方法进行诊断可能是识别纯形式并将其与混合形式区分开来的唯一途径。目的1：本研究的目的是确定一组生物标志物，用于在疾病病程早期诊断患有SIVD形式的VCI患者的算法。这项研究的总体目标是从临床、神经心理学、影像和脑脊液研究中确定最佳的生物标记物集，以准确地将患者分开进行治疗试验。目标2：这项研究的目的是识别血管疾病和阿尔茨海默病的生物标记物，这将有助于选择混合患者。本研究的目的是确定SIVD患者脑脊液中淀粉样蛋白和tau蛋白的意义。对AD、VCI和非痴呆正常受试者的大规模尸检研究表明，单纯形式的AD或SIVD比两者都存在的情况要少，而且这两种类型的病理证据通常都存在于正常受试者中，识别AD和VCI生物标志物将提高诊断水平。目的3：确定炎症在WMHs生长和认知功能减退中的作用，并检验SIVD量表的预测能力。在特定目标1和2中收集的数据将在目标3中使用，目标3是确定一组生物标志物，这些生物标志物将患者分开，可以对照最终诊断进行测试，并且可以用来指示自然病史。总体目标是从临床检查、神经心理测试、核磁共振和脑脊液中确定一组最小的生物标记物，这些标记物可以在最初的评估中获得，并且可以最好地预测自然病史，哪些可以 用于选择一组更同质的临床试验。

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.