Unraveling the earliest phases of vascular cognitive impairment and dementia using CADASIL--a monogenic form of small vessel cerebrovascular disease

使用 CADASIL（一种单基因形式的小血管脑血管疾病）揭示血管性认知障碍和痴呆的最早阶段

• 批准号: 10317234
• 负责人: MICHAEL D GESCHWIND
• 金额: $ 1382.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317234
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Arterial Disorder; Atrial Fibrillation; Atrophic; Behavioral; Biological; Biological Markers; Blood; Brain; Brain imaging; Cerebral small vessel disease; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Characteristics; Clinic; Clinical; Clinical Research; Clinical Trials; Cognitive; Data; Data Reporting; Dementia; Diabetes Mellitus; Diffusion Magnetic Resonance Imaging; Disease; Disease Outcome; Disease Progression; Disease model; Dominant Genes; Enrollment; Epidermal Growth Factor; European; Family; Family member; Future; Gene Mutation; Genes; Genetic; Genetic Variation; Genotype; Health; Heavy Drinking; Heritability; Heterogeneity; Hyperlipidemia; Hypertension; Image; Impaired cognition; Impairment; Inflammatory; Interleukin-18; Knowledge; Lead; Life Style; Liquid substance; Longevity; Longitudinal cohort; MRI Scans; Magnetic Resonance Imaging; Measures; Medical History; Memory; Mendelian disorder; Microvascular Dysfunction; Modeling; Mutation; NOTCH3 gene; Neurologic; North America; Obesity; Outcome; Participant; Patients; Persons; Phase; Positioning Attribute; Questionnaires; Research; Research Project Grants; Rest; Risk Factors; Sample Size; Secondary to; Severities; Severity of illness; Site; Smoking; Staging; Study models; Subcortical Infarctions; Subcortical Leukoencephalopathy; Symptoms; Syndrome; Tablets; Testing; Thick; United States; United States National Institutes of Health; Variant; Vascular Dementia; Vascular Diseases; White Matter Hyperintensity; apolipoprotein E-4; axon injury; base; cohort; comorbidity; design; executive function; exome; functional decline; genome-wide; hypercholesterolemia; imaging modality; improved; insight; lifestyle factors; mixed dementia; molecular phenotype; multidisciplinary; mutation carrier; neuroimaging; novel; polygenic risk score; prognostic; receptor; recruit; tau-1; vascular cognitive impairment and dementia; vascular factor

Project Summary/Abstract The project addresses vascular contributions to cognitive impairment and dementia (VCID) using a design that exploits the enrollment of persons with the autosomal dominant gene for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Exploration of VCID by focusing on the rare heritable monogenic disorder, CADASIL, will advance knowledge of the full spectrum of vascular dementia from presymptomatic gene carriers through dementia and will facilitate an examination of mixed dementia in CADASIL participants also having AD. This research is novel from any other in its efforts to study a single-gene vascular dementia group throughout the life span in an effort to reduce vascular dementia heterogeneities selecting persons enriched for certain future vascular disease secondary to NOTCH3 gene mutation. CADASIL is caused by a mutation in the gene NOTCH3, which encodes a receptor protein. Although rare, CADASIL is the most common heritable cause (due to a single gene mutation) of vascular dementia. Many consider CADASIL to be a good single gene model of small vessel disease and vascular dementia. By improving our understanding of CADASIL and its progression, we will be better able to understand VCID as well as mixed dementias having both CADASIL and the most common sporadic dementia, Alzheimer's disease. This is particularly important because of the fact that many cases of Alzheimer's disease have co- occurring vascular dementia. More than 200 genetic variations in NOTCH3 have been identified, but it is not known which cause milder, or more severe, forms of VCID. Furthermore, among the NOTCH3 mutations known to cause CADASIL, and even within CADASIL families, there is wide variability in age at onset, disease progression, brain imaging abnormalities and presentation of symptoms. Some recent data reported by the CADASIL European Consortium suggests that patients with mutations in certain parts of NOTCH3 cause a more severe form of CADASIL than do mutations in other parts of the gene. It's also likely that variations in other genes influence the effect of NOTCH3 mutations on VCID. Unfortunately, no large cohort of CADASIL patients for clinical research has been organized in North America. Better understanding of the associations between clinical presentation, potential disease modifiers (i.e., risk factors) and NOTCH3, as well as other gene variations in a new cohort in the United States could improve understanding of the causes and severity contributions to various forms of small-vessel disease and vascular dementia. To accomplish this, we will recruit, characterize and follow longitudinally a cohort of 400 NOTCH3 variant/mutation carriers, plus 100 non- carriers as controls, from U.S. CADASIL families. Participants will be evaluated every 18 months with detailed neurological, cognitive, behavioral, functional, blood, genetic and brain MRI assessments. This study will provide critical information regarding CADASIL that will also advance understanding for the most common type of mixed dementias (viz., VCID and AD).

项目概要/摘要 该项目采用以下设计来解决血管对认知障碍和痴呆症 (VCID) 的影响： 利用具有常染色体显性基因的人进行脑常染色体显性遗传登记 伴有皮质下梗死和白质脑病的动脉病（CADASIL）。 VCID 的探索 专注于罕见的遗传性单基因疾病 CADASIL，将增进对全谱疾病的了解 血管性痴呆从症状前基因携带者到痴呆，并将有助于检查 患有 AD 的 CADASIL 参与者出现混合性痴呆。这项研究与其他研究相比是新颖的 研究整个生命周期的单基因血管性痴呆群体，努力减少血管性痴呆 异质性选择富集某些未来继发于 NOTCH3 基因的血管疾病的人 突变。 CADASIL 是由编码受体蛋白的 NOTCH3 基因突变引起的。虽然 罕见的是，CADASIL 是血管性痴呆最常见的遗传原因（由于单基因突变）。 许多人认为 CADASIL 是小血管疾病和血管性痴呆的良好单基因模型。经过 提高我们对 CADASIL 及其进展的理解，我们将能够更好地将 VCID 理解为 以及同时患有 CADASIL 和最常见的散发性痴呆（阿尔茨海默病）的混合性痴呆 疾病。这一点尤其重要，因为许多阿尔茨海默氏病病例都患有以下疾病： 发生血管性痴呆。已鉴定出 NOTCH3 的 200 多个遗传变异，但尚未发现 已知哪些会导致较轻微或更严重的 VCID。此外，在NOTCH3突变中 已知会导致 CADASIL，即使在 CADASIL 家族中，发病年龄、疾病也存在很大差异 进展、脑成像异常和症状表现。最近报告的一些数据 CADASIL 欧洲联盟建议，NOTCH3 某些部分发生突变的患者会导致 CADASIL 的形式比基因其他部分的突变更为严重。也有可能存在以下变化： 其他基因影响 NOTCH3 突变对 VCID 的影响。不幸的是，没有大量的 CADASIL 已在北美组织患者进行临床研究。更好地了解协会 临床表现、潜在疾病修饰因素（即危险因素）和 NOTCH3 以及其他因素之间的关系 美国新队列中的基因变异可以提高对原因和严重程度的了解 导致各种形式的小血管疾病和血管性痴呆。为了实现这一目标，我们将 招募、描述和纵向跟踪 400 名 NOTCH3 变异/突变携带者以及 100 名非携带者 载体作为对照，来自美国 CADASIL 系列。参与者将每 18 个月接受一次评估，其中包含详细信息 神经、认知、行为、功能、血液、遗传和大脑 MRI 评估。这项研究将 提供有关 CADASIL 的关键信息，这也将促进对最常见类型的理解 混合性痴呆（即 VCID 和 AD）。