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

项目总结/摘要 该项目采用一种设计， 利用常染色体显性遗传的大脑常染色体显性遗传基因的人的登记， 动脉病伴皮质下动脉瘤和白质脑病（CADASIL）。VCID的探索， 关注罕见的遗传性单基因疾病CADASIL，将促进对全谱疾病的认识。 血管性痴呆从症状前基因携带者通过痴呆，并将有助于检查 CADASIL参与者中也患有AD的混合性痴呆。这项研究是新颖的，从任何其他的努力， 在整个生命周期中研究单基因血管性痴呆组，以减少血管性痴呆 选择富集某些未来继发于NOTCH 3基因的血管疾病的人的异质性 突变CADASIL是由编码受体蛋白的基因NOTCH 3突变引起的。虽然 CADASIL是血管性痴呆最常见的遗传原因（由于单个基因突变）。 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。通过 提高我们对CADASIL及其进展的理解，我们将能够更好地理解VCID， 以及同时具有CADASIL和最常见的散发性痴呆症阿尔茨海默氏症的混合性痴呆症 疾病这是特别重要的，因为事实上，许多情况下，阿尔茨海默氏病有共同的- 血管性痴呆已经确定了NOTCH 3中的200多个遗传变异，但它不是 已知引起较轻或较严重形式的VCID。此外，在NOTCH 3突变中， 已知引起CADASIL，甚至在CADASIL家族中，发病年龄、疾病 进展、脑成像异常和症状表现。报告的一些最新数据 CADASIL欧洲联盟认为，NOTCH 3某些部分突变的患者会导致 CADASIL比基因其他部分的突变更严重。也有可能是 其它基因影响NOTCH 3突变对VCID的作用。不幸的是，没有大的CADASIL队列 在北美组织了临床研究的患者。更好地了解协会 在临床表现，潜在的疾病修饰物（即，风险因素）和NOTCH 3，以及其他 在美国的一个新的队列中，基因变异可以提高对病因和严重性的理解。 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、表征并纵向跟踪400名NOTCH 3变异/突变携带者加上100名非NOTCH 3突变携带者的队列。 携带者作为对照，来自美国CADASIL家族。参与者将每18个月进行一次评估， 神经、认知、行为、功能、血液、遗传和脑MRI评估。本研究将 提供有关CADASIL的关键信息，这也将促进对最常见类型的理解 混合型痴呆（即，VCID和AD）。

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).