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

项目摘要/摘要 该项目使用一种设计来解决血管对认知障碍和痴呆(VCID)的影响 利用具有常染色体显性基因的人登记脑常染色体显性遗传 伴有皮质下梗塞和白质脑病的动脉病(CADASIL)。对VCID的探索 关注罕见的可遗传性单基因疾病CADASIL，将促进对全谱 从症状前基因携带者到痴呆症的血管性痴呆，将有助于检查 患有AD的CADASIL参与者中的混合性痴呆。这项研究与其他任何一项研究的努力都是不同的 终身研究单基因血管性痴呆组以努力减少血管性痴呆症 NOTCH3基因继发性血管疾病致病基因的异质性筛选 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是研究小血管疾病和血管性痴呆的良好单基因模型。通过 加深对CADASIL及其进展的理解，我们将能够更好地理解VCID为 以及患有CADASIL和最常见的散发性痴呆-阿尔茨海默氏症的混合性痴呆 疾病。这一点尤其重要，因为许多阿尔茨海默病患者都有共同的 正在发生的血管性痴呆。NOTCH3的200多个遗传变异已经被识别出来，但它还没有 已知哪些会导致较轻或较严重的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、疾病也有很大差异 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，NOTCH3某些部分发生突变的患者会导致 比基因其他部分的突变更严重的CADASIL。也有可能是因为 其他基因影响NOTCH3突变对VCID的影响。不幸的是，没有大量的CADASIL队列 北美已经组织了临床研究的患者。更好地理解这些联系 临床表现、潜在的疾病修饰物(即风险因素)和NOTCH3以及其他 美国一个新队列中的基因变异可以提高对病因和严重性的理解 对各种形式的小血管疾病和血管性痴呆的贡献。为了实现这一目标，我们将 招募、鉴定和纵向跟踪400名NOTCH3变异/突变携带者，外加100名非 航空公司作为控制，来自美国CADASIL家族。参与者将每18个月接受一次评估，详细说明 神经、认知、行为、功能、血液、遗传和脑核磁共振检查。这项研究将 提供有关CADASIL的关键信息，这也将有助于加深对最常见类型的了解 混合性痴呆(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).