Structural and Functional Neuroanatomy of Memory in Familial Alzheimer's Disease

描述(申请人提供)：目前有多达530万美国人患有阿尔茨海默病(AD)。这种进行性和致命性的神经退行性疾病是痴呆症最常见的形式，但治愈方法仍然难以找到。情景记忆减退是阿尔茨海默病的首批认知症状之一，并与内侧颞叶区域的功能和结构退化有关。特别是，海马体结构和内嗅觉皮质已经被证明在AD的早期阶段就受到了病理影响，甚至在临床症状明显之前就已经受到影响。神经成像工具如结构和功能磁共振成像(sMRI，fMRI)有可能识别AD进展早期的细微病理变化，并可能作为AD的潜在生物标志物。这项建议的主要目标是使用结构和功能磁共振成像技术(sMRI和fMRI)来检查症状前期和早期症状个体的大脑变化，这些人携带PS1突变，并将在生命的第四个十年发展为阿尔茨海默病。PS1基因突变是一种完全穿透性的常染色体显性遗传改变，这意味着携带PS1突变的人注定会几乎100%确定地患上早发性阿尔茨海默病。因此，这些对象提供了一个独特的机会来研究与阿尔茨海默病相关的症状前和临床前的变化。在这项申请中提出的研究将使用核磁共振方法来检验这样的假设，即导致阿尔茨海默病的突变携带者的大脑中与疾病相关的变化发生在阿尔茨海默病症状前的早期阶段的MTL结构中。这项研究可能直接导致一种诊断测试，使人们能够检测到在以后的生活中将发展为散发性阿尔茨海默病的个人，从而使早期开始治疗。 公共卫生相关性：我建议研究症状前期和早期症状受试者的大脑结构和功能变化，这些受试者携带E280A PS1突变，并将发展为早发性家族性阿尔茨海默病。在这一人群中发现的结构和功能模式有可能直接导致一种诊断测试，该测试可以识别那些后来会患上散发性阿尔茨海默病的人，使他们能够在认知症状出现之前接受疾病修饰药物的治疗。

DESCRIPTION (provided by applicant): As many as 5.3 million Americans are presently living with Alzheimer's disease (AD). This progressive and fatal neurodegenerative disorder is the most common form of dementia, yet a cure remains elusive. Deterioration of episodic memory is one of the first cognitive symptoms of AD, and has been associated with functional and structural degeneration of the medial temporal lobe regions (MTL). In particular, the hippocampal formation and entorhinal cortex have been shown to be pathologically affected in early phases of AD, even before clinical symptoms are evident. Neuroimaging tools such as structural and functional MRI (sMRI, fMRI) have the potential to identify subtle pathologic changes earlier in the AD progression and could be used as potential biomarkers of AD. The primary goals of this proposal are to use both structural and functional magnetic resonance imaging techniques (sMRI and fMRI) to examine changes in the brains of pre- symptomatic and early-symptomatic individuals who carry a PS1 mutation and who will develop Alzheimer's disease during the 4th decade of life. The PS1 genetic mutation is a fully penetrant, autosomal dominant genetic alteration, meaning that people that carry the PS1 mutation are destined to develop early-onset Alzheimer's disease with near 100% certainty. These subjects therefore provide a unique opportunity to study pre-symptomatic and pre-clinical changes related to Alzheimer's disease. The research proposed in this application will use MRI methods to examine the hypothesis that disease-related changes in the brains of carriers of an Alzheimer's-causing mutation occur within MTL structures in early pre-symptomatic stages of the Alzheimer's disease. This research may lead directly to a diagnostic test that will enable the detection of individuals who will develop sporadic AD later in life, allowing to early initiation of treatments. PUBLIC HEALTH RELEVANCE: I propose to study structural and functional brain changes in pre-symptomatic and early-symptomatic subjects who carry the E280A PS1 mutation and will develop early-onset familial Alzheimer's disease. Structural and functional patterns found in this population have the potential to lead directly to a diagnostic test that can identify those individuals who will later develop sporadic Alzheimer's disease, allowing them to be treated with disease modifying medications before the onset of cognitive symptoms.