Early macrostructural and microstructural cortical changes in Alzheimer's disease: longitudinal and cross-sectional studies of early change

阿尔茨海默氏症是痴呆症最常见的原因。阿尔茨海默病不仅对个人和家庭造成毁灭性的影响，而且是一个日益严重的公共卫生问题。因此，痴呆症研究是国家和全球的一个关键优先事项。阿尔茨海默病与大脑中异常蛋白质的积累和脑细胞的丧失有关，这两者都早于记忆问题的出现，可能要早很多年。一旦脑细胞丢失，这种损害是不可逆转的。因此，当可以阻止或减缓阿尔茨海默病进展的药物出现时，理想情况下，我们希望能够在症状开始之前识别和治疗有患痴呆症风险的人。然而，这种不可逆转的损害究竟多早开始发生目前尚不清楚，而且很难检测到这些早期变化。迫切需要更好的技术来识别阿尔茨海默氏症的风险个体，分期他们的疾病，并监测其进展。大脑皮层是大脑表面最外层的神经组织(灰质)。大脑皮层在我们的思维过程中起着关键作用，从语言和计算到计划和注意力。在阿尔茨海默病中，大脑皮层的异常发生得很早。许多新的大脑扫描技术已经开发出来，这些技术可能能够很早就发现皮质厚度和结构的变化，以及它与其他大脑区域的联系。除了这些大脑扫描技术外，还开发了新的记忆测试，当大脑结构开始受损时，这种测试可能能够检测到非常早期的变化。综上所述，这些大脑成像技术和记忆测试可能会提供有关阿尔茨海默病大脑变化的重要信息。家族性阿尔茨海默病是一种罕见的疾病形式(占病例的不到1%)，这种疾病通常在年轻时由于基因缺陷而遗传。来自已知基因突变家庭的个人慷慨地同意参加我们在痴呆症研究中心进行了多年的纵向研究。我们建议评估上述技术，以研究来自受家族性阿尔茨海默氏症影响的家庭的个人，他们身体健康，但患阿尔茨海默病的风险很高。我们还将评估已经有症状的阿尔茨海默病患者和一些健康的人进行比较。我们将通过获取详细的(MRI)脑扫描，包括新技术，以及详细的临床和心理评估来做到这一点。我们将检查这些技术中的每一种都能多好地检测阿尔茨海默病的早期特征，以及每种技术在测量随时间变化方面的好坏。我们还将致力于提高我们对大脑第一次损伤开始发生的时间和地点的理解。这些信息将被用来确定如何最好地在患有阿尔茨海默病的风险人群中进行临床试验，这最终将增加我们找到有效治疗方法的机会。

Alzheimer's disease is the commonest cause of dementia. Not only is Alzheimer's disease devastating for individuals and families but also represents a growing public health problem. Dementia research is therefore a key national and global priority. Alzheimer's disease is associated with the build up of abnormal proteins in the brain and loss of brain cells, both of which precede the onset of memory problems, probably by many years. Once loss of brain cells occurs, the damage is irreversible. Therefore, when drugs that can stop or slow the progression of Alzheimer's disease become available, ideally we would want to be able to identify and treat individuals at risk of developing dementia before symptoms had started. However, exactly how early this irreversible damage begins to occur is currently unclear, and detecting these early changes is difficult. Better techniques are urgently needed for identifying individuals at risk of Alzheimer's, for staging their disease, and for monitoring its progression.The cerebral cortex is the thin outermost layer of neural tissue (grey matter) on the brain's surface. The cerebral cortex plays a key role in our thought processes, from language and calculation to planning and attention. Abnormalities within the cerebral cortex occur very early in Alzheimer's disease. A number of new brain scanning techniques which may be able to detect very early changes in both the thickness and structure of the cortex, and its connections with other brain areas, have been developed. In addition to these brain scanning techniques, new memory tests have been developed which may be able to detect very early changes as the brain structures starts to become impaired. Taken together, these brain imaging techniques and memory tests may provide important information about the brain changes in Alzheimer's disease. Familial Alzheimer's disease is a rare form of the disease (accounting for less than 1% of cases) where the disease is inherited - usually at a young age - due to a genetic defect. Individuals from families with known genetic mutations have generously agreed to take part in longitudinal studies, which we have been running at the Dementia Research Centre for many years.We propose to evaluate the techniques described above to study individuals from families affected by familial Alzheimer's who are well, but who are at high risk of developing Alzheimer's disease. We will also assess people who already have symptomatic Alzheimer's disease and some healthy individuals for comparison. We will do this by acquiring detailed (MRI) brain scans, including the new techniques, in conjunction with detailed clinical and psychological assessments. We will examine how well each of these techniques can detect the earliest features of Alzheimer's disease, and how good each is at measuring change over time. We will also aim to improve our understanding of how early and where in the brain the first damage begins to occur. This information will be used to determine how best to run clinical trials in individuals at risk of developing Alzheimer's disease, which will ultimately increase our chances of finding an effective treatment.