LonDownsPREVENT: A longitudinal study of the mechanisms of cerebral amyloid angiopathy and neurodegeneration in Down syndrome to inform AD prevention

这个项目将探索随着唐氏综合症(DS)患者年龄的增长，血液和大脑发生的变化。DS患者罹患阿尔茨海默病(AD)的风险极高，因为他们基因的差异会导致一种名为淀粉样蛋白的蛋白质过度产生，这种蛋白质最终会聚集在大脑中形成斑块。这些斑块是阿尔茨海默病的标志，在35岁左右的所有患有DS的成年人中都能发现。淀粉样蛋白也可以进入大脑中的血管，称为脑淀粉样血管病(CAA)，可导致脑出血和中风。我们感兴趣的是这两种形式的淀粉样蛋白沉积与DS患者大脑损伤(神经退化)和随后的能力下降之间的联系。由于DS患者有过量的淀粉样蛋白，但其他健康问题的风险较低，这些问题可能会影响血管并导致痴呆症，如吸烟或高血压，因此他们是了解淀粉样蛋白沉积如何最终导致AD的重要人群。尽管有这些已知的风险，但出于伦理和后勤原因，DS患者历来被排除在预防或治疗试验之外。由于所有患有DS的成年人都会有AD的标志性斑块，而且大多数人会继续发展为临床痴呆症，我们认为，研究治疗甚至预防这种日益加重的健康负担的方法在伦理上是当务之急。为了在DS人群中开发这些亟需的临床试验，我们需要可靠的数据来显示不同的生物标记物，包括通过血液样本测量的淀粉样蛋白或脑结构的MRI扫描，如何随着时间的推移而变化，以及这些变化如何与痴呆症的临床进展相关。在我们之前的工作中，我们招募了大约450名患有DS的成年人，他们热衷于参与研究，并开发了一系列敏感的认知测试，可以用来跟踪这一人群的下降情况。我们还发现，一种名为神经丝光(NFL)的血液蛋白质可以为患有DS的成年人提供神经退行性变的重要生物标志物。在目前的研究中，我们希望了解不同的基于血液的生物标记物(包括NFL和淀粉样蛋白的测量)以及通过磁共振成像(MRI)扫描测量的大脑结构和血流的变化与DS中的CAA和AD的临床症状之间的关系。我们计划每隔12个月观察80名年龄在35-54岁之间、尚未被诊断为痴呆症的成人DS患者三次。在每个时间点，参与者将提供血液样本，进行核磁共振扫描，并完成认知测试，以评估他们的能力，包括智商、记忆力、反应时间和言语技能。我们还将从照顾者那里收集有关日常技能、个性和行为变化的信息。然后，我们将探索这些衡量标准如何随着时间的推移而变化，并使用数据模型来显示不同生物标志物和脑结构的变化顺序，以及这些变化与痴呆症的临床症状是如何相关的。我们还将在40名18-30岁的DS年轻人中完成一次相同的测试，作为对照组，他们将不会显示出与老年人相同程度的淀粉样蛋白负担。该项目将提供有关阿尔茨海默病患者大脑变化的基本信息，并将为未来临床试验的发展提供重要数据。我们希望解开一些导致AD的机制，这不仅对DS患者，而且对所有AD患者都很重要。

This project will explore changes in the blood and brain that happen as people with Down syndrome (DS) get older. People with DS are at ultra-high risk of developing Alzheimer's disease (AD), because differences in their genes lead to excess production of a protein called 'amyloid', which can eventually clump together in the brain in plaques. These plaques are a hallmark of Alzheimer's disease and are found in all adults with DS by their mid-30s. Amyloid protein can also enter the blood vessels in the brain, called cerebral amyloid angiopathy (CAA) and can cause brain bleeding and strokes. We are interested in the mechanisms that link these two forms of amyloid deposits with damage to the brain (neurodegeneration) and subsequent decline in abilities in people with DS. Because people with DS have this excess of amyloid, but a lower risk of other health problems that can affect the blood vessels and cause dementia, such as smoking or high blood pressure, they are an important population for understanding how amyloid deposits eventually lead to AD. Despite these known risks, people with DS have historically been excluded from prevention or treatment trials, for ethical and logistical reasons. As all adults with DS will have the hallmark plaques of AD, and most will go on to develop clinical dementia, we argue that there is an ethical imperative to research into ways to treat, or even prevent, this increasing health burden. To develop these much-needed clinical trials in the DS population, we require sound data showing how different biomarkers, which can include proteins like amyloid measured by blood samples, or MRI scans of brain structure, change over time in adults with DS, and how these changes relate to the clinical progression of dementia. In our previous work, we recruited a group of around 450 adults with DS who are keen to be involved in research, and have developed a battery of sensitive cognitive tests that can be used to track decline in this population. We also found that a blood-based protein called 'neurofilament light' (NfL) can provide an important biomarker of neurodegeneration in adults with DS. For the current study, we want to see how different blood based biomarkers (including measures of NfL and amyloid) and changes in the structure and blood flow of the brain measured through magnetic resonance imaging (MRI) scans are related to CAA and the clinical symptoms of AD in DS. We plan to see 80 adults with DS aged 35-54 who do not yet have a diagnosis of dementia three times, at 12-month intervals. At each time point, participants will provide blood samples, have an MRI scan and complete cognitive tests that will assess their abilities, including IQ, memory, reaction time and verbal skills. We will also collect information from caregivers regarding changes in everyday skills, personality and behaviour. We will then explore how each of these measures changes over time and use data models to show the order that changes in different biomarkers and brain structure happen, and how these changes are related to the clinical symptoms of dementia. We will also complete the same tests once in a group of 40 younger adults with DS aged 18-30 to act as a control group who will not be showing the same degree of amyloid burden as the older adults. This project will provide essential information about changes in the brain that happen with AD in people with DS, and will provide important data to allow the development of future clinical trials. We hope to unpick some of the mechanisms that lead to AD, which will be of importance not only for people with DS, but for all people who develop AD.