Impact of vascular burden on preclinical Alzheimer’s disease pathology and identification of potential interventional targets

血管负荷对临床前阿尔茨海默病病理学的影响和潜在干预靶点的识别

• 批准号: 396637112
• 负责人: Dr. Theresa Köbe
• 金额: --
• 依托单位: Arbeitsgruppe Kognitive Neurologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/396637112?language=en
• 关键词: Impact; vascular; burden; preclinical; Alzheimer

Alzheimer’s disease poses a growing global challenge with an increasing prevalence caused by the aging population and the limited treatment success. Currently, effective non-pharmacological approaches are searched, since transmitter replacement therapies provide no efficient modification of the disease course. The pathophysiological process of Alzheimer’s disease begins more than two decades prior to the manifestation of clinical symptoms. This preclinical phase is considered as the most appropriate time window for effective disease-modifying therapies or prevention strategies, as irreversible brain and cognitive changes might still be preventable. Vascular factors, such as hypertension, dyslipidemia, diabetes, obesity and smoking, are established risk factors for the development of Alzheimer’s disease at the clinical level; however, the relationship between vascular risk factors and the underlying disease pathology remains to be fully elucidated. To better understand the mechanisms by which vascular risk factors increase the risk of Alzheimer’s disease, we propose a multimodal cross-sectional study enrolling asymptomatic older adults with a higher risk for Alzheimer’s disease based on family history and in part subjective cognitive concerns. We will make use of the PREVENT-AD cohort, consisting of more than 300 cognitively normal individuals at high risk of Alzheimer’s disease dementia, of the StoP-AD Center at the Douglas Hospital Research Center in Montréal, Canada. First, the impact of modifiable vascular risk factors on both Alzheimer’s disease pathological hallmarks amyloid-ß and tau will be studied simultaneously in vivo, using positron emission tomography. The identification of characteristic topological patterns that mirror the influence of vascular risk factors on disease pathologies is aimed to provide a better understanding of disease expression in the preclinical stage of Alzheimer’s disease. In a second step, we will investigate whether an interaction between vascular risk factors and amyloid-ß/ tau modulate brain structural and cognitive decline that could underlie the higher risk of Alzheimer’s disease. Therefore, individual cognitive performance will be assessed with a standard neuropsychological test battery and brain integrity will be evaluated via brain volumetry, cortical thickness measurements and diffusion-tensor analyses, using 3-Tesla magnetic resonance imaging. Finally, it will be explored, if a potential beneficial effect of higher lifetime physical activity can buffer the negative effect of vascular risk factors on early Alzheimer’s disease pathology. The overall goal of this research project is to identify novel strategies that may delay or even prevent the onset of the disease.

由于人口老龄化和治疗成功率有限，阿尔茨海默病的患病率不断上升，对全球构成了日益严峻的挑战。目前，寻找有效的非药物治疗方法，因为递质替代疗法不能有效地改变病程。阿尔茨海默病的病理生理过程比临床症状的表现早20多年。这一临床前阶段被认为是进行有效的疾病改善疗法或预防策略的最合适的时间窗口，因为不可逆转的大脑和认知变化可能仍然是可以预防的。血管因素，如高血压、血脂异常、糖尿病、肥胖和吸烟，是临床层面上确定的阿尔茨海默病发展的危险因素；然而，血管危险因素与潜在疾病病理之间的关系仍有待充分阐明。为了更好地了解血管危险因素增加阿尔茨海默病风险的机制，我们提出了一项多模式横断面研究，基于家族史和部分主观认知问题，招募无症状阿尔茨海默病风险较高的老年人。我们将使用prevention - ad队列，由300多名认知正常但阿尔茨海默病痴呆高风险的个体组成，这些个体来自加拿大蒙特兰塔尔道格拉斯医院研究中心的StoP-AD中心。首先，可改变的血管危险因素对阿尔茨海默病病理标志淀粉样蛋白- β和tau的影响将在体内同时进行，使用正电子发射断层扫描。识别反映血管危险因素对疾病病理影响的特征拓扑模式，旨在更好地了解阿尔茨海默病临床前阶段的疾病表达。在第二步，我们将研究血管危险因素和淀粉样蛋白- β / tau之间的相互作用是否调节大脑结构和认知能力下降，这可能是阿尔茨海默病高风险的基础。因此，个体认知能力将通过标准的神经心理学测试来评估，大脑完整性将通过脑容量测量、皮质厚度测量和扩散张量分析来评估，使用3-特斯拉磁共振成像。最后，我们将探讨终生高体力活动的潜在有益作用是否可以缓冲血管危险因素对早期阿尔茨海默病病理的负面影响。这项研究项目的总体目标是确定可能延迟甚至预防疾病发作的新策略。