Cognitive and Brain Changes in Preclinical Alzheimer's Disease

阿尔茨海默病(AD)的发病机制尚不清楚，尽管越来越多的人支持 血管功能障碍与淀粉样蛋白-β和神经原纤维积聚的协同关系 唐格斯。脑血管疾病(CVD)危险因素在退伍军人中普遍存在，与 认知能力下降和患痴呆症的风险更高，可能是治疗年龄相关疾病的潜在目标 认知能力下降。[心血管危险因素与外周血管相关(例如，脉搏波速度增加 [PWV]表明动脉僵硬)和脑血管改变(例如，脑血流量[CBF]减少)； 脑血管反应性降低[CVR]表明脑血管调节能力减弱 CBF)。]脑血流量(CBF)通过增加局部脑血流与基础认知代谢密切相关 提供氧气和葡萄糖以支持神经功能，因此是神经活动的间接测量 和血管功能。[动物模型显示脑血流量减少(又名低灌注量)与类AD有关 淀粉样蛋白β积聚和tau磷酸化增加引起的神经退行性变--标志 阿尔茨海默病的神经病理学。将这些发现翻译到人类身上，对于识别和提炼AD的生物标记物至关重要 并最终改进早期发现和治疗。]我们发现前额叶和内侧的脑血流量改变。 遗传性(载脂蛋白Eε4携带者)或认知性(轻度认知障碍； MCI)与记忆和执行功能相关的AD风险，暗示CBF是潜在的 AD的生物标志物。这项应用旨在阐明血管和神经退行性变之间的联系 阿尔茨海默病的病理生理过程和临床症状的出现导致机制的改善 对认知衰退的理解。因此，当前的应用程序：[1]检查了 高危老年退伍军人神经血管和脑血管功能及认知功能测试 与AD相关的潜在机制(例如，脑脊液[CSF]AD生物标志物)对此起调节作用 关系，2)检查脑血管功能是否调节脑血流和脑脊液之间的关系 生物标志物，以及3)检查单个危险因素(例如，动脉僵硬增加， 久坐时间延长，APOEε4)。]这项研究将检查120名受试者的认知、血管和脑功能 65岁以上、有至少两个心血管疾病危险因素的讲英语的非痴呆退伍军人，使他们处于增加的状态 认知能力下降的风险。评估包括经过充分验证和标准化的认知测试(例如，NIH 工具箱)、最先进的磁共振成像(测量CBF和CVR)、全面的血管功能 评估(包括颈动脉-股动脉脉搏波速度、血压、颈动脉超声)、腰椎 穿刺法测定脑脊液AD生物标记物(包括Aβ42、p-tau181和总tau)，加速度法评估 体力活动/久坐水平和载脂蛋白E基因分型。[这项新颖的提议旨在测试中央 假设CBF和/或CVR支持认知表现，这种关系通过 AD神经变性的脑脊液生物标志物的存在，表明神经血管的协同作用 老年高危退伍军人中脑血管功能障碍与神经退化和认知能力下降的关系。]这个 拟议目标的完成将实现以下目标，这些目标可以在早期指导未来的研究 痴呆的检测和预防：1)完善阿尔茨海默病的流行生物标记物模型 神经病理和脑血管AD危险因素的独立或联合作用 诱发AD的一连串事件，2)建立成像、神经心理学、 神经病理和血管生物标记物检测认知功能下降，以及3)改善机制 了解AD风险并确定潜在的治疗目标，最终将为干预措施提供信息 预防或推迟阿尔茨海默病的发病。

The pathogenesis of Alzheimer’s disease (AD) remains unclear, though there is growing support for a synergistic relationship between vascular dysfunction and accumulation of amyloid-β and neurofibrillary tangles. Cerebrovascular disease (CVD) risk factors are prevalent in the VA population, have been linked to cognitive decline and higher risk for dementia, and may represent potential targets for remediating age-related cognitive decline. [CVD risk factors are associated with peripheral vascular (e.g., increased pulse wave velocity [PWV] indicating arterial stiffness) and cerebrovascular changes (e.g., reduced cerebral blood flow [CBF]; decreased cerebrovascular reactivity [CVR] indicating reduced ability of the cerebral vasculature to adjust CBF).] Cerebral blood flow (CBF) is tightly coupled with metabolism underlying cognition by increasing local delivery of oxygen and glucose to support neural function, and as such is an indirect measure of neural activity and vascular function. [Animal models suggest reduced CBF (aka, hypoperfusion) contributes to AD-like neurodegeneration by increasing amyloid-β accumulation and tau phosphorylation--the hallmark neuropathology of AD. Translating these findings to humans is critical to identify and refine biomarkers of AD and ultimately improve early detection and treatment.] We have shown altered CBF in prefrontal and medial temporal lobe regions in older adults at genetic (APOE ε4 carriers) or cognitive (mild cognitive impairment; MCI) risk for AD that is associated with memory and executive function, implicating CBF as a potential biomarker of AD. This application aims to elucidate the link between the vascular and neurodegenerative pathophysiological process of AD and the emergence of clinical symptoms to lead to an improved mechanistic understanding of cognitive decline. Thus, the current application: [1) examines the association between neurovascular (CBF) and cerebrovascular (CVR) function and cognition in at-risk older Veterans and tests potential AD-related mechanisms (e.g., cerebral spinal fluid [CSF] AD biomarkers) that mediate this relationship, 2) examines whether cerebrovascular function moderates the relationship between CBF and CSF biomarkers, and 3) examines moderating effects of individual risk factors (e.g., increased arterial stiffness, elevated sedentary time, APOE ε4).] This study will examine cognitive, vascular, and brain function in 120 English-speaking non-demented Veterans aged 65+ with at least 2 CVD risk factors, placing them at increased risk for cognitive decline. Assessments include well-validated and standardized cognitive testing (e.g., NIH Toolbox), state-of-the-art MR imaging (to measure CBF and CVR), comprehensive vascular function assessment (including carotid-femoral pulse wave velocity, blood pressure, carotid ultrasound), lumbar puncture to assay CSF AD biomarkers (including Aβ42, p-tau181, and total tau), accelerometry to assess physical activity/sedentary level, and APOE genotyping. [This novel proposal aims to test the central hypothesis that CBF and/or CVR support cognitive performance and this relationship is mediated by the presence of CSF biomarkers of AD neurodegeneration, suggesting a synergistic contribution of neurovascular and cerebrovascular dysfunction to neurodegeneration and cognitive decline in older at-risk Veterans.] The completion of the proposed aims will achieve the following goals that could guide future research in early dementia detection and prevention: 1) refine the prevailing biomarker model of AD by more firmly establishing the independent or combined contribution of neuropathological and cerebrovascular AD risk factors in the cascade of events precipitating AD, 2) establish prognostic utility of imaging, neuropsychological, neuropathological, and vascular biomarkers to detect cognitive decline, and 3) improve mechanistic understanding of AD risk and identify potential therapeutic targets that will ultimately inform interventions to prevent or delay the onset of AD.