Blood-based biomarkers of microvascular pathology in Alzheimer's disease.
Blood-based biomarkers of microvascular pathology in Alzheimer's disease.
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DOI：
10.1016/j.exger.2009.09.005
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发表时间：
2010-01
影响因子：
3.9
通讯作者：
Hampel, Harald
中科院分区：
文献类型：
--
作者：
Ewers, Michael;Mielke, Michelle M.;Hampel, Harald
关键词：
散发性阿尔茨海默病（AD）是一种遗传复杂的慢性进行性神经退行性疾病，其分子机制和神经病理以淀粉样蛋白生成途径、tau蛋白的过度磷酸化和聚集以及神经原纤维变性为中心。虽然脑血管的变化传统上并不被认为是阿尔茨海默病的核心病理部分，但越来越多的证据表明，它们实际上也可能是阿尔茨海默病大脑的一个特征。特别是，大脑内的微血管异常与病理性阿尔茨海默病的特征有关，并且可能先于神经退行性变。微血管病理的体内评估为开发有用的生物标志物提供了一种有前途的方法，可用于阿尔茨海默病的早期发现和病理表征。本文综述了阿尔茨海默病微血管病理的已建立的血液生物标志物候选物。这些候选因素包括AD患者血浆中血管细胞粘附分子-1 （VCAM-1）和细胞间粘附分子-1 （ICAM-1）的浓度升高。内皮血管舒张功能的测量，包括内皮素（ET-1）、肾上腺素（ADM）和心房钠肽（ANP），以及鞘脂也在轻度AD或轻度认知障碍（MCI）的痴呆前阶段显著改变，表明这些生物标志物对早期发现和诊断的敏感性。总之，基于血液的微血管生物标志物在阿尔茨海默病中的价值的新临床诊断证据是有希望的，然而，仍需要在II期和III期诊断试验中进行验证。此外，目前尚不清楚所描述的蛋白质失衡是早期还是下游病理事件，以及检测到的系统性微血管改变如何与AD脑中的脑血管和神经元病理相关。
SporadicAlzheimer’s disease (AD) is a genetically complex and chronically progressive neurodegenerative disorder with molecular mechanisms and neuropathologies centering around the amyloidogenic pathway, hyperphosphorylation and aggregation of tau protein, and neurofibrillary degeneration. While cerebrovascular changes have not been traditionally considered to be a central part of AD pathology, a growing body of evidence demonstrates that they may, in fact, be a characteristic feature of the AD brain as well. In particular, microvascular abnormalities within the brain have been associated with pathological AD hallmarks and may precede neurodegeneration. In-vivo assessment of microvascular pathology provides a promising approach to develop useful biological markers for early detection and pathological characterization of AD. This review focuses on established blood-based biological marker candidates of microvascular pathology in AD. These candidates include plasma concentration of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) that are increased in AD. Measures of endothelial vasodilatory function including endotheline (ET-1), adrenomedulline (ADM), and atrial natriuretic peptide (ANP), as well as sphingolipids are also significantly altered in mild AD or during the predementia stage of mild cognitive impairment (MCI), suggesting sensitivity of these biomarkers for early detection and diagnosis. In conclusion, the emerging clinical diagnostic evidence for the value of blood-based microvascular biomarkers in AD is promising, hoewever, still requires validation in phase II and III diagnostic trials. Moreover, it is still unclear whether the described protein dysballances are early or downstream pathological events and how the detected systemic microvascular alterations relate to cerebrovascular and neuronal -pathologies in the AD brain.
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