Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers
Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers
复制标题
DOI：
10.1001/jamaneurol.2014.754
复制
发表时间：
2014-07-01
期刊：
影响因子：
29
通讯作者：
van der Flier, Wiesje M.
中科院分区：
文献类型：
--
作者：
Kester, Maartje I.;Goos, Jeroen D. C.;van der Flier, Wiesje M.
重要性目前尚不清楚脑小血管疾病和阿尔茨海默病（AD）病理学之间的关联是否以及如何导致认知能力下降和dementia.Objective To determine associations between small vessel disease and AD pathology.DESIGN，SETTING，AND PARTICIPANTS横断面研究从2002年1月至2012年12月使用记忆诊所为基础的阿姆斯特丹痴呆队列。该研究纳入了914名连续的患者，这些患者具有可用的脑脊液（CSF）和磁共振成像; 547名患者被诊断为患有AD（54%女性，平均值[SD]，67 [8];简易精神状态检查评分，平均值[SD]，21 [5]），30例患者被诊断为血管性痴呆（37%女性，平均值[SD]，76 [9];简易精神状态检查评分，平均值[SD]，24 [4]），337名对照参与者有主观记忆投诉（42%女性，平均值[SD]，59 [59];简易精神状态检查评分，平均值[SD]，28 [2]）。采用CSF生物标志物（对数转换）作为因变量，磁共振成像测量（二分）作为独立变量，进行线性回归，调整性别、年龄、中颞叶萎缩和诊断。主要结果和测量我们检查了磁共振成像白色高信号（WMH）、腔隙、微出血与CSF β-淀粉样蛋白42的相关性，（A β 42），总tau，和在苏氨酸181处磷酸化的tau（P-tau（181））以及载脂蛋白E（APOE）的一个子集结果AD和血管性痴呆患者微出血的存在与较低的CSF A β 42相关（标准化β =-0.09，P = 0.003;标准化β =-0.30，P = 0.01），对照组CSF tau水平较高（标准化β = 0.10，P = 0.03）。对P-tau无影响（181）。在对照组和血管性痴呆患者中，WMH的存在与较低的A β 42相关（标准化β =-0.18，P = 0.002;标准化β =-0.32，P = 0.02），但在AD患者中则不然。对tau或P-tau无影响（181）。腔隙的存在与血管性痴呆中较高的A β 42（标准化β = 0.17，P = 0.07）和AD中较低的tau（标准化β =-0.07，P = 0.05）相关，但对A β 42或P-tau没有影响（181）。分层载脂蛋白E基因型显示，这些影响主要是由于到104 carriers.CONCLUSIONS和RELEVANCE沉积淀粉样蛋白出现加重脑小血管疾病患者，特别是在载脂蛋白E 104载体，这3个生物因素之间的病理生理协同作用提供证据。
IMPORTANCE It remains unclear if and how associations between cerebral small-vessel disease and Alzheimer disease (AD) pathology lead to cognitive decline and dementia.OBJECTIVE To determine associations between small-vessel disease and AD pathology.DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study from January 2002 to December 2012 using the memory clinic-based Amsterdam Dementia Cohort. The study included 914 consecutive patients with available cerebrospinal fluid (CSF) and magnetic resonance imaging; 547 were patients diagnosed as having AD (54% female, mean [SD], 67 [8]; Mini-Mental State Examination score, mean [SD], 21 [5]), 30 were patients diagnosed as having vascular dementia (37% female, mean [SD], 76 [9]; Mini-Mental State Examination score, mean [SD], 24 [4]), and 337 were control participants with subjective memory complaints (42% female, mean [SD], 59 [59]; Mini-Mental State Examination score, mean [SD], 28 [2]). Linear regressions were performed with CSF biomarkers (log transformed) as dependent variables and magnetic resonance imaging measures (dichotomized) as independent, adjusted for sex, age, mediotemporal lobe atrophy, and diagnosis. An interaction term for diagnosis by magnetic resonance imaging measures was used for estimates per diagnostic group.MAIN OUTCOMES AND MEASURES We examined the associations of magnetic resonance imaging white matter hyperintensities (WMH), lacunes, microbleeds with CSF beta-amyloid 42 (A beta 42), total tau, and tau phosphorylated at threonine 181 (P-tau(181)) as well as for a subset of apolipoprotein E (APOE) epsilon 4 carriers and noncarriers.RESULTS Microbleed presence was associated with lower CSF A beta 42 in AD and vascular dementia (standardized beta = -0.09, P = .003; standardized beta = -0.30, P = .01), and higher CSF tau in controls (standardized beta = 0.10, P = .03). There were no effects for P-tau(181). The presence of WMH was associated with lower A beta 42 in control participants and patients with vascular dementia (standardized beta = -0.18, P = .002; standardized beta = -0.32, P = .02) but not in patients with AD. There were no effects for tau or P-tau(181). The presence of lacunes was associated with higher A beta 42 in vascular dementia (standardized beta = 0.17, P = .07) and lower tau in AD (standardized beta = -0.07, P = .05) but there were no effects for A beta 42 or P-tau(181). Stratification for apolipoprotein E genotype revealed that these effects were mostly attributable to epsilon 4 carriers.CONCLUSIONS AND RELEVANCE Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E epsilon 4 carriers, providing evidence for pathophysiological synergy between these 3 biological factors.