Biochemical markers in persons with preclinical familial Alzheimer disease
Biochemical markers in persons with preclinical familial Alzheimer disease
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DOI：
10.1212/01.wnl.0000303973.71803.81
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发表时间：
2008-07-08
期刊：
影响因子：
9.9
通讯作者：
Cummings, J. L.
中科院分区：
文献类型：
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作者：
Ringman, J. M.;Younkin, S. G.;Cummings, J. L.
背景资料：有家族性阿尔茨海默病（FAD）风险的人提供了一个模型，其中生物标志物可以研究在前驱diseases.Methods：21例受试者在早老素-1（n = 17）或淀粉样前体蛋白（n = 4）突变的风险进行了评估与临床痴呆评级（CDR）量表。我们获得了所有受试者的血浆和11例受试者的CSF。血浆（A β（40）、A β（42）、F-2-异前列腺素）和CSF在FAD突变携带者（MC）和非携带者（NC）之间比较（F-2-异前列腺素、t-tau、p-tau 181、A β（40）、A β（42）和A β（42）/A β（40）比率）水平。症状前MC的血浆A β（42）水平（25.1 pM vs 15.5 pM，p = 0.031）和A β（42）/A β（40）比值（0.16 vs 0.11，p = 0.045）较高。在MC中，CDR评分为0.5的患者血浆A β（42）水平低于CDR评分为0的患者（14.1 pM vs 25.1，p = 0.02）。与NC相比，非痴呆MC的CSF中A β（42）与A β（40）的比值也降低（0.08 vs 0.15，p = 0.046）。在症状前FAD MC中，总CSF tau和p-tau（181）水平升高。MCs的CSF F-2-异前列腺素水平也升高，（n = 7，48.6 pg/mL）与NC相比（n = 4，21.6 pg/mL，p = 0.031）。我们的数据表明，A β（42）在家族性阿尔茨海默病（FAD）突变携带者（MC）的血浆中升高并提示在发展为明显痴呆之前，该水平可能随着疾病进展而降低。我们还证实了非痴呆MC的CSF中A β（42）与A β（40）的比值降低，并且t-tau和p-tau升高（181）是症状前疾病的敏感指标。我们发现临床前FAD MCs的CSF中F-2-异前列烷水平升高，这表明氧化应激发生在淀粉样前体蛋白代谢不良的下游。
Background: Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers can be studied in presymptomatic disease.Methods: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (A beta(40), A beta(42), F-2-isoprostanes) and CSF (F-2-isoprostanes, t-tau, p-tau 181, A beta(40), A beta(42), and A beta(42)/A beta(40) ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs).Results: Plasma A beta(42) levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of A beta(42)/A beta(40) (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma A beta(42) levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of A beta(42) to A beta(40) was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau(181) levels were elevated in presymptomatic FAD MCs. CSF levels of F-2-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031).Conclusions: Our data indicate that A beta(42) is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of A beta(42) to A beta(40) was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau(181) are sensitive indicators of presymptomatic disease. Our finding of elevated F-2-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.