阿爾茨海?。ˋlzheimer’s Disease, AD）是一種隱匿、緩慢的神經(jīng)退行性疾病，是老年失智癥中最為常見(jiàn)的一種，據(jù)估計(jì)約占總失智病例的60%—80%[1]。短期記憶障礙是AD最常見(jiàn)的早期癥狀，其標(biāo)志性的病理特征是大腦神經(jīng)元外部淀粉樣斑塊沉積和神經(jīng)元內(nèi)部tau蛋白過(guò)度磷酸化導(dǎo)致的神經(jīng)原纖維纏結(jié)。隨病程的發(fā)展，患者逐漸喪失溝通能力、判斷力、方向感和生活的自理能力，最終失去語(yǔ)言功能、活動(dòng)能力和吞咽能力[1]。
截至2015 年，全世界共4600 萬(wàn)人患有AD。預(yù)計(jì)到2050 年，全球患病人數(shù)將增加到1.3億，總醫(yī)療成本超1萬(wàn)億美元，意味著僅AD醫(yī)療護(hù)理就可構(gòu)筑世界第18 大經(jīng)濟(jì)體[2]。目前，我國(guó)現(xiàn)存AD患者已超過(guò)1000萬(wàn)，并將保持較快增長(zhǎng)。而預(yù)計(jì)到2030 年，我國(guó)AD 患者人數(shù)將達(dá)到約1600 萬(wàn)。我國(guó)已成為受AD 影響程度最大的國(guó)家。因此，深入研究AD 病因和病理機(jī)制，加速開(kāi)發(fā)有效的AD 預(yù)防和診療方案，已成為我國(guó)乃至全世界神經(jīng)科醫(yī)生和生物醫(yī)藥企業(yè)的一項(xiàng)重要任務(wù)。
圖 1. 阿爾茨海默病的全球影響[2]
AD 的發(fā)病具隱匿性，在確診之前通常已經(jīng)經(jīng)歷了15-20 年，甚至是更長(zhǎng)時(shí)間的發(fā)展， 這一階段被稱為 AD 的“前臨床期”[3]。隨著病程不斷發(fā)展，患者發(fā)生“輕度認(rèn)知障礙期”（Mild Cognitive Impairment, MCI），此時(shí)患者出現(xiàn)癥狀并進(jìn)行性加重，逐步發(fā)展到“輕度癡呆期”、“中度癡呆期”和“重度癡呆期”[4-7]。由于早期癥狀缺乏特異性，臨床上對(duì)AD患者很難做到早發(fā)現(xiàn)、早治療。AD最終會(huì)是致命的，多數(shù)患者確診后的預(yù)期壽命僅有4-8 年。
圖 2. 阿爾茨海默病的病程[1]
AD 生物標(biāo)志物水平的改變常發(fā)生于前臨床期。除影像學(xué)檢查外，腦脊液(Cerebrospinal Fluid, CSF) 生化分析也是 AD 篩查的常用手段[1]。相當(dāng)多AD患者CSF檢查可發(fā)現(xiàn)可溶性β-淀粉樣蛋白 (β-Amyloid, Aβ)，特別是Aβ42的含量下降，而總tau和磷酸化tau (p-tau) 含量上升。CSF神經(jīng)絲輕鏈蛋白 (Neurofilament Light-chain, NfL) 是一種新興的生物標(biāo)志物。NfL在生理?xiàng)l件下分布于神經(jīng)細(xì)胞內(nèi)部。因此，釋放到CSF中NfL的異常增加被認(rèn)為可以用來(lái)指示所有原因造成的神經(jīng)細(xì)胞變性[8,9]
由于血腦屏障的存在，大腦中的生物標(biāo)志物很難高效地進(jìn)入外周血液循環(huán)，因此CSF樣本相比于血清樣本能為AD臨床診斷提供更多有價(jià)值的信息[10]。CSF中Aβ42含量下降是最早出現(xiàn)的改變，通常在患者出現(xiàn)顯著的認(rèn)知障礙前若干年即可檢出，而且具有很高的診斷靈敏度，因此在AD的早期篩查方面具有很大價(jià)值[11]。此外，與單獨(dú)檢測(cè)Aβ42含量相比，腦脊液中Aβ42/Aβ40的比值與大腦淀粉樣蛋白負(fù)荷具有更高的一致性，能更好地將AD與血管性癡呆、克雅氏病、路易氏體癡呆等其他神經(jīng)退行性疾病鑒別開(kāi)。因此，針對(duì)Aβ42和Aβ40等不同片段的特異性檢測(cè)，將成為下階段體外診斷發(fā)展的重要方向[12-14]。
【博奧森Aβ42相關(guān)產(chǎn)品】
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Anti-Beta-Amyloid(1-42) mAb （Mouse anti Human） |
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Cat# |
Matched pair (Capture-Detection) |
Application |
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V5301-V5302 |
ELISA, WB |
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V5301-V5302 |
ELISA, WB |
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V5301-V5304 |
ELISA, WB |
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V5303-V5302 |
ELISA |
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Anti-Beta-Amyloid(1-40) mAb （Mouse anti Human） |
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—— |
ELISA, WB |
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與Aβ42的下降相比，CSF中總tau和P-tau顯著上升發(fā)生在疾病進(jìn)程中較晚的時(shí)間點(diǎn)，與臨床可檢出的癡呆癥狀出現(xiàn)的時(shí)間非常接近[11]。因此，tau蛋白相關(guān)的生物標(biāo)志物很難在AD早期篩查中發(fā)揮關(guān)鍵作用。檢測(cè)CSF中tau的意義在于彌補(bǔ)單檢Aβ特異性差的問(wèn)題。同時(shí)檢測(cè)CSF中Aβ42、總tau和p-tau181聯(lián)合判讀診斷法經(jīng)多年優(yōu)化后，敏感度和特異性均穩(wěn)定達(dá)到80%的閾值[15]。此外，一些最新研究表明：與p-tau181相比，p-tau217在鑒別AD與額顳葉癡呆患者時(shí)具有獨(dú)到的優(yōu)勢(shì)[16]。p-tau217與現(xiàn)有標(biāo)志物聯(lián)合診斷可獲得診斷效率的進(jìn)一步提升[17]，為tau相關(guān)生物標(biāo)志物的臨床應(yīng)用提供了有力的證據(jù)。
【博奧森Tau相關(guān)產(chǎn)品】
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Anti-Tau antibody mAb （Mouse anti Human） |
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Cat# |
Matched pair (Capture-Detection) |
Application |
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V5205-V5204 |
ELISA, WB |
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V5205-V5203 |
ELISA, WB |
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V5205-V5203 |
ELISA |
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V5206-V5203 |
ELISA |
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— — |
ELISA |
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W5201-V5203 |
ELISA, WB |
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Anti-phospho-Tau (Thr217) mAb （Mouse anti Human） |
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— — |
ELISA |
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NfL是神經(jīng)元完整性的另一個(gè)重要標(biāo)志物，它反映了腦白質(zhì)中軸突的損傷情況。因此，NfL被認(rèn)為是包括AD在內(nèi)，多種神經(jīng)退行性疾病的重要標(biāo)志物[18-20]。由于NfL水平與神經(jīng)細(xì)胞的損傷情況高度相關(guān)，CSF中NfL含量與經(jīng)典指標(biāo)聯(lián)合應(yīng)用可進(jìn)一步提高診斷特異性和敏感度，并為AD病理發(fā)展階的劃分提供更多依據(jù)[21]。此外，NfL是目前唯一一個(gè)被證明能直接從腦脊液轉(zhuǎn)移到血漿的標(biāo)志物[22]。因此，抽取CSF之前檢測(cè)患者的血清NfL水平，很可能成為減少患者痛苦、提高醫(yī)療資源使用效率的更好方法。
【博奧森NfL相關(guān)產(chǎn)品】
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Anti-NfL antibody mAb （Mouse anti Human） |
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Cat# |
Matched pair (Capture-Detection) |
Application |
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V5501-V5505 |
ELISA, WB |
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— — |
ELISA, WB |
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V5503-V5505 |
ELISA, WB |
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V5505-V5504 |
ELISA, WB |
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V5505-V5504 |
ELISA, WB |
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參考文獻(xiàn)
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