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。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)
[1] Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures [J]. Alzheimers Dement, 2020,16(3):391-460.[2] Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures [J]. Alzheimers Dement, 2015,11(3):332-384.[3] Justin M. Long & David M. Holtzman. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies [J]. Cell, 2019, 179(10):1-28.
[4] Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s dis ease [J]. Alzheimers Dement, 2011;7(3):280-92.
[5] Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox N, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease [J]. Alzheimers Dement, 2011;7(3):270-9.
[6] McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s dis ease [J]. Alzheimers Dement, 2011;7(3):263-9. 77Flavanone accelerates Aβ aggregation and relieves cognitive impairment in AD model mice.
[7] Jack CR, Albert MS, Knopman DS, Khann Mc, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease [J]. Alzheimers Dement, 2011;7(3):257-62.
[8] Bridel C., van Wieringen W.N., Zetterberg H., et al. Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis [J]. JAMA Neurol,2019;17(7).
[9] Mielke M.M., Syrjanen J.A., Blennow, K., Zetterberg H., Vemuri P., et al. Plasma and CSF neurofilament light: Relation to longitudinal neuroimaging and cognitive measures [J]. Neurology, 2019;93:252-260.
[10] Bjerke M, Engelborghs S. Cerebrospinal Fluid Biomarkers for Early and Differential Alzheimer's Disease Diagnosis [J]. J Alzheimers Dis. 2018;62(3):1199-1209.
[11] Buchhave P, Minthon L, Zetterberg H., et al. Cerebrospinal fluid levels of betaamyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia [J]. Arch Gen Psychiatry 69, 2012;98-106.[12] Niemantsverdriet E, Ottoy J., et al. The cerebrospinal fluid Abeta1-42/Abeta1-40 ratio improves concordance with amyloid-PET for diagnosing Alzheimer’s disease in a clinical setting [J]. J Alzheimers Dis 60, 2017;561-576.
[13] Janelidze S, Zetterberg H, Mattsson N, Palmqvist S., et al. CSF Abeta42/Abeta40 and Abeta42/Abeta38 ratios: Better diagnostic markers of Alzheimer disease [J]. Ann Clin Transl Neurol 3, 2016;154-165.
[14] Lewczuk P, Matzen A, Blennow K, Parnetti L., et al. Cerebrospinal fluid Abeta42/40 corresponds better than Abeta42 to amyloid PET in Alzheimer’s disease [J]. J Alzheimers Dis 55, 2017;813-822.
[15] Engel. S., De Vreese K., et al. Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia [J]. Neurobiol Aging 29, 2008;1143-1159.
[16] Thijssen EH, La Joie R, Strom A, Fonseca C, Iaccarino L., et al. Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study [J]. Lancet Neurol. 2021 Sep;20(9):739-752.
[17] Karikari TK, Emer?i? A, Vrillon A., et al. Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis [J]. Alzheimers Dement. 2021 May;17(5):755-767.
[18] Wallin A, Ohrfelt A, Bjerke M.Characteristic clinical presentation and CSF biomarker pattern in CSVD [J]. J Neurol Sci 322, 2012;192-196.
[19] Rosenberg GA, Bjerke M, Wallin A. Multimodal markers of inflammation in the subcortical ischemic vascular disease type of vascular cognitive impairment. Stroke45, 2014;1531-1538.
[20] Wallin A, Kapaki E, Boban M, Engelborghs S., et al. Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease -A consensus report [J]. BMC Neurol 17, 2017;102.
[21] Somers C, Goossens J., et al. Selecting Abeta isoforms for an Alzheimer’s disease cerebrospinal fluid biomarker panel [J]. Biomark Med 11, 2014;169-178.
[22] Zetterberg H, Skillback T, Mattsson N., et al. Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression [J]. JAMA Neurol 73, 2016;60-67.
