Shahzad Ahmad, Wei Yang, Adelina Orellana, Lutz Frölich, Itziar de Rojas, Amanda Cano, Mercè Boada, Isabel Hernández, Lucrezia Hausner, Amy C Harms, Margot H M Bakker, Alfredo Cabrera-Socorro, Najaf Amin, Alfredo Ramírez, Agustín Ruiz, Cornelia M Van Duijn, Thomas Hankemeier
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In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects.</p><p><strong>Methods: </strong>Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression.</p><p><strong>Results: </strong>Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression.</p><p><strong>Conclusions: </strong>Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"171"},"PeriodicalIF":7.9000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287840/pdf/","citationCount":"0","resultStr":"{\"title\":\"Association of oxidative stress and inflammatory metabolites with Alzheimer's disease cerebrospinal fluid biomarkers in mild cognitive impairment.\",\"authors\":\"Shahzad Ahmad, Wei Yang, Adelina Orellana, Lutz Frölich, Itziar de Rojas, Amanda Cano, Mercè Boada, Isabel Hernández, Lucrezia Hausner, Amy C Harms, Margot H M Bakker, Alfredo Cabrera-Socorro, Najaf Amin, Alfredo Ramírez, Agustín Ruiz, Cornelia M Van Duijn, Thomas Hankemeier\",\"doi\":\"10.1186/s13195-024-01542-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects.</p><p><strong>Methods: </strong>Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression.</p><p><strong>Results: </strong>Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. 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引用次数: 0
摘要
背景:异前列腺素和前列腺素是氧化应激和炎症的生物标志物。它们在阿尔茨海默病(AD)病理生理学中的作用尚不清楚。在本研究中,我们旨在确定异前列腺素和前列腺素与轻度认知障碍(MCI)受试者的淀粉样蛋白、Tau、神经变性(ATN)生物标志物(Aβ-42、p-tau 和 t-tau)之间的关系:采用液相色谱-质谱法(LCMS)对巴塞罗那王牌阿尔茨海默中心的147份血浆-脑脊液配对样本和曼海姆/海德堡队列的58份MCI患者脑脊液样本进行了靶向代谢组学分析。我们采用线性回归法评估了代谢物与整个样本中ATN生物标记物CSF水平的关系,并根据Aβ-42病理学和APOE基因型进行了分层。我们进一步评估了代谢物在MCI向AD痴呆发展过程中的作用:结果:PGF2α、8,12-iso-iPF2α VI 和 5-iPF2α VI 的 CSF 水平升高有显著相关性(假发现率 (FDR)氧化应激(8,12-异-iPF2α VI)和炎症(PGF2α)生物标志物与AD前驱期病理生物标志物相关,PGF2α与tau病理标志物的关系可能受APOE基因型的影响。
Association of oxidative stress and inflammatory metabolites with Alzheimer's disease cerebrospinal fluid biomarkers in mild cognitive impairment.
Background: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects.
Methods: Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression.
Results: Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression.
Conclusions: Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype.
期刊介绍:
Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.