The impact of kidney function on Alzheimer's disease blood biomarkers: implications for predicting amyloid-β positivity.

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Burak Arslan, Wagner S Brum, Ilaria Pola, Joseph Therriault, Nesrine Rahmouni, Jenna Stevenson, Stijn Servaes, Kübra Tan, Paolo Vitali, Maxime Montembeault, Jesse Klostranec, Arthur C Macedo, Cecile Tissot, Serge Gauthier, Juan Lantero-Rodriguez, Eduardo R Zimmer, Kaj Blennow, Henrik Zetterberg, Pedro Rosa-Neto, Andrea L Benedet, Nicholas J Ashton
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引用次数: 0

Abstract

Background: Impaired kidney function has a potential confounding effect on blood biomarker levels, including biomarkers for Alzheimer's disease (AD). Given the imminent use of certain blood biomarkers in the routine diagnostic work-up of patients with suspected AD, knowledge on the potential impact of comorbidities on the utility of blood biomarkers is important. We aimed to evaluate the association between kidney function, assessed through estimated glomerular filtration rate (eGFR) calculated from plasma creatinine and AD blood biomarkers, as well as their influence over predicting Aβ-positivity.

Methods: We included 242 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, comprising cognitively unimpaired individuals (CU; n = 124), mild cognitive impairment (MCI; n = 58), AD dementia (n = 34), and non-AD dementia (n = 26) patients all characterized by [18F] AZD-4694. Plasma samples were analyzed for Aβ42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), tau phosphorylated at threonine 181 (p-tau181), 217 (p-tau217), 231 (p-tau231) and N-terminal containing tau fragments (NTA-tau) using Simoa technology. Kidney function was assessed by eGFR in mL/min/1.73 m2, based on plasma creatinine levels, age, and sex. Participants were also stratified according to their eGFR-indexed stages of chronic kidney disease (CKD). We evaluated the association between eGFR and blood biomarker levels with linear models and assessed whether eGFR provided added predictive value to determine Aβ-positivity with logistic regression models.

Results: Biomarker concentrations were highest in individuals with CKD stage 3, followed by stages 2 and 1, but differences were only significant for NfL, Aβ42, and Aβ40 (not Aβ42/Aβ40). All investigated biomarkers showed significant associations with eGFR except plasma NTA-tau, with stronger relationships observed for Aβ40 and NfL. However, after adjusting for either age, sex or Aβ-PET SUVr, the association with eGFR was no longer significant for all biomarkers except Aβ40, Aβ42, NfL, and GFAP. When evaluating whether accounting for kidney function could lead to improved prediction of Aβ-positivity, we observed no improvements in model fit (Akaike Information Criterion, AIC) or in discriminative performance (AUC) by adding eGFR to a base model including each plasma biomarker, age, and sex. While covariates like age and sex improved model fit, eGFR contributed minimally, and there were no significant differences in clinical discrimination based on AUC values.

Conclusions: We found that kidney function seems to be associated with AD blood biomarker concentrations. However, these associations did not remain significant after adjusting for age and sex, except for Aβ40, Aβ42, NfL, and GFAP. While covariates such as age and sex improved prediction of Aβ-positivity, including eGFR in the models did not lead to improved prediction for any biomarker. Our findings indicate that renal function, within the normal to mild impairment range, does not seem to have a clinically relevant impact when using highly accurate blood biomarkers, such as p-tau217, in a biomarker-supported diagnosis.

肾功能对阿尔茨海默病血液生物标志物的影响:预测淀粉样蛋白-β阳性的意义
背景:肾功能受损对血液生物标志物水平有潜在的混淆作用,包括阿尔茨海默病(AD)的生物标志物。鉴于在疑似AD患者的常规诊断检查中即将使用某些血液生物标志物,了解合并症对血液生物标志物应用的潜在影响是很重要的。我们旨在通过血浆肌酐和AD血液生物标志物估算肾小球滤过率(eGFR)来评估肾功能之间的关系,以及它们对预测a β阳性的影响。方法:我们纳入了来自衰老和痴呆(TRIAD)转化生物标志物队列的242名参与者,包括认知未受损个体(CU;n = 124),轻度认知障碍(MCI;n = 58)、AD痴呆(n = 34)和非AD痴呆(n = 26)患者均以[18F] AZD-4694为特征。采用Simoa技术分析血浆样品中Aβ42、Aβ40、胶质纤维酸性蛋白(GFAP)、神经丝轻链(NfL)、苏氨酸181磷酸化的tau蛋白(p-tau181)、217 (p-tau217)、231 (p-tau231)和含tau片段n端(NTA-tau)。根据血浆肌酐水平、年龄和性别,以eGFR (mL/min/1.73 m2)评估肾功能。参与者还根据他们的egfr指数慢性肾脏疾病(CKD)分期进行分层。我们使用线性模型评估了eGFR与血液生物标志物水平之间的关系,并使用逻辑回归模型评估了eGFR是否为确定a β阳性提供了额外的预测价值。结果:生物标志物浓度在CKD 3期患者中最高,其次是2期和1期,但差异仅在NfL、Aβ42和Aβ40中显著(而不是Aβ42/Aβ40)。除血浆NTA-tau外,所有研究的生物标志物均与eGFR有显著相关性,其中Aβ40和NfL的相关性更强。然而,在调整年龄、性别或Aβ-PET SUVr后,除Aβ40、Aβ42、NfL和GFAP外,所有生物标志物与eGFR的相关性不再显著。在评估考虑肾功能是否可以改善a β阳性的预测时,我们观察到通过将eGFR添加到包括每种血浆生物标志物、年龄和性别的基础模型中,模型拟合(Akaike Information Criterion, AIC)或判别性能(discriminative performance, AUC)没有改善。虽然年龄和性别等协变量改善了模型拟合,但eGFR贡献最小,并且基于AUC值的临床歧视没有显着差异。结论:我们发现肾功能似乎与AD血液生物标志物浓度有关。然而,除Aβ40、Aβ42、NfL和GFAP外,这些相关性在调整年龄和性别后并不显著。虽然年龄和性别等协变量改善了对a β阳性的预测,但模型中包括eGFR并没有改善对任何生物标志物的预测。我们的研究结果表明,当在生物标志物支持的诊断中使用高度精确的血液生物标志物(如p-tau217)时,在正常到轻度损害范围内的肾功能似乎没有临床相关的影响。
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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
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.
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