PDF(Pubmed)
Abstract：
OBJECTIVE: Neuroinflammation, particularly early astrocyte reactivity, is a significant driver of Alzheimer disease (AD) pathogenesis. It is unclear how the levels of astrocyte biomarkers change in patients across the AD continuum and which best reflect AD-related change. We performed a systematic review and meta-analysis of 3 blood astrocyte biomarkers (glial fibrillary acidic protein [GFAP], chitinase-3-like protein 1 [YKL-40], and S100B) in patients clinically diagnosed with AD.
METHODS: MEDLINE and Web of Science were searched on March 23, 2023, without restrictions on language, time, or study design, for studies reporting blood levels of the astrocyte biomarkers GFAP, YKL-40, or S100B in patients on the AD continuum (including those with mild cognitive impairment [MCI] and dementia) and a cognitively unimpaired (CU) control population. AD diagnosis was based on established diagnostic criteria and/or comprehensive multidisciplinary clinical consensus. Studies reporting indirect biomarker measures (e.g., levels of biomarker autoantibodies) were excluded. Risk of bias assessment was performed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. Pooled effect sizes were determined using the Hedge g method with a random-effects model. The review was prospectively registered on PROSPERO (registration number CRD42023458305).
RESULTS: The search identified 1,186 studies; 36 met inclusion criteria (AD continuum n = 3,366, CU n = 4,115). No study was assessed to have a high risk of bias. Compared with CU individuals, patients on the AD continuum had higher GFAP and YKL-40 levels (GFAP effect size 1.15, 95% CI 0.94-1.36, p < 0.0001; YKL-40 effect size 0.38, 95% CI 0.28-0.49, p < 0.0001). Both biomarkers were elevated in more advanced clinical stages of the disease (i.e., in AD dementia compared with MCI due to AD: GFAP effect size 0.48, 95% CI 0.19-0.76, p = 0.0009; YKL-40 effect size 0.34, 95% CI 0.10-0.57, p = 0.0048). No significant differences in blood S100B levels were identified.
CONCLUSIONS: We demonstrated significant elevations in blood GFAP and YKL-40 levels in patients on the AD continuum compared with CU individuals. Furthermore, within the AD clinical spectrum, significant elevation correlated with more advanced disease stage. Our findings suggest that both biomarkers reflect AD-related pathology. Our findings are limited by the lack of cultural and linguistic diversity in the study populations meta-analyzed. Future meta-analyses using a biomarker-defined AD population are warranted.
METHODS: MEDLINE and Web of Science were searched on March 23, 2023, without restrictions on language, time, or study design, for studies reporting blood levels of the astrocyte biomarkers GFAP, YKL-40, or S100B in patients on the AD continuum (including those with mild cognitive impairment [MCI] and dementia) and a cognitively unimpaired (CU) control population. AD diagnosis was based on established diagnostic criteria and/or comprehensive multidisciplinary clinical consensus. Studies reporting indirect biomarker measures (e.g., levels of biomarker autoantibodies) were excluded. Risk of bias assessment was performed using the revised Quality Assessment of Diagnostic Accuracy Studies tool. Pooled effect sizes were determined using the Hedge g method with a random-effects model. The review was prospectively registered on PROSPERO (registration number CRD42023458305).
RESULTS: The search identified 1,186 studies; 36 met inclusion criteria (AD continuum n = 3,366, CU n = 4,115). No study was assessed to have a high risk of bias. Compared with CU individuals, patients on the AD continuum had higher GFAP and YKL-40 levels (GFAP effect size 1.15, 95% CI 0.94-1.36, p < 0.0001; YKL-40 effect size 0.38, 95% CI 0.28-0.49, p < 0.0001). Both biomarkers were elevated in more advanced clinical stages of the disease (i.e., in AD dementia compared with MCI due to AD: GFAP effect size 0.48, 95% CI 0.19-0.76, p = 0.0009; YKL-40 effect size 0.34, 95% CI 0.10-0.57, p = 0.0048). No significant differences in blood S100B levels were identified.
CONCLUSIONS: We demonstrated significant elevations in blood GFAP and YKL-40 levels in patients on the AD continuum compared with CU individuals. Furthermore, within the AD clinical spectrum, significant elevation correlated with more advanced disease stage. Our findings suggest that both biomarkers reflect AD-related pathology. Our findings are limited by the lack of cultural and linguistic diversity in the study populations meta-analyzed. Future meta-analyses using a biomarker-defined AD population are warranted.
摘要：
目的：神经炎症，特别是早期星形胶质细胞反应性，是阿尔茨海默病（AD）发病机制的重要驱动因素。目前尚不清楚患者的星形胶质细胞生物标志物水平在整个AD连续体中如何变化，以及哪个能最好地反映AD相关的变化。我们对3种血液星形胶质细胞生物标志物（胶质纤维酸性蛋白[GFAP]，几丁质酶-3-样蛋白1[YKL-40]，和S100B）在临床诊断为AD的患者中。
方法：MEDLINE和WebofScience于2023年3月23日进行了搜索，没有语言限制，时间,或研究设计，对于报道星形胶质细胞生物标志物GFAP的血液水平的研究，YKL-40或S100B在AD连续体患者（包括患有轻度认知障碍[MCI]和痴呆的患者）和认知未受损（CU）对照人群中。AD诊断基于已建立的诊断标准和/或综合多学科临床共识。报告间接生物标志物测量的研究(例如，生物标志物自身抗体水平)被排除。使用修订后的诊断准确性研究质量评估工具进行偏倚风险评估。使用具有随机效应模型的Hedgeg方法确定集合效应大小。该审查已在PROSPERO上注册（注册号CRD42023458305）。
结果：搜索确定了1,186项研究；36项符合纳入标准（AD连续体n=3,366，CUn=4,115）。没有一项研究被评估为具有高偏倚风险。与CU个体相比，AD连续体患者的GFAP和YKL-40水平较高(GFAP效应大小1.15,95%CI0.94-1.36,p<0.0001;YKL-40效应大小0.38,95%CI0.28-0.49,p<0.0001).两种生物标志物在疾病的更晚期临床阶段均升高(即，与由AD引起的MCI相比，在AD痴呆中：GFAP效应大小0.48，95％CI0.19-0.76，p=0.0009；YKL-40效应大小0.34，95％CI0.10-0.57，p=0.0048）。没有发现血液S100B水平的显著差异。
结论：我们证明，与CU个体相比，AD连续体患者的血液GFAP和YKL-40水平显著升高。此外，在AD临床范围内，显著升高与更晚期的疾病阶段相关。我们的发现表明，这两种生物标志物都反映了AD相关的病理学。我们的发现受到荟萃分析的研究人群中缺乏文化和语言多样性的限制。使用生物标志物定义的AD群体的未来荟萃分析是有必要的。
方法：MEDLINE和WebofScience于2023年3月23日进行了搜索，没有语言限制，时间,或研究设计，对于报道星形胶质细胞生物标志物GFAP的血液水平的研究，YKL-40或S100B在AD连续体患者（包括患有轻度认知障碍[MCI]和痴呆的患者）和认知未受损（CU）对照人群中。AD诊断基于已建立的诊断标准和/或综合多学科临床共识。报告间接生物标志物测量的研究(例如，生物标志物自身抗体水平)被排除。使用修订后的诊断准确性研究质量评估工具进行偏倚风险评估。使用具有随机效应模型的Hedgeg方法确定集合效应大小。该审查已在PROSPERO上注册（注册号CRD42023458305）。
结果：搜索确定了1,186项研究；36项符合纳入标准（AD连续体n=3,366，CUn=4,115）。没有一项研究被评估为具有高偏倚风险。与CU个体相比，AD连续体患者的GFAP和YKL-40水平较高(GFAP效应大小1.15,95%CI0.94-1.36,p<0.0001;YKL-40效应大小0.38,95%CI0.28-0.49,p<0.0001).两种生物标志物在疾病的更晚期临床阶段均升高(即，与由AD引起的MCI相比，在AD痴呆中：GFAP效应大小0.48，95％CI0.19-0.76，p=0.0009；YKL-40效应大小0.34，95％CI0.10-0.57，p=0.0048）。没有发现血液S100B水平的显著差异。
结论：我们证明，与CU个体相比，AD连续体患者的血液GFAP和YKL-40水平显著升高。此外，在AD临床范围内，显著升高与更晚期的疾病阶段相关。我们的发现表明，这两种生物标志物都反映了AD相关的病理学。我们的发现受到荟萃分析的研究人群中缺乏文化和语言多样性的限制。使用生物标志物定义的AD群体的未来荟萃分析是有必要的。
