PDF(Pubmed)
Abstract：
The increasing burden of Alzheimer\'s disease (AD) emphasizes the need for effective diagnostic and therapeutic strategies. Despite available treatments targeting amyloid beta (Aβ) plaques, disease-modifying therapies remain elusive. Early detection of mild cognitive impairment (MCI) patients at risk for AD conversion is crucial, especially with anti-Aβ therapy. While plasma biomarkers hold promise in differentiating AD from MCI, evidence on predicting cognitive decline is lacking. This study\'s objectives were to evaluate whether plasma protein biomarkers could predict both cognitive decline in non-demented individuals and the conversion to AD in patients with MCI. This study was conducted as part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a prospective, community-based cohort. Participants were based on plasma biomarker availability and clinical diagnosis at baseline. The study included MCI (n = 50), MCI-to-AD (n = 21), and cognitively unimpaired (CU, n = 40) participants. Baseline plasma concentrations of six proteins-total tau (tTau), phosphorylated tau at residue 181 (pTau181), amyloid beta 42 (Aβ42), amyloid beta 40 (Aβ40), neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP)-along with three derivative ratios (pTau181/tTau, Aβ42/Aβ40, pTau181/Aβ42) were analyzed to predict cognitive decline over a six-year follow-up period. Baseline protein biomarkers were stratified into tertiles (low, intermediate, and high) and analyzed using a linear mixed model (LMM) to predict longitudinal cognitive changes. In addition, Kaplan-Meier analysis was performed to discern whether protein biomarkers could predict AD conversion in the MCI subgroup. This prospective cohort study revealed that plasma NFL may predict longitudinal declines in Mini-Mental State Examination (MMSE) scores. In participants categorized as amyloid positive, the NFL biomarker demonstrated predictive performance for both MMSE and total scores of the Korean version of the Consortium to Establish a Registry for Alzheimer\'s Disease Assessment Packet (CERAD-TS) longitudinally. Additionally, as a baseline predictor, GFAP exhibited a significant association with cross-sectional cognitive impairment in the CERAD-TS measure, particularly in amyloid positive participants. Kaplan-Meier curve analysis indicated predictive performance of NFL, GFAP, tTau, and Aβ42/Aβ40 on MCI-to-AD conversion. This study suggests that plasma GFAP in non-demented participants may reflect baseline cross-sectional CERAD-TS scores, a measure of global cognitive function. Conversely, plasma NFL may predict longitudinal decline in MMSE and CERAD-TS scores in participants categorized as amyloid positive. Kaplan-Meier curve analysis suggests that NFL, GFAP, tTau, and Aβ42/Aβ40 are potentially robust predictors of future AD conversion.
摘要：
阿尔茨海默病（AD）负担的增加强调了对有效诊断和治疗策略的需求。尽管有针对淀粉样蛋白β（Aβ）斑块的治疗方法，疾病改善疗法仍然难以捉摸。早期发现有AD转化风险的轻度认知障碍（MCI）患者至关重要，尤其是抗Aβ治疗。虽然血浆生物标志物有望区分AD和MCI，但缺乏预测认知衰退的证据。这项研究的目的是评估血浆蛋白生物标志物是否可以预测非痴呆个体的认知下降和MCI患者向AD的转化。这项研究是韩国认知老化和痴呆纵向研究（KLOSCAD）的一部分，一个潜在的，基于社区的队列。参与者基于基线时的血浆生物标志物可用性和临床诊断。这项研究包括MCI(n=50)，MCI至AD（n=21），和认知障碍(CU，n=40)参与者。六种蛋白质的基线血浆浓度-总tau（tTau），残基181处的磷酸化tau（pTau181），淀粉样β42（Aβ42），淀粉样β40（Aβ40），神经丝轻链(NFL),和胶质纤维酸性蛋白（GFAP）-以及三个衍生比率（pTau181/tTau，分析了Aβ42/Aβ40，pTau181/Aβ42）以预测六年随访期内的认知能力下降。基线蛋白质生物标志物被分层为三元(低，中间,和高)，并使用线性混合模型(LMM)进行分析，以预测纵向认知变化。此外,进行Kaplan-Meier分析以辨别蛋白质生物标志物是否可以预测MCI亚组中的AD转化。这项前瞻性队列研究表明，血浆NFL可以预测迷你精神状态检查（MMSE）得分的纵向下降。在被归类为淀粉样蛋白阳性的参与者中，NFL生物标志物显示了对MMSE和韩国版阿尔茨海默病注册评估分组联盟(CERAD-TS)总分的预测性能.此外,作为基线预测器，GFAP在CERAD-TS测量中表现出与横断面认知障碍的显着关联，特别是在淀粉样蛋白阳性参与者中。Kaplan-Meier曲线分析表明NFL的预测性能，GFAP,ttau,和Aβ42/Aβ40对MCI至AD转化的影响。这项研究表明，非痴呆参与者的血浆GFAP可能反映了基线横截面CERAD-TS评分，衡量整体认知功能。相反，血浆NFL可预测淀粉样蛋白阳性参与者的MMSE和CERAD-TS评分的纵向下降.卡普兰-迈耶曲线分析表明，NFL，GFAP,ttau,和Aβ42/Aβ40是未来AD转化的潜在稳健预测因子。
