Brum Wagner S, de Bastiani Marco Antônio, Bieger Andrei, Therriault Joseph, Ferrari-Souza João P, Benedet Andréa L, Saha-Chaudhuri Paramita, Souza Diogo O, Ashton Nicholas J, Zetterberg Henrik, Pascoal Tharick A, Karikari Thomas, Blennow Kaj, Rosa-Neto Pedro, Zimmer Eduardo R
Graduate Program in Biological Sciences: Biochemistry Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre Brazil.
Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden.
Alzheimers Dement (N Y). 2022 Mar 13;8(1):e12270. doi: 10.1002/trc2.12270. eCollection 2022.
Alzheimer's disease consensus recommends biomarker dichotomization, a practice with well-described clinical strengths and methodological limitations. Although neuroimaging studies have explored alternative biomarker interpretation strategies, a formally defined three-range approach and its prognostic impact remains under-explored for cerebrospinal fluid (CSF) biomarkers .
With two-graph receiver-operating characteristics based on different reference schemes, we derived three-range cut-points for CSF Elecsys biomarkers. According to baseline CSF status, we assessed the prognostic utility of this in predicting risk of clinical progression and longitudinal trajectories of cognitive decline and amyloid-beta (Aβ) positron emission tomography (PET) accumulation in non-demented individuals (Alzheimer's Disease Neuroimaging Initiative [ADNI]; n = 1246). In all analyses, we compared herein-derived three-range CSF cut-points to previously described binary ones.
In our main longitudinal analyses, we highlight CSF p-tau/Aβ three-range cut-points derived based on the cognitively normal Aβ-PET negative versus dementia Aβ-PET positive reference scheme for best depicting a prognostically relevant biomarker abnormality range. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization and a clearly abnormal group at higher risk for cognitive decline, with power analyses suggesting the latter group as potential trial enrichment candidates. Furthermore, we demonstrate that individuals with intermediate-range CSF status have similar rates of Aβ deposition to those in the clearly abnormal group.
The proposed approach can refine clinico-biological prognostic assessment and potentially enhance trial recruitment, as it captures faster biomarker-related cognitive decline in comparison to binary cut-points. Although this approach has implications for trial recruitment and observational studies, further discussion is needed regarding clinical practice applications.
阿尔茨海默病共识推荐生物标志物二分法，这种做法具有已充分描述的临床优势和方法学局限性。尽管神经影像学研究已经探索了替代的生物标志物解释策略，但脑脊液（CSF）生物标志物的正式定义的三分法及其预后影响仍未得到充分探索。
基于不同的参考方案，利用双图接收器操作特征，我们得出了CSF Elecsys生物标志物的三分法切点。根据基线脑脊液状态，我们评估了其在预测非痴呆个体（阿尔茨海默病神经影像学倡议[ADNI]；n = 1246）临床进展风险、认知衰退纵向轨迹以及淀粉样β蛋白（Aβ）正电子发射断层扫描（PET）积累方面的预后效用。在所有分析中，我们将此处得出的CSF三分法切点与先前描述的二分法切点进行了比较。
在我们主要的纵向分析中，我们强调基于认知正常Aβ-PET阴性与痴呆Aβ-PET阳性参考方案得出的CSF磷酸化tau蛋白/Aβ三分法切点，以最佳描绘与预后相关的生物标志物异常范围。纵向来看，我们的方法揭示了二分法未检测到的不同的中间认知轨迹，以及认知衰退风险较高的明显异常组，功效分析表明后一组是潜在的试验富集候选对象。此外，我们证明CSF处于中间范围状态的个体与明显异常组的个体具有相似的Aβ沉积率。
所提出的方法可以完善临床生物学预后评估，并可能加强试验招募，因为与二分法切点相比，它能捕捉到更快的与生物标志物相关的认知衰退。尽管这种方法对试验招募和观察性研究有影响，但对于临床实践应用还需要进一步讨论。
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