Hok-A-Hin Yanaika S, Vermunt Lisa, Peeters Carel F W, van der Ende Emma L, de Boer Sterre C M, Meeter Lieke H, van Swieten John C, Hu William T, Lleó Alberto, Alcolea Daniel, Engelborghs Sebastiaan, Sieben Anne, Chen-Plotkin Alice, Irwin David J, van der Flier Wiesje M, Pijnenburg Yolande A L, Teunissen Charlotte E, Del Campo Marta
Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam UMC, The Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
medRxiv. 2024 Aug 20:2024.08.19.24312100. doi: 10.1101/2024.08.19.24312100.
Diagnosis of Frontotemporal dementia (FTD) and the specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD- Tau and FTLD-TDP) is challenging, and thus fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort including patients with FTD (n = 189), Alzheimer's Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 68). Forty three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (AUC: 0.96) or AD (AUC: 0.91). Custom multiplex panels confirmed the highly accurate discrimination between FTD and controls (AUCs > 0.96) or AD (AUCs > 0.88) in three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau, but no reproducible classification model could be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic setting.
额颞叶痴呆（FTD）及其特定的潜在神经病理学特征（额颞叶变性；FTLD-Tau和FTLD-TDP）的诊断具有挑战性，因此需要生物标志物来提高诊断准确性。我们使用邻近延伸分析方法，对来自一个多中心队列的脑脊液（CSF）样本中的665种蛋白质进行了分析，该队列包括FTD患者（n = 189）、阿尔茨海默病痴呆患者（AD；n = 232）以及认知未受损个体（n = 196）。在一个子集中，根据表型或基因型确定了FTLD神经病理学特征（FTLD-Tau = 87例，FTLD-TDP = 68例）。与对照组和AD组相比，FTD组中有43种蛋白质的表达存在差异调节，反映了轴突发育、突触组装调节和细胞间粘附介质活性途径。分类分析确定了一个由14种和13种脑脊液蛋白质组成的panel，可将FTD与对照组（曲线下面积：0.96）或AD组（曲线下面积：0.91）区分开来。定制的多重panel在三个验证队列中证实了FTD与对照组（曲线下面积> 0.96）或AD组（曲线下面积> 0.88）之间具有高度准确的区分能力，其中一个队列有尸检确认（曲线下面积> 0.90）。FTLD-TDP和FTLD-Tau之间有6种蛋白质的表达存在差异调节，但无法生成可重复的分类模型（曲线下面积：0.80）。总体而言，本研究引入了具有潜在诊断应用价值的新型FTD特异性生物标志物panel。
