Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Barcelona, Spain.
Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia.
JAMA Neurol. 2018 Jun 1;75(6):738-745. doi: 10.1001/jamaneurol.2018.0118.
Cerebrospinal fluid (CSF) core Alzheimer disease (AD) biomarkers have shown an excellent capacity for the in vivo detection of AD. Previous studies have shown that CSF levels of phosphorylated tau (p-tau) also correlate with tau pathology in frontotemporal lobar degeneration (FTLD) after accounting for AD copathology.
To develop an algorithm based on core AD CSF measures to exclude cases with AD pathology and then differentiate between FTLD-tau and FTLD transactive response DNA-binding protein of approximately 43kDa (FTLD-TDP).
DESIGN, SETTING, AND PARTICIPANTS: A case-control study at the University of Pennsylvania. Participants were selected from a database of 1796 patients included between 1992 and 2016 with different neurodegenerative diseases with available CSF. Three patient cohorts were included: a cohort of patients with sporadic, autopsy-confirmed FTLD and AD (n = 143); a cohort of patients with frontotemporal degeneration (FTD) with TDP-associated or tau-associated mutations (n = 60); and a living cohort of patients with syndromes highly predictive of FTLD (progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis; n = 62).
Cerebrospinal fluid values of amyloid β1-42 (Aβ1-42), total tau (t-tau), and p-tau obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay or INNOTEST enzyme-linked immunosorbent assay transformed using a previously validated algorithm. Sensitivities and specificities for differentiating AD from FTLD groups were calculated.
This autopsy cohort included FTLD-tau (n = 27; mean [SD] age at onset, 60.8 [9.7] years), FTLD-TDP (n = 13; mean [SD] age at onset, 62.4 [8.5] years), AD (n = 89, mean [SD] age at onset, 66.5 [9.7] years); and mixed FTLD-AD (n = 14, mean [SD] age at onset, 70.6 [8.5] years).The p-tau/Aβ1-42 ratio showed an excellent diagnostic accuracy to exclude AD cases in the autopsy cohort with single neurodegenerative pathologies (area under the curve [AUC], 0.98; 95% CI, 0.96-1.00). Cerebrospinal fluid p-tau levels showed a good AUC (0.87; 95% CI, 0.73-1.00) for discriminating pure FTLD-TDP from pure FTLD-tau. The application of an algorithm using cutpoints of CSF p-tau to Aβ1-42 ratio and p-tau allowed a good discrimination of pure FTLD-TDP cases from the remaining FTLD-tau and mixed FTLD cases. The diagnostic value of this algorithm was confirmed in an independent cohort of living patients with progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis (AUC, 0.9; 95% CI, 0.81-0.99). However, the algorithm was less useful in FTD cases carrying a pathogenic mutation (AUC, 0.58; 95% CI, 0.38-0.77) owing to elevated p-tau levels in TDP-associated mutation carriers.
Alzheimer disease CSF core biomarkers can be used with high specificity for the in vivo identification of patients with pure FTLD-TDP and FTLD-tau when accounting for comorbid AD and genetic status.
脑脊液（CSF）核心阿尔茨海默病（AD）生物标志物在 AD 的体内检测方面具有出色的能力。先前的研究表明，在考虑 AD 共病病理后，磷酸化 tau（p-tau）的 CSF 水平也与额颞叶变性（FTLD）中的 tau 病理学相关。
开发一种基于核心 AD CSF 测量的算法，以排除具有 AD 病理的病例，然后区分 FTLD-tau 和 FTLD 转导反应 DNA 结合蛋白约 43kDa（FTLD-TDP）。
设计、设置和参与者：宾夕法尼亚大学的病例对照研究。参与者选自 1992 年至 2016 年间数据库中不同神经退行性疾病的患者，这些患者均有可用的 CSF。包括三个患者队列：一组散发性、尸检证实的 FTLD 和 AD（n=143）的患者；一组额颞叶变性（FTD）患者，具有 TDP 相关或 tau 相关突变（n=60）；一组具有高度预测 FTLD 的综合征的患者（进行性核上性麻痹和 FTD-肌萎缩侧索硬化；n=62）。
使用 INNO-BIA AlzBio3（xMAP；Luminex）测定或 INNOTEST 酶联免疫吸附测定转化的 CSF 值，包括淀粉样β 1-42（Aβ1-42）、总 tau（t-tau）和 p-tau。计算了区分 AD 与 FTLD 组的敏感性和特异性。
该尸检队列包括 FTLD-tau（n=27；发病年龄的平均值[标准差]，60.8[9.7]岁）、FTLD-TDP（n=13；发病年龄的平均值[标准差]，62.4[8.5]岁）、AD（n=89，发病年龄的平均值[标准差]，66.5[9.7]岁）；以及混合性 FTLD-AD（n=14，发病年龄的平均值[标准差]，70.6[8.5]岁）。在具有单一神经退行性病变的尸检队列中，p-tau/Aβ1-42 比值显示出出色的诊断准确性，可以排除 AD 病例（曲线下面积[AUC]，0.98；95%CI，0.96-1.00）。CSF p-tau 水平对区分纯 FTLD-TDP 与纯 FTLD-tau 具有良好的 AUC（0.87；95%CI，0.73-1.00）。应用 p-tau 至 Aβ1-42 比值和 p-tau 的 CSF 比值的算法可很好地区分纯 FTLD-TDP 病例与剩余的 FTLD-tau 和混合性 FTLD 病例。该算法在一组具有进行性核上性麻痹和 FTD-肌萎缩侧索硬化的存活患者的独立队列中得到了证实（AUC，0.9；95%CI，0.81-0.99）。然而，由于 TDP 相关突变携带者中 p-tau 水平升高，该算法在携带致病性突变的 FTD 病例中作用较小（AUC，0.58；95%CI，0.38-0.77）。
在考虑共病 AD 和遗传状态的情况下，AD CSF 核心生物标志物可以高度特异性地用于识别纯 FTLD-TDP 和 FTLD-tau 的患者。
