Constantinides Vasilios C, Paraskevas George P, Boufidou Fotini, Bourbouli Mara, Pyrgelis Efstratios-Stylianos, Stefanis Leonidas, Kapaki Elisabeth
First Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece.
Neurochemistry and Biological Markers Unit, First Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Eginition Hospital, Vass. Sophias Ave. 74, 11528 Athens, Greece.
Diagnostics (Basel). 2023 Feb 19;13(4):783. doi: 10.3390/diagnostics13040783.
Alzheimer's disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τ and τ), and amyloid beta with 42 and 40 amino acids (Aβ and Aβ) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ to Aβ/Aβ ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: = 98; bvFTD: = 49; PSP: = 50; CBD: = 45; controls: = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ/Aβ; τ/τ; τ/Aβ; τ/Aβ) and composite markers (t-tau: τ/(Aβ/Aβ40); p-tau: τ/(Aβ/Aβ) were calculated. ROC curve analysis was performed to compare AUCs of Aβ and Aβ/Aβ ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τ, τ Aβ, Aβ/Aβ ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ and Aβ/Aβ; Results: Aβ did not differ from Aβ/Aβ ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; = 0.212). The τ/Aβ ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ/Aβ ratio was superior to Aβ in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses.
Aβ/Aβ ratio is superior to Aβ in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers.
阿尔茨海默病性痴呆（ADD）可能表现为非典型表型，类似于行为变异型额颞叶痴呆（bvFTD）和皮质基底节综合征（CBS），这些表型通常具有潜在的伴tau蛋白病的额颞叶变性（FTLD-tau），如Pick病、皮质基底节变性（CBD）、进行性核上性麻痹（PSP）或伴TDP-43蛋白病的FTLD（FTLD-TDP）。脑脊液生物标志物总tau蛋白和磷酸化tau蛋白（τ和p-τ）以及含42和40个氨基酸的淀粉样β蛋白（Aβ42和Aβ40）是AD病理的生物标志物。本研究的主要目的是比较Aβ42/Aβ40比值与Aβ42在以下方面的诊断准确性：（a）区分ADD与额颞叶痴呆；（b）患有AD病理的患者与非AD病理的患者；（c）在区分AD与FTD时，比较生物标志物比值和复合标志物与单一脑脊液生物标志物。方法：共纳入263名受试者（ADD：n = 98；bvFTD：n = 49；PSP：n = 50；CBD：n = 45；对照组：n = 21）。脑脊液生物标志物通过市售酶联免疫吸附测定法（EUROIMMUN）进行检测。计算了多个生物标志物比值（Aβ42/Aβ40；p-τ/τ；τ/Aβ42；τ/Aβ40）和复合标志物（总tau蛋白：τ/（Aβ42/Aβ40）；磷酸化tau蛋白：p-τ/（Aβ42/Aβ40））。进行ROC曲线分析，以比较ADD和FTD之间Aβ42和Aβ42/Aβ40比值以及相关复合标志物的曲线下面积（AUC），临床定义为FTD。使用BIOMARKAPD/ABSI标准（异常的τ、p-τ、Aβ42、Aβ42/Aβ40比值）将所有患者重新分类为患有AD病理和非AD病理，并重复进行ROC曲线分析以比较Aβ42和Aβ42/Aβ40。结果：在区分ADD与FTD方面，Aβ42与Aβ42/Aβ40比值无差异（AUC分别为0.752和0.788；P = 0.212）。τ/Aβ42比值在区分ADD与FTD方面提供了最大的辨别力（AUC：0.893；敏感性88.8%，特异性80%）。BIOMARKAPD/ABSI标准将60名患者分类为患有AD病理，211名患者分类为非AD病理。共有22名患者结果不一致，被排除。在区分AD病理与非AD病理方面，Aβ42/Aβ40比值优于Aβ42（AUC分别为0.939和0.831；P < 0.001）。总体而言，在两项分析中，生物标志物比值和复合标志物均优于单一脑脊液生物标志物。结论：无论临床表型如何，Aβ42/Aβ40比值在识别AD病理方面优于Aβ42。与单一脑脊液生物标志物相比，脑脊液生物标志物比值和复合标志物提供了更高的诊断准确性。
