Department of Neurology, Memory and Aging Center, University of California San Francisco Weill Institute for Neurosciences, University of California, San Francisco.
Lawrence Berkeley National Laboratory, Berkeley, California.
JAMA Neurol. 2023 May 1;80(5):495-505. doi: 10.1001/jamaneurol.2023.0488.
Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology.
To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS.
DESIGN, SETTING, AND PARTICIPANTS: This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort.
Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling.
Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005).
In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.
血浆磷酸化 tau217（p-tau217）是阿尔茨海默病（AD）的生物标志物，在皮质基底节综合征（CBS）中特别重要，因为尸检研究表明 AD 是高达 40%病例的驱动神经病理学。这将 CBS 与其他四重复tau 病（4RT）相关综合征区分开来，如进行性核上性麻痹 Richardson 综合征（PSP-RS）和非流利性原发性进行性失语症（nfvPPA），其中潜在的额颞叶变性（FTLD）通常是主要的神经病理学。
验证血浆 p-tau217 在 4RT 相关综合征，特别是 CBS 中与正电子发射断层扫描（PET）的相关性。
设计、地点和参与者：本研究为多队列研究，招募了 2011 年 1 月至 2020 年 9 月间在 4RT 神经影像学倡议（4RTNI）的 8 个三级护理中心的成年参与者，随访时间为 6、12 和 24 个月。所有 CBS（n=113）、PSP-RS（n=121）和 nfvPPA（n=39）患者均包括在内；由于罕见（n=29）而排除了其他诊断。在加利福尼亚大学旧金山分校评估了 PET 确诊 AD（n=54）和 PET 阴性认知正常对照个体（n=59）。操作人员对队列情况不知情。
通过 Meso Scale Discovery 电化学发光法测量血浆 p-tau217，与淀粉样β（Aβ）和 flortaucipir（FTP）PET 进行验证。成像分析使用基于体素的形态测量和贝叶斯线性混合效应模型。使用纵向混合效应模型评估临床生物标志物相关性。
在 386 名参与者中，有 199 名（52%）为女性，平均（SD）年龄为 68（8）岁。CBS 患者中，PET 阳性 Aβ PET 结果（平均[SD]，0.57[0.43]pg/mL）或 FTP PET（平均[SD]，0.75[0.30]pg/mL）的血浆 p-tau217 升高，浓度与 AD 控制个体（平均[SD]，0.72[0.37]）相当，而 PSP-RS 和 nfvPPA 与对照个体相比没有升高。在 CBS 中，p-tau217 具有出色的诊断性能，Aβ PET 的曲线下面积（AUC）为 0.87（95%CI，0.76-0.98；P<.001），FTP PET 的 AUC 为 0.93（95%CI，0.83-1.00；P<.001）。在基线时，根据 PET 验证的血浆 p-tau217 截断值 0.25pg/mL 或更高，12 名 CBS-AD 患者（n=12）的颞顶叶萎缩较明显，与 39 名 CBS-FTLD 患者（n=39）相比，而在纵向研究中，CBS-FTLD 患者的脑干萎缩速度更快。与 CBS-AD 患者相比，CBS-FTLD 患者的 PSP 评分量表（mean[SD]，3.5[0.5]vs 0.8[0.8]分/年；P=0.005）进展更快。
在本队列研究中，血浆 p-tau217 在识别 CBS 中 Aβ 或 FTP PET 阳性方面具有出色的诊断性能，可能存在潜在的 AD 病理学。血浆 P-tau217 可能是一种有用且经济的生物标志物，用于选择 CBS 临床试验的患者。
