Detection of Alzheimer Neuropathology in Alzheimer and Non-Alzheimer Clinical Syndromes With Blood-Based Biomarkers

IF 20.4 1区医学 Q1 CLINICAL NEUROLOGY

JAMA neurology Pub Date : 2025-02-10 DOI:10.1001/jamaneurol.2024.5017

Lawren VandeVrede, Hanna Cho, Mark Sanderson-Cimino, Fattin Wekselman, Yann Cobigo, Maria Luisa Gorno-Tempini, Hilary W. Heuer, Joel H. Kramer, Argentina Lario Lago, Dana Leichter, Peter Ljubenkov, Bruce L. Miller, David C. Perry, Gil D. Rabinovici, Julio C. Rojas, Howard J. Rosen, Rowan Saloner, Adam Staffaroni, Gallen Triana-Baltzer, Salvatore Spina, William W. Seeley, Lea T. Grinberg, Hartmuth C. Kolb, Renaud La Joie, Adam L. Boxer

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引用次数: 0

Abstract

ImportanceBlood-based biomarkers for Alzheimer disease (AD) are clinically available, but their value is not well understood in syndromes typically associated with frontotemporal lobar degeneration syndromes (FTLD).ObjectiveTo investigate the clinical importance and detectability of AD in FTLD-related neurodegenerative syndromes using 3 plasma biomarkers, phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).Design, Setting, and ParticipantsThis clinicopathological study took place at the University of California San Francisco Alzheimer Disease Research Center from August 2008 to July 2022. Autopsied individuals with clinical evaluation and neuropathological examination, diagnosed with clinical syndromes related to AD (n = 125), frontotemporal lobar degeneration (FTLD; n = 198), or cognitively unimpaired (CU) at the time of evaluation (n = 16) were included.ExposuresAD-related or FTLD-related clinical syndromes or CU.Main Outcomes and MeasuresP-tau217, NfL, and GFAP were measured with single-molecule array (SIMOA). AD was defined as intermediate or high AD neuropathological change (ADNC) at autopsy. Clinical biomarker associations were evaluated using linear regressions. Imaging analyses used bayesian linear mixed-effects modeling.ResultsA total of 349 individuals (191 [55%] male; mean [SD] age at death, 72 [11] years) were included. AD was common in both AD-related syndromes (110/125 [88%]) and FTLD-related syndromes (45/198 [23%]). Neuropathological stage at autopsy was higher in AD-related syndromes (high ADNC: 82/88 [93%] AD vs 13/23 [56%] FTLD), and AD was frequently considered a copathology in FTLD-related syndromes (30/198 [15%]). Plasma p-tau217 concentrations were higher in AD-related syndromes (mean [SD], 0.28 [0.16] pg/mL) than FTLD-related syndromes (mean [SD], 0.10 [0.09] pg/mL) (P &lt; .05). Plasma p-tau217 concentrations were highest in atypical AD-related syndromes (mean [SD], 0.33 [0.02] pg/mL), followed by typical late-onset amnestic syndromes (mean [SD], 0.27 [0.03] pg/mL). FTLD-related syndromes with AD (mean [SD], 0.19 [0.02] pg/mL) were higher compared to without (mean [SD], 0.07 [0.00] pg/mL). Plasma p-tau217 detected AD neuropathology across syndromes (area under the receiver operating characteristic curve [AUC], 0.95; 95% CI, 0.93-0.97), with slightly better performance in AD-related syndromes (AUC, 0.98; 95% CI, 0.95-1.00) compared to FTLD-related syndromes (AUC, 0.89; 95% CI, 0.83-0.94). NfL and GFAP had lower performance for detecting AD (AUC, 0.73; 95% CI, 0.68-0.78 and AUC, 0.75; 95% CI, 0.67-0.80, respectively) and added little to no diagnostic value either alone or in combinations with p-tau217. The presence of AD in FTLD-related syndromes was associated with lower Mini-Mental State Examination score (mean [SD], −2.90 [1.09]; P &lt; .05), worse performance on memory (mean [SD] z score, −0.64 [0.32]), executive (mean [SD] z score, −0.74 [0.19]), and visuospatial composites (mean [SD] z score, −0.88 [0.37]) as well as increased rates of posterior cortical atrophy.ConclusionClinically relevant AD was prevalent across neurodegenerative syndromes and detectable with plasma p-tau217. Plasma p-tau217 may be a useful tool to investigate the clinical impact of AD copathology in non-AD neurodegenerative syndromes, including the effect of disease-modifying therapies.

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用基于血液的生物标志物检测阿尔茨海默病和非阿尔茨海默病临床综合征的阿尔茨海默病神经病理学

阿尔茨海默病（AD）的血液生物标志物临床可用，但其在与额颞叶变性综合征（FTLD）典型相关的综合征中的价值尚不清楚。目的利用磷酸化tau217 （p-tau217）、神经丝轻链（NfL）和胶质纤维酸性蛋白（GFAP） 3种血浆生物标志物，探讨AD在ftld相关神经退行性综合征中的临床意义和可检出性。设计、环境和参与者本临床病理研究于2008年8月至2022年7月在加州大学旧金山分校阿尔茨海默病研究中心进行。经临床评估和神经病理学检查的尸检个体，诊断为AD相关临床综合征（n = 125），额颞叶变性（FTLD）；n = 198)，或评估时认知未受损（CU）（n = 16）。暴露于ad相关或ftld相关的临床综合征或CU。采用单分子阵列（SIMOA）检测r -tau217、NfL和GFAP。尸检时将AD定义为中度或高度AD神经病理改变（ADNC）。使用线性回归评估临床生物标志物的相关性。成像分析采用贝叶斯线性混合效应建模。结果共349只，其中雄性191只（55%）；平均[SD]死亡年龄，72岁)。AD在AD相关综合征（110/125[88%]）和ftld相关综合征（45/198[23%]）中都很常见。尸检时AD相关综合征的神经病理分期较高（高ADNC: AD: 82/88 [93%] vs FTLD: 13/23 [56%]）， AD常被认为是FTLD相关综合征的一种病理（30/198[15%]）。ad相关综合征血浆P -tau217浓度（平均[SD]， 0.28 [0.16] pg/mL）高于ftld相关综合征（平均[SD]， 0.10 [0.09] pg/mL） (P &lt；. 05)。血浆p-tau217浓度在非典型ad相关综合征中最高（平均[SD]， 0.33 [0.02] pg/mL），其次是典型迟发性遗忘综合征（平均[SD]， 0.27 [0.03] pg/mL）。伴有AD的ftld相关综合征（平均[SD]， 0.19 [0.02] pg/mL）高于无AD的ftld相关综合征（平均[SD]， 0.07 [0.00] pg/mL）。血浆p-tau217检测AD各综合征的神经病理(受试者工作特征曲线下面积[AUC]， 0.95；95% CI, 0.93-0.97)，在ad相关综合征中表现稍好(AUC, 0.98；95% CI, 0.95-1.00)与ftld相关综合征相比(AUC, 0.89；95% ci, 0.83-0.94)。NfL和GFAP对AD的检测效果较差(AUC, 0.73；95% CI, 0.68-0.78， AUC, 0.75；95% CI分别为0.67-0.80)，单独或与p-tau217联合使用几乎没有诊断价值。ftld相关综合征中AD的存在与较低的迷你精神状态检查得分相关(平均[SD]，−2.90 [1.09]；P, amp;肝移植;.05)，记忆力（平均[SD] z得分，−0.64[0.32]）、执行力（平均[SD] z得分，−0.74[0.19]）和视觉空间复合能力（平均[SD] z得分，−0.88[0.37]）的表现更差，以及后皮层萎缩率增加。结论临床相关性AD在神经退行性综合征中普遍存在，血浆p-tau217可检测到。血浆p-tau217可能是研究AD病理在非AD神经退行性综合征中的临床影响的有用工具，包括疾病改善治疗的效果。

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来源期刊

JAMA neurology CLINICAL NEUROLOGY-

CiteScore

41.90

自引率

1.70%

发文量

250

期刊介绍： JAMA Neurology is an international peer-reviewed journal for physicians caring for people with neurologic disorders and those interested in the structure and function of the normal and diseased nervous system. The Archives of Neurology & Psychiatry began publication in 1919 and, in 1959, became 2 separate journals: Archives of Neurology and Archives of General Psychiatry. In 2013, their names changed to JAMA Neurology and JAMA Psychiatry, respectively. JAMA Neurology is a member of the JAMA Network, a consortium of peer-reviewed, general medical and specialty publications.