Dawn C. Matthews, Jefferson W. Kinney, Aaron Ritter, Randolph D. Andrews, Erin N. Toledano Strom, Ana S. Lukic, Lauren N. Koenig, Carolyn Revta, Howard M. Fillit, Kate Zhong, Babak Tousi, James B. Leverenz, Howard H. Feldman, Jeffrey Cummings
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We evaluated these to understand biomarker distributions and relationships within this population.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (<i>N</i> = 47 at baseline and <i>N</i> = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years).</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (<i>p</i> = 0.0002, <i>p</i> = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: <i>p</i> = 0.0007, <i>p</i> = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (<i>p</i> = 0.0007) and volume (<i>p</i> = 0.0006). Lateral temporal FDG PET (<i>p</i> = 0.006) and volume (<i>p</i> = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>\n <p>Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.</p>\n </li>\n \n <li>\n <p>NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.</p>\n </li>\n \n <li>\n <p>Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.</p>\n </li>\n \n <li>\n <p>Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.</p>\n </li>\n \n <li>\n <p>Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.</p>\n </li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 3","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233274/pdf/","citationCount":"0","resultStr":"{\"title\":\"Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients\",\"authors\":\"Dawn C. 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引用次数: 0
摘要
导言：A/T/N"（淀粉样蛋白/tau/神经变性）框架为阿尔茨海默病（AD）的诊断提供了生物学基础，并可包括炎症（"I"）等其他变化。在一项针对轻度至中度阿尔茨海默病患者的拉沙吉林 2 期临床试验中，我们获得了一系列 T/N/I 成像和血浆生物标记物。我们对这些指标进行了评估，以了解这一人群中生物标志物的分布和关系：血浆中的 pTau-181、神经丝蛋白轻链（NfL）、神经胶质纤维酸性蛋白（GFAP）、其他炎症相关蛋白等生物标记物，以及包括氟脱氧葡萄糖（FDG）正电子发射断层扫描（PET）、氟噻嘧啶正电子发射断层扫描（PET）和容积磁共振在内的成像测量、和容积磁共振成像（MRI）以及认知终点进行了分析，以评估总体人群（基线时为 47 人，纵向认知比较时为 21 人）和年龄十年亚组（57-69 岁、70-79 岁、80-90 岁）的特征和关系。结果数据显示，受年龄和性别影响，该人群的临床和生物标志物具有广泛的异质性。血浆 pTau-181 和 GFAP 与 tau PET 相关性最强的是左下颞皮质（分别为 p = 0.0002 和 p = 0.0006）。在颞皮层以外的区域，pTau-181或GFAP浓度相同时，tau PET摄取量随年龄增长而降低。在许多区域，FDG PET 和脑容量与 tau PET 相关（如颞下部：分别为 p = 0.0007 和 p = 0.00001）。NfL、GFAP和所有成像模式都与基线MMSE相关；基线海马旁和颞外侧tau PET（p = 0.0007）和体积（p = 0.0006）可预测随后的MMSE下降。外侧颞叶 FDG PET（p = 0.006）和体积（p = 0.0001）与随后的 ADAS-cog 下降关系最为密切。NfL与FDG PET和基线MMSE相关，但与tau PET无关。炎症生物标志物相互关联，但只有最年轻的一组与其他生物标志物相关：讨论：本研究中观察到的血浆生物标志物、成像生物标志物和认知状态之间的关联，有助于深入了解轻度至中度AD的生物过程之间的关系。研究结果表明，在可能的tau病理学、神经退行性变、前瞻性临床衰退以及年龄等协变因素的重要性方面，有可能对AD患者进行特征描述：NfL与FDG PET和认知终点相关，但与血浆pTau-181或tau PET无关.体积和FDG PET与tau PET、相互之间以及认知状态都有密切关系.颞叶体积对MMSE和ADAS-cog的衰退有最强烈的预测作用.体积和血浆生物标志物可以丰富tau PET的升高，而年龄则是一个重要的协变量.
Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients
INTRODUCTION
The “A/T/N” (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation (“I”). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population.
METHODS
Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years).
RESULTS
Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group.
DISCUSSION
Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age.
Highlights
Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.
NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.
Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.
Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.
Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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