PDF(Pubmed)
Abstract：
BACKGROUND: 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.
CONCLUSIONS: 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.
UNASSIGNED: 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.
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.
CONCLUSIONS: 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.
UNASSIGNED: 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.
摘要：
背景：“A/T/N”（淀粉样蛋白/tau/神经变性）框架为阿尔茨海默病（AD）诊断提供了生物学基础，并且可以包括其他变化，例如炎症（“I”）。在轻度至中度AD患者中雷沙吉兰的2期临床试验中获得了T/N/I成像和血浆生物标志物的谱。我们对这些进行了评估，以了解该人群中的生物标志物分布和关系。
方法：pTau-181的血浆生物标志物，神经丝轻链（NfL），胶质纤维酸性蛋白（GFAP），其他炎症相关蛋白，成像措施包括氟脱氧葡萄糖（FDG）正电子发射断层扫描（PET），flortaucipirPET，和体积磁共振成像（MRI），和认知终点进行了分析,以评估总体人群(基线时N=47,纵向认知比较时N=21)和10岁以下亚组(57-69,70-79,80-90岁)的特征和关系.
结果：数据表明，受年龄和性别影响，该人群具有广泛的临床和生物标志物异质性。血浆pTau-181和GFAP与tauPET相关，左侧颞下皮质最强（分别为p=0.0002，p=0.0006）。在颞叶皮层以外的区域，对于相同的pTau-181或GFAP浓度，tauPET摄取随年龄的增加而降低。FDGPET和脑体积与许多区域的tauPET相关（例如颞下：分别为p=0.0007，p=0.00001）。NFL,GFAP,所有成像方式与基线MMSE相关;随后的MMSE下降是通过基线海马旁和颞侧tauPET(p=0.0007)和体积(p=0.0006)预测的。颞侧FDGPET（p=0.006）和体积（p=0.0001）与随后的ADAS-cog下降密切相关。NfL与FDGPET和基线MMSE相关，但与tauPET无关。炎症生物标志物是相互关联的,但仅在最年轻的组中与其他生物标志物相关。
结论：血浆生物标志物之间的关联，成像生物标志物，在这项研究中观察到的认知状态可以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，关于可能的tau病理，有可能表征AD患者，神经变性,前瞻性临床下降，以及年龄等协变量的重要性。
■轻度至中度AD患者血浆pTau-181和GFAP与区域和全球tauPET相关。NfL与FDGPET和认知终点相关，但与血浆pTau-181或tauPET无关。体积和FDGPET与tauPET有很强的关系，彼此,和认知状态。时间量最强烈地预测了MMSE和ADAS-cog的下降。体积和血浆生物标志物可以随着年龄的增加而丰富tauPET的显着协变量。
方法：pTau-181的血浆生物标志物，神经丝轻链（NfL），胶质纤维酸性蛋白（GFAP），其他炎症相关蛋白，成像措施包括氟脱氧葡萄糖（FDG）正电子发射断层扫描（PET），flortaucipirPET，和体积磁共振成像（MRI），和认知终点进行了分析,以评估总体人群(基线时N=47,纵向认知比较时N=21)和10岁以下亚组(57-69,70-79,80-90岁)的特征和关系.
结果：数据表明，受年龄和性别影响，该人群具有广泛的临床和生物标志物异质性。血浆pTau-181和GFAP与tauPET相关，左侧颞下皮质最强（分别为p=0.0002，p=0.0006）。在颞叶皮层以外的区域，对于相同的pTau-181或GFAP浓度，tauPET摄取随年龄的增加而降低。FDGPET和脑体积与许多区域的tauPET相关（例如颞下：分别为p=0.0007，p=0.00001）。NFL,GFAP,所有成像方式与基线MMSE相关;随后的MMSE下降是通过基线海马旁和颞侧tauPET(p=0.0007)和体积(p=0.0006)预测的。颞侧FDGPET（p=0.006）和体积（p=0.0001）与随后的ADAS-cog下降密切相关。NfL与FDGPET和基线MMSE相关，但与tauPET无关。炎症生物标志物是相互关联的,但仅在最年轻的组中与其他生物标志物相关。
结论：血浆生物标志物之间的关联，成像生物标志物，在这项研究中观察到的认知状态可以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，关于可能的tau病理，有可能表征AD患者，神经变性,前瞻性临床下降，以及年龄等协变量的重要性。
■轻度至中度AD患者血浆pTau-181和GFAP与区域和全球tauPET相关。NfL与FDGPET和认知终点相关，但与血浆pTau-181或tauPET无关。体积和FDGPET与tauPET有很强的关系，彼此,和认知状态。时间量最强烈地预测了MMSE和ADAS-cog的下降。体积和血浆生物标志物可以随着年龄的增加而丰富tauPET的显着协变量。
