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Abstract：
OBJECTIVE: Plasma β-amyloid-1-42/1-40 (Aβ42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB.
METHODS: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aβ42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models.
RESULTS: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aβ42/40 ratio (decreased in amyloid abnormal: β = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: β = 0.246, 95% CI 0.011-0.481; P-tau231: β = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (β = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (β = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (β = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without.
CONCLUSIONS: Our study suggests a possible utility of plasma Aβ42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.
METHODS: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aβ42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models.
RESULTS: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aβ42/40 ratio (decreased in amyloid abnormal: β = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: β = 0.246, 95% CI 0.011-0.481; P-tau231: β = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (β = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (β = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (β = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without.
CONCLUSIONS: Our study suggests a possible utility of plasma Aβ42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.
摘要：
目的:血浆β-淀粉样蛋白-1-42/1-40(Aβ42/40),磷酸化-tau（P-tau），胶质纤维酸性蛋白（GFAP），和神经丝光(NfL)已经在阿尔茨海默病(AD)中被广泛检查，但是对它们对共形病理学的反映知之甚少，临床重要性，和路易体痴呆（DLB）的预测价值。我们旨在评估这些生物标志物与CSF淀粉样蛋白的关联，认知，和DLB中的核心功能。
方法：这项具有前瞻性成分的横断面多中心队列研究包括患有DLB的个体，AD,和健康对照（HCs），从2002年到2020年招募，每年随访5年，来自欧洲-路易体痴呆症联盟。通过单分子阵列(Neurology4-PlexE试剂盒)测量血浆生物标志物。淀粉样蛋白状态由CSFAβ42浓度确定，认知通过简易精神状态检查(MMSE)进行评估。各组间的生物标志物差异，与淀粉样蛋白状态有关，和临床核心特征通过协方差分析进行评估。通过线性回归和线性混合效应模型评估与认知障碍和下降的关联。
结果：在我们由562名个体组成的队列中（HCn=89，DLBn=342，ADn=131；250名女性[44.5%]，平均[SD]年龄71[8]岁)，组间性别分布无差异.DLB患者明显年龄较大，与HC相比，受教育年限较少，基线认知较差，但不是AD。按淀粉样蛋白状态分层的DLB参与者血浆Aβ42/40比率显着不同（淀粉样蛋白异常中降低：β=-0.008，95％CI-0.016至-0.0003，p=0.01）和P-tau（淀粉样蛋白异常中升高，P-tau181：β=0.246，95％CI0.011-0.481；P-tau231：β=0.227，95％CI0.035-0.419，均p<0.05），但不在GFAP中(β=0.068，95%CI-0.018至0.153，p=0.119)，和NfL(β=0.004，95%CI-0.087至0.096，p=0.923)浓度。较高的基线GFAP，NFL,和P-tau浓度与DLB中较低的MMSE评分相关，GFAP和NfL与更快的认知能力下降相关(GFAP：-2.11MMSE点的年度变化，95%CI-2.88至-1.35MMSE点，p<0.001；NFL：-2.13MMSE点的年度变化，95%CI-2.97至-1.29MMSE点，p<0.001)。患有帕金森病的DLB参与者的NfL浓度较高（β=0.08，95％CI0.02-0.14，p=0.006）。
结论：我们的研究表明，血浆Aβ42/40，P-tau181和P-tau231可能作为非侵入性生物标志物用于评估DLB中的淀粉样蛋白共病理学，血浆GFAP和NfL作为DLB认知症状的监测生物标志物。
方法：这项具有前瞻性成分的横断面多中心队列研究包括患有DLB的个体，AD,和健康对照（HCs），从2002年到2020年招募，每年随访5年，来自欧洲-路易体痴呆症联盟。通过单分子阵列(Neurology4-PlexE试剂盒)测量血浆生物标志物。淀粉样蛋白状态由CSFAβ42浓度确定，认知通过简易精神状态检查(MMSE)进行评估。各组间的生物标志物差异，与淀粉样蛋白状态有关，和临床核心特征通过协方差分析进行评估。通过线性回归和线性混合效应模型评估与认知障碍和下降的关联。
结果：在我们由562名个体组成的队列中（HCn=89，DLBn=342，ADn=131；250名女性[44.5%]，平均[SD]年龄71[8]岁)，组间性别分布无差异.DLB患者明显年龄较大，与HC相比，受教育年限较少，基线认知较差，但不是AD。按淀粉样蛋白状态分层的DLB参与者血浆Aβ42/40比率显着不同（淀粉样蛋白异常中降低：β=-0.008，95％CI-0.016至-0.0003，p=0.01）和P-tau（淀粉样蛋白异常中升高，P-tau181：β=0.246，95％CI0.011-0.481；P-tau231：β=0.227，95％CI0.035-0.419，均p<0.05），但不在GFAP中(β=0.068，95%CI-0.018至0.153，p=0.119)，和NfL(β=0.004，95%CI-0.087至0.096，p=0.923)浓度。较高的基线GFAP，NFL,和P-tau浓度与DLB中较低的MMSE评分相关，GFAP和NfL与更快的认知能力下降相关(GFAP：-2.11MMSE点的年度变化，95%CI-2.88至-1.35MMSE点，p<0.001；NFL：-2.13MMSE点的年度变化，95%CI-2.97至-1.29MMSE点，p<0.001)。患有帕金森病的DLB参与者的NfL浓度较高（β=0.08，95％CI0.02-0.14，p=0.006）。
结论：我们的研究表明，血浆Aβ42/40，P-tau181和P-tau231可能作为非侵入性生物标志物用于评估DLB中的淀粉样蛋白共病理学，血浆GFAP和NfL作为DLB认知症状的监测生物标志物。
