Université Paris Cité, Inserm U1144, Paris, France.
Université Paris Cité, Center of Cognitive Neurology, Lariboisière Fernand-Widal Hospital, APHP, 200 rue du Faubourg Saint-Denis, 75010, Paris, France.
Alzheimers Res Ther. 2022 May 23;14(1):71. doi: 10.1186/s13195-022-01014-7.
Synaptic dysfunction is an early core feature of Alzheimer's disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest.
To measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers.
This retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD-MCI, n = 27) and at dementia stage (n = 35), non-AD dementia (n = 26, Aβ-negative), non-AD MCI (n = 19), and neurological controls (n=20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho-tau, and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP-43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP-25.
Plasma NRG1 concentration was higher in AD-MCI and AD dementia patients compared with neurological controls (respectively P = 0.005 and P < 0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (β = 0.372, P = 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ-positive patients (β = -0.197-0.423). Plasma NRG1 correlated with CSF GAP-43, neurogranin, and SNAP-25 (β = 0.278-0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ-positive patients (all, β = -0.188, P = 0.038; Aβ+: β = -0.255, P = 0.038).
Plasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers and cognitive status. Thus, plasma NRG1 is a promising non-invasive biomarker to monitor synaptic impairment in AD.
突触功能障碍是阿尔茨海默病（AD）的早期核心特征，与认知症状密切相关。神经调节蛋白 1（NRG1）是一种生长和分化因子，在突触传递的发育和维持中起着关键作用。先前的报告表明，脑脊液（CSF）NRG1 浓度的变化与认知状态和 AD 病理的生物标志物证据有关。反映突触损伤的血浆生物标志物将具有重要的临床意义。
比较 AD 患者与其他神经退行性疾病和神经对照组（NC）的血浆 NRG1 浓度，并研究其与 CSF 核心 AD 和突触生物标志物的关系。
这项回顾性研究纳入了 127 名参与者，包括轻度认知障碍（AD-MCI，n=27）和痴呆（n=35）阶段的 AD 患者、非 AD 痴呆（n=26，Aβ 阴性）、非 AD MCI（n=19）和神经对照组（n=20）。使用 ELISA 测量血浆和 CSF NRG1 以及 CSF 核心 AD 生物标志物（Aβ42/Aβ40 比值、磷酸化 tau 和总 tau）。使用 ELISA 测量 CSF 突触标志物 GAP-43 和神经颗粒蛋白，并通过免疫沉淀质谱法测量 SNAP-25。
与神经对照组相比，AD-MCI 和 AD 痴呆患者的血浆 NRG1 浓度更高（分别为 P=0.005 和 P<0.001）。血浆 NRG1 区分 AD MCI 患者和神经对照组的曲线下面积为 88.3%，区分 AD 痴呆患者和 NC 的曲线下面积为 87.3%。血浆 NRG1 与 CSF NRG1 相关（β=0.372，P=0.0056，调整年龄和性别）。在整个队列和 Aβ 阳性患者中，血浆 NRG1 与 CSF 核心 AD 生物标志物相关（β=-0.197-0.423）。血浆 NRG1 与 CSF GAP-43、神经颗粒蛋白和 SNAP-25 相关（β=0.278-0.355）。血浆 NRG1 浓度与整个队列和 Aβ 阳性患者的 MMSE 呈负相关（均为β=-0.188，P=0.038；Aβ+：β=-0.255，P=0.038）。
AD 患者的血浆 NRG1 浓度升高，并与 CSF 核心 AD 和突触生物标志物以及认知状态相关。因此，血浆 NRG1 是一种很有前途的非侵入性生物标志物，可用于监测 AD 中的突触损伤。
