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关键作用。先前的报道表明,脑脊液(CSF)NRG1浓度的变化与AD病理的认知状态和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极大的临床兴趣。
与其他神经退行性疾病和神经对照(NC)相比,测量AD患者的血浆NRG1浓度,并研究其与脑脊液(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,包括轻度认知障碍阶段(AD-MCI,n=27)和痴呆阶段(n=35)的AD患者。非AD痴呆(n=26,Aβ阴性),非ADMCI(n=19),和神经对照(n=20)。血浆和CSFNRG1,以及CSF核心AD生物标志物(Aβ42/Aβ40比率,磷酸-tau,和总tau),使用ELISA测量。使用GAP-43和神经颗粒蛋白的ELISA并通过SNAP-25的免疫沉淀质谱法测量CSF突触标志物。
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)。神经对照组血浆NRG1分化型ADMCI患者的曲线下面积为88.3%,和AD痴呆患者来自NC,曲线下面积为87.3%。血浆NRG1与CSFNRG1相关(β=0.372,P=0.0056,根据年龄和性别进行调整)。在整个队列和Aβ阳性患者中,血浆NRG1与ADCSF核心生物标志物相关(β=-0.197-0.423)。血浆NRG1与CSFGAP-43、神经颗粒素、和SNAP-25(β=0.278-0.355)。在整个队列和Aβ阳性患者中,血浆NRG1浓度与MMSE呈负相关(所有,β=-0.188,P=0.038;Aβ+:β=-0.255,P=0.038)。
AD患者的血浆NRG1浓度增加,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是一种有前途的非侵入性生物标志物,用于监测AD的突触损伤。
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.