German Center for Neurodegenerative Diseases (DZNE E.V.), Helmholtzstr. 8/1, 89081, Ulm, Germany.
Department of Neurology, Ulm University Hospital, Helmholtzstr. 8/1, 89081, Ulm, Germany.
J Neurol. 2024 Dec;271(12):7516-7524. doi: 10.1007/s00415-024-12694-6. Epub 2024 Sep 25.
The proteins contactin (CNTN) 1-6 are synaptic proteins for which there is evidence that they are dysregulated in neurodegenerative dementias. Less is known about CNTN changes and differences in cerebrospinal fluid (CSF) of dementias, which can provide important information about alterations of the CNTN network and be of value for differential diagnosis.
We developed a mass spectrometry-based multiple reaction monitoring (MRM) method to simultaneously determine all six CNTNs in CSF samples using stable isotope-labeled standard peptides. The analytical performance of the method was evaluated for peptide stability, dilution linearity and precision. CNTNs were measured in 82 CSF samples from patients with Alzheimer's disease (AD, n = 19), behavioural variant frontotemporal dementia (bvFTD, n = 18), Parkinson's disease dementia/dementia with Lewy bodies (PDD/DLB, n = 18) and non-neurodegenerative controls (n = 27) and compared with core AD biomarkers.
The MRM analysis revealed down-regulation of CNTN2 (fold change (FC) = 0.77), CNTN4 (FC = 0.75) and CNTN5 (FC = 0.67) in bvFTD and CNTN3 (FC = 0.72), CNTN4 (FC = 0.75) and CNTN5 (FC = 0.73) in PDD/DLB compared to AD. CNTN levels strongly correlated with each other in controls (r = 0.73), bvFTD (r = 0.86) and PDD/DLB (r = 0.70), but the correlation was significantly lower in AD (r = 0.41). CNTNs in AD did not show correlation even with core AD biomarkers. Combined use of CNTN1-6 levels increased diagnostic performance of AD core biomarkers.
Our data show CNTNs differentially altered in dementias and indicate CNTN homeostasis being selectively dysregulated in AD. The combined use of CNTNs with AD core biomarkers might help to improve differential diagnosis.
接触蛋白（CNTN）1-6 是突触蛋白，有证据表明它们在神经退行性痴呆中失调。关于痴呆症中 CNTN 的变化和差异知之甚少，这些变化和差异可以提供关于 CNTN 网络改变的重要信息，并有助于鉴别诊断。
我们开发了一种基于质谱的多重反应监测（MRM）方法，使用稳定同位素标记的标准肽，同时测定 CSF 样本中的所有 6 种 CNTN。评估了该方法的肽稳定性、稀释线性和精密度。在 82 例阿尔茨海默病（AD，n=19）、行为变异额颞叶痴呆（bvFTD，n=18）、帕金森病痴呆/路易体痴呆（PDD/DLB，n=18）和非神经退行性对照组（n=27）的 CSF 样本中测量了 CNTN，并与核心 AD 生物标志物进行了比较。
MRM 分析显示，在 bvFTD 中 CNTN2（折叠变化（FC）=0.77）、CNTN4（FC=0.75）和 CNTN5（FC=0.67）下调，在 PDD/DLB 中 CNTN3（FC=0.72）、CNTN4（FC=0.75）和 CNTN5（FC=0.73）下调。与 AD 相比，CNTN 水平在对照组（r=0.73）、bvFTD（r=0.86）和 PDD/DLB（r=0.70）中彼此强烈相关，但在 AD 中相关性显著降低（r=0.41）。AD 中的 CNTN 甚至与核心 AD 生物标志物也没有相关性。CNTN1-6 水平的联合使用增加了 AD 核心生物标志物的诊断性能。
我们的数据显示 CNTN 在痴呆症中发生了差异变化，并表明 CNTN 内稳态在 AD 中选择性失调。AD 核心生物标志物与 CNTN 联合使用可能有助于改善鉴别诊断。
