一种糖类生物标志物可预测淀粉样蛋白和 tau 阴性患者的认知能力下降。

IF 4.1 Q1 CLINICAL NEUROLOGY
Brain communications Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI:10.1093/braincomms/fcae371
Robin Ziyue Zhou, Frida Duell, Michael Axenhus, Linus Jönsson, Bengt Winblad, Lars O Tjernberg, Sophia Schedin-Weiss
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引用次数: 0

摘要

早期发现阿尔茨海默病对于及时治疗至关重要。现有的阿尔茨海默病生物标志物反映了淀粉样蛋白和 tau 相关的病理变化,但是否能在观察到脑淀粉样蛋白沉积之前就检测到这种疾病还不得而知。N-糖基化被认为是淀粉样蛋白和 tau 病理学的上游调节因子,而在疾病的临床前期阶段,N-糖基结构双截 N-乙酰葡糖胺(GlcNAc)的水平就已经与血液和脑脊液中的 tau 相关。因此,我们旨在评估根据淀粉样蛋白/tau 状态分层的记忆门诊队列中的患者,其 GlcNAc 双截面是否能预测其未来的认知能力下降。我们纳入了瑞典斯德哥尔摩卡罗林斯卡大学医院记忆诊所 GEDOC 队列中的 251 名患者(平均年龄:65.6 ± 10.6 岁,60.6% 为女性)。根据脑脊液生物标志物将患者分为淀粉样蛋白/tau阳性和阴性。认知能力的下降以纵向小型精神状态检查评分来衡量,平均跟踪10.7 ± 4.1年,并采用非线性混合效应模型进行建模。此外,我们还利用凝集素免疫组化技术测量了 10 例阿尔茨海默氏症患者和对照组大脑海马和皮层中的双链GlcNAc水平。我们发现,与 tau 阴性个体相比,tau 阳性个体的 CSF 双链 GlcNAc 水平升高,但与淀粉样蛋白阳性个体相比,淀粉样蛋白阴性个体的 CSF 双链 GlcNAc 水平并不升高。在整个样本中,高水平的脑脊液双链GlcNAc预示着认知能力的提前衰退。令人震惊的是,淀粉样蛋白/tau分层显示,高水平的CSF双链GlcNAc可预测淀粉样蛋白阴性患者(β = 2.53 ± 0.85岁,P = 0.003)和tau阴性患者(β = 2.43 ± 1.01岁,P = 0.017)的认知能力提前衰退,而淀粉样蛋白或tau阳性患者则不能预测。最后,组织化学分析显示,与对照组相比,阿尔茨海默氏症患者海马和皮层神经元中的双叉GlcNAc水平升高(折叠变化=1.44-1.49,P < 0.001)。总之,高水平的CSF双截GlcNAc反映了神经元的病理变化,并预示着淀粉样蛋白和tau阴性个体的认知能力下降,这表明糖基化异常先于阿尔茨海默病的脑淀粉样变和tau过度磷酸化。双截GlcNAc是一种很有希望的新型阿尔茨海默病早期生物标记物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A glycan biomarker predicts cognitive decline in amyloid- and tau-negative patients.

Early detection of Alzheimer's disease is vital for timely treatment. Existing biomarkers for Alzheimer's disease reflect amyloid- and tau-related pathology, but it is unknown whether the disease can be detected before cerebral amyloidosis is observed. N-glycosylation has been suggested as an upstream regulator of both amyloid and tau pathology, and levels of the N-glycan structure bisecting N-acetylglucosamine (GlcNAc) correlate with tau in blood and CSF already at pre-clinical stages of the disease. Therefore, we aimed to evaluate whether bisecting GlcNAc could predict future cognitive decline in patients from a memory clinic cohort, stratified by amyloid/tau status. We included 251 patients (mean age: 65.6 ± 10.6 years, 60.6% female) in the GEDOC cohort, from the Memory Clinic at Karolinska University Hospital, Stockholm, Sweden. Patients were classified as amyloid/tau positive or negative based on CSF biomarkers. Cognitive decline, measured by longitudinal Mini-Mental State Examination scores, was followed for an average of 10.7 ± 4.1 years and modelled using non-linear mixed effects models. Additionally, bisecting GlcNAc levels were measured in hippocampus and cortex with lectin-based immunohistochemistry in 10 Alzheimer's disease and control brains. We found that CSF bisecting GlcNAc levels were elevated in tau-positive individuals compared with tau-negative individuals, but not in amyloid-positive individuals compared with amyloid-negative individuals. In the whole sample, high levels of CSF bisecting GlcNAc predicted earlier cognitive decline. Strikingly, amyloid/tau stratification showed that high CSF bisecting GlcNAc levels predicted earlier cognitive decline in amyloid-negative patients (β = 2.53 ± 0.85 years, P = 0.003) and tau-negative patients (β = 2.43 ± 1.01 years, P = 0.017), but not in amyloid- or tau-positive patients. Finally, histochemical analysis of bisecting GlcNAc showed increased levels in neurons in hippocampus and cortex of Alzheimer's disease compared with control brain (fold change = 1.44-1.49, P < 0.001). In conclusion, high CSF levels of bisecting GlcNAc reflected neuronal pathology and predicted cognitive decline in amyloid- and tau-negative individuals, suggesting that abnormal glycosylation precedes cerebral amyloidosis and tau hyper-phosphorylation in Alzheimer's disease. Bisecting GlcNAc is a promising novel early biomarker for Alzheimer's disease.

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