Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
MOE Frontier Science Center for Brain Science and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China.
Acta Neuropathol Commun. 2024 Mar 5;12(1):38. doi: 10.1186/s40478-024-01727-w.
Accurate differential diagnosis among various dementias is crucial for effective treatment of Alzheimer's disease (AD). The study began with searching for novel blood-based neuronal extracellular vesicles (EVs) that are more enriched in the brain regions vulnerable to AD development and progression. With extensive proteomic profiling, GABRD and GPR162 were identified as novel brain regionally enriched plasma EVs markers. The performance of GABRD and GPR162, along with the AD molecule pTau217, was tested using the self-developed and optimized nanoflow cytometry-based technology, which not only detected the positive ratio of EVs but also concurrently presented the corresponding particle size of the EVs, in discovery (n = 310) and validation (n = 213) cohorts. Plasma GABRD- or GPR162-carrying pTau217-EVs were significantly reduced in AD compared with healthy control (HC). Additionally, the size distribution of GABRD- and GPR162-carrying pTau217-EVs were significantly different between AD and non-AD dementia (NAD). An integrative model, combining age, the number and corresponding size of the distribution of GABRD- or GPR162-carrying pTau217-EVs, accurately and sensitively discriminated AD from HC [discovery cohort, area under the curve (AUC) = 0.96; validation cohort, AUC = 0.93] and effectively differentiated AD from NAD (discovery cohort, AUC = 0.91; validation cohort, AUC = 0.90). This study showed that brain regionally enriched neuronal EVs carrying pTau217 in plasma may serve as a robust diagnostic and differential diagnostic tool in both clinical practice and trials for AD.
在各种痴呆症中进行准确的鉴别诊断对于阿尔茨海默病（AD）的有效治疗至关重要。本研究首先寻找新型血源性神经元细胞外囊泡（EVs），这些 EVs 在易受 AD 发展和进展影响的脑区中更为丰富。通过广泛的蛋白质组学分析，鉴定出 GABRD 和 GPR162 是新型脑区丰富的血浆 EVs 标志物。使用自行开发和优化的纳流细胞术技术测试了 GABRD 和 GPR162 以及 AD 分子 pTau217 的性能，该技术不仅检测了 EVs 的阳性率，还同时呈现了 EVs 的相应粒径，在发现（n=310）和验证（n=213）队列中均如此。与健康对照（HC）相比，AD 患者血浆中的 GABRD 或 GPR162 携带 pTau217-EVs 明显减少。此外，AD 与非 AD 痴呆（NAD）之间 GABRD 和 GPR162 携带 pTau217-EVs 的粒径分布也存在显著差异。一个整合模型，结合年龄、GABRD 或 GPR162 携带 pTau217-EVs 的数量及其相应粒径分布，能够准确、敏感地区分 AD 与 HC（发现队列，曲线下面积（AUC）=0.96；验证队列，AUC=0.93），并有效地将 AD 与 NAD 区分开（发现队列，AUC=0.91；验证队列，AUC=0.90）。本研究表明，血浆中携带 pTau217 的富含脑区的神经元 EVs 可能成为 AD 临床实践和临床试验中强有力的诊断和鉴别诊断工具。
