Johansen Michelle C, Chen Jinyu, Walker Keenan A, Wang Ziqiao, Wang Wendy, Chen Lin Yee, Kalani Rizwan, Floyd James, Fornage Myriam, Pike James Russell, Gottesman Rebecca F, Coresh Josef
The Johns Hopkins University School of Medicine, Baltimore, MD.
University of North Carolina School of Medicine, Chapel Hill, NC.
Ann Neurol. 2025 Aug 4. doi: 10.1002/ana.70011.
Personalized approaches to ischemic stroke diagnosis are needed. We determine differences in proteomic signatures of incident embolic (EIS) and thrombotic stroke (TIS) by age and resultant pathways using large-scale proteomics.
Participants in the Atherosclerosis Risk in Communities Study (ARIC) from visit 2 (V2, 1990-1992) until 2020 without prevalent stroke with available SomaScan data (4,955 protein targets) at V2 (mid-life, n = 10,929), and then again at visit 5 (V5, 2011-2013, n = 4,463) were included. Covariate adjusted Cox hazard models determined the association between proteins, and adjudicated incident EIS or TIS from V2 to V5 and from V5 to 2020.
Among 10,929 participants (56% female, 23% Black, follow-up ~20 years), 20 proteins measured in mid-life were associated with either EIS (n = 168) or TIS (n = 459) in mid-life, and 4 measured in late-life were associated with late-life stroke (73 EIS and 124 TIS events) at the Bonferroni threshold p < 1E-5. In mid-life, N-terminal pro-B-type natriuretic peptide (NPPB) was significantly associated with EIS, but not TIS (p-difference = 9.14E-7). Nineteen mid-life proteins were strongly associated with TIS; 7 strongly associated with TIS and only nominally (p < 0.05) with EIS and the remaining 12 with TIS only. In late-life, NPPB, serine protease inhibitor Kazal-type 4, oligodendrocyte-myelin-glycoprotein, and neurocan-core protein were significantly associated with EIS, but not TIS. Ingenuity Pathway Analysis tools implicated cancer for EIS-associated proteins, whereas TIS pathways reflected cell-structure and atherogenesis.
We identified plasma proteins associated with risk of EIS versus TIS reflecting distinct stroke mechanisms: cardiac dysfunction protein in EIS (eg, NPPB) and inflammation dysregulation in TIS (eg, interleukins). ANN NEUROL 2025.
缺血性中风的诊断需要个性化方法。我们使用大规模蛋白质组学，按年龄和相关途径确定新发栓塞性缺血性中风（EIS）和血栓性中风（TIS）的蛋白质组学特征差异。
社区动脉粥样硬化风险研究（ARIC）中，从第2次访视（V2，1990 - 1992年）至2020年，在V2（中年，n = 10929）时无中风病史且有可用SomaScan数据（4955个蛋白质靶点）、之后在第5次访视（V5，2011 - 2013年，n = 4463）时也符合条件的参与者被纳入研究。协变量调整后的Cox风险模型确定蛋白质之间的关联，并判定从V2到V5以及从V5到2020年的新发EIS或TIS。
在10929名参与者中（56%为女性，23%为黑人，随访约20年），中年时检测的20种蛋白质与中年时的EIS（n = 168）或TIS（n = 459）相关，老年时检测的4种蛋白质在Bonferroni阈值p < 1E - 5时与老年中风（73例EIS和124例TIS事件）相关。中年时，N末端前B型利钠肽（NPPB）与EIS显著相关，但与TIS无关（p差异 = 9.14E - 7）。19种中年蛋白质与TIS密切相关；7种与TIS密切相关且仅与EIS有名义上的关联（p < 0.05），其余12种仅与TIS相关。老年时，NPPB、丝氨酸蛋白酶抑制剂Kazal型4、少突胶质细胞髓磷脂糖蛋白和神经黏蛋白核心蛋白与EIS显著相关，但与TIS无关。通路分析工具显示，与EIS相关的蛋白质涉及癌症，而TIS通路反映细胞结构和动脉粥样硬化形成。
我们确定了与EIS和TIS风险相关的血浆蛋白质，反映了不同的中风机制：EIS中的心脏功能障碍蛋白（如NPPB）和TIS中的炎症失调（如白细胞介素）。《神经病学》2025年。
