Multimodal Imaging of Neurodegenerative Disease (MIND) Unit (J.C., M.R.D., Z.P., H.E.D., K.A.W.), National Institute on Aging, Baltimore, MD.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD (G.T.G., A.L., A.M.).
Stroke. 2023 Nov;54(11):2853-2863. doi: 10.1161/STROKEAHA.123.043908. Epub 2023 Oct 10.
Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease.
Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009-2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging-defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990-2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period.
Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk.
In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.
脑内皮细胞（BEC）表达的蛋白质可能作为神经和神经血管状况（包括脑小血管疾病）的敏感血浆生物标志物，BEC 是血脑屏障的主要细胞类型。
利用 BLSA（巴尔的摩纵向老龄化研究；n=886；2009-2020 年）的数据，使用一种自动注释算法，在经过内皮细胞转录物过滤后，通过与单细胞 RNA 测序研究中报告的 BEC 特异性转录物交叉引用，从 7268 种血浆蛋白（用 SomaScanv4.1 测量）中鉴定出 BEC 丰富的蛋白质。为了确定与神经和神经血管健康维持最相关的血浆中富含 BEC 的蛋白质，我们选择了与 3T 磁共振成像定义的白质病变体积显著相关的蛋白质。然后，我们研究了这些候选 BEC 生物标志物与 ARIC 研究（社区动脉粥样硬化风险；美国多地点；1990-2017 年）中的白质病变体积、脑微出血和腔隙性梗死的关系。最后，我们确定了这些候选 BEC 生物标志物在中年测量时是否与 25 年随访期间的痴呆风险相关。
在鉴定为 BEC 丰富的 28 种蛋白质中，有 4 种与白质病变体积显著相关（CDH5[钙黏蛋白 5]、CD93[分化群 93]、ICAM2[细胞间黏附分子 2]、GP1BB[糖蛋白 1b 血小板亚单位β]），而另一种则接近显著（RSPO3[R-Spondin 3]）。基于这 3 种 BEC 蛋白的综合评分，可解释 BLSA 参与者白质病变体积的 11%。我们在 ARIC 中复制了 BEC 复合评分、CDH5 和 RSPO3 与白质病变体积之间的关联，并进一步表明 BEC 复合评分和 RSPO3 与存在≥1 个脑微出血有关。我们还表明，BEC 复合评分、CDH5 和 RSPO3 与 25 年痴呆风险相关。
除了鉴定与脑小血管疾病和痴呆风险相关的血浆 BEC 蛋白外，我们还开发了一种血浆 BEC 蛋白的综合评分，可用于估计血脑屏障的完整性和不良神经血管结局的风险。
