Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
Octave Bioscience, Menlo Park, CA, USA.
Mult Scler Relat Disord. 2024 Jul;87:105687. doi: 10.1016/j.msard.2024.105687. Epub 2024 May 15.
Brain hypoperfusion is linked with worse physical, cognitive and MRI outcomes in multiple sclerosis (MS). Understanding the proteomic signatures related to hypoperfusion could provide insights into the pathophysiological mechanism.
140 people with MS (pwMS; 86 clinically isolated syndrome (CIS)/relapsing-remitting (RRMS) and 54 progressive (PMS)) were included. Cerebral arterial blood flow (CABF) was determined using ultrasound Doppler measurement as the sum of blood flow in the bilateral common carotid arteries and vertebral arteries. Proteomic analysis was performed using the Multiple Sclerosis Disease Activity (MSDA) test assay panel performed on the Olink™ platform. The MSDA test measures the concentrations of 18 proteins that are age and sex-adjusted. It utilizes a stacked classifier logistic regression model to determine 4 disease pathway scores (immunomodulation, neuroinflammation, myelin biology, and neuroaxonal integrity) as well as an overall disease activity score (1 to 10). MRI measures of T2 lesion volume (LV) and whole brain volume (WBV) were derived.
The pwMS were on average 54 years old and had an average CABF of 951 mL/min. There were no differences in CABF between CIS/RRMS vs. PMS groups. Lower CABF levels were correlated with the overall disease activity score (r = -0.26, p = 0.003) and with the neuroinflammation (r = -0.29, p = 0.001), immunomodulation (r = -0.26, p = 0.003) and neuroaxonal integrity (r = -0.23, p = 0.007) pathway scores. After age and body mass index (BMI)-adjustment, lower CABF remained associated with the neuroinflammatory (r = -0.23, p = 0.011) and immunomodulation (r = -0.20, p = 0.024) pathway scores. The relationship between CABF and the neuroinflammation pathway score remained significant after adjusting for T2-LV and WBV (p = 0.038). Individual analyses identified neurofilament light chain, CCL-20 and TNFSF13B as contributors. When compared to the highest quartile (>1133.5 mL/min), the pwMS in the lowest CABF quartile (<764 mL/min) had greater overall disease activity score (p = 0.003), neuroinflammation (p = 0.001), immunomodulation (p = 0.004) and neuroaxonal integrity pathway scores (p = 0.007).
Lower cerebral arterial perfusion in MS is associated with changes in neuroinflammatory/immunomodulation pathways and their respective proteomic biomarkers. These findings may suggest a relationship between the hypoperfusion and pro-inflammatory MS changes rather than being merely an epiphenomenon subsequent to lower energy demands.
脑灌注不足与多发性硬化症（MS）患者的身体、认知和 MRI 结果较差有关。了解与灌注不足相关的蛋白质组学特征可以深入了解病理生理机制。
纳入 140 名 MS 患者（pwMS；86 例临床孤立综合征（CIS）/复发缓解型（RRMS）和 54 例进展型（PMS））。使用超声多普勒测量确定脑动脉血流（CABF），即双侧颈总动脉和椎动脉血流的总和。使用 OlinkTM 平台上的多发性硬化症疾病活动（MSDA）测试分析面板进行蛋白质组学分析。MSDA 测试测量了经过年龄和性别调整的 18 种蛋白质的浓度。它利用堆叠分类器逻辑回归模型来确定 4 种疾病途径评分（免疫调节、神经炎症、髓鞘生物学和神经轴突完整性）以及整体疾病活动评分（1 到 10）。衍生出 T2 病变体积（LV）和全脑体积（WBV）的 MRI 测量值。
pwMS 的平均年龄为 54 岁，平均 CABF 为 951mL/min。CIS/RRMS 组与 PMS 组之间的 CABF 无差异。较低的 CABF 水平与整体疾病活动评分（r=-0.26，p=0.003）以及神经炎症（r=-0.29，p=0.001）、免疫调节（r=-0.26，p=0.003）和神经轴突完整性（r=-0.23，p=0.007）途径评分相关。在年龄和体重指数（BMI）调整后，较低的 CABF 仍然与神经炎症（r=-0.23，p=0.011）和免疫调节（r=-0.20，p=0.024）途径评分相关。在调整 T2-LV 和 WBV 后，CABF 与神经炎症途径评分之间的关系仍然显著（p=0.038）。个体分析确定了神经丝轻链、CCL-20 和 TNFSF13B 为贡献者。与最高四分位（>1133.5mL/min）相比，CABF 最低四分位（<764mL/min）的 pwMS 具有更高的整体疾病活动评分（p=0.003）、神经炎症（p=0.001）、免疫调节（p=0.004）和神经轴突完整性途径评分（p=0.007）。
MS 患者的脑动脉灌注减少与神经炎症/免疫调节途径及其各自的蛋白质组学生物标志物的变化有关。这些发现可能表明灌注不足与促炎 MS 变化之间存在关系，而不仅仅是能量需求降低后的附带现象。
