Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
摘要：
背景：大脑灌注不足与身体恶化有关，多发性硬化症（MS）的认知和MRI结果。了解与灌注不足相关的蛋白质组特征可以提供对病理生理机制的见解。
方法：包括140名MS患者（pwMS；86名临床孤立综合征（CIS）/复发缓解（RRMS）和54名进行性（PMS））。使用超声多普勒测量确定脑动脉血流（CABF），作为双侧颈总动脉和椎动脉的血流量总和。使用在Olink™平台上进行的多发性硬化疾病活性(MSDA)测试测定面板进行蛋白质组学分析。MSDA测试测量年龄和性别调整的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种疾病途径得分(免疫调节，神经炎症，髓鞘生物学，和神经轴突完整性）以及总体疾病活动评分（1至10）。得出T2病变体积（LV）和全脑体积（WBV）的MRI测量值。
结果：pwMS平均为54岁，平均CABF为951mL/min。CIS/RRMS与CABF之间没有差异PMS组。较低的CABF水平与总体疾病活动评分（r=-0.26，p=0.003）和神经炎症（r=-0.29，p=0.001）相关，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。经过年龄和体重指数（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.校正T2-LV和WBV后，CABF与神经炎症途径评分之间的关系仍然显着（p=0.038）。个别分析确定神经丝轻链，CCL-20和TNFSF13B作为贡献者。与最高四分位数（>1133.5mL/min）相比，最低CABF四分位数（<764mL/min）的pwMS具有更大的总体疾病活动评分（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）。
结论：MS患者大脑下动脉灌注与神经炎症/免疫调节通路及其各自的蛋白质组生物标志物的变化有关。这些发现可能表明灌注不足和促炎MS变化之间的关系，而不仅仅是能量需求降低之后的附加现象。
方法：包括140名MS患者（pwMS；86名临床孤立综合征（CIS）/复发缓解（RRMS）和54名进行性（PMS））。使用超声多普勒测量确定脑动脉血流（CABF），作为双侧颈总动脉和椎动脉的血流量总和。使用在Olink™平台上进行的多发性硬化疾病活性(MSDA)测试测定面板进行蛋白质组学分析。MSDA测试测量年龄和性别调整的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种疾病途径得分(免疫调节，神经炎症，髓鞘生物学，和神经轴突完整性）以及总体疾病活动评分（1至10）。得出T2病变体积（LV）和全脑体积（WBV）的MRI测量值。
结果：pwMS平均为54岁，平均CABF为951mL/min。CIS/RRMS与CABF之间没有差异PMS组。较低的CABF水平与总体疾病活动评分（r=-0.26，p=0.003）和神经炎症（r=-0.29，p=0.001）相关，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。经过年龄和体重指数（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.校正T2-LV和WBV后，CABF与神经炎症途径评分之间的关系仍然显着（p=0.038）。个别分析确定神经丝轻链，CCL-20和TNFSF13B作为贡献者。与最高四分位数（>1133.5mL/min）相比，最低CABF四分位数（<764mL/min）的pwMS具有更大的总体疾病活动评分（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）。
结论：MS患者大脑下动脉灌注与神经炎症/免疫调节通路及其各自的蛋白质组生物标志物的变化有关。这些发现可能表明灌注不足和促炎MS变化之间的关系，而不仅仅是能量需求降低之后的附加现象。
