Lower Arterial Cerebral Blood Flow is Associated with Worse Neuroinflammation and Immunomodulation Composite Proteomic Scores

BackgroundBrain 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.Methods140 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.ResultsThe 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).ConclusionLower 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.