Lower cerebral arterial blood flow is associated with greater serum neurofilament light chain levels in multiple sclerosis patients

Dejan Jakimovski; Brianna L. Gibney; Karen Marr; Deepa P. Ramasamy; Michael G. Dwyer; Niels Bergsland; Bianca Weinstock-Guttman; Murali Ramanathan; Robert Zivadinov

doi:10.4081/vl.2022.10952

Authors

Dejan Jakimovski
djakimovski@bnac.net
Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Brianna L. Gibney Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Karen Marr Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Deepa P. Ramasamy Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Michael G. Dwyer Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Niels Bergsland IRCCS, Fondazione Don Carlo Gnocchi, Milan, Italy, Italy.
Bianca Weinstock-Guttman Department of Neurology, Jacobs Comprehensive MS Treatment and Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Murali Ramanathan Department of Pharmaceutical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, United States.
Robert Zivadinov Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, United States.

Background: Hypoperfusion, vascular pathology, and cardiovascular risk factors are associated with disease severity in multiple sclerosis (MS).^1,2 In particular, the total cerebral arterial blood flow (CABF), measured as a sum of all arterial flow in the neck, was associated with the cognitive performance of MS patients.³

Objective: To assess relationships between CABF and serum neurofilament light chain (sNfL), as neuronal damage biomarker with good prognostic value and treatment responsiveness.⁴ If the cerebrovascular changes are an independent pathophysiological factor in MS, a relationship should remain significant after controlling for common MS-based disease measures (i.e., T2 lesion volume and brain volume).

Materials and methods: Total CABF was measured in 137 patients (86 clinically isolated syndrome (CIS)/relapsing-remitting (RR) and 51 progressive MS (PMS)) and 48 healthy controls (HCs) using Doppler ultrasound. sNfL was quantitated using a single molecule assay (Simoa). Three point zero T magnetic resonance imaging (MRI) examination allowed quantification of T2 lesion and whole-brain volume (WBV). Multiple linear regression models determined the sNfL associated with CABF after correction for demographic and MRI-derived variables.

Results: After adjustment for age, sex and body mass index (BMI), total CABF remained statistically significant and model comparisons showed that CABF explained additional 2.6% of the sNfL variance (β=-0.167, p=0.044). (Table 1) CABF also remained significant in a step-wise regression model (β=0.18, p=0.034) upon the inclusion of T2 lesion burden and WBV effects. The explained sNfL variance improved from 17.4%, 22.7% with the presence of at least 2 CVD variable and 25.8% with both CVD and CABF predictors. Lastly, the disease-modifying therapy was not kept in the final model as an independent predictor of sNfL. Patients in the lowest CABF quartile (CABF≤761 mL/min) had significantly higher sNfL (34.6 pg/mL versus 23.9 pg/mL, adjusted-p=0.042) when compared to the highest quartile (CABF≥1130 mL/min).

Conclusions: Lower CABF is associated with increased sNfL in MS patients, highlighting direct and independent relationship between cerebral hypoperfusion and axonal pathology. This relationship remained significant in the CIS/RRMS after adjusting for age, sex, and BMI effects.

1. Jakimovski D, Gandhi S, Paunkoski I, et al. Hypertension and heart disease are associated with development of brain atrophy in multiple sclerosis: a 5-year longitudinal study. Eur J Neurol 2019;26:87-e88.
2. Jakimovski D, Topolski M, Genovese AV, et al. Vascular aspects of multiple sclerosis: emphasis on perfusion and cardiovascular comorbidities. Expert Rev Neurother 2019;19:445-458.
3. Jakimovski D, Benedict RH, Marr K, et al. Lower total cerebral arterial flow contributes to cognitive performance in multiple sclerosis patients. Mult Scler 2020;26:201-209.
4. Jakimovski D, Dwyer MG, Bergsland N, et al. Disease biomarkers in multiple sclerosis: current serum neurofilament light chain perspectives. Neurodegener Dis Manag 2021;11:329-340.

Jakimovski, D., Gibney, B. L., Marr, K., Ramasamy, D. P., Dwyer, M. G., Bergsland, N., Weinstock-Guttman, B., Ramanathan, M., & Zivadinov, R. (2022). Lower cerebral arterial blood flow is associated with greater serum neurofilament light chain levels in multiple sclerosis patients. Veins and Lymphatics, 11(1). https://doi.org/10.4081/vl.2022.10952