Lower arterial cerebral blood flow is associated with worse neuroinflammation and immunomodulation composite
Dejan Jakimovski1, Ferhan Qureshi2, Murali Ramanathan3
1Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
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).
Conclusion:
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.
Insights
Reduced cerebral blood flow in multiple sclerosis (MS) is linked to increased neuroinflammation and immunomodulation pathways. These findings suggest hypoperfusion may drive MS disease activity, not just result from it.
Area of Science:
- Neuroscience
- Immunology
- Biomarker Discovery
Background:
- Brain hypoperfusion is a known factor associated with poorer physical, cognitive, and MRI outcomes in multiple sclerosis (MS).
- Understanding the proteomic signatures linked to hypoperfusion is crucial for elucidating the underlying pathophysiological mechanisms in MS.
Purpose of the Study:
- To investigate the relationship between cerebral arterial blood flow (CABF) and proteomic signatures in people with MS (pwMS).
- To explore how CABF correlates with specific disease pathway scores and MRI outcomes in MS.
Main Methods:
- 140 pwMS (86 CIS/RRMS, 54 PMS) underwent cerebral arterial blood flow (CABF) measurement via ultrasound Doppler.
- Proteomic analysis used the Olink™ platform's MSDA test to assess 18 proteins and calculate disease pathway scores (immunomodulation, neuroinflammation, myelin biology, neuroaxonal integrity) and an overall disease activity score.
- MRI measures included T2 lesion volume (LV) and whole brain volume (WBV).
Main Results:
- Lower CABF correlated significantly with higher overall disease activity, neuroinflammation, immunomodulation, and neuroaxonal integrity pathway scores.
- These associations remained significant after adjusting for age, BMI, T2 lesion volume, and whole brain volume.
- Specific proteins like neurofilament light chain, CCL-20, and TNFSF13B were identified as contributors. pwMS in the lowest CABF quartile exhibited significantly higher disease activity and pathway scores.
Conclusions:
- Reduced cerebral arterial perfusion in MS is associated with distinct changes in neuroinflammatory and immunomodulation pathways.
- The identified proteomic biomarkers suggest a potential causal link between hypoperfusion and pro-inflammatory processes in MS.
- These findings challenge the notion that hypoperfusion is merely a consequence of reduced energy demand, pointing towards its active role in MS pathogenesis.
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