Imaging immunomodulatory treatment responses in a multiple sclerosis mouse model using hyperpolarized 13C metabolic MRI
Year: 2023
Type: article
Abstract: Background In recent years, the ability of conventional magnetic resonance imaging (MRI), including T 1 contrast-enhanced (CE) MRI, to monitor high-efficacy therapies and predict long-term disability in multiple sclerosis (MS) has been challenged. Therefore, non-invasive methods to improve MS lesions detection and monitor therapy response are needed. Methods We studied the combined cuprizone and experimental autoimmune encephalomyelitis (CPZ-EAE) mouse model of MS, which presents inflammatory-mediated demyelinated lesions in the central nervous system as commonly seen in MS patients. Using hyperpolarized 13 C MR spectroscopy (MRS) metabolic imaging, we measured cerebral metabolic fluxes in control, CPZ-EAE and CPZ-EAE mice treated with two clinically-relevant therapies, namely fingolimod and dimethyl fumarate. We also acquired conventional T 1 CE MRI to detect active lesions, and performed ex vivo measurements of enzyme activities and immunofluorescence analyses of brain tissue. Last, we evaluated associations between imaging and ex vivo parameters. Results We show that hyperpolarized [1- 13 C]pyruvate conversion to lactate is increased in the brain of untreated CPZ-EAE mice when compared to the control, reflecting immune cell activation. We further demonstrate that this metabolic conversion is significantly decreased in response to the two treatments. This reduction can be explained by increased pyruvate dehydrogenase activity and a decrease in immune cells. Importantly, we show that hyperpolarized 13 C MRS detects dimethyl fumarate therapy, whereas conventional T 1 CE MRI cannot. Conclusions In conclusion, hyperpolarized MRS metabolic imaging of [1- 13 C]pyruvate detects immunological responses to disease-modifying therapies in MS. This technique is complementary to conventional MRI and provides unique information on neuroinflammation and its modulation.
Source: Communications Medicine
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,390
Funders: U.S. Department of Health and Human Services, Conrad N. Hilton Foundation, Multiple Sclerosis Society, National Institutes of Health, University of California, San Francisco, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering
Awards: G1397756794, Imaging innate and adaptive immune response in MS using using [18F]F-AraG PET and hyperpolarized 13C MRSI, G3363981458, G4839587823, G5133243947, Real time imaging of immune cells and glutamate dynamics by PET and metabolic MRI, MR Metabolic Imaging of Multiple Sclerosis, G8619625316, Wide field-of-view Spinning Disk Confocal with Photoactivation and Photobleaching, Hyperpolarized MRI Technology Resource Center, G987915127
OpenAlex ID: W4377288169