Imaging immunomodulatory treatment responses in a multiple sclerosis mouse model using hyperpolarized 13C metabolic MRI

BackgroundIn 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.MethodsWe 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 C-13 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.ResultsWe show that hyperpolarized [1-C-13]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 C-13 MRS detects dimethyl fumarate therapy, whereas conventional T-1 CE MRI cannot.ConclusionsIn conclusion, hyperpolarized MRS metabolic imaging of [1-C-13]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. Guglielmetti et al. show the potential for monitoring response to immunomodulatory treatment in a model of multiple sclerosis using hyperpolarized C-13 metabolic MRI. The authors observe reduced pyruvate-to-lactate flux in vivo after treatment with fingolimod or dimethyl fumarate, as well as changes in immune cell populations. Plain language summaryMagnetic resonance imaging (MRI) is widely used in the clinic to diagnose multiple sclerosis (MS), which affects the central nervous system and leads to a range of disabling symptoms. However, MRI is often not capable of detecting how well a patient responds to therapies, in particular those targeting the immune system. We questioned whether an advanced MRI method called hyperpolarized C-13 MRS could help. Using a mouse model for MS, we showed that hyperpolarized C-13 MRS can detect response to two therapies used in the clinic, namely fingolimod and dimethyl fumarate when conventional MRI could not. We also showed that this method is sensitive to the immune response. As hyperpolarized C-13 MRS is becoming available in many centers worldwide, it could be used to evaluate existing and new treatments for people living with MS, improving care and quality of life.