Imaging pathophysiological events and therapeutic modulation in the cuprizone mouse model for Multiple Sclerosis

Date: 20 April 2016

Venue: UAntwerp, Stadscampus, Promotiezaal Grauwzusters - Lange Sint-Annastraat 7 - 2000 Antwerp

Time: 3:00 PM - 5:00 PM

PhD candidate: Caroline Guglielmetti

Principal investigator: Annemie Van der Linden, Peter Ponsaerts

Co-principal investigator: Myriam M. Chaumeil

Short description: PhD defence Caroline Guglielmetti - Department of Biomedical Sciences

To date, the clinical standard of care for multiple sclerosis (MS) diagnosis, monitoring disease progression and response to therapy is magnetic resonance (MR) imaging. However, clinically available imaging methods provide only limited information of the underlying pathophysiology associated to MS lesions. It has been shown that MS lesions display a complex interplay between peripheral inflammatory cells and resident cells from the central nervous system (CNS) that later results in either successful remyelination and recovery or lead to permanent damage of the tissue and loss of motor or cognitive functions.

In this doctoral thesis, we used the cuprizone mouse model for MS to answer fundamental biological questions related to neuroinflammation and demyelination as well as for the validation of in-vivo non-invasive imaging tools.

First, using in-vivo non-invasive cell-tracking technologies we were able to show that the remyelination of lesions did not essentially rely on the involvement of stem/progenitor cells from the subventricular zone as previously suggested. Furthermore, we uncovered a potential link between neuroinflammatory processes and neurogenesis.

Next, we validated a novel MR method, diffusion kurtosis imaging, for providing new and complementary information about the tissue microstructure in both white and grey matter. Diffusion kurtosis imaging notably presented the aptitude to distinguish between several stages of the cuprizone-induced pathology, including acute inflammatory demyelination, spontaneous remyelination and long lasting axonal damage.

In the following study, we used a gene therapy approach to modulate the neuroinflammatory state of microglia and macrophages in-vivo. Non-invasive monitoring of the lesion formation was achieved using two MR methods, conventional T2 imaging and magnetization transfer imaging. Interleukin 13 and interleukin 4 gene therapy resulted in the induction of alternatively activated microglia and macrophages, promoting the shift from a pro-inflammatory environment towards an anti-inflammatory environment. The latter was associated with the protection against cuprizone induced demyelination, thereby highlighting the potential of interleukin 13 and interleukin 4 to intervene with pro-inflammatory responses and to improve disease outcome. These results are of particular interest for the design of new drug based therapies targeting microglia and macrophages function to preserve tissue homeostasis and support remyelination in MS and other demyelinating diseases.

Finally, we applied a recently developed MR technique, hyperpolarized 13C MR spectroscopy, for the first time to our knowledge, to the study of neuroinflammation. We demonstrated that hyperpolarized in-vivo 13C MR spectroscopy of 13C pyruvate is able to monitor the increased lactate production from pro-inflammatory microglia and macrophages in MS lesions. We identified pyruvate dehydrogenase kinase 1 as a key enzyme mediating the observed increase in lactate from activated microglia and macrophages. Altogether, these results highlight the potential of hyperpolarized 13C MR spectroscopy for the rapid, non-invasive imaging of neuroinflammation in real time and would represent a tremendous tool for testing potential immune modulatory MS therapies. Eventually, this will lead to an improvement in the diagnosis and prognosis of MS patients, help refine therapeutic regimens and, ultimately, lead to better clinical outcome and patient quality of life.