Pathophysiology and imaging of early memory impairment in multiple sclerosis
Defended on December 16, 2016
Memory impairment is frequent in multiple sclerosis (MS) but its anatomical and biological substrates are poorly understood. The objective of this translational thesis was to understand the pathophysiological mechanisms of early memory impairment in MS, to find new potential therapeutic targets and to define new imaging biomarkers related to memory impairment. We used neuropsychological and MRI experiments in patients with early MS and we explored experimental autoimmune encephalomyelitis (EAE) mice (a mouse model of MS) at the early stage of the disease with a combination of behavioral, in vivo MRI, histological, electrophysiological and pharmacological approaches. In patients with MS, we demonstrated that hippocampal damage occurs early during the course of the disease and that it correlates with memory impairment. In EAE-mice, we identified that dentate gyrus structure and function are more vulnerable than other hippocampal subfields at the early stage of the disease and we translated this finding back to humans by demonstrating loss of pattern separation performances in patients with early MS.
From a mechanistic point of view, we demonstrated that early microglial activation causes dentate gyrus disruption and memory impairment in EAE-mice and that this pathophysiological cascade can be prevented with minocycline. From the imaging point of view, we demonstrated that hippocampal microstructural damage and early dentate gyrus degeneration can be monitored in vivo with diffusion tensor imaging (DTI). We are currently developing more specific imaging approaches with optimization of the Neurite Orientation Dispersion and Density Imaging (NODDI) to assess hippocampal subfields.
Our results link early memory impairment in MS to a selective disruption of the dentate gyrus. We were able to prevent this neurodegenerative process with microglial inhibitors in EAE-mice and to capture these features non-invasively with DTI in both humans and rodents, paving the way toward new clinical perspectives in MS.
Keywords Episodic memory, hippocampus, dentate gyrus, microglia, multiple sclerosis, experimental-autoimmune encephalomyelitis, MRI, diffusion tensor imaging.
• Planche V, Panatier A, Hiba B, Ducourneau EG, Raffard G, Nadège Dubourdieu, Marlène Maitre, Thierry Lesté-Lasserre, Brochet B, Dousset V, Desmedt A, Oliet SH, Tourdias T. Selective dentate gyrus disruption causes early memory impairment in experimental multiple sclerosis. Brain Behav Immun. 2016. doi:10.1016/j.bbi.2016.11.010.
• Planche V, Ruet A, Coupé P, Lamargue-Hamel D, Deloire, M, Pereira B, Manjon JV, Munsch F, Moscufo N, Meier DS, Guttmann CRG, Dousset V, Brochet B, Tourdias T. Hippocampal microstructural damage correlates with memory impairment in clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler. 2016. doi:10.1177/1352458516675750.
Sridar Narayanan, PU
Mc Gill University, Montreal.
Pierre Clavelou, PU
Université Clermont Auvergne.
Charles R.G. Guttmann, PU
Harvard University, Boston.
Stéphane Kremer, PU
Université de Strasbourg.
Romain Marignier, Dct
Université de Lyon.
Agnès Nadjar, MC
Université de Bordeaux.
Directeur de thèse
Thomas Tourdias, MD, PhD, Associate Professor (PHU) in medical imaging at Bordeaux University and hospital practitioner at Bordeaux University Hospital. Dr. Tourdias is also a member of INSERM Unit U1215 “Pathophysiology of neural plasticity” Neurocentre Magendie team Dr. Oliet “neuron-glia interactions,” University of Bordeaux.