GLIal metabolic dysfunctions investigated with brain multimodal magnetic resonance: from inherited METAbolic diseases to neurodeGENerative diseases – GLIMETAGEN

Proper neurotransmission in the brain is conditioned by the metabolic support from the glia. Glial cells play a key role in neurodegeneration. Strikingly, brain metabolic dysfunctions are common in neurodegenerative diseases, in particular in Huntington’s disease (HD) and Parkinson’s disease (PD), both displaying early alterations of glucose and lipid metabolism. Yet, the role of metabolic dysfunctions in HD and PD is elusive, and whether they can be corrected by metabolic treatments is unknown. We have recently found that rare neurometabolic diseases related to primary metabolic defects in glial cells, which cause neurological symptoms mimicking features of neurodegenerative diseases, respond remarkably to metabolic treatments. Hence, I proposed a new concept based on the study of four neurometabolic diseases (affecting glucose, glycogen, cholesterol or fatty acid metabolism) as models to understand how metabolic dysfunctions affect the human brain. My hypothesis is that neurometabolic and neurodegenerative diseases share glial metabolic features. My proposal GLIMETAGEN wished to test this directly from the study of the human brain, using cutting-edge, multimodal magnetic resonance technologies that offer an unprecedented opportunity to characterise in vivo brain structure (fixel based analysis), function (connectivity) and metabolism (1H spectroscopy and diffusion weighted spectroscopy). Using innovative integrative analyses to study the relationships between alterations, we wish to determine whether (i) distinct glial metabolic dysfunctions cause distinct brain alterations, (ii) common alterations exist between neurometabolic and neurodegenerative diseases (HD and PD), and (iii) an original therapy targeting the Krebs cycle (i.e. triheptanoin) improves brain alterations.
The ERC-CoG reviewers perceived this combination of methods as a unique asset to profile many dimensions of metabolic, structural, functional defects in the human brain in vivo. They also stressed out the potential of my proposal for developing new therapies for neurological diseases. Yet, some reviewers expressed concerns regarding the lack of wet biomarkers and/or cellular or preclinical approaches in order to yield a more mechanistic angle to the project, and questioned whether MR techniques are sensitive enough to detect metabolic changes. GLIMETAGEN shall not change its nature but keep its strength and focus on humans. Instead, with the ANR-Tremplin, I wish to reinforce the understanding of metabolic dysfunction and complement multimodal brain MR approaches with metabolomic and lipidomic analyses of blood samples from patients. This will be illustrated in a pilot study in HD. I will also provide preliminary data supporting the sensitivity of MR techniques to unravel metabolic regulations in the human brain, as ultimate compelling evidence of the completeness of our human approach, by conducting a multimodal imaging study in patients with HD and GLUT1-DS after metabolic treatment with triheptanoin.