B40 In vivo imaging of brain glutamate defects in a knock-in mouse model of huntington’s disease

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disease characterised by motor, cognitive and psychiatric symptoms. Although classically considered as a good biomarker of disease progression in HD gene carriers, atrophy of the striatum does not provide any information about the biological mechanisms linked to HD pathogenesis. Consequently, there is an urgent need to identify novel functional biomarkers of disease progression to better understand pathological processes and to monitor HD patients in clinical trials. Changes in brain metabolites have been also consistently seen in HD patients and animal models using Magnetic Resonance Spectroscopy (MRS), but measurements are generally limited to a large volume. Thus, novel methods that could measure the metabolic defects with a precise anatomical resolution would be of major interest. We propose to use a new MRI contrast modality named gluCEST (for Chemical Exchange Saturation Transfer imaging of glutamate) in order to map glutamate distribution in the brain of a HD mouse model. We demonstrated that both heterozygous and homozygous mice with pathological CAG repeat expansion in gene encoding huntingtin exhibited an atrophy of the striatum, a significant alteration of their metabolic profile in the striatum and lower gluCEST effects as compared to wild type littermate controls. The most striking result of this study was that gluCEST imaging also revealed a strong and significant decrease of glutamate level in the corpus callosum in both heterozygous and homozygous mice. This suggests that this structure could be highly vulnerable in HD and could be impacted early during disease progression. We evaluated for the first time gluCEST imaging as a potential biomarker of HD and demonstrated its potential for characterising metabolic defects in neurodegenerative diseases in specific regions.

Glutamate‐weighted CEST (gluCEST) imaging for mapping neurometabolism: An update on the state of the art and emerging findings from in vivo applications

“…It has been applied extensively in rodents and humans and to a limited degree in primates, and interest has even been expressed in using gluCEST to probe the mysteries of aquatic invertebrate neurophysiology. 3 Preclinical applications in rodents include the study of Alzheimer's disease, 41 Parkinson's disease (PD), 42,43 Huntington's disease, [44][45][46] the general etiology of tau pathology, 47 Friedreich's ataxia, 48 stroke, 23 inflammation, encephalitis and TBI, 38,49,50 and cancer metabolism. 51 Alzheimer's disease has been studied using gluCEST in primates 52 and humans.…”