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 characterized by motor, cognitive and psychiatric symptoms. Atrophy of the striatum has been proposed for several years as a biomarker to assess disease progression in HD gene carriers. However, it does not provide any information about the biological mechanisms linked to HD pathogenesis. Changes in brain metabolites have been also consistently seen in HD patients and animal models using Magnetic Resonance Spectroscopy (MRS), but metabolite measurements are generally limited to a single voxel. In this study, we used Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) in order to map glutamate distribution in the brain of a knock-in mouse model (Ki140CAG) with a precise anatomical resolution. We demonstrated that both heterozygous and homozygous mice with pathological CAG repeat expansion in gene encoding huntingtin exhibited an atrophy of the striatum and a significant alteration of their metabolic profile in the striatum as compared to wild type littermate controls. The striatal decrease was then confirmed by gluCEST imaging. Surprisingly, CEST imaging also revealed that the corpus callosum was the most affected structure in both genotype groups, suggesting that this structure could be highly vulnerable in HD. We evaluated for the first time gluCEST imaging as a potential biomarker of HD and demonstrated its potential for characterizing metabolic defects in neurodegenerative diseases in specific regions.

CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease

“…The contralateral striatum was injected with AAV-HTT-gRNA or AAV-CMV-Cas9 alone, which allowed us to rigorously examine the efficiency of HTT-gRNA/Cas9-mediated mHTT knockdown. HD140Q-KI mice are known to develop age-dependent motor deficits and nuclear accumulation of mHTT (9,14). We found that most of the striatum and the needle pathway in the cortex and hippocampus were transduced by AAVs 3 weeks after injection ( Figure 1B).…”

CEST imaging of fast exchanging amine pools with corrections for competing effects at 9.4 T

“…glutamate amine and protein lysine amine protons) and hydroxyl protons ( k sw is several thousand s −1 and Δ r = 1–3 ppm) are in a fast exchange regime. Imaging of fast exchanging amine pools at 3 ppm at high field strength is of special interest, because these protons are part of important molecules such as glutamate and proteins . However, these pools are not well suited to produce CEST signals, because they break the CEST condition that exchange should be slow‐intermediate on the NMR time scale (i.e.…”

Reproducibility of 2DGluCEST in healthy human volunteers at 7 T

“…In the mouse model of Parkinson's disease, increased GluCEST was measured from the striatum compared with the healthy controls . This method was also used in studying the Huntington's disease mouse model in which the decreased GluCEST was measured in the striatal region of the brain . This technique has also been demonstrated in a proof‐of‐principle study in human brain and was recently used in small studies to show differences in brain glutamate levels between patients compared with healthy controls …”