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

Abstract

Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system. As such, its proper regulation is essential to the healthy function of the human brain, and dysregulation of glutamate metabolism and compartmentalization underlies numerous neurological and neuropsychiatric pathologies. Glutamate‐weighted chemical exchange saturation transfer (gluCEST) MRI is one of the only ways to non‐invasively observe the relative concentration and spatial distribution of glutamate in the human brain. In the past 10 years, gluCEST has developed from a proof‐of‐concept experiment carried out in imaging phantoms and model systems to an increasingly sophisticated technique applied to reveal deviations from baseline neural metabolism in human beings, most notably in patients experiencing seizures of various origins or those on the psychosis spectrum. This article traces that progress, including in‐depth discussion of the technical specifics of gluCEST and potential challenges to performing these experiments rigorously. We discuss the neurobiological context of glutamate, including the widely accepted hypotheses and models in the literature regarding its involvement in neurodegenerative diseases and other pathology. We then review the state of the art of in vivo glutamate detection by magnetic resonance imaging and the limitations on this front of in vivo MR spectroscopy. The gluCEST experiment is introduced and its advantages, challenges and limitations are thoroughly explored, beginning with the phantom experiment results demonstrated in the initial publication, through the latest approaches to correcting human brain images for B1 inhomogeneity. We then give a comprehensive overview of preclinical applications demonstrated to date, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Traumatic brain injury and cancer, followed by a similar discussion of human studies. Finally, we highlight emerging applications, and discuss technical improvements on the horizon that hold promise for improving the robustness and versatility of gluCEST and its increasing presence in the arena of translational and precision medicine.

Ultra-high field neuroimaging in psychosis: A narrative review

“…Using a more spatially resolved 2D approach for glutamate quantification based on chemical exchange saturation (GluCEST), Roalf et al ( 26 ) noted an overall decline in glutamate levels in patients with early stage psychosis. The advantage of GluCEST is the ability to quantify regional brain glutamate distribution across multiple cross-sectional whole brain slices in a reasonably short time period ( 27 ), thus promising more extensive studies of glutamate physiology in the near future.…”

Repeatability of B1+ inhomogeneity correction of volumetric (3D) glutamate CEST via High‐permittivity dielectric padding at 7T

“…It requires both an ultra‐high B 0 field (≥7T) and a high and uniform B 1 + strength across the tissue to generate adequate contrast. As data acquisition has moved from single‐slice (two‐dimensional: 2D) to volumetric slabs (three‐dimensional: 3D), the absolute spread of B 1 + amplitude over the field of view increases and, because one now needs to collect more points in k ‐space per saturation pulse, the minimum B 1 + amplitude required to maintain glutamate derived contrast at an acceptable level increase as well 9,10 …”

“…As data acquisition has moved from single-slice (two-dimensional: 2D) to volumetric slabs (three-dimensional: 3D), the absolute spread of B 1 + amplitude over the field of view increases and, because one now needs to collect more points in k-space per saturation pulse, the minimum B 1 + amplitude required to maintain glutamate derived contrast at an acceptable level increase as well. 9,10 One of the primary ways in which B 1 + inhomogeneity has been mitigated recently has been through the use of parallel transmit (PTX). There have been many studies that have used PTX based approaches to correct for B 1 + inhomogeneity, [11][12][13] even in the case of CEST imaging; however, it has not been shown that PTX can maintain a high absolute B 1 + power over the entire field of view.…”

Radiofrequency labeling strategies in chemical exchange saturation transfer MRI

“…environments or molecular dynamics, exchange and cross-relaxation rates can vary by several orders of magnitude. This broad scope hints at the potential for using magnetization exchange methods (e.g., CEST, MTC, rNOE) to study a large number of biological systems in situ, including signals from mobile proteins and peptides, [12][13][14][15][16] creatine and phosphocreatine, [17][18][19][20] small sugars and sugar polymers, 10,[21][22][23][24][25][26][27] glutamate, [28][29][30] myo-inositol, 31 urea, 32,33 and glycosaminoglycans, 34 but it can be challenging to separate these multiple signal sources in vivo.…”