Abstract:Introduction
Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50–90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively.
Methods
We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 … Show more
“…Evaluation in epilepsy patients indicated a higher GluCEST signal in the hippocampus ipsilateral to the location of seizure onset, again suggesting an increase in glutamate levels during the interictal phase [143]. Furthermore, increased peritumoral GluCEST contrast in glioma patients was associated with both recent seizures and drug-refractory epilepsy [144]. Taken together, the evidence reported in these studies indicates that an increase in glutamate tone is important for the establishment of irritable status in epilepsy.…”
It is widely accepted that glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major clinical research targets. It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, perampanel, has been approved for the treatment of some forms of epilepsy. These results suggest that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety. Accumulating knowledge of both NMDA and AMPA receptors, including pathological gene mutations, roles in autoimmune epilepsy, and evidence from drug-discovery research and pharmacological studies, may provide valuable information enabling the roles of both receptors in ictogenesis to be reconsidered. This review aimed to integrate information from several studies in order to further elucidate the specific roles of NMDA and AMPA receptors in epilepsy.
“…Evaluation in epilepsy patients indicated a higher GluCEST signal in the hippocampus ipsilateral to the location of seizure onset, again suggesting an increase in glutamate levels during the interictal phase [143]. Furthermore, increased peritumoral GluCEST contrast in glioma patients was associated with both recent seizures and drug-refractory epilepsy [144]. Taken together, the evidence reported in these studies indicates that an increase in glutamate tone is important for the establishment of irritable status in epilepsy.…”
It is widely accepted that glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major clinical research targets. It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, perampanel, has been approved for the treatment of some forms of epilepsy. These results suggest that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety. Accumulating knowledge of both NMDA and AMPA receptors, including pathological gene mutations, roles in autoimmune epilepsy, and evidence from drug-discovery research and pharmacological studies, may provide valuable information enabling the roles of both receptors in ictogenesis to be reconsidered. This review aimed to integrate information from several studies in order to further elucidate the specific roles of NMDA and AMPA receptors in epilepsy.
“…Excessive accumulation of extracellular Glu induces excitotoxicity in CNS neurons, which may lead to various brain disorders, such as epilepsy, schizophrenia, depression, tumors, etc. (Davis et al, 2015;Roalf et al, 2017;Neal et al, 2019;Kaminski et al, 2020). It was also recently reported that glutamate is closely implicated in microglial activation and that activated microglia play a key role in encephalitis.…”
Background: Encephalitis is a common central nervous system inflammatory disease that seriously endangers human health owing to the lack of effective diagnostic methods, which leads to a high rate of misdiagnosis and mortality. Glutamate is implicated closely in microglial activation, and activated microglia are key players in encephalitis. Hence, using glutamate chemical exchange saturation transfer (GluCEST) imaging for the early diagnosis of encephalitis holds promise. Methods: The sensitivity of GluCEST imaging with different concentrations of glutamate and other major metabolites in the brain was validated in phantoms. Twenty-seven Sprague-Dawley (SD) rats with encephalitis induced by Staphylococcus aureus infection were used for preclinical research of GluCEST imaging in a 7.0-Tesla scanner. For the clinical study, six patients with encephalitis, six patients with lacunar infarction, and six healthy volunteers underwent GluCEST imaging in a 3.0-Tesla scanner. Results: The number of amine protons on glutamate that had a chemical shift of 3.0 ppm away from bulk water and the signal intensity of GluCEST were concentrationdependent. Under physiological conditions, glutamate is the main contributor to the GluCEST signal. Compared with normal tissue, in both rats and patients with encephalitis, the encephalitis areas demonstrated a hyper-intense GluCEST signal, while the lacunar infarction had a decreased GluCEST signal intensity. After intravenous immunoglobulin therapy, patients with encephalitis lesions showed a decrease in GluCEST signal, and the results were significantly different from the pre-treatment signal (1.34 ± 0.31 vs 5.0 ± 0.27%, respectively; p = 0.000).
“…recently demonstrated that increased peritumoural GluCEST contrast is associated with both recent seizures and drug refractory epilepsy in patients with glioma (Fig. 2) (75). Fig.…”
Section: Glutamatementioning
confidence: 85%
“…Axial GluCEST image (right) demonstrating increased GluCEST contrast in a glioma patient. From Neal et al (2019).…”
HighlightsAbnormal cerebral glutamate release has been implicated in the pathogenesis of stroke and epilepsy.Glutamate levels in acute stroke may be a biomarker for the development of post-stroke epilepsy.7T MRI technology enables non-invasive quantification of cerebral glutamate levels.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
