An Imbalance Between Excitatory and Inhibitory Neurotransmitters in Amyotrophic Lateral Sclerosis Revealed by Use of 3-T Proton Magnetic Resonance Spectroscopy

Foerster, Bradley R.; Pomper, Martin G.; Callaghan, Brian C.; Petrou, M.D. Ilya; Edden, Richard A.E.; Mohamed, Mona A.; Welsh, Robert C.; Carlos, Ruth C.; Barker, Peter B.; Feldman, Eva L.

doi:10.1001/jamaneurol.2013.234

Cited by 122 publications

(127 citation statements)

References 51 publications

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“…However, reports of Glx alterations in the motor cortex are not consistent, perhaps partly owing to the effects of riluzole, a glutamate antagonist used for ALS treatment. Several studies did not explicitly report whether imaged patients were treated with this medication [57,[60][61][62]. Reduced GABA levels have been reported in the motor cortex of patients with ALS, which is consistent with the results of an earlier PET [ 11 C]flumazenil study [62,63].…”

Section: Mrssupporting

confidence: 64%

“…Several studies did not explicitly report whether imaged patients were treated with this medication [57,[60][61][62]. Reduced GABA levels have been reported in the motor cortex of patients with ALS, which is consistent with the results of an earlier PET [ 11 C]flumazenil study [62,63]. These results indicate an Binterneuronopathy^in which a relative GABA deficiency may contribute to increased glutamatergic activity and subsequent neuronal damage [64].…”

Section: Mrssupporting

confidence: 57%

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Neuroimaging as a New Diagnostic Modality in Amyotrophic Lateral Sclerosis

Verstraete

Foerster

2015

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of upper and lower motor neurons, with variable involvement of extramotor brain regions. Currently, there are no established objective markers of upper motor neuron and extramotor involvement in ALS. Here, we review the potential diagnostic value of advanced neuroimaging techniques that are increasingly being used to study the brain in ALS. First, we discuss the role of different imaging modalities in our increasing understanding of ALS pathogenesis, and their potential to contribute to objective upper motor neuron biomarkers for the disease. Second, we discuss the challenges to be overcome and the required phases of diagnostic test development to translate imaging technology to clinical care. We also present examples of multidimensional imaging approaches to achieve high levels of diagnostic accuracy. Last, we address the role of neuroimaging in clinical therapeutic trials. Advanced neuroimaging techniques will continue to develop and offer significant opportunities to facilitate the development of new effective treatments for ALS.

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Section: Mrssupporting

confidence: 64%

Section: Mrssupporting

confidence: 57%

Neuroimaging as a New Diagnostic Modality in Amyotrophic Lateral Sclerosis

Verstraete

Foerster

2015

Neurotherapeutics

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“…Glutamate excitotoxicity has been implicated as a pathophysiologic mechanism in many neurodegenerative syndromes, including ALS [1,2]. A lack of neuroinhibitory function may result in unopposed excitotoxic neuronal damage in Amyotrophic Lateral Sclerosis (ALS) [6]. It has been reported that glutamate levels in cerebrospinal fluid are elevated in patients with ALS [1].…”

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confidence: 99%

“…Over recent years there has been a particular interest in using this technique to detect biologically relevant alterations in GABA concentrations [10,11]. High field strengths have improved signal-to-noise with a better separation of metabolic peaks, such as glutamate and GABA, which play an important role in the ALS pathogenesis [6,11,12]. MRS studies have confirmed the finely tuned balancing act between glutamate and GABA in the human brain both biochemically, as the huge majority of GABA is metabolized from glutamate, and functionally, with regard to the strict control of the inhibitory/excitability balance in healthy [6,12].…”

mentioning

confidence: 99%

“…High field strengths have improved signal-to-noise with a better separation of metabolic peaks, such as glutamate and GABA, which play an important role in the ALS pathogenesis [6,11,12]. MRS studies have confirmed the finely tuned balancing act between glutamate and GABA in the human brain both biochemically, as the huge majority of GABA is metabolized from glutamate, and functionally, with regard to the strict control of the inhibitory/excitability balance in healthy [6,12]. However, it has been reported that MRS gives a less accurate reflection of glutaminergic actions than GABAergic activity [10,11].…”

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And what about Gaba Magnetic Resonance Spectroscopy as an Indirect Tool to Evaluate Riluzole Efficacy in Amyotrophic Lateral Sclerosis?

Mazzei¹

2013

J Mol Biomark Diagn

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Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis

Foerster

Carlos

Dwamena

et al. 2014

Ann Clin Transl Neurol

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ObjectiveReliable biomarkers for amyotrophic lateral sclerosis (ALS) are needed, given the clinical heterogeneity of the disease. Here, we provide proof-of-concept for using multimodal magnetic resonance imaging (MRI) as a diagnostic biomarker for ALS. Specifically, we evaluated the added diagnostic utility of proton magnetic resonance spectroscopy (MRS) to diffusion tensor imaging (DTI).MethodsTwenty-nine patients with ALS and 30 age- and gender-matched healthy controls underwent brain MRI which used proton MRS including spectral editing techniques to measure γ-aminobutyric acid (GABA) and DTI to measure fractional anisotropy of the corticospinal tract. Data were analyzed using logistic regression, t-tests, and generalized linear models with leave-one-out analysis to generate and compare the resulting receiver operating characteristic (ROC) curves.ResultsThe diagnostic accuracy is significantly improved when the MRS data were combined with the DTI data as compared to the DTI data only (area under the ROC curves (AUC) = 0.93 vs. AUC = 0.81; P = 0.05). The combined MRS and DTI data resulted in sensitivity of 0.93, specificity of 0.85, positive likelihood ratio of 6.20, and negative likelihood ratio of 0.08 whereas the DTI data only resulted in sensitivity of 0.86, specificity of 0.70, positive likelihood ratio of 2.87, and negative likelihood ratio of 0.20.InterpretationCombining multiple advanced neuroimaging modalities significantly improves disease discrimination between ALS patients and healthy controls. These results provide an important step toward advancing a multimodal MRI approach along the diagnostic test development pathway for ALS.

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An Imbalance Between Excitatory and Inhibitory Neurotransmitters in Amyotrophic Lateral Sclerosis Revealed by Use of 3-T Proton Magnetic Resonance Spectroscopy

Cited by 122 publications

References 51 publications

Neuroimaging as a New Diagnostic Modality in Amyotrophic Lateral Sclerosis

Neuroimaging as a New Diagnostic Modality in Amyotrophic Lateral Sclerosis

And what about Gaba Magnetic Resonance Spectroscopy as an Indirect Tool to Evaluate Riluzole Efficacy in Amyotrophic Lateral Sclerosis?

Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis

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