1H Magnetic Resonance Spectroscopy to Understand the Biological Basis of ALS, Diagnose Patients Earlier, and Monitor Disease Progression

Abstract

At present, limited biomarkers exist to reliably understand, diagnose, and monitor the progression of amyotrophic lateral sclerosis (ALS), a fatal neurological disease characterized by motor neuron death. Standard MRI technology can only be used to exclude a diagnosis of ALS, but 1H-MRS technology, which measures neurochemical composition, may provide the unique ability to reveal biomarkers that are specific to ALS and sensitive enough to diagnose patients at early stages in disease progression. In this review, we present a summary of current theories of how mitochondrial energetics and an altered glutamate/GABA neurotransmitter flux balance play a role in the pathogenesis of ALS. The theories are synthesized into a model that predicts how pathogenesis impacts glutamate and GABA concentrations. When compared with the results of all MRS studies published to date that measure the absolute concentrations of these neurochemicals in ALS patients, results were variable. However, when normalized for neuronal volume using the MRS biomarker N-acetyl aspartate (NAA), there is clear evidence for an elevation of neuronal glutamate in nine out of thirteen studies reviewed, an observation consistent with the predictions of the model of increased activity of glutamatergic neurons and excitotoxicity. We propose that this increase in neuronal glutamate concentration, in combination with decreased neuronal volume, is specific to the pathology of ALS. In addition, when normalized to glutamate levels, there is clear evidence for a decrease in neuronal GABA in three out of four possible studies reviewed, a finding consistent with a loss of inhibitory regulation contributing to excessive neuronal excitability. The combination of a decreased GABA/Glx ratio with an elevated Glx/NAA ratio may enhance the specificity for 1H-MRS detection of ALS and ability to monitor glutamatergic and GABAergic targeted therapeutics. Additional longitudinal studies calculating the exact value of these ratios are needed to test these hypotheses and understand how ratios may change over the course of disease progression. Proposed modifications to the experimental design of the reviewed 1H MRS studies may also increase the sensitivity of the technology to changes in these neurochemicals, particularly in early stages of disease progression.

Movement-related beta modulation in amyotrophic lateral sclerosis depends on muscle strength: A magnetoencephalography study

“…A glutamate/GABA imbalance and hyperexcitability has been hypothesized as the cause of ALS. Several studies have investigated these neurotransmitters using magnetic resonance spectroscopy with some evidence for elevated glutamate and decreased GABA levels, suggesting a piece in the puzzle of neuronal excitability in ALS (29)…”

“…A glutamate/GABA imbalance and hyperexcitability has been hypothesized as the cause of ALS. Several studies have investigated these neurotransmitters using magnetic resonance spectroscopy with some evidence for elevated glutamate and decreased GABA levels, suggesting a piece in the puzzle of neuronal excitability in ALS (29) To further understand the interaction of ALS on the beta frequencies in our data we investigated the relationship between ERD/ERS changes and motor function in ALS and created a simple strength stratification of our ALS group based on the strength of the investigated limb. The results show that beta power for both ERD and ERS, changes depending on the severity of muscle deficits in the tested limb (right arm), likely driven by the progression of the disease.…”

“…In this study we investigate the neural oscillations occurring in the beta band (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) of the sensorimotor cortex in both active and passive movement tasks, using magnetoencephalography (MEG). This enables us to investigate whether ALS impacts only the movement output or also leads to changes in processing of input to the sensorimotor cortex.…”

Simultaneous PET/MRI: The future gold standard for characterizing motor neuron disease—A clinico-radiological and neuroscientific perspective

“…Numerous studies using varying techniques (single voxel or multivoxel) have consistently revealed reduced N-acetylaspartate (NAA, a chemical marker of neuronal integrity) in motor and extra-motor regions in ALS. Other metabolites of interest include myo-inositol (mIns, a glial marker), and the excitatory and inhibitory neurotransmitter system involving glutamate, glutamine, and GABA ( 159 ). Technological advances in MR hardware and spectral acquisition and editing methods have increased the ability to more readily resolve such metabolites.…”

Impact of acquisition and modeling parameters on test-retest reproducibility of edited GABA+

“…Prior work has reported differences in brain GABA levels across the healthy lifespan [1][2][3] , as well as in various psychiatric 4,5 and neurodegenerative conditions [6][7][8] .…”