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

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 (1)H-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 (1)H-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 (1)H MRS studies may also increase the sensitivity of the technology to changes in these neurochemicals, particularly in early stages of disease progression.