Abstract
Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.
Highlights
Neurodegeneration and neuroinflammation are the two major mechanisms in amyotrophic lateral sclerosis (ALS)
MR imaging and spectroscopic data are shown in Figure 1 for a subject with a high ALSFRS-R score and Percent (n) or mean (SD)
Rate of disease progression is presented as monthly change in ALSFRS-R total score
Summary
Neurodegeneration and neuroinflammation are the two major mechanisms in amyotrophic lateral sclerosis (ALS). The dynamics of biological events is uncertain, heterogeneous, and variable in human ALS, yet it determines the clinical trajectory of disease progression in patients. Oxidative stress [7] has been implicated as a key factor in the mechanisms of ALS disease. Reduced glutathione (GSH) is the major antioxidant used by mammalian cells to reduce reactive oxidative species (ROS), and the imbalance between the reductive capacity of the brain tissue and the production of reactive oxygen species results in a cellular environment that denaturates proteins [8], DNA, RNA, and unsaturated fatty acids. Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients
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