Abstract
The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; Rρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; Rρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; Rρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, Rρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T 1H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons leading to muscle atrophy, weakness, and death due to respiratory failure
ALS as well as healthy controls (HC) participants reported dizziness when moved within the fringe field of the 7T, which subsided after lying still in the scanner
There was no significant difference between ALS and HC subjects in the ratios of cerebrospinal fluid (CSF) (P = 0.76), gray matter (P = 0.71) and white mater (P = 0.39)
Summary
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons leading to muscle atrophy, weakness, and death due to respiratory failure. To this date, no treatment prevents, halts, or reverses the disease; though the FDA-approved drug riluzole provides a modest survival benefit. Proposed pathogenic mechanisms include mitochondrial dysfunction, glutamate-mediated excitotoxicity, endoplasmic reticulum stress, free radical-mediated oxidative cytotoxicity, and neuroinflammation including microglia activation and astrogliosis [2]. These mechanisms lead to progressive neuronal loss. Studies of the SOD1 rodent models of ALS suggest that glutamate excitotoxicity and neuroinflammation are the drivers of neuronal death and ALS progression [3, 4]
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