Brain Metabolite Profiles are Associated with Selective Neuronal Vulnerability and Underlying Mechanisms in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurological syndrome accompanied by selective degeneration of somatic motor neurons and neurochemistry alterations. Nevertheless, eye movement's nuclei are relatively spared from ALS damage. This survey was to probe metabolite changes in the primary motor cortex (PMC) and interstitial nucleus of Cajal (INC) of ALS patients using proton magnetic resonance spectroscopy (¹H-MRS). In this case-control study, 20 patients with ALS and 20 healthy controls underwent 1.5 T MRI and multivoxel ¹H-MRS. ¹H-MRS spectra to determine metabolite profiles including tNAA, mIns, tCr, tCho, and also tNAA/tCr, tNAA/tCho, and mIns/tNAA metabolite ratios from the PMC and INC were quantified via a point resolved spectroscopy pulse (PRESS) sequence in two groups. Further, the associations between ¹H-MRS markers with forced vital capacity (FVC), ALS functional rating scale (ALSFRS-R), and disease progression rate (ΔFS) were investigated. In the PMC, tNAA and tNAA/tCr were significantly lower in ALS patients than the healthy controls, but mIns and mIns/tNAA were significantly greater in these patients (<i>p</i> < 0.05). In the INC, tCho and mIns concentrations, and mIns/tNAA ratio were significantly increased (<i>p</i> < 0.05) in ALS patients, while tNAA and tNAA/tCr ratio did not show significant discriminations between the two groups (<i>p</i> > 0.05). The PMC tNAA/Cr ratio is associated with ALSFRS-R (<i>p</i> = 0.001, <i>r</i> = 0.71), FVC (<i>p</i> = 0.03, <i>r</i> = 0.58), and ΔFS (<i>p</i> = 0.01, <i>r</i> = -0.33). The mIns/tNAA ratio in PMC is also associated with ΔFS (<i>p</i> = 0.02, <i>r</i> = 0.41). In the INC, tCho concentrations (<i>p</i> = 0.04, <i>r</i> = -0.54) and mIns/tNAA ratio (<i>p</i> = 0.02, <i>r</i> = -0.38) were negatively associated with ALSFRS-R and positively correlated with ΔFS (<i>p</i> = 0.01, <i>r</i> = 0.33) and (<i>p</i> = 0.001, <i>r</i> = 0.61), respectively. The study suggests that neurochemistry changes in ALS patients' brains are linked to selective neuronal vulnerability and the underlying pathophysiology of the disease.