Glutamine and NAA dissociate in ALS across somatotopically defined motor regions using 7T MRSI

Amyotrophic lateral sclerosis (ALS) is increasingly understood as a progressive neurodegenerative disorder with distributed cortical and subcortical involvement, but in vivo metabolic mapping has been limited by the spatial coverage of single-voxel proton magnetic resonance spectroscopy (MRS). We acquired high-resolution whole-brain 7T 3D-CRT-FID-MRSI alongside motor-cortex single-voxel sLASER in five rapidly progressing people living with ALS (plALS) and seven non-neurodegenerative controls (NCs), with up to three sessions per participant. Regional metabolite ratios (N-Acetylaspartate [tNAA], glutamate [Glu], glutamine [Gln] to creatine [tCr], and Glu+Gln [Glx] to tNAA) were modelled with Bayesian hierarchical mixed-effects models, and the primary motor cortex was subdivided along its dorsoventral somatotopic axis (bulbar/face, hand/upper-limb, foot/lower-limb). At baseline, plALS showed a motor-cortex-selective tNAA/tCr deficit (motor composite −8.7%, 95% credible Interval [CrI] −16.1 to −1.1, posterior probability=0.99) accompanied by cortically diffuse glutamatergic elevation (Gln/tCr +25.6%, posterior probability=0.96; Glx/tNAA +10.4%, posterior probability=0.95). Reliable separation of the J-coupled glutamine and glutamate resonances at 7T revealed Gln/tCr as a more sensitive marker of glutamatergic dysregulation than Glu/tCr alone in this cohort. Within the somatotopic subdivision, all five plALS showed their peak Gln/tCr increase in the bulbar/face zone irrespective of clinical onset, including three lower-limb-onset patients. Annualised metabolite slope by zone correlated with the matched ALSFRS-R domain decline (Glx/tNAA r=0.82, p<0.001). Group-level longitudinal interactions were modest. Bayesian assurance simulations indicated Glx/tNAA as the most efficient candidate primary endpoint for a confirmatory cross-sectional study. These findings demonstrate that 7T whole-brain MRSI can resolve a metabolic dissociation between motor-selective neuronal compromised and somatotopically patterned glutamatergic dysregulation in ALS and provide design-ready endpoint and sample-size guidance for utility as a structural biomarker of brain function in clinical trials.