Cerebellar involvement in sporadic amyotrophic lateral sclerosis: a magnetic resonance spectroscopy study

Abstract Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem neurodegenerative disorder, and recent evidence suggests that the cerebellum may contribute to disease pathology, although cerebellar metabolic alterations have not previously been demonstrated in vivo. This study investigated cerebellar metabolic and structural changes using proton magnetic resonance spectroscopy (1H-MRS) and volumetric imaging. Thirty patients with ALS (21 M, mean age 59.7 ± 7.6 years), 22 healthy controls (HC, 10 M, mean age 59.8 ± 9.6 years), and 16 individuals with hereditary spastic paraplegia type 4 (SPG4, 8 M, mean age 50.8 ± 12.5 years), a potential clinical mimic, underwent 3T MRI and 1H-MRS with a single-voxel positioned in the left cerebellar hemisphere. Patients with ALS showed significant reductions in myo-inositol/creatine (p=0.01) and glutathione/creatine (p = 0.005), compared with HC, together with selective volume loss in cerebellar lobules I–IV, V, VI, and Crus I. Among metabolites, glutathione/creatine had the highest discriminative accuracy for ALS vs both HC and SPG4, with areas under the curve of 0.80 and 0.71, respectively. These findings reveal distinct cerebellar metabolic alterations in ALS, providing further evidence for cerebellar involvement in disease pathology and highlighting cerebellar 1H-MRS as a potential adjunct to diagnostic evaluation.