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Diffusion tensor spectroscopy (DTS) combines features of magnetic resonance spectroscopy and diffusion tensor imaging and permits evaluating cell-type specific properties of microstructure by probing the diffusion of intracellular metabolites. This exploratory study investigates for the first time microstructural changes in the neuronal and glial compartments of the brain of patients with amyotrophic lateral sclerosis (ALS) using DTS. To this end, the diffusion properties of the neuronal metabolite tNAA (N-acetylaspartate + N-acetylaspartylglutamate) and the predominantly glial metabolites tCr (creatine + phosphocreatine) and tCho (choline-containing compounds) were evaluated in the primary motor cortex of 24 ALS patients and 27 healthy controls. Significantly increased values in the diffusivities of all three metabolites were found in ALS patients relative to controls. Further analysis revealed more pronounced microstructural alterations in ALS patients with limb onset than with bulbar onset relative to controls. This observation may be related to the fact that the spectroscopic voxel was positioned in the part of the motor cortex where the motor functions of the limbs are represented. The higher diffusivities of tNAA may reflect neuronal damage and/or may be a consequence of mitochondrial dysfunction in ALS. Increased diffusivities of tCr and tCho are in line with reactive microglia and astrocytes surrounding degenerating motor neurons in the primary motor cortex of ALS patients. This pilot study demonstrates for the first time that cell-type specific microstructural alterations in the brain of ALS patients may be explored in vivo and non-invasively with DTS. In conjunction with other microstructural magnetic resonance imaging techniques, DTS may provide further insights into the pathogenic mechanisms that underlie neurodegeneration in ALS.