Current findings, application, and diagnosis of magnetic resonance imaging in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder within the motor neuron disease (MND) spectrum, characterized by progressive degeneration of upper and lower motor neurons. The clinical phenotype ranges from pure motor syndromes to forms with cognitive and behavioral impairment, and the pathological burden extends beyond the motor system. Diagnosis remains primarily clinical, supported by electrophysiology and exclusion of mimics. Therefore, objective imaging biomarkers are urgently needed. Magnetic resonance imaging (MRI) is widely used as an auxiliary and differential diagnostic tool in ALS. T1- and T2-weighted imaging can assess cortical thickness, gray matter atrophy, and signal changes. Diffusion tensor imaging probes white matter microstructure. Magnetic resonance spectroscopy detects neurochemical alterations. Resting-state functional MRI assesses functional connectivity and network organization. Susceptibility-weighted imaging is sensitive to iron and calcium deposition. Ultra-high-field MRI provides higher resolution and improved metabolite quantification. This critical review summarizes current findings on MRI in ALS, but importantly organizes the evidence by the specific question being addressed: pathological/histological correlates, diagnostic or discriminatory performance, and clinical associations with phenotype, severity, progression, and prognosis. We also discuss major limitations, including methodological heterogeneity, limited standardization, small and clinically heterogeneous cohorts, frequent use of healthy rather than disease controls, and scarce multicenter validation. Although advanced MRI has revealed robust group-level alterations, none of these techniques has yet become established in routine clinical diagnosis of ALS. We, therefore, distinguish promising research findings from validated clinical biomarkers and outline priorities for future translation.