Differential tractography detects white matter microstructural impairments in amyotrophic lateral sclerosis

The pathogenesis of amyotrophic lateral sclerosis (ALS) critically involves white matter (WM) degeneration. This study aimed to employ differential tractography to investigate WM microstructural alterations in ALS and their associations with disease severity. This study enrolled 40 ALS patients and 66 healthy controls who underwent diffusion MRI. Quantitative anisotropy (QA), a diffusion metric reflecting axonal density, was used to assess microstructural alterations in WM tracts. Differential tractography was applied to identify WM tracts affected by significant reductions in QA, thereby mapping the distribution of axonal injury in ALS. Correlational tractography was employed to assess the association between WM tract damage and clinical disease severity. Differential tractography revealed a relatively consistent pattern of WM tracts exhibiting decreased QA, primarily involving the bilateral corticospinal tracts (CST), bilateral superior corticostriatal tracts, bilateral medial lemnisci, body and forceps minor of the corpus callosum, left parietal corticopontine tract, and left anterior thalamic radiation. The most significant and extensive decline in QA was observed in bilateral CST. Positive correlations were observed between ALSFRS-R decline and QA reduction in several WM tracts, particularly the left CST, which correlated most closely with clinical progression, as well as the body and forceps major of the corpus callosum, the left parietal corticopontine tract, and the left corticobulbar tract. Our findings confirmed that axonal injury and myelination were pivotal pathophysiological processes in ALS. The prominent axonal impairment in the CST, coupled with its strong correlation with clinical severity, suggested that CST integrity measurement might serve as a favorable imaging biomarker for ALS. • Differential tractography enables direct visualization of white matter tracts with significant neuronal damage in ALS by identifying specific segments of affected fiber tracts. • Affected tracts exhibited significantly reduced axonal density, with the bilateral CSTs showing the most prominent and extensive decline. • Axonal damage in several WM tracts, particularly the left corticospinal tract and corpus callosum, correlated with disease progression, supporting the potential of the tractography-based measurement as an imaging marker for monitoring ALS.