Objective: SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive retrograde degeneration, or "dying-back" phenomenon, of the corticospinal tract's longest axons. Neuroimaging studies mainly focus on white matter changes and, although previous studies reported cortical thinning in complicated HSP forms, cortical changes remain unclear in SPG4 patients. This work aimed to compare changes in white matter microstructure and cortical thickness between 12 SPG4 patients and 22 healthy age-matched controls. We also explore whether white matter alterations are related to cortical thickness and their correlation with clinical symptoms. Methods: we used fixel-based analysis, an advanced diffusion-weighted imaging technique, and probabilistic tractography of the corticospinal tracts. We also analyzed cortical morphometry using whole-brain surface-based and atlas-based methods in sensorimotor areas. Results: SPG4 patients showed bilateral involvement in the corticospinal tracts; this was more intense in the distal portion than in the upper segments and was associated with the degree of clinical impairment. We found a significant correlation between disease severity and fiber density and cross-section of the corticospinal tracts. Furthermore, corticospinal tract changes were significantly correlated with bilateral cortical thinning in the precentral gyrus in SPG4 patients. Conclusions: Our data point to axonal damage of the corticospinal motor neurons in SPG4 patients might be related to cortical thinning in motor regions.
Keywords: Hereditary spastic paraparesis; SPG4; cortical thickness; corticospinal; neuroimaging.