Structural brain changes contributing to motor signs in pure hereditary spastic paraplegia type 4

Background/Objectives: Spastic paraplegia type 4 (SPG4; also known as SPAST-HSP), the most prevalent variant among pure Hereditary Spastic Paraplegias (HSPs), is clinically characterized by progressive spasticity and weakness in the lower limbs. The present neuroimaging study specifically investigated possible changes in the corticospinal (CST) and thalamo-cortical tracts (TCT) structural integrity and broader cortical, subcortical and spinal pathways, topographically related to upper and lower limbs in SPG4. Methods: Forty patients with SPG4 and 40 age- and sex-matched healthy controls underwent 3 T MRI scanning. MRI analyses included: (1) global and primary motor areas cortical thickness; (2) cortical, basal ganglia, thalamic and cerebellar volumetry; (3) diffusion-based probabilistic tractography of CST and TCT serving the arms and legs; and (4) spinal cord area. Results: SPG4 patients showed significant reductions in thalamic volumes as well as spinal cord area when compared with controls. The volume reduction in thalamic regions correlated with disease severity and spasticity-related impairments. Structural changes in CST and TCT tracts in SPG4 patients were prominent in bundles topographically related to the lower limbs compared with the upper limbs. Conclusions: Our findings point to significant thalamic atrophy as well as white matter tract degeneration topographically related to the lower limbs in SPG4 patients. The findings overall suggest new potential markers for disease progression and functional decline in SPG4 patients.