Reorganization of functional brain network architecture in SPG4: Evidence from resting-state fMRI

Background/objectives: Spastic paraplegia type 4 (SPG4), the most prevalent pure Hereditary Spastic Paraplegia (HSP), is mainly characterized by progressive lower limb spastic weakness, due to corticospinal system degeneration. However, more recent studies suggest a widespread pathophysiologic involvement of additional systems. We here investigated alterations in resting-state functional connectivity (FC) and large-scale brain network topology in SPG4, and their relationship with clinical features. Methods: Forty patients with SPG4 and 40 age- and sex-matched healthy controls underwent 3T MRI scanning. Resting-state fMRI data were analyzed using seed-based FC from limb-specific primary motor cortex regions and graph-theoretical measures of whole-brain network topology. Between-group comparisons and correlations with clinical scores (Spastic Paraplegia Rating Scale (SPRS), Modified Ashworth Scale (MAS)) were performed (p < 0.05, FDR-correction). Results: Compared with controls, SPG4 patients showed increased FC between the lower-limb motor seed and motor-premotor areas. Also, SPG4 patients showed widespread FC reductions between upper- and lower-limb motor seeds and posterior cortical/cerebellar regions. Graph-theoretical analyses showed reduced global efficiency and increased small-world metrics in SPG4 compared with controls. At the nodal level, local efficiency and clustering were increased in fronto-parietal regions. In patients, better motor status was associated with stronger motor-premotor FC and weaker motor-posterior coupling. Likewise, greater local network organization was associated with better clinical status. Conclusions: SPG4 pathophysiology is mainly characterized by widespread disruption of large-scale functional pathways and local compensatory reorganization, associated with progressive spasticity and motor impairment, as shown by alterations of resting-state FC and network topology. Our findings support the clinical application of functional measures as biomarkers of disease-related changes in SPG4.