Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. Most MR studies on HSP include very heterogeneous samples of patients, and findings were inconsistent. Here, we examined six patients with pure HSP and SPG4 mutations by clinical evaluation, detailed neuropsychological testing, and neuroimaging analyses, including conventional MRI, diffusion tensor imaging (DTI), and brain volumetry. Differences of voxel-wise statistics and ROI-based analysis of DTI data between patients and 32 healthy volunteers were evaluated. Although conventional MRI and brain volumetry were normal, DTI revealed widespread disturbance of white matter (WM) integrity (P < 0.001), mainly affecting the corticospinal tract. With longer disease duration, frontal regions were also involved. The WM changes were also present in subclinical subjects harbouring the pathogenic mutation. These subtle WM abnormalities have functional relevance because they correlated with clinical symptoms. Thus, early alterations of nerve fibres, which can be detected by DTI, might serve as a biological marker in HSP, in particular with respect to future longitudinal studies.
