Multimodal MRI-based study in patients with SPG4 mutations

Abstract

Mutations in the SPG4 gene (SPG4-HSP) are the most frequent cause of hereditary spastic paraplegia, but the extent of the neurodegeneration related to the disease is not yet known. Therefore, our objective is to identify regions of the central nervous system damaged in patients with SPG4-HSP using a multi-modal neuroimaging approach. In addition, we aimed to identify possible clinical correlates of such damage. Eleven patients (mean age 46.0 ± 15.0 years, 8 men) with molecular confirmation of hereditary spastic paraplegia, and 23 matched healthy controls (mean age 51.4 ± 14.1years, 17 men) underwent MRI scans in a 3T scanner. We used 3D T1 images to perform volumetric measurements of the brain and spinal cord. We then performed tract-based spatial statistics and tractography analyses of diffusion tensor images to assess microstructural integrity of white matter tracts. Disease severity was quantified with the Spastic Paraplegia Rating Scale. Correlations were then carried out between MRI metrics and clinical data. Volumetric analyses did not identify macroscopic abnormalities in the brain of hereditary spastic paraplegia patients. In contrast, we found extensive fractional anisotropy reduction in the corticospinal tracts, cingulate gyri and splenium of the corpus callosum. Spinal cord morphometry identified atrophy without flattening in the group of patients with hereditary spastic paraplegia. Fractional anisotropy of the corpus callosum and pyramidal tracts did correlate with disease severity. Hereditary spastic paraplegia is characterized by relative sparing of the cortical mantle and remarkable damage to the distal portions of the corticospinal tracts, extending into the spinal cord.

Fig 1. TBSS analyses showing microstructural damage in SPG4-HSP.

TBSS results showing areas of reduced FA and increased MD, RD and AD in patients with SPG4 mutations after comparison with age and sex matched controls. Areas with reduced FA and increased MD, RD and AD are shown in yellow-red and represent cluster based values (p<0.05, corrected). Results are shown on the MNI152 1 mm template.

Fig 2. Segmentation of spinal cord using Spineseg software.

Spineseg layout showing the segmentation of the cervical spinal cord at C2-C3 level in a control and a patient with SPG4-HSP.

Fig 3. Correlation Analyses of TBSS results and clinical data.

Upper lane—TBSS results showing white matter regions that presented significant negative correlation between disease duration and DTI parameters (first column—FA, Second column—MD, third column—RD). Lower lane—TBSS results showing white matter regions that presented significant negative correlation between Spastic paraplegia rating scale scores and DTI parameters (first column—FA, Second column—MD, third column—RD). Results are shown on the MNI152 1 mm template.