Brain White Matter Involvement in Hereditary Spastic Paraplegias: Analysis with Multiple Diffusion Tensor Indices

BACKGROUND AND PURPOSE:The hereditary spastic paraplegias are a group of genetically heterogeneous neurodegenerative disorders, characterized by progressive spasticity and weakness of the lower limbs. Although conventional brain MR imaging findings are normal in patients with pure hereditary spastic paraplegia, microstructural alteration in the cerebral WM can be revealed with DTI. Concomitant investigation of multiple intrinsic diffusivities may shed light on the neurobiologic substrate of the WM degeneration pattern in patients with pure hereditary spastic paraplegia across the whole brain.MATERIALS AND METHODS:Tract-based spatial statistics analysis was performed to compare fractional anisotropy and mean, axial, and radial diffusivities of the WM skeleton in a group of 12 patients with pure hereditary spastic paraplegia and 12 healthy volunteers. Data were analyzed counting age and sex as nuisance covariates. The threshold-free cluster-enhancement option was applied, and the family-wise error rate was controlled by using permutation tests for nonparametric statistics.RESULTS:In pure hereditary spastic paraplegia, group widespread fractional anisotropy decreases and radial diffusivity and mean diffusivity increases (P < .05, corrected) were found. No voxelwise difference was observed for the axial diffusivity map. Percentage of voxels within the WM skeleton that passed the significance threshold were 51%, 41.6%, and 11.9%, respectively, for radial diffusivity, fractional anisotropy, and mean diffusivity clusters. An anteroposterior pattern with preferential decrease of fractional anisotropy in the frontal circuitry was detected.CONCLUSIONS:In patients with pure hereditary spastic paraplegia, alterations in multiple DTI indices were found. Radial diffusivity seems more sensitive to hereditary spastic paraplegia–related WM pathology and, in line with the lack of axial diffusivity changes, might indicate a widespread loss of myelin integrity. A decrease of fractional anisotropy alone in the frontal circuitry may reflect subtle disruption of the frontal connections.

The hereditary spastic paraplegias (HSPs), also called familial spastic paraparesis or Strümpell-Lorrain disease, represent a genetically and clinically heterogeneous group of neurodegenerative disorders.¹ The main clinical feature is progressive spasticity due to slowly progressing “dying back” axonal degeneration, which is maximal in the terminal portions of the longest descending and ascending tracts.² On the basis of clinical symptoms, HSPs are classified into pure or uncomplicated, in which the spastic paraplegia is the major clinical manifestation; and complex or complicated forms, presenting with additional neurologic signs, such as intellectual disability or cognitive decline, deafness, cerebellar ataxia, epilepsy, dysarthria, peripheral neuropathy, optic atrophy, and visual dysfunction.³ Autosomal dominant, autosomal recessive, or X-linked inheritance is associated with multiple genes or loci and leads to genetic heterogeneity of this disorder. The HSP loci are designated as spastic paraplegia loci and are numbered 1–56 according to their discovery.⁴ There is scarce evidence about the epidemiology of HSP, though its prevalence is estimated at 1.27:100,000 population in Europe.⁵Findings of conventional MR imaging of the brain are usually normal in pure hereditary spastic paraplegia (pHSP). In contrast, nonspecific findings such as cortical atrophy and subcortical and periventricular WM alterations are present in complicated HSP.⁶ Distinct MR imaging findings may accompany complicated HSP; for instance, a common form of autosomal recessive HSP with SPG11 mutation (linked to the 15q13-q15 chromosome) is frequently associated with a thin corpus callosum.⁷ Optic nerve and cerebellar atrophy may be revealed when visual symptoms and cerebellar ataxia are present.⁸DTI is an efficient technique used to characterize the in vivo microstructural organization of the WM.⁹ The common DTI indices are fractional anisotropy (FA) (sensitive to microstructural changes and associated with the presence of oriented structures in tissue) and mean diffusivity (MD) (characterizes mean-square displacement of molecules and the overall presence of obstacles to diffusion).¹⁰ Other indices, axial diffusivity (AD) and radial diffusivity (RD), offer suggestive elements to differentiate axonal injury and demyelination.¹¹ To extend our knowledge of the neurobiologic basis of WM pathology, using multiple diffusivity matrices (FA, MD, RD, and AD) is recommended.¹²The present study was set up to investigate WM alterations across the whole brain in a group of patients with pHSP with SPG4, SPG5, SPG3a, and SPG10 mutations, applying tract-based spatial statistics (TBSS) analysis with multiple DTI indices.