Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations

Abstract

Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous disorders with the hallmark of progressive spastic gait disturbance. We used advanced neuroimaging to identify brain regions involved in SPG4, the most common HSP genotype. Additionally, we analyzed correlations between imaging and clinical findings. We performed 3T MRI scans including isotropic high-resolution 3D T1, T2-FLAIR, and DTI sequences in 15 adult patients with genetically confirmed SPG4 and 15 age- and sex-matched healthy controls. Brain volume loss of gray and white matter was evaluated through voxel-based morphometry (VBM) for supra- and infratentorial regions separately. DTI maps of axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), and measured anisotropy (MA1) were analyzed through tract-based special statistics (TBSS). VBM and TBSS revealed a widespread affection of gray and white matter in SPG4 including the corpus callosum, medio-dorsal thalamus, parieto-occipital regions, upper brainstem, cerebellum, and corticospinal tract. Significant correlations with correlation coefficients r > 0.6 between clinical data and DTI findings could be demonstrated for disease duration and disease severity as assessed by the spastic paraplegia rating scale for the pontine crossing tract (AD) and the corpus callosum (RD and FA). Imaging also provided evidence that SPG4 underlies a primarily axonal rather than demyelinating damage in accordance with post-mortem data. DTI is an attractive tool to assess subclinical affection in SPG4. The correlation of imaging findings with disease duration and severity suggests AD, RD, and FA as potential progression markers in interventional studies.

Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

“…The common DTI indices are: fractional anisotropy, a measure of sensitivity to changes in orientation of axons along the tracts; mean diffusivity, a measure of magnitude of water diffusion and the presence of obstacles to diffusion [14,15], and radial diffusion, used to differentiate axonal injury from demyelination [13]. The most common radiological changes in a variety of HSP gene mutations are alterations in the corticospinal tract (70% of all studies, 71% of SPAST studies) and corpus callosum (80% of all studies, 86% of SPAST studies) [16,17,18,19,20,21,22,23,24,25]. Loss or damage to axons in the corticospinal tract are consistent with the motor symptoms of the disease, although white matter disturbances are not confined to the corticospinal tract and corpus callosum with involvement at the whole brain level, frontal and temporal lobes, cerebellum, and other regions.…”

“…These changes are consistent with widely distributed axonal damage in the white matter of the brain, including the corticospinal tract, which contains the axons of the motor neurons projecting to the lower motor neurons in the distal spinal cord, whose degeneration is responsible for the clinical manifestations of HSP. There is evidence for correlation between radiological findings and disease severity and duration [16,17,19,24]. Future clinical investigations could consider examining late-stage SPAST HSP patients for evidence of non-motor manifestations that are seen in patients with other HSP mutations [27].…”

Hereditary spastic paraplegia from 1880 to 2017: an historical review

“…Both authors showed correlations between white matter tract disruption and disease severity, indicating that diffusion tensor imaging measures could be used as biomarkers. Rezende and colleagues also demonstrated the absence of cortical thinning as a hallmark of this pure subtype of HSP 44,45 . Regarding HSP-SPG11, both França et al 46 and Pan et al 47 revealed widespread white matter microstructural disruption.…”

“…They demonstrated that microstructural brain abnormalities are rather diffuse and not restricted to motor pathways, when one analyzes multiple subtypes of HSP. Lindig 44 and Rezende 45 , both in 2015, made substantial contributions to the delineation of the extent of neurodegeneration specifically associated with HSP-SPG4. Both authors showed correlations between white matter tract disruption and disease severity, indicating that diffusion tensor imaging measures could be used as biomarkers.…”

Translation and validation into Brazilian Portuguese of the Spastic Paraplegia Rating Scale (SPRS)

“…This tool is easy to use in the clinic, and presented good reliability and validity as a measure of disease severity 6 . Several studies employed SPRS in cohorts of patients with HSP 3,7,8,9,10 . Taking into account that there are no such instruments available in our language, we designed this study to validate the Brazilian Portuguese version of SPRS.…”