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.

Cortical Damage Associated With Cognitive and Motor Impairment in Hereditary Spastic Paraplegia: Evidence of a Novel SPAST Mutation

“…Our findings are consistent with those of Faber et al (26), who found decreased cortical thickness in the precentral and paracentral motor cortices, superior parietal cortices, superior temporal gyrus, and cingulate cortices in SPG11-HSP, which suggests that SPG4-HSP and SPG11-HSP have similar cortical mechanisms. However, Rezende et al (15) did not find cortical thinning in SPG4-HSP on FreeSurfer analysis. This difference in the results of their study and our study may be attributable to the fact that our patients were recruited from a family.…”

“…It is linked to abnormal brain function in terms of the cerebral blood flow (9), neuronal biochemistry (10), cortical sensorimotor function (11), and resting-state neuronal activity (12). Moreover, damage has been found in brain structures in the white matter, including the corticospinal tracts, cingulum, cerebral pedicle, internal capsule, cerebellum, and corpus callosum (3,(13)(14)(15).…”

Multiparametric 3T MRI evaluation of hereditary spastic paraplegia: A case report

“…In the complicated form, there is widespread grey matteratrophy, particularly at the basal ganglia, which explains the more heterogeneous phenotype that frequently includes parkinsonism and dystonia. [ 6 ] These findings in isolation are not useful in diagnosis but when present simultaneously along with spinal cord changes are highly suggestive of HSP. Additional reported findings include bilateral medial frontal atrophy, widening of interhemispheric fissure, and reduced size of thalamus.…”

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.…”