SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage

Abstract

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

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

“…To measure cortical thickness, we used FreeSurfer, an automatic segmentation-based post-processing algorithm with advantages over VBM (25). 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.…”

“…VBM also showed significantly decreased gray-matter volume in the thalamus and lentiform nuclei in SPG11-HSP (27). Using the T1-MultiAtlas tool, Faber et al (26) found significantly decreased thalamus, accumbens nucleus, putamen, substantia nigra, amygdala, and red nucleus volumes in SPG11-HSP. These findings are consistent with our results of FIRST analysis, which demonstrated extensive deep gray-matter abnormality.…”

SPG11‐related parkinsonism: Clinical profile, molecular imaging and l‐dopa response

“…The 22 patients described belonged to 14 families; seven harbored homozygous mutations, and seven were compound heterozygous (details in Table ) . Eleven of the 22 patients were men.…”

“…Another example is provided by DBS surgery, which promotes symptomatic improvement in PD patients through inhibition of the thalamus or globus pallidus internus. SPG11 is indeed characterized by widespread deep gray matter damage …”

Cross sign T2 hyperintensities in atrophic spinal cord of hereditary spastic paraplegia type 5

“…Upon further investigation, we found that the spinal cord of SPG5 patients was atrophied but without correlation to the extent of disability or duration of disease, as reported for other subtypes of HSP (14). The lack of correlation may be partially explained by slow progression of SPG5 and low sensitivity of the imaging biomarker (spinal cord area).…”