Cerebello-Cortical Alterations Linked to Cognitive and Social Problems in Patients With Spastic Paraplegia Type 7: A Preliminary Study

Abstract

Spastic paraplegia type 7 (SPG7), which represents one of the most common forms of autosomal recessive spastic paraplegia (MIM#607259), often manifests with a complicated phenotype, characterized by progressive spastic ataxia with evidence of cerebellar atrophy on brain MRI. Recent studies have documented the presence of peculiar dentate nucleus hyperintensities on T2-weighted images and frontal executive dysfunction in neuropsychological tests in SPG7 patients. Therefore, we decided to assess whether any particular MRI pattern might be specifically associated with SPG7 mutations and possibly correlated with patients' cognitive profiles. For this purpose, we evaluated six SPG7 patients, studying the cerebello-cortical network by MRI voxel-based morphometry and functional connectivity techniques, compared to 30 healthy control subjects. In parallel, we investigated the cognitive and social functioning of the SPG7 patients. Our results document specific cognitive alterations in language, verbal memory, and executive function in addition to an impairment of social task and emotional functions. The MRI scans showed a diffuse symmetric reduction in the cerebellar gray matter of the right lobule V, right Crus I, and bilateral lobule VI, together with a cerebral gray matter reduction in the lingual gyrus, precuneus, thalamus, and superior frontal gyrus. The evidence of an over-connectivity pattern between both the right and left cerebellar dentate nuclei and specific cerebral regions (the lateral occipital cortex, precuneus, left supramarginal gyrus, and left superior parietal lobule) confirms the presence of cerebello-cortical dysregulation in different networks involved in cognition and social functioning in SPG7 patients.

Comparison of Cerebellar Grey Matter Alterations in Bipolar and Cerebellar Patients: Evidence from Voxel-Based Analysis

“…In line with the presence of typical cerebellar motor syndrome [ 19 , 55 , 69 ], an extensive pattern of GM loss involved motor anterior (i.e., I−IV, V) and posterior cerebellar regions (i.e., VIIIA and VIIIB). On the other hand, a pattern of GM loss was also found to extensively affect cognitive posterior cerebellar lobules, specifically crus I, crus II and lobe VI, in line with the presence of cognitive and emotional alterations as reported in CCAS [ 46 , 54 , 55 , 69 , 70 , 71 , 72 ]. Finally, when directly comparing BD and CD patients, significantly reduced cerebellar GM was found in the CD compared to the BD patients, only involving motor anterior cerebellar regions.…”

“…The comparison between cerebellar-related neurodegenerative syndromes (such as SCA) and BD mainly arises from the growing evidence of a cerebellar involvement in manic symptoms of BD [ 49 ] and the presence of mood disturbance in cerebellar diseases [ 46 ]. As largely demonstrated, the posterior cerebellum is involved in the processing of cognitive and emotional information and takes part in the network involved in mentalizing and social interactions [ 16 , 40 , 41 , 49 , 52 , 53 , 54 , 55 , 56 ]. Indeed, the cerebellar cortex receives direct and indirect inputs from cortical associative areas and the midbrain, and in turn, the cerebellar nuclei send signals back to the limbic lobe and hypothalamic and thalamic nuclei, important relay stations that connect cortical and subcortical structures [ 19 ].…”

“…On the other hand, the extended pattern of GM reductions in hemispheric and vermal posterior cerebellar regions may be linked to the specific cognitive alterations described in BD studies in light of the cerebellar role in several emotional and cognitive domains [ 16 , 19 , 40 , 48 , 49 , 54 , 56 , 59 ], that characterize bipolar disorder [ 6 , 7 , 38 , 60 , 61 , 62 , 63 ].…”

Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes

“…Novel techniques enable separate evaluation of cerebral gray (GM) and white (WM) matter structures, as well as the cerebellar lobules. Few studies, however, have employed such a comprehensive approach in HSP 8,10,16‐19 . Many reports also had small sample sizes 20,21 .…”

Recent advances in understanding hereditary spastic paraplegias and emerging therapies

“…On the contrary, patients carrying at least one Ala510Val variant showed more frequent cerebellar ataxia and later onset 24 . Although cerebellar atrophy is known to be a hallmark of SPG7 , a specific pattern of gray matter cerebellar atrophy that affects long-distance regions of the brain was recently shown to be associated with cognitive and social-ability impairment 25 . SPG7 is not the only SPG associated with cerebral atrophy.…”