Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes

Abstract

A BS TRACT: Background: Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes. Objective: We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates. Methods: We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n = 84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum. Results: Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum. Conclusions: Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease.

Positive DAT-SCAN in SPG7: a case report mimicking possible MSA-C

“…Despite the lack of evidence of basal ganglia abnormalities on MRI in previous studies and in our MRI imaging [ 32 ], we observed nigrostriatal degeneration on the DAT-SCAN imaging, which could be related either to nigral degeneration or to dysfunction of the nigrostriatal synapses.…”

Neuropsychology and MRI correlates of neurodegeneration in SPG11 hereditary spastic paraplegia

“…Our observation of a rostro-caudal gradient of white matter volume decrease in SPG11 matches findings of previous studies: a frontal predominant decrease of fractional anisotropy was described in a study on 5 SPG11 patients [25]. Widespread and severe white matter damage was also observed in a combined VBM/DTI study on 24 SPG11 patients, with inverse correlations of ACE-R scores and fractional anisotropy for most tracts [15,26]. In this VBM-based analysis, cortical grey matter involvement was limited to motor regions and associative cortices whereas subcortical grey matter regions were predominantly affected.…”

Phosphorylation of Spastin Promotes the Surface Delivery and Synaptic Function of AMPA Receptors

“…Although increasing research has shown that SPG4-linked HSP is associated with cognitive dysfunction (Orlacchio et al, 2004 ; Murphy et al, 2009 ; Chelban et al, 2017 ; Akaba et al, 2021 ; Erfanian Omidvar et al, 2021 ; Giordani et al, 2021 ), the studies on its mechanism remain few. Brain abnormalities in regions including the cerebral cortex, corpus callosum, hippocampus, and thalamus were observed in patients with SPG4-HSP (Orlacchio et al, 2004 ; Murphy et al, 2009 ; Servelhere et al, 2021 ). In addition, mice with spastin depletion exhibited working and associative memory deficits and reduced function of hippocampal synapses (Lopes et al, 2020 ).…”