Different damage patterns depending on type
Patterns of brain abnormalities were found to be specific to HSP types in this study of SPG3A, SPG4, SPG7, SPG8 and SPG11.
As well, differences were found between autosomal dominant (mostly ‘pure’) and autosomal recessive (mostly ‘complicated’) forms of HSP. Notably, brain damage was not found in SPG3A.
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.
SOURCE: Mov Disord. 2021 Feb 11. doi: 10.1002/mds.28519. Online ahead of print. PMID: 33576112 © 2021 International Parkinson and Movement Disorder Society.
Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes
Katiane R Servelhere # 1 , Thiago Junqueira Ribeiro Rezende # 1 , Fabrício Diniz de Lima 1 , Mariana Rabelo de Brito 1 , Renan Flávio de França Nunes 1 , Raphael F Casseb 2 , José Luiz Pedroso 3 , Orlando Graziani P Barsottini 3 , Fernando Cendes 1 , Marcondes C França Jr 1
1. Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.
2. Seaman Family MR Research Center, University of Calgary, Calgary, Alberta, Canada.
3. Department of Neurology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
# Contributed equally.
* Ms. Emma Vought