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Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations

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Abstract

Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous disorders with the hallmark of progressive spastic gait disturbance. We used advanced neuroimaging to identify brain regions involved in SPG4, the most common HSP genotype. Additionally, we analyzed correlations between imaging and clinical findings. We performed 3T MRI scans including isotropic high-resolution 3D T1, T2-FLAIR, and DTI sequences in 15 adult patients with genetically confirmed SPG4 and 15 age- and sex-matched healthy controls. Brain volume loss of gray and white matter was evaluated through voxel-based morphometry (VBM) for supra- and infratentorial regions separately. DTI maps of axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), and measured anisotropy (MA1) were analyzed through tract-based special statistics (TBSS). VBM and TBSS revealed a widespread affection of gray and white matter in SPG4 including the corpus callosum, medio-dorsal thalamus, parieto-occipital regions, upper brainstem, cerebellum, and corticospinal tract. Significant correlations with correlation coefficients r > 0.6 between clinical data and DTI findings could be demonstrated for disease duration and disease severity as assessed by the spastic paraplegia rating scale for the pontine crossing tract (AD) and the corpus callosum (RD and FA). Imaging also provided evidence that SPG4 underlies a primarily axonal rather than demyelinating damage in accordance with post-mortem data. DTI is an attractive tool to assess subclinical affection in SPG4. The correlation of imaging findings with disease duration and severity suggests AD, RD, and FA as potential progression markers in interventional studies.

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Notes

  1. SPG21, SPG46–SPG50, SPG54, SPG56, SPG63, SPG65–67 and SPG71.

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Acknowledgments

The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 2012–305121 “Integrated European—omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)” (to TR und LS) and was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (grant 1970-0-0 to RS), the European Union ((PIOF-GA-2012-326681) HSP/CMT genetics) to RS, and the German HSP-Selbsthilfegruppe e.V. (grant to RS and LS).

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical standard

The study protocol was approved by the local ethics review board. Informed written consent was obtained from all subjects prior to examinations. The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Correspondence to Ludger Schöls.

Electronic supplementary material

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415_2015_7791_MOESM1_ESM.pdf

Supplementary material 1 (PDF 220 kb) Online resource 1: Clinical data table. The clinical data table lists the identified mutations in SPG4 and specifies clinical findings like reflexes, spasticity and weakness as well as sensory testing in each patient with an overview of age of onset and disease duration. The total SPRS score and the spasticity subscore are listed as well as electrophysiological findings and routine MRI.

415_2015_7791_MOESM2_ESM.pdf

Supplementary material 2 (PDF 195 kb) Online resource 2: Correlation analysis table. Correlation analysis of DTI parameters from 5 preselected white matter fiber tracts with clinical data are presented. DTI results correlated closely (correlation coefficients r > 0.6, p < 0.0005 corrected for multiple comparisons) with disease duration for the pontine crossing tract (AD) and with disease severity (SPRS total score and SPRS spasticity subscore) for the corpus callosum (RD and FA).

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Lindig, T., Bender, B., Hauser, TK. et al. Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations. J Neurol 262, 1961–1971 (2015). https://doi.org/10.1007/s00415-015-7791-7

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