Corticospinal tract and motor cortex degeneration in pure hereditary spastic paraparesis type 4 (SPG4)

Abstract

Objective: SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive retrograde degeneration, or “dying-back” phenomenon, of the corticospinal tract’s longest axons. Neuroimaging studies mainly focus on white matter changes and, although previous studies reported cortical thinning in complicated HSP forms, cortical changes remain unclear in SPG4 patients. This work aimed to compare changes in white matter microstructure and cortical thickness between 12 SPG4 patients and 22 healthy age-matched controls. We also explore whether white matter alterations are related to cortical thickness and their correlation with clinical symptoms. Methods: we used fixel-based analysis, an advanced diffusion-weighted imaging technique, and probabilistic tractography of the corticospinal tracts. We also analyzed cortical morphometry using whole-brain surface-based and atlas-based methods in sensorimotor areas. Results: SPG4 patients showed bilateral involvement in the corticospinal tracts; this was more intense in the distal portion than in the upper segments and was associated with the degree of clinical impairment. We found a significant correlation between disease severity and fiber density and cross-section of the corticospinal tracts. Furthermore, corticospinal tract changes were significantly correlated with bilateral cortical thinning in the precentral gyrus in SPG4 patients. Conclusions: Our data point to axonal damage of the corticospinal motor neurons in SPG4 patients might be related to cortical thinning in motor regions.

Keywords:

• Hereditary spastic paraparesis
• SPG4
• neuroimaging
• corticospinal
• cortical thickness

This article refers to:

The neuroradiology of upper motor neuron degeneration: PLS, HSP, ALS

Acknowledgements

All the authors wish to express our appreciation for the invaluable contribution of the late Dr. Santiago Reig to this study. We are grateful to the patients for their collaboration and to the “Asociación Española de Paraparesia Espástica Familiar” (AEPEF) for supporting patient recruitment.

Ethical approval

The study was approved by the Ethics and Clinical Research Board of Hospital Gregorio Marañón. Written informed consent was obtained from all patients before they participated in the study. This manuscript has been reviewed and approved by each author.

Author contributions

Included conception and study design (FG and MD), data collection or acquisition (FJNS, YAG, JAGdV, PFG, IC, LL, JLMB, MJS and FG), genetic tests (BQ, AOU and MJS), image processing and statistical analysis (FJNS, DMdB, AFP, ALC, and LMV), interpretation of results (FJNS, DMdB, SC, FG), drafting the manuscript work or revising it critically for important intellectual content (FJNS, DMdB, AFP, LMV, SC, FG and MD) and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (All authors).

Declaration of interest

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets generated from the statistical analyses during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by Ministerio de Ciencia, Innovación y Universidades and by Instituto de Salud Carlos III projects PS09/01830; PS09/01685; PS09/00839. The ASPIDE project received funding from the European Union’s Horizon 2020 research and innovation programme under [grant agreement No 801091]. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505). S. Carmona, funded by Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III, co‐funded by European Social Fund “Investing in your future” [CP16/00096].