Widespread structural brain involvement in ALS is not limited to the C9orf72 repeat expansion

Henk Jan Westeneng, Renée Walhout, Milou Straathof, Ruben Schmidt, Jeroen Hendrikse, Jan H. Veldink, Martijn P. Van Den Heuvel, Leonard H. Van Den Berg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: In patients with a C9orf72 repeat expansion (C9+), a neuroimaging phenotype with widespread structural cerebral changes has been found. We aimed to investigate the specificity of this neuroimaging phenotype in patients with amyotrophic lateral sclerosis (ALS). Methods: 156 C9- and 14 C9+ patients with ALS underwent high-resolution T1-weighted MRI; a subset (n=126) underwent diffusion-weighted imaging. Cortical thickness, subcortical volumes and white matter integrity were compared between C9+ and C9-patients. Using elastic net logistic regression, a model defining the neuroimaging phenotype of C9+ was determined and applied to C9-patients with ALS. Results: C9+ patients showed cortical thinning outside the precentral gyrus, extending to the bilateral pars opercularis, fusiform, lingual, isthmus-cingulate and superior parietal cortex, and smaller volumes of the right hippocampus and bilateral thalamus, and reduced white matter integrity of the inferior and superior longitudinal fasciculus compared with C9-patients (p<0.05). Among 128 C9-patients, we detected a subgroup of 27 (21%) with a neuroimaging phenotype congruent to C9+ patients, while 101 (79%) C9-patients showed cortical thinning restricted to the primary motor cortex. C9-patients with a 'C9+' neuroimaging phenotype had lower performance on the frontal assessment battery, compared with other C9-patients with ALS (p=0.004). Conclusions: This study shows that widespread structural brain involvement is not limited to C9+ patients, but also presents in a subgroup of C9-patients with ALS and relates to cognitive deficits. Our neuroimaging findings reveal an intermediate phenotype that may provide insight into the complex relationship between genetic factors and clinical characteristics.

Original languageEnglish
Pages (from-to)1354-1360
Number of pages7
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume87
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016

Cite this

Westeneng, H. J., Walhout, R., Straathof, M., Schmidt, R., Hendrikse, J., Veldink, J. H., ... Van Den Berg, L. H. (2016). Widespread structural brain involvement in ALS is not limited to the C9orf72 repeat expansion. Journal of Neurology, Neurosurgery and Psychiatry, 87(12), 1354-1360. https://doi.org/10.1136/jnnp-2016-313959