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J Neurol Neurosurg Psychiatry. 2016 Dec;87(12):1354-1360. doi: 10.1136/jnnp-2016-313959. Epub 2016 Oct 18.

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

Author information

1
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
2
Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, The Netherlands.
3
Department of Radiology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
4
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

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.

PMID:
27756805
PMCID:
PMC5136726
DOI:
10.1136/jnnp-2016-313959
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

LHvdB reports grants from ALS Foundation Netherlands, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community's Health Seventh Framework Programme (grant agreement n° 259867 (EuroMOTOR)), and grants from The Netherlands Organization for Health Research and Development: SOPHIA, funded through the EU Joint Programme—Neurodegenerative Disease Research, JPND, during the conduct of the study; personal fees from Biogen, personal fees from Cytokinetics, grants and personal fees from Baxalta outside the submitted work.

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