Abstract Details

Title The Neuroimaging Signature of the C9orf72 Hexanucleotide Repeat in Amyotrophic Lateral Sclerosis - A Multimodal MRI Study

Topic Anterior Horn

Presentation(s) S06 - (-)

Poster/Presentation
Number 005

Objective

Background The main pathological and clinical features of the C9orf72 hexanucleotide repeat expansion in Amyotrophic lateral sclerosis are currently being established.

Design/Methods A prospective, single-centre, single-protocol, multimodal grey and white matter magnetic resonance imaging study was undertaken with thirty C9orf72 negative ALS patients, nine ALS patients carrying the C9orf72 hexanucleotide repeat expansion and forty-four healthy controls. Groups were carefully matched for disease duration, age and handedness. Tract-based spatial statistics of white matter tracts using multiple diffusion parameters and cortical thickness analyses were carried out. All patients underwent comprehensive neuropsychological profiling and were screened for other mutations in genes previously implicated in ALS.

Results A distinct pattern of cortical and subcortical involvement unique to the C9orf72 genotype was identified, affecting fusiform, opercular, pars triangularis, supramarginal and orbitofrontal regions. The subcortical changes identified by multi-parametric diffusion tensor imaging matched the location of grey matter pathology highlighted by cortical thickness analyses. The C9orf72 negative cohort demonstrated the "classical" distribution of ALS pathology affecting primarily the motor cortex, motor pathways and cerebellar regions with strikingly limited extra-motor expansion. The imaging findings were consistent with the neuropsychological characterisation. While two-third of the C9orf72 positive patients fulfilled the diagnostic criteria for frontotemporal dementia(FTD), only 10 % of the C9orf72 negative group had FTD.

Conclusions The C9orf72 expansion is associated with extensive cortical and subcortical frontotemporal involvement that can be reliably distinguished from C9orf72 negative ALS patients. These findings provide important in vivo insights into the structural and functional changes underpinning the clinical phenotype. Given the very strong neuropathological signature of the C9orf72 genotype, we suggest that future imaging, neuropsychology and pharmaceutical studies in ALS be stratified for the presence of this mutation.

Authors/Disclosures
Peter Bede, MD, PhD (Academic Unit of Neurology) PRESENTER	Dr. Bede has nothing to disclose.
	No disclosure on file
Fulton Velez	No disclosure on file
Susan C. Byrne, MD	No disclosure on file
Marwa Elamin, MD (University College Hospital Galway)	Dr. Elamin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche .
	No disclosure on file
	No disclosure on file
	No disclosure on file
Niall Pender, PhD	No disclosure on file
	No disclosure on file
Orla Hardiman, MD, FRCPI, FAAN (Trinity Biomedical Sciences Institute)	Dr. Hardiman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Wave Pharmaceuticals. Dr. Hardiman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cytokinetics . Dr. Hardiman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hardiman has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Taylor and Francis. The institution of Dr. Hardiman has received research support from Science Foundation Ireland. The institution of Dr. Hardiman has received research support from HRB.

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