Abstract Details

Title Genetic Polymorphisms Associate with Frontotemporal Cortical Thickness in Sporadic Amyotrophic Lateral Sclerosis

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 9-017

Objective To evaluate whether single nucleotide polymorphisms (SNPs) conferring risk for amyotrophic lateral sclerosis (ALS) - frontotemporal degeneration (FTD) spectrum disease associate with distribution of cortical thinning in patients with sporadic ALS.

Background An estimated 40% of patients with ALS develop symptoms consistent with FTD, with ~10% developing frank FTD. While ALS and FTD share underlying TDP-43 pathology and pathogenic mutations (e.g. C9orf72 expansions), 90-95% of ALS patients have no known genetic mutation or low familial disease history and thus have sporadic forms of disease. Genome-wide association studies have identified SNPs conferring risk for sporadic ALS and FTD, but the quantitative trait (qT) associations between these SNPs and disease neuroanatomy in ALS remain under-investigated.

Design/Methods We evaluated 71 ALS patients with T1 MRI processed using advanced normalization tools (ANTs) to compute cortical thickness. All patients screened negative for C9orf72 mutations; patients with familial disease history additionally screened negative for other pathogenic mutations (e.g. TARDBP, SOD1). Peripheral blood DNA was genotyped using a custom genotyping panel including 25 SNPs previously associated with ALS, FTD, or TDP-43. We coded SNPs using an additive model and calculated mean cortical thickness in 113 anatomically-defined cortical regions. We used sparse canonical correlation analysis – a data-driven multivariate tool - to identify parsimonious associations between SNPs and regional cortical thickness.

Results Our results revealed a significant qT association (R=0.45) between SNPs and cortical thickness (gene; canonical weights): rs2225389 (MOB3B; 0.96) and rs2708909 (SUN3; 0.28) related to mean cortical thickness in the left temporal pole (-0.47), bilateral posterior insula (R:-0.44, L:-0.37), left supplementary motor cortex (-0.38), right frontal operculum (-0.35), and left superior frontal operculum (-0.32).

Conclusions

SNPs associated with ALS-FTD spectrum disease may contribute to variation in frontotemporal cortical thickness in sporadic ALS, consistent with evidence of common genetic links between sporadic ALS and FTD.

Authors/Disclosures
Katerina Placek PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
James M. Gee (University of Utah)	No disclosure on file
	No disclosure on file
Lauren B. Elman, MD	Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Dr. Elman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Edgewise Therapeutics. Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics. Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Apellis Pharamaceuticals. Dr. Elman has received publishing royalties from a publication relating to health care.
Leo McCluskey, MD (Atrium Health Neurosciences Institute)	No disclosure on file
	No disclosure on file
Murray Grossman, MD, FAAN (University of Pennsylvania)	Dr. Grossman has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology. The institution of Dr. Grossman has received research support from NIH.
Corey McMillan, PhD (University of Pennsylvania)	Dr. McMillan has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. McMillan has received research support from Biogen. The institution of Dr. McMillan has received research support from NIH.

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