Abstract Details

Title Neuropsychological and neuropsychiatric traits among asymptomatic relatives from C9orf72 repeat expansion kindreds

Topic Behavioral and Cognitive Neurology

Presentation(s) S2 - Behavioral Neurology (1:12 PM-1:24 PM)

Poster/Presentation
Number 002

Background The hexanucleotide repeat expansion in C9orf72 is associated with ALS, FTD and other less common phenotypes. The reasons for this variability in clinical phenotype remain to be determined. Clinical and genomic studies to date have frequently used asymptomatic familial non-carriers of the variant as a comparison group, despite a lack of clarity as to the extent to which oligogenic inheritance patterns may modify shared cognitive and neuropsychiatric traits.

Objective

To characterise the cognitive and neuropsychiatric profile of asymptomatic C9orf72 carriers and non-carriers from the same kindreds.

Design/Methods 231 asymptomatic relatives of Irish ALS patients (C9orf72 positive [37]; negative [194]) and 207 healthy controls completed comprehensive neuropsychological and neuropsychiatric batteries. C9orf72 repeat expansion status was determined using repeat-primed PCR with amplicon length analysis (positive cut-off: ≥ 30 repeats). Jonckheere-Terpstra tests were applied to compare performance across age categories specifying decreasing and increasing trends for cognitive and neuropsychiatric tasks respectively.

Results

C9orf72 positive ALS relatives and C9orf72 negative ALS relatives from C9orf72-positive kindreds performed worse than controls on verbal fluency performance (p<0.001]. Cognitive performance (ECAS language, verbal fluency and executive function) declined with increasing age among “asymptomatic” C9orf72 carriers (p=0.003, p=0.001 and p=0.04 respectively). Furthermore, this cohort showed paradoxical high levels of self-control (BIS [p=0.017]), and cognitive complexity (BIS [p=0.034]) among younger repeat expansion carriers, with self-control rapidly declining with increasing age (p=0.004).

Similar patterns of declining cognitive performance (ECAS language [p=0.033], executive function [p=0.002]) with increasing age were observed for familial non-carriers. These C9orf72 negative relatives from C9orf72 kindreds also showed higher levels of anxiety (p=0.033) and reduced openness to experience (p=0.034).

Conclusions Early and progressive cognitive and behavioural decline predates the onset of motor dysfunction in ALS. The observation that C9orf72 non-carriers from C9orf72 kindreds share similar neuropsychological patterns suggests the presence of additional genomic modifiers of cognition and behaviour within these kindreds.

Authors/Disclosures
Marie Ryan, MRCPI PRESENTER	Dr. Ryan has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Niall Pender, PhD	No disclosure on file
Orla Hardiman, MD, FRCP, 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.