Abstract Details

Title Cognitive dysfunction in pre-symptomatic C9orf72 carriers

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S35 - Amyotrophic Lateral Sclerosis (4:42 PM-4:54 PM)

Poster/Presentation
Number 007

Objective To identify the earliest cognitive changes that occur in pre-symptomatic C9orf72 carriers.

Background The pathogenic C9orf72 repeat expansion is associated with an increased risk of severe cognitive and behavioural changes among patients with ALS. Equally, relatives of C9orf72 carriers are at increased risk of developing certain neuropsychiatric disorders e.g. schizophrenia. Cognitive endophenotypes are quantitative biological traits that link genes to more complex clinical disorders. As they are measurable in both affected and unaffected individuals, they may further augment the statistical power of genotype-phenotype studies.

Design/Methods ALS patients (diagnosed 2008-2018), their unaffected relatives and healthy controls were recruited into the Irish ALS Endophenotype study. Cognitive testing was performed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and full neuropsychological batteries. Neuropsychiatric status was determined using UK Biobank Thoughts and Feelings Questionnaire and Community Assessment of Psychic Experiences (CAPE-P15). C9orf72 repeat expansion status was determined using repeat-primed PCR with amplicon length analysis with those exceeding a cut-off of 30 deemed positive.

Results 151 relatives of ALS patients (including 20 pre-symptomatic C9orf72 carriers) and 207 healthy controls were assessed (mean age 44.2 v 63.5 years, p=0.001). ALS-specific cognitive impairment was found in pre-symptomatic C9orf72 carriers at a higher rate than in healthy controls (30% v 11%, p=0.024). Segregation by expected age of disease onset revealed that 92% of those who were younger than the expected age of onset were cognitively normal. By contrast 71% of older pre-symptomatic carriers, were cognitively abnormal (p=0.003). Over 40% of ALS relatives were at high risk of developing psychosis (CAPE-P15>1.5), independent of C9orf72 status (44% [8/18] carriers, 43% [39/91] non-carriers, p=0.90).

Conclusions With the emergence of potential genetic therapies targeting C9orf72 carriers, definition of disease onset is important. Our data demonstrate that cognitive changes likely presage the onset of more characteristic features of ALS.

Authors/Disclosures
Marie Ryan, MRCPI PRESENTER	Dr. Ryan has nothing to disclose.
	No disclosure on file
	No disclosure on file
Caroline A. McHutchison, BSc, MSc	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Niall Pender, PhD	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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