Abstract Details

Title Functional Connectivity Alterations in C9ORF72 Mutation Carriers

Topic Aging and Dementia

Presentation(s) P05 - (-)

Poster/Presentation
Number 105

Objective

Background BACKGROUND: Mutations in C9ORF72 represent the most common genetic cause of familial and sporadic bvFTD and amyotrophic lateral sclerosis. No studies have explored intrinsic connectivity in C9+.

Design/Methods DESIGN/METHODS: We studied 14 C9+ (8 bvFTD, 6 bvFTD-MND; age 58.4±7.6 years, 4 females), 14 non-carriers (C9-, 8 bvFTD, 6 bvFTD-MND; age 60.1±7.0 years, 4 females) and 14 age- and sex-matched healthy controls (HC). Neuropsychological data, structural MRI, and 8 minutes of tf-fMRI were obtained. Gray matter atrophy was assessed using voxel-based morphometry. Seed-based tf-fMRI correlation analyses mapped 3 intrinsic connectivity networks (ICNs), the salience network (SN), sensorimotor network, and default mode network (DMN). We compared ICNs between groups using two-sample t-tests thresholded at joint cluster and extent thresholds of p<0.05.

Results RESULTS: C9+ and C9- groups showed no differences in age at symptom onset, disease duration, or clinical severity. VBM showed more severe frontal and temporal atrophy in C9- than C9+ compared to HC. C9+ exhibited additional atrophy in dorsal frontal and parietal cortex compared to HC. Tf-fMRI analyses revealed similar SN connectivity reductions for C9+ and C9- compared with HC in bilateral anterior cingulate cortex (ACC), dorsolateral prefrontal cortex, and rostral pons. For the motor network, C9+ and C9- showed supplementary motor area and cuneus reductions compared with HC; C9- had increased connectivity in right striatum compared with HC. Both C9+ and C9- showed reductions throughout the DMN, however C9- had reduced DMN connectivity in ACC compared with C9+.

Conclusions CONCLUSIONS: Despite greater atrophy in C9- than C9+, tf-fMRI analyses revealed similar connectivity reductions in the SN, motor network, and DMN. Further studies are needed to explore the discrepancy between atrophy and intrinsic connectivity in C9+ and C9-.

Authors/Disclosures
Suzee Lee, MD PRESENTER	Dr. Lee has nothing to disclose.
	No disclosure on file
	No disclosure on file
Christine C. Guo, PhD	No disclosure on file
Jennifer S. Yokoyama, PhD (UCSF, Memory and Aging Center)	The institution of Dr. Yokoyama has received research support from NIH. The institution of Dr. Yokoyama has received research support from Alzheimer's Association . The institution of Dr. Yokoyama has received research support from Mary Oakley Foundation. The institution of Dr. Yokoyama has received research support from Alector. The institution of Dr. Yokoyama has received research support from Transposon. The institution of Dr. Yokoyama has received research support from Rainwater Charitable Foundation.
Gavin Giovannoni, MD (QMUL)	Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck KGaA. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche-Genentech. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Astoria Biologica. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zenas. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medscape.
Sharon Sha, MD (Stanford Univeristy)	Dr. Sha has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Global. Dr. Sha has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ExpertConnect. Dr. Sha has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Sha has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cognition Therapeutics. Dr. Sha has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Forefront Collaborative. Dr. Sha has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ReachMD. Dr. Sha has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PeerView. Dr. Sha has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Medscape. Dr. Sha has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for medlearning group. Dr. Sha has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for webmd. The institution of Dr. Sha has received research support from Biogen. The institution of Dr. Sha has received research support from Jannssen. The institution of Dr. Sha has received research support from Eisai. The institution of Dr. Sha has received research support from Eli Lilly. The institution of Dr. Sha has received research support from Aribio. The institution of Dr. Sha has received research support from cognition therapeutics. The institution of Dr. Sha has received research support from EIP pharma. Dr. Sha has received publishing royalties from a publication relating to health care.
Anna Karydas (UCSF)	No disclosure on file
	No disclosure on file
Howard J. Rosen, MD (UCSF)	Dr. Rosen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly . Dr. Rosen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alector. The institution of Dr. Rosen has received research support from NIH. The institution of Dr. Rosen has received research support from State of CA. Dr. Rosen has a non-compensated relationship as a Consultant with Prevail Therapeutics that is relevant to AAN interests or activities. Dr. Rosen has a non-compensated relationship as a consultant with Alchemab that is relevant to AAN interests or activities.
Bruce L. Miller, MD, FAAN (University of California, San Francisco)	Dr. Miller has nothing to disclose.
William W. Seeley, MD	Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG Council. Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Global Consulting. Dr. Seeley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BridgeBio. Dr. Seeley has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Seeley has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lyterian Therapeutics. The institution of Dr. Seeley has received research support from NIH. The institution of Dr. Seeley has received research support from Rainwater Charitable Foundation. The institution of Dr. Seeley has received research support from Bluefield Project to Cure FTD. The institution of Dr. Seeley has received research support from Chan-Zuckerberg Initiative.

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