Poster No:
1730
Submission Type:
Abstract Submission
Authors:
Jolina Lombardi1, Liwen Zhang1, Taru Flagan1, Andrea Gorham Vargas1, Maria Luisa Mandelli1, Jesse Brown1, Howard Rosen1, Kejal Kantarci2, Eliana Ramos3, John van Swieten4, Lize Jiskoot4, Harro Seelaar4, Jonathan Rohrer5, Arabella Bouzigues5, Lucy Chisman-Russell5, Phoebe Foster5, Eve Ferry-Bolder5, Raquel Sanchez-Valle6, Maria Carmela Tartaglia7, Mario Masellis8, Barbara Borroni9, James Rowe10, Elizabeth Finger11, Matthis Synofzik12, Robert Laforce13, Daniela Galimberti14, Rik Vandenberghe15, Pietro Tiraboschi16, Isabelle Le Ber17, Bruce Miller1, Maria Luisa Gorno-Tempini1, William Seeley1, Suzee Lee on behalf of the ALLFD Consortia & the Frontotemporal Dementia Prevention Initiative1
Institutions:
1Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF, San Francisco, USA, 2Department of Radiology, Division of Neuroradiology, Mayo Clinic Rochester, Rochester, USA, 3Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, USA, 4Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands, 5Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom, 6Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut, Barcelona, Spain, 7Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada, 8Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada, 9Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy, 10Dept. of Clinical Neurosciences & Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, United Kingdom, 11Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada, 12Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of, Tuebingen, Germany, 13Clinique Interdisciplinaire de Mémoire, CHU de Québec & Faculté de Médecine, Université Laval, Quebec, Canada, 14Fondazione Ca’ Granda, IRCCS Ospedale Policlinico, Milan, Italy, 15Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium, 16Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, 17Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, Paris, France
First Author:
Jolina Lombardi
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Co-Author(s):
Liwen Zhang
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Taru Flagan
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Andrea Gorham Vargas
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Maria Luisa Mandelli
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Jesse Brown
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Howard Rosen
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Kejal Kantarci
Department of Radiology, Division of Neuroradiology, Mayo Clinic Rochester
Rochester, USA
Eliana Ramos
Department of Neurology, David Geffen School of Medicine, UCLA
Los Angeles, USA
John van Swieten
Department of Neurology, Erasmus Medical Centre
Rotterdam, Netherlands
Lize Jiskoot
Department of Neurology, Erasmus Medical Centre
Rotterdam, Netherlands
Harro Seelaar
Department of Neurology, Erasmus Medical Centre
Rotterdam, Netherlands
Jonathan Rohrer
Dementia Research Centre, UCL Queen Square Institute of Neurology
London, United Kingdom
Arabella Bouzigues
Dementia Research Centre, UCL Queen Square Institute of Neurology
London, United Kingdom
Lucy Chisman-Russell
Dementia Research Centre, UCL Queen Square Institute of Neurology
London, United Kingdom
Phoebe Foster
Dementia Research Centre, UCL Queen Square Institute of Neurology
London, United Kingdom
Eve Ferry-Bolder
Dementia Research Centre, UCL Queen Square Institute of Neurology
London, United Kingdom
Raquel Sanchez-Valle
Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut
Barcelona, Spain
Maria Carmela Tartaglia
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
Toronto, Canada
Mario Masellis
Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto
Toronto, Canada
Barbara Borroni
Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia
Brescia, Italy
James Rowe
Dept. of Clinical Neurosciences & Cambridge University Hospitals NHS Trust, University of Cambridge
Cambridge, United Kingdom
Elizabeth Finger
Department of Clinical Neurological Sciences, University of Western Ontario
London, Canada
Matthis Synofzik
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of
Tuebingen, Germany
Robert Laforce
Clinique Interdisciplinaire de Mémoire, CHU de Québec & Faculté de Médecine, Université Laval
Quebec, Canada
Rik Vandenberghe
Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven
Leuven, Belgium
Isabelle Le Ber
Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225
Paris, France
Bruce Miller
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Maria Luisa Gorno-Tempini
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
William Seeley
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, UCSF
San Francisco, USA
Introduction:
Presymptomatic C9orf72 expansion carriers as young as their thirties display gray matter (GM) deficits and alterations in connectivity networks targeted during the symptomatic phase (Lee et al. 2017; Bertrand et al. 2018; Finger et al. 2023). These studies raise the question of a neurodevelopmental role of the C9orf72 expansion, yet sufficient research in young adults (ages 18-30) is lacking.
Methods:
Leveraging 3T MRI scans from Frontotemporal Dementia Prevention Initiative sites in Europe, Canada, and the United States, we identified 28 presymptomatic C9orf72 expansion carriers [PreSx-C9, mean age: 25.8±3.4] and 55 demographically-matched healthy controls [HC; mean age: 26.0±2.8] with T1-weighted (T1w) and T2*-weighted echo-planar imaging sequence.
Preprocessing: For preprocessing, structural MRI (sMRI) data were visually inspected for quality and manually reoriented before segmentation, normalization, and smoothing (8mm full width at half maximum (FWHM) isotropic Gaussian kernel) in SPM12. Task-free functional MRI (tf-fMRI) data were preprocessed using fmriprep. After coregistration to the T1w reference, blood-oxygen level dependent (BOLD) data were corrected for slice-timing, head motion, and susceptibility distortions, then smoothed (6mm FWHM Gaussian kernel) and regressed for motion-related artifacts before linear detrending, bandpass filtering (0.008-0.08 Hz), and nuisance regression (including global signal).
Harmonization: To control for batch-effects, we applied a post-acquisition data harmonization approach: ComBat for structural (Fortin et al. 2018) and functional (Yu et al. 2018) data. Using a customized approach, ComBat parameters were estimated from a sample of 329 HC (55 young adult HC and 274 additional HC) and administered to harmonize study cohort data. ComBat was applied on individual smoothed gray matter maps (sMRI) and seed-based intrinsic connectivity network maps (tf-fMRI) prior to group comparisons.
Analyses: We performed voxel-based morphometry (VBM) to compare GM volume between groups (HC > PreSx-C9 and PreSx-C9 > HC) using a 2-sample t-test (SPM12), thresholded at p<0.001 uncorrected and p<0.05 familywise error corrected (pFWE<0.05). Seed-based tf-fMRI analysis examined salience network (SN), sensorimotor network (SMN), and default mode network (DMN) connectivity. To create intrinsic connectivity networks, a 4mm radius sphere ("seed") was set on peak atrophy coordinates in patients for the SN, SMN, and DMN (Seeley et al. 2008; Seeley et al. 2009; Zielinski et al. 2010). Connectivity was assessed using bivariate regression between the mean BOLD time series within each seed and the time series in the remaining voxels per subject. Single-subject connectivity maps were compared between groups using 2-sample t-tests, thresholded at a joint height and extent of p<0.05 and masked to the relevant network. For all analyses, nuisance covariates included age, sex, education, handedness, TIV (sMRI only), and eyes-open/closed status (tf-fMRI only).
Results:
At an uncorrected threshold, PreSx-C9 carriers had low gray matter intensity vs. HC within the right medial pulvinar thalamus and within small clusters of frontotemporoparietal and insular cortices (p<0.001, uncorrected). No significant GM differences were detected between PreSx-C9 carriers and HC at pFWE<0.05. PreSx-C9 carriers displayed regions of SN (right frontal and parietal lobe) and SMN (bilateral supplementary motor area) hypoconnectivity alongside DMN hyperconnectivity (parietal lobe) compared with HC.
Conclusions:
Despite a lack of significant GM deficits in adult presymptomatic C9orf72 expansion carriers ages 18 to 30, tf-fMRI analyses detected alterations in the SN, SMN, and DMN, suggesting that network abnormalities appear early in the lifespan. These findings indicate that C9orf72 expansions might play a crucial role in neurodevelopment.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 2
Genetics:
Genetics Other
Lifespan Development:
Early life, Adolescence, Aging
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 1
Novel Imaging Acquisition Methods:
BOLD fMRI
Keywords:
FUNCTIONAL MRI
MRI
STRUCTURAL MRI
Thalamus
Other - C9orf72; genetic FTD; young adults; presymptomatic; frontotemporal dementia (FTD)
1|2Indicates the priority used for review
Provide references using author date format
Bertrand, A. (2018), 'Early cognitive, sturctural, and microstructural changes in presymptomatic C9orf72 carriers younger than 40 years', JAMA Neurology, vol. 75, no. 2, pp. 236-245
Finger, E. (2023), 'Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers', Brain, vol. 146, no. 5, pp. 2120-2131
Fortin, J.-P. (2018), 'Harmonization of cortical thickness measurements across scanners and sites', Neuroimage, vol. 167, pp. 104–120
Lee, S.E. (2017), 'Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers', NeuroImage Clinical, vol. 14, pp.286-297
Seeley, W. W (2008), 'Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia', Archives of Neurology, vol. 65, no. 2, pp. 249–255
Seeley, W. W. (2009), 'Neurodegenerative diseases target large-scale human brain networks', Neuron, vol. 62, pp. 42–52
Yu, M. (2018), 'Statistical harmonization corrects site effects in functional connectivity measurements from multi-site fMRI data', Human Brain Mapping, vol. 39, pp. 4213–4227
Zielinski, B. A. (2010), 'Network-level structural covariance in the developing brain', PNAS, vol. 107, pp. 18191–18196