Intracranial Volume Differences Reveal Neurodevelopmental Effects in Genetic Frontotemporal Dementia
Poster No:
97
Submission Type:
Abstract Submission
Authors:
Chung Yan Isis So1,2, Arabella Bouzigues3, Lucy Russell3, Phoebe Foster3, Eve Ferry-Bolder3, Jon van Swieten4, Lize Jiskoot4, Harro Seelaar4, Raquel Sanchez-Valle5, Robert Laforce6, Caroline Graff7, Daniela Galimberti8, Rik Vandenberghe9, Alexandre de Mendonça10, Pietro Tiraboschi11, Isabel Santana12, Alexander Gerhard13, Johannes Levin14, Sandro Sorbi15, Markus Otto16, Florence Pasquier17, Simon Ducharme18, Chris Butler19, Isabelle Le Ber20, Carmela Tartaglia21, Mario Masellis22, James Rowe23, Matthis Synofzik24, Fermin Moreno25, Barbara Borroni26, Tyler Kolander27, Carly Mester28, Danielle Brushaber28, Hilary Heuer29, Leah Forsberg29, Jonathan Rohrer3, Bradley Boeve27, Adam Boxer29, Howard Rosen29, Elizabeth Finger1,2,30, On behalf of Frontotemporal Dementia Prevention Initiative31
Institutions:
1Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada, 2Lawson Health Research Institute, Parkwood Institute, London, Ontario, Canada, 3UCL Queen Square Institute of Neurology, London, United Kingdom, 4Erasmus Medical Centre, Rotterdam, Netherlands, 5University of Barcelona, Barcelona, Spain, 6Université Laval, Quebec City, Canada, 7Karolinska Institutet, Solna, Sweden, 8IRCCS Ospedale Policlinico, Milan, Italy, 9KU Leuven, Leuven, Belgium, 10University of Lisbon, Lisbon, Portugal, 11Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, 12University of Coimbra, Coimbra, Portugal, 13University of Manchester, Manchester, United Kingdom, 14Ludwig-Maximilians Universität München, Munich, Germany, 15University of Florence, Florence, Italy, 16University of Ulm, Ulm, Germany, 17University of Lille, Lille, France, 18McGill University Health Centre, Montreal, Quebec, 19University of Oxford, Oxford, United Kingdom, 20Paris Brain Institute – Institut du Cerveau – ICM, Paris, France, 21Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, 22Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, 23University of Cambridge, Cambridge, United Kingdom, 24University of Tübingen, Tübingen, Germany, 25Hospital Universitario Donostia, San Sebastián, Spain, 26University of Brescia, Brescia, Italy, 27Department of Neurology, Mayo Clinic, Rochester, MN, 28Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 29Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 30Dept. Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, Univ. Western Ontario, London, Ontario, Canada, 31FPI with GENFI and ALLFTD Consortia, Europe, Canada, United States
First Author:
Chung Yan Isis So, MSc
Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario|Lawson Health Research Institute, Parkwood Institute
London, Ontario, Canada|London, Ontario, Canada
Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario|Lawson Health Research Institute, Parkwood Institute
London, Ontario, Canada|London, Ontario, Canada
Co-Author(s):
Carmela Tartaglia
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
Toronto, Ontario
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
Toronto, Ontario
Hilary Heuer, PhD
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Leah Forsberg
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Adam Boxer, MD, PhD
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Howard Rosen, MD
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Weill Institute for Neurosciences, University of California San Francisco
San Francisco, CA
Elizabeth Finger, MD
Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario|Lawson Health Research Institute, Parkwood Institute|Dept. Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, Univ. Western Ontario
London, Ontario, Canada|London, Ontario, Canada|London, Ontario, Canada
Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario|Lawson Health Research Institute, Parkwood Institute|Dept. Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, Univ. Western Ontario
London, Ontario, Canada|London, Ontario, Canada|London, Ontario, Canada
On behalf of Frontotemporal Dementia Prevention Initiative
FPI with GENFI and ALLFTD Consortia
Europe, Canada, United States
FPI with GENFI and ALLFTD Consortia
Europe, Canada, United States
Introduction:
Frontotemporal dementia (FTD) is widely recognized as a neurodegenerative disease, but converging evidence hints at neurodevelopmental effects in genetic FTD. The most commonly affected genes in FTD, C9orf72, GRN, and MAPT, are highly penetrant and involved during neurodevelopment. Preclinical models (Hendricks, 2023; Petkau, 2012; Verheyen, 2018) and clinical studies in persons at risk for or affected by FTD (Finger, 2023; Geschwind, 2001; van Veenhuijzen, 2023; Yokoyama, 2017) are also supportive of the neurodevelopmental hypothesis in genetic FTD. Recent findings observed differences in total intracranial volume (TIV) and cognition in young adult mutation carriers compared to familial non-mutation carriers (Finger, 2023). TIV includes the volume of all cranial tissues and the surrounding cerebrospinal fluid, stabilizes at around late adolescence, serves as an estimate measure of premorbid brain growth (Matsumae, 1996), and has been used as a neuroimaging correlate of neurodevelopment in Huntington's disease, another adult-onset neurodegenerative disease (Nopoulos, 2011). The present study extended the examination of neurodevelopmental effects of FTD mutations into adults, investigating TIV and education attainment differences between gene mutation carriers and familial non-carriers, as measures of the structural and functional neurodevelopmental outcomes of the FTD-causing genes.
Methods:
This cross-sectional cohort study was facilitated through the FTD Prevention Initiative (FPI) across North America and Europe. Participants, aged 18 to 86 years, were pathogenic mutation carriers of GRN, MAPT, or C9orf72, or familial non-carriers. T1-weighted MRI on 1.5T or 3T scanners were used, with image acquisition and preprocessing protocols reported elsewhere (Finger, 2023; Staffaroni, 2022). ANCOVAs were computed per gene to compare outcome means for the main effect of carrier status, while controlling for birth decade, sex, and visit site (to account for unique scanners and educational systems). Pearson's correlations were used to examine associations between TIV and education.
Results:
Nine-hundred two mutation carriers (mean±SD; age=50.0±13.2 years, sex=55% female, n(GRN)=298, n(MAPT)=187, n(C9orf72)=417) were compared to 532 familial non-carriers (age=48.0±12.9 years, sex=58% female, n(GRN)=201, n(MAPT)=114), n(C9orf72)=217). Consistent with prior findings in young adults, GRN carriers showed larger TIV compared to familial non-carriers (95% CI=1431994-1457123, p=0.049, ηp2=0.008) (Fig. 1a). Larger TIV correlated with higher years of education in GRN carriers (95% CI=0.01-0.24, r(295)=0.12, p=0.03) and GRN non-carriers (95% CI=0.08-0.34, r(198)=0.21, p=0.002). MAPT carriers demonstrated smaller TIV than non-carriers (95% CI=1417819-1450628, p=0.039, ηp2=0.02) (Fig. 1b). Models of C9orf72 (Fig. 1c) and those with education as the outcome (Fig. 2) did not reveal significant differences. Findings from sensitivity analyses, where males and females were analyzed separately, and where sites containing only one participant were removed, were consistent with that of the primary analysis.
Conclusions:
In support of neurodevelopmental effects in genetic FTD, this investigation revealed that a neuroimaging correlate of neurodevelopment, TIV, differed in GRN and MAPT mutation carriers. The now replicated finding that GRN mutation carriers have larger TIV than non-carriers, and the preserved association between TIV and educational attainment, indicate this genetic variation influences brain structure and is potentially associated with advantageous functional effects during early development. These findings will motivate further research to identify mechanisms by which FTD mutations impact neurodevelopment and ascertain their suitability as targets for clinical interventions.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Lifespan Development:
Early life, Adolescence, Aging 2
Lifespan Development Other
Modeling and Analysis Methods:
Univariate Modeling
Novel Imaging Acquisition Methods:
Anatomical MRI
Keywords:
Degenerative Disease
Development
MRI
Other - frontotemporal dementia; hereditary dementia; GRN; MAPT; C9orf72; total intracranial volume
1|2Indicates the priority used for review
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