Structure-function decoupling in genetic frontotemporal dementia
Poster No:
1746
Submission Type:
Abstract Submission
Authors:
Kamen Tsvetanov1, Simon Jones2, Maura Malpetti2, Timothy Rittman3, Arabella Bouzigues4, John van Swieten5, Lize Jiskoot6, Harro Seelaar7, Barbara Borroni8, Enrico Premi8, Raquel Sanchez-Valle9, Fermin Moreno10, Robert Laforce Jr11, Caroline Graff12, Matthis Synofzik13, Daniela Galimberti14, Mario Masellis15, Maria Tartaglia16, Elizabeth Finger17, Rik Vandenberghe18, Alexandre de Mendonça19, Fabrizio Tagliavini20, Isabel Santana21, Simon Ducharme22, Chris Butler23, Alexander Gerhard24, Johannes Levin25, Markus Otto26, Sandro Sorbi27, Lucy Russell28, Jonathan Rohrer28, James Rowe29
Institutions:
1University of Cambridge, Cambridge, Cambridgeshire, 2University of Cambridge, Cambridge, 3Department of Clinical Neurosciences, University of Cambridge, Cambridge, Cambridgeshire, 4University College London, London, 5Erasmus Medical Center, Rotterdam, 6Erasmus Medical Center, Rotterdam, Netherlands, 7Erasmus Medical Center, Rotterdam, United Kingdom, 8University of Brescia, Brescia, Italy, 9University of Barcelona, Barcelona, Spain, 10Hospital Universitario Donostia, San Sebastian, Spain, 11Université Laval, Quebec, Canada, 12Karolinska Institutet, Stockholm, Sweden, 13German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany, 14University of Milan, Milan, Italy, 15Sunnybrook Research Institute, Toronto, ., 16Tanz Centre for Research in Neurodegenerative Disease, Toronto, ., 17University of Western Ontario, London, ON, 18UZ Leuven, Leuven, Belgium, 19University of Lisbon, Lisbon, Portugal, 20Istituto Neurologico Carlo Besta, Milan, Italy, 21University of Coimbra, Coimbra, Portugal, 22McGill University, Montreal, ., 23University of Oxford, Oxford, United Kingdom, 24University of Manchester, Manchester, United Kingdom, 25Department of Neurology, LMU University Hospital, LMU Munich, Munich, Bavaria, 26University Hospital Halle/Saale, Halle/Saale, Sachsen-Anhalt, 27University of Florence, Florence, Italy, 28University College London, London, United Kingdom, 29Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom
First Author:
Co-Author(s):
Timothy Rittman
Department of Clinical Neurosciences, University of Cambridge
Cambridge, Cambridgeshire
Department of Clinical Neurosciences, University of Cambridge
Cambridge, Cambridgeshire
James Rowe
Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust
Cambridge, United Kingdom
Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust
Cambridge, United Kingdom
Introduction:
Functional network integrity is important for maintaining cognitive performance during the 10-20 year presymptomatic period of frontotemporal dementia (FTD), conferring resilience to advancing neuropathology and atrophy [1]. The extent to which functional integrity relies on preserved structural connectivity is unclear. Here, we test the relationship between functional connectivity and structural connectivity, termed structure-function coupling, against genetic risk for FTD and disease progression.
Methods:
We studied 56 symptomatic and 165 pre-symptomatic FTD-mutation carriers, and 141 family members without mutations from the GENFI cohort [2]. Diffusion weighted imaging and functional magnetic resonance imaging were acquired and analysed using established approaches (Siemens MR platforms) [3], [4] to quantify participant-level structural and functional connectomes (Figure 1-(1)). Connectomes were defined in the Brainnetome Atlas[5] and re-mapped onto a subcortical network and seven resting-state networks based on the Yeo Networks[6] (Figure 1-(2)). An inter-subject regularized canonical correlation analysis (CCA) with permutation-based cross-validation was used to jointly analyse the structural and functional connectomes (Figure 1-(3-4)). Second-level analysis with robust multiple linear regression models [1] tested for differences between non-carriers, pre-symptomatic carriers and symptomatic carriers in the strength of association between structural and functional CCA subject scores. Age, sex, head motion and scanner site were included as covariates.
Results:
Canonical correlation analysis identified significant components linking structural and functional connectivity patterns. The first component (r=0.656, p<0.001) reflected a structural connectivity pattern with high within- and between-networks loadings (Figure 1-(5)) with strong within-networks functional connectivity and weak-to-negative between-network functional connectivity (Figure 1-(6)). This component associated structural integrity with function segregation, whereby individuals with high structural connectivity within and between networks exhibit greater functional network segregation as shown by strong within-network functional connectivity and weak between network connectivity [7]. The strength of this structure-function coupling was greater for non-carriers compared to pre-symptomatic carriers (Figure 1-(7)). Symptomatic carriers showed minimal relationship between structural and functional scores, indicating structure-function decoupling, consistent with the hypothesis that cognitive decline is triggered by critical decoupling of previously synergistic neural systems.
·Analytical strategy (top panel) and Results (lower panel)
Conclusions:
Our findings demonstrate progressive de-coupling between structural connectivity and functional segregation over the course of genetic frontotemporal dementia. These results have implications for designing pre-symptomatic disease-modifying 'preventative' trials, supported by imaging-based surrogate markers of neural system dynamics.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 2
Modeling and Analysis Methods:
Diffusion MRI Modeling and Analysis
fMRI Connectivity and Network Modeling 1
Multivariate Approaches
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems
Keywords:
Degenerative Disease
MRI
Multivariate
Neurological
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
Other - Multimodal
1|2Indicates the priority used for review
Provide references using author date format
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