Cortical thickness changes in Genetic Frontotemporal Dementia Mutation Carriers
Poster No:
286
Submission Type:
Abstract Submission
Authors:
Arabella Bouzigues1, Matthieu Joulot1, Nicolas Gensollen2, Lucy Russell3, James Rowe4, Barbara Borroni5, Daniela Galimberti6, Pietro Tiraboschi7, Mario Masellis8, Carmela Tartaglia9, John van Swieten10, Harro Seelaar11, Lize Jiskoot12, Sandro Sorbi13, Chris Butler14, Caroline Graff15, Alexander Gerhard16, Tobias Langheinrich16, Robert Laforce Jr17, Raquel Sanchez-Valle18, Alexandre de Mendonça19, Fermin Moreno20, Matthis Synofzik21, Rik Vandenberghe22, Simon Ducharme23, Johannes Levin24, Markus Otto25, Florence Pasquier26, Isabel Santana27, Matthias Schroeter28, Isabelle Le Ber1, Jonathan Rohrer3, Raffaella Lara Migliaccio1
Institutions:
1Paris Brain Institute, Paris, County, 2INRIA Paris center, Paris, Other, 3University College London, London, United Kingdom, 4Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom, 5University of Brescia, Brescia, Italy, 6University of Milan, Milan, Italy, 7Instituto Carlo Besta, Milan, Italy, 8Sunnybrook Research Institute, Toronto, ., 9University of Toronto, Toronto, Ontario, 10Erasmus Medical Center, Rotterdam, cc, 11Erasmus Medical Center, Rotterdam, United Kingdom, 12Erasmus Medical Center, Rotterdam, Netherlands, 13University of Florence, Florence, Italy, 14University of Oxford, Oxford, United Kingdom, 15Karolinska Institutet, Stockholm, Sweden, 16University of Manchester, Manchester, United Kingdom, 17Université Laval, Quebec, AK, 18University of Barcelona, Barcelona, Spain, 19University of Lisbon, Lisbon, Portugal, 20Hospital Universitario Donostia, San Sebastian, Spain, 21University of Tubingen, Tubinegen, Germany, 22UZ Leuven, Leuven, Belgium, 23McGill University, Montreal, ., 24Department of Neurology, LMU University Hospital, LMU Munich, Munich, Bavaria, 25University Hospital Halle/Saale, Halle/Saale, Sachsen-Anhalt, 26Université de Lille, Lille, France, 27University of Coimbra, Coimbra, Portugal, 28Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Saxony
First Author:
Co-Author(s):
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
Matthias Schroeter, MD, PhD
Max Planck Institute for Human Cognitive and Brain Sciences
Leipzig, Saxony
Max Planck Institute for Human Cognitive and Brain Sciences
Leipzig, Saxony
Introduction:
Frontotemporal dementia (FTD) is a neurodegenerative syndrome with a broad range of clinical manifestations. Up to 30% of cases are familial, caused by a dominantly inherited genetic mutation. The age at which symptoms present, the phenotype and disease duration are variable, even within a family 1. Previous work in FTD presymptomatic mutation carriers (MC) has shown grey-matter volume reductions precede clinical symptoms and diagnosis by up to 15 years 2,3. More recently, some papers have investigated cortical thickness in presymptomatic MC which may be a more sensitive metric for detecting subtle grey-matter changes from the earliest stages of FTD 4,5,6,7. Thus, a refined understanding of cortical thickness changes throughout the disease-course may help in early disease detection and in clarifying to what extent this measure of atrophy may be of use in future FTD preventive trials.
Methods:
We assessed cortical thickness within the Genetic Frontotemporal dementia Initiative (GENFI) cohort of 301 mutation negative controls and 504 MC divided across three most common FTD genetic groups: C9orf72, MAPT and GRN. MCs were further divided into 5 stages according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal/mildly symptomatic) and 1/2/3 (varying degrees of fully symptomatic). We used a set of automated tools (Freesurfer's recon-all) to reconstruct the brain's cortical surface from T1-weighted structural MRI data and extracted cortical thickness across all vertices. We compared cortical thickness of these vertices within each of the 9 MC groups compared to controls using mixed effects regression models, including age, sex and education as covariables.
Results:
We found that C9orf72 MC showed a thinner cortical layer throughout the brain compared to controls starting in the asymptomatic phase, during which clinicians see no signs of behavioural, psychiatric or language changes (Fig 1, left panel). A very different picture was found in GRN MC who showed no cortical thinning at the asymptomatic stage compared to controls. Cortical thinning started to appear at the prodromal stage within bilateral frontal lobes and left supramarginal/angular gyri before spreading to the left anterior temporal lobe and posterior cingulate cortex at the earliest symptomatic stage and finally, involving bilateral frontal, temporal and parietal lobes completely at the latest stages (Fig 1, middle panel). Finally, MAPT MC also showed a pattern of progressive cortical thinning which was very sparse in asymptomatic and prodromal stages of the disease. Cortical thinning then progressed within anterior temporal lobe, mostly on the left, remaining very focal to this region. It was only at the symptomatic phase, that cortical thinning involved bilateral anterior temporal poles and then spread to bilateral medial and superior frontal lobe and supramarginal/angular gyri (Fig 1, left panel). Next, we wish to use such cortical thickness metrics to predict symptom onset in each genetic group Finally, we will use individual MC longitudinal data to investigate to what extent their trajectory maps onto our cohort-based quasi-longitudinal models of cortical thickness progression.
· Fig 1. Significant vertex clusters for each FTD gene group and for varying levels of disease severity according to the FTLD-CDR score, p<0.05, cluster threshold = 0.01, FDR corrected.
Conclusions:
If FTD preventive trials are to be successful, we need to be able to identify individuals in late presymptomatic stages most likely to benefit from therapies. Our findings suggest that cortical thickness is unlikely to be useful in C9orf72 MCs as these individuals show widespread cortical thinning extremely early on at the asymptomatic stage. In line with this, previous work suggests that C9orf72 carriers have a neurodevelopmental condition 7. Another biomarker may be better suited for this group. However, cortical thinning appears very suddenly in GRN MC and more insidiously in MAPT MC at prodromal and early symptomatic stages. Thus, cortical thinning of the regions showing the earliest changes may be of specific interest for future therapeutic trials within these FTD genetic groups.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Neurodevelopmental/ Early Life (eg. ADHD, autism)
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping 2
Novel Imaging Acquisition Methods:
Anatomical MRI
Keywords:
Aging
Cortex
Degenerative Disease
Neurological
1|2Indicates the priority used for review
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