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S. Borrego-Ecija is a recipient of the Joan Rodes Josep Baselga grant from the FBBVA. This study was partially funded by Fundacio Marato de TV3, and Instituto de Salud Carlos III, Spain (grant nos. 20143810 and PI20/0448 to RSV). M. Vandebergh received funding from the Queen Elisabeth Medical Foundation of Neurosciences (GSKE). The GENFI study has been supported by the Medical Research Council United Kingdom, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimer's Society PhD studentship. JDR acknowledges support from the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the UK Dementia Research Institute, Alzheimer's Research UK, the Brain Research Trust and the Wolfson Foundation. J.C. Van Swieten was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. C. Graff has received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schorling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. D. Galimberti has received support from the EU Joint Programme-Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. J.B. Rowe is funded by the Wellcome Trust (103838) and the NIHR Cambridge Biomedical Research Centre. M. Masellis has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. R. Vandenberghe has received funding from the Mady Browaeys Fund for Research into FTD. E. Ferry-Bolder has received funding from a CIHR grant #327387. J.D. Rohrer is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. M. Synofzik was supported by a grant 779257 " Solve-RD" from the Horizon 2020 research and innovation programme.

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Association of Initial Side of Brain Atrophy With Clinical Features and Disease Progression in Patients With GRN Frontotemporal Dementia

Publicated to:Neurology. 103 (11): e209944- - 2024-12-10 103(11), DOI: 10.1212/WNL.0000000000209944

Authors: Borrego-Ecija, Sergi; Junca-Parella, Jordi; Vandebergh, Marijne; Millan, Agnes Perez; Balasa, Mircea; Llado, Albert; Bouzigues, Arabella; Russell, Lucy Louise; Foster, Phoebe H; Ferry-Bolder, Eve; Van Swieten, John C; Jiskoot, Lize Corrine; Seelaar, Harro; Laforce Jr, Robert; Graff, Caroline; Galimberti, Daniela; Vandenberghe, Rik; de Mendonca, Alexandre; Tiraboschi, Pietro; Santana, Isabel; Gerhard, Alexander; Levin, Johannes; Sorbi, Sandro; Otto, Markus; Pasquier, Florence; Ducharme, Simon; Butler, Christopher; Le Ber, Isabelle; Finger, Elizabeth; Tartaglia, Maria Carmela; Masellis, Mario; Rowe, James B; Synofzik, Matthis; Moreno, Fermin; Borroni, Barbara; Rademakers, Rosa; Rohrer, Jonathan Daniel; Sanchez-Valle, Raquel

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Abstract

Background and Objectives Pathogenic variants in the GRN gene cause frontotemporal dementia (FTD-GRN) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD-GRN depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease. Methods Retrospective examination of data from the prospective Genetic Frontotemporal Initiative (GENFI) cohort study that recruits individuals who carry or were at risk of carrying a pathogenic variant causing FTD. GENFI participants underwent a standardized clinical and neuropsychological assessment, MRI, and a blood sample test yearly. We generated an asymmetry index for brain MRI to characterize brain asymmetry in participants with or at risk of FTD-GRN. Depending on the side of the asymmetry, we classified symptomatic GRN patients as right-GRN or left-GRN and compared their clinical features and disease progression. We generated generalized additive models to study how the asymmetry index evolves in carriers and noncarriers and compare its models with others created with volumetric values and plasma neurofilament light chain. Results A total of 399 participants (mean age 49.7 years, 59% female) were included (63 symptomatic carriers, 177 presymptomatic carriers, and 159 noncarriers). Symptomatic carriers showed higher brain asymmetry (11.6) than noncarriers (1.0, p < 0.001) and presymptomatic carriers (1.0, p < 0.001), making it possible to classify most of them as right-GRN (n = 21) or left-GRN (n = 36). Patients with right-GRN showed more disease severity at baseline (beta = 6.9, 95% CI 2.4-11.0, p = 0.003) but a lower deterioration by year (beta = -1.5, 95% CI -2.7 to -0.31, p = 0.015) than patients with left-GRN. Brain asymmetry could be found in GRN carriers 10.4 years before the onset of the symptoms (standard difference 0.85, CI 0.01-1.68). Discussion FTD-GRN affects the brain hemispheres asymmetrically and causes 2 anatomical asymmetry patterns depending on the side of the disease onset. We demonstrated that these 2 anatomical asymmetry patterns present different symptoms, severity at the time of the first visit, and different disease courses. Our results also suggest brain asymmetry as a possible biomarker of conversion in GRN carriers.

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