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      Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross‐sectional diffusion tensor imaging study

      research-article
      1 , 2 , 3 , 2 , 2 , 4 , 2 , 5 ,   2 , 5 , 2 , 5 , 2 , 5 , 3 , 6 , 7 , 1 , 1 , 1 , 3 , 8 , 1 , 3 , 1 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , the Genetic Frontotemporal dementia Initiative (GENFI), 1 , 1 , 25 , 2 ,
      Annals of Clinical and Translational Neurology
      John Wiley and Sons Inc.

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          Abstract

          Objective

          We aimed to investigate mutation‐specific white matter ( WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72, MAPT , and GRN mutations by use of diffusion‐weighted imaging within the Genetic Frontotemporal dementia Initiative ( GENFI) study.

          Methods

          One hundred and forty mutation carriers (54 C9orf72, 30 MAPT , 56 GRN ), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72, MAPT , and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on GRN mutation carriers versus noncarriers.

          Results

          Diffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers – characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN . Restricting analyses to presymptomatic mutation carriers only, similar – albeit less extensive – patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT , and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN , most tracts showed significant left–right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC.

          Interpretation

          This study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic “fingerprint.” Our findings corroborate the notion of FTD as a network‐based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease‐tracking and ‐staging in presymptomatic to early‐stage familial FTD.

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          Most cited references30

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          Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease.

          Neuroimaging in mild cognitive impairment (MCI) and Alzheimer disease (AD) generally shows medial temporal lobe atrophy and diminished glucose metabolism and cerebral blood flow in the posterior cingulate gyrus. However, it is unclear whether these abnormalities also impact the cingulum fibers, which connect the medial temporal lobe and the posterior cingulate regions. To use diffusion tensor imaging (DTI), by measuring fractional anisotropy (FA), to test 1) if MCI and AD are associated with DTI abnormalities in the parahippocampal and posterior cingulate regions of the cingulum fibers; 2) if white matter abnormalities extend to the neocortical fiber connections in the corpus callosum (CC); 3) if DTI improves accuracy to separate AD and MCI from healthy aging vs structural MRI. DTI and structural MRI were preformed on 17 patients with AD, 17 with MCI, and 18 cognitively normal (CN) subjects. FA of the cingulum fibers was significantly reduced in MCI, and even more in AD. FA was also significantly reduced in the splenium of the CC in AD, but not in MCI. Adding DTI to hippocampal volume significantly improved the accuracy to separate MCI and AD from CN. Assessment of the cingulum fibers using diffusion tensor imaging may aid early diagnosis of Alzheimer disease.
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            Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia.

            To use diffusion tensor imaging (DTI) to assess gray matter and white matter tract diffusion in behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SMD), and progressive nonfluent aphasia (PNFA). This was a case-control study where 16 subjects with bvFTD, 7 with PNFA, and 4 with SMD were identified and matched by age and gender to 19 controls. All subjects had 3-T head MRI with a DTI sequence with diffusion encoding in 21 directions. Gray matter mean diffusivity (MD) was assessed using a region-of-interest (ROI) and voxel-level approach, and voxel-based morphometry was used to assess patterns of gray matter loss. White matter tract diffusivity (fractional anisotropy and radial diffusivity) was assessed by placing ROIs on tracts of interest. In bvFTD, increased gray matter MD and gray matter loss were identified bilaterally throughout frontal and temporal lobes, with abnormal diffusivity observed in white matter tracts that connect to these regions. In SMD, gray matter loss and increased MD were identified predominantly in the left temporal lobe, with tract abnormalities observed in the inferior longitudinal fasciculus and uncinate fasciculus. In PNFA, gray matter loss and increased MD were observed in left inferior frontal lobe, insula, and supplemental motor area, with tract abnormalities observed in the superior longitudinal fasciculus. The diffusivity of gray matter is increased in regions that are atrophic in frontotemporal dementia, suggesting disruption of the cytoarchitecture of remaining tissue. Furthermore, damage was identified in white matter tracts that interconnect these regions, supporting the hypothesis that these diseases involve different and specific brain networks.
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              Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers

              Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise. To gain insights into this question, we compared 15 presymptomatic carriers (age 43.7 ± 10.2 years, nine females) to matched healthy controls. We used voxel-based morphometry to assess gray matter, diffusion tensor imaging to interrogate white matter tracts, and task-free functional MRI to probe the salience, sensorimotor, default mode, and medial pulvinar thalamus-seeded networks. We further used a retrospective chart review to ascertain psychiatric histories in carriers and their non-carrier family members. Carriers showed normal cognition and behavior despite gray matter volume and brain connectivity deficits that were apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those in patients with behavioral variant frontotemporal dementia due to C9ORF72, with major foci in cingulate, insula, thalamus, and striatum. Reduced white matter integrity was found in the corpus callosum, cingulum bundles, corticospinal tracts, uncinate fasciculi and inferior longitudinal fasciculi. Intrinsic connectivity deficits were detected in all four networks but most prominent in salience and medial pulvinar thalamus-seeded networks. Carrier and control groups showed comparable relationships between imaging metrics and age, suggesting that deficits emerge during early adulthood. Carriers and non-carrier family members had comparable lifetime histories of psychiatric symptoms. Taken together, the findings suggest that presymptomatic C9ORF72 expansion carriers exhibit functionally compensated brain volume and connectivity deficits that are similar, though less severe, to those reported during the symptomatic phase. The early adulthood emergence of these deficits suggests that they represent aberrant network patterning during development, an early neurodegeneration prodrome, or both.
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                Author and article information

                Contributors
                j.rohrer@ucl.ac.uk
                Journal
                Ann Clin Transl Neurol
                Ann Clin Transl Neurol
                10.1002/(ISSN)2328-9503
                ACN3
                Annals of Clinical and Translational Neurology
                John Wiley and Sons Inc. (Hoboken )
                2328-9503
                11 July 2018
                September 2018
                : 5
                : 9 ( doiID: 10.1002/acn3.2018.5.issue-9 )
                : 1025-1036
                Affiliations
                [ 1 ] Department of Neurology Erasmus Medical Center Rotterdam the Netherlands
                [ 2 ] Dementia Research Center University College London London United Kingdom
                [ 3 ] Department of Radiology Leiden University Medical Center Leiden the Netherlands
                [ 4 ] Department of Medical Statistics London School of Hygiene & Tropical Medicine London United Kingdom
                [ 5 ] Centre for Medical Image Computing (CMIC) University College London London United Kingdom
                [ 6 ] Institute of Psychology Leiden University Leiden the Netherlands
                [ 7 ] Leiden Institute for Brain and Cognition Leiden University Leiden the Netherlands
                [ 8 ] Department of Clinical Genetics Erasmus Medical Center Rotterdam the Netherlands
                [ 9 ] Department of Clinical Genetics Leiden University Medical Center Leiden the Netherlands
                [ 10 ] Department of Neurology Alzheimer Center Neuroscience Campus Amsterdam Amsterdam the Netherlands
                [ 11 ] Neurology Unit Department of Clinical and Experimental Sciences University of Brescia Brescia Italy
                [ 12 ] Department of Pathophysiology and Transplantation Dino Ferrari Center University of Milan Fondazione Ca` Granda IRCCS Ospedale Maggiore Policlinico Milan Italy
                [ 13 ] LC Campbell Cognitive Neurology Research Unit Sunnybrook Research Institute Toronto Ontario Canada
                [ 14 ] Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto Ontario Canada
                [ 15 ] Department of Clinical Neurosciences University of Cambridge Cambridge United Kingdom
                [ 16 ] Department of Geriatric Medicine Karolinska University Hospital‐Huddinge Stockholm Sweden
                [ 17 ] Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologica Carlo Besta Milan Italy
                [ 18 ] Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy
                [ 19 ] Memory Clinic LANVIE‐Laboratory of Neuroimaging of Aging University Hospitals University of Geneva Geneva Switzerland
                [ 20 ] Clinique Interdisciplinaire de Mémoire Département des Sciences Neurologiques Université Laval Québec Quebec Canada
                [ 21 ] Department of Clinical Neurological Sciences University of Western Ontario Toronto Ontario Canada
                [ 22 ] Faculty of Medicine University of Lisbon Lisbon Portugal
                [ 23 ] Department of NEUROFARBA University of Florence Florence Italy
                [ 24 ] Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Don Gnocchi” Florence Italy
                [ 25 ] Department of Clinical Genetics VU Medical Center Amsterdam the Netherlands
                Author notes
                [*] [* ] Correspondence

                Jonathan D. Rohrer, Dementia Research Center, University College London (UCL), 8‐11 Queen Square, Box 16, National Hospital for Neurology and Neurosurgery, WC1N 3BG London, United Kingdom. Tel: +44 (0)20 3448 4773; Fax: +44 (0)20 3448 3104; E‐mail: j.rohrer@ 123456ucl.ac.uk

                [†]

                Authors contributed equally to this work

                [‡]

                See Data S1 for a list of GENFI consortium members

                Author information
                http://orcid.org/0000-0001-6023-0391
                Article
                ACN3601
                10.1002/acn3.601
                6144447
                30250860
                91d13de1-23bb-4e4d-be7a-0aada4637e03
                © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 May 2018
                : 08 June 2018
                Page count
                Figures: 2, Tables: 3, Pages: 12, Words: 8191
                Funding
                Funded by: Centres of Excellence in Neurodegeneration Grant
                Funded by: Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility
                Funded by: NIHR Queen Square Dementia Biomedical Research Unit
                Funded by: NIHR UCL/H
                Funded by: H Biomedical Research Centre
                Funded by: MRC UK GENFI
                Award ID: MR/M023664/1
                Funded by: Dioraphte Foundation grant
                Award ID: 09‐02‐03‐00
                Funded by: the Association for Frontotemporal Dementias Research Grant 2009
                Funded by: The Netherlands Organization for Scientific Research
                Award ID: HCMI 056‐13‐018
                Funded by: Alzheimer Nederland and Memorabel ZonMw
                Award ID: 733050102
                Funded by: the EU Joint Programme – Neurodegenerative Disease Research (JPND)
                Funded by: the Netherlands Organization for Health Research and Development
                Award ID: 733051042
                Funded by: Bluefield Project
                Funded by: UK Medical Research Council
                Funded by: the Italian Ministry of Health
                Funded by: Alzheimer's Research UK
                Funded by: Brain Research Trust
                Funded by: The Wolfson Foundation
                Funded by: MRC Clinician Scientist Fellowship
                Award ID: MR/M008525/1
                Funded by: NIHR Rare Disease Translational Research Collaboration
                Award ID: BRC149/NS/MH
                Funded by: Alzheimer Nederland
                Award ID: WE.09‐2014‐04
                Funded by: Vici
                Award ID: 016‐130‐677
                Funded by: Wellcome Trust
                Award ID: 103838
                This work was funded by Centres of Excellence in Neurodegeneration Grant grant ; Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility grant ; NIHR Queen Square Dementia Biomedical Research Unit grant ; NIHR UCL/H grant ; H Biomedical Research Centre grant ; MRC UK GENFI grant MR/M023664/1; Dioraphte Foundation grant grant 09‐02‐03‐00; the Association for Frontotemporal Dementias Research Grant 2009 grant ; The Netherlands Organization for Scientific Research grant HCMI 056‐13‐018; Alzheimer Nederland and Memorabel ZonMw grant 733050102; the EU Joint Programme – Neurodegenerative Disease Research (JPND) grant ; the Netherlands Organization for Health Research and Development grant 733051042; Bluefield Project grant ; UK Medical Research Council grant ; the Italian Ministry of Health grant ; Alzheimer's Research UK grant ; Brain Research Trust grant ; The Wolfson Foundation grant ; MRC Clinician Scientist Fellowship grant MR/M008525/1; NIHR Rare Disease Translational Research Collaboration grant BRC149/NS/MH; Alzheimer Nederland grant WE.09‐2014‐04; Vici grant 016‐130‐677; Wellcome Trust grant 103838.
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                acn3601
                September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.9 mode:remove_FC converted:19.09.2018

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