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Gray and white matter changes in presymptomatic genetic frontotemporal dementia: a longitudinal MRI study.

Published on Apr 1, 2019in Neurobiology of Aging4.398
· DOI :10.1016/j.neurobiolaging.2018.12.017
Jessica L. Panman5
Estimated H-index: 5
(EUR: Erasmus University Rotterdam),
Lize C. Jiskoot9
Estimated H-index: 9
(EUR: Erasmus University Rotterdam)
+ 10 AuthorsJanne M. Papma9
Estimated H-index: 9
(EUR: Erasmus University Rotterdam)
Abstract
Abstract In genetic frontotemporal dementia, cross-sectional studies have identified profiles of presymptomatic neuroanatomical loss for C9orf72 repeat expansion, MAPT, and GRN mutations. In this study, we characterize longitudinal gray matter (GM) and white matter (WM) brain changes in presymptomatic frontotemporal dementia. We included healthy carriers of C9orf72 repeat expansion (n = 12), MAPT (n = 15), GRN (n = 33) mutations, and related noncarriers (n = 53), that underwent magnetic resonance imaging at baseline and 2-year follow-up. We analyzed cross-sectional baseline, follow-up, and longitudinal GM and WM changes using voxel-based morphometry and cortical thickness analysis in SPM and tract-based spatial statistics in FSL. Compared with noncarriers, C9orf72 repeat expansion carriers showed lower GM volume in the cerebellum and insula, and WM differences in the anterior thalamic radiation, at baseline and follow-up. MAPT mutation carriers showed emerging GM temporal lobe changes and longitudinal WM degeneration of the uncinate fasciculus. GRN mutation carriers did not show presymptomatic neurodegeneration. This study shows distinct presymptomatic cross-sectional and longitudinal patterns of GM and WM changes across C9orf72 repeat expansion, MAPT, and GRN mutation carriers compared with noncarriers.
  • References (61)
  • Citations (4)
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References61
Newest
#1Lize C. Jiskoot (EUR: Erasmus University Rotterdam)H-Index: 9
#2Jessica L. Panman (EUR: Erasmus University Rotterdam)H-Index: 5
Last. Janne M. Papma (EUR: Erasmus University Rotterdam)H-Index: 9
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Introduction We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD).
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#1Lieke H.H. Meeter (EUR: Erasmus University Rotterdam)H-Index: 8
#2Tania D Gendron (Mayo Clinic)H-Index: 23
Last. Suzee E. Lee (UCSF: University of California, San Francisco)H-Index: 18
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Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomat...
9 CitationsSource
#1Sonja Schönecker (LMU: Ludwig Maximilian University of Munich)H-Index: 4
#2Christiane Neuhofer (LMU: Ludwig Maximilian University of Munich)H-Index: 4
Last. Johannes Levin (LMU: Ludwig Maximilian University of Munich)H-Index: 14
view all 30 authors...
Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determ...
9 CitationsSource
#1David M. Cash (UCL: University College London)H-Index: 26
#2Martina Bocchetta (UCL: University College London)H-Index: 22
view all 21 authors...
Frontotemporal dementia (FTD) is a highly heritable condition with multiple genetic causes. In this study, similarities and differences of gray matter (GM) atrophy patterns were assessed among 3 common forms of genetic FTD (mutations in C9orf72, GRN, and MAPT). Participants from the Genetic FTD Initiative (GENFI) cohort with a suitable volumetric T1 magnetic resonance imaging scan were included (319): 144 nonmutation carriers, 128 presymptomatic mutation carriers, and 47 clinically affected muta...
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#1Anne BertrandH-Index: 17
#2Junhao Wen (French Institute of Health and Medical Research)H-Index: 1
Last. Isabelle Le Ber (French Institute of Health and Medical Research)H-Index: 18
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Importance Presymptomatic carriers of chromosome 9 open reading frame 72 ( C9orf72 ) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. Objectives To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic ...
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#1Kirsi M. Kinnunen (UCL Institute of Neurology)H-Index: 9
#2David M. Cash (UCL: University College London)H-Index: 26
Last. Nick C. Fox (UCL Institute of Neurology)H-Index: 115
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Abstract Introduction Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Methods Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from no...
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#1Janne M. Papma (Erasmus University Medical Center)H-Index: 5
#2Lize C. Jiskoot (Erasmus University Medical Center)H-Index: 4
Last. John VanSwietenH-Index: 71
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Objective: To investigate cognitive function, gray matter volume, and white matter integrity in the presymptomatic stage of chromosome 9 open reading frame 72 repeat expansion ( C9orf72RE ). Methods: Presymptomatic C9orf72RE carriers (n = 18) and first-degree family members without a pathogenic expansion (healthy controls [HC], n = 15) underwent a standardized protocol of neuropsychological tests, T1-weighted MRI, and diffusion tensor imaging within our cohort study of autosomal dominant frontot...
24 CitationsSource
#1Lieke H.H. MeeterH-Index: 8
#2Laura Donker KaatH-Index: 9
Last. John VanSwietenH-Index: 71
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Reliable biomarkers for frontotemporal dementia (FTD) are required for accurate discrimination between dementia types, prediction of clinical progression and tailoring of pharmacological interventions. This Review discusses the increasing number of available biomarkers for FTD — including novel imaging modalities and fluid biomarkers — and the future challenges in their implementation.
34 CitationsSource
#2Julie van der Zee (University of Antwerp)H-Index: 35
Last. C. Van Broeckhoven (University of Antwerp)H-Index: 113
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Importance Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors. Objective To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations. Design, Setting, and Participants This cohort study was performed from J...
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#1Suzee E. Lee (UCSF: University of California, San Francisco)H-Index: 18
#2Ana C. Sias (UCSF: University of California, San Francisco)H-Index: 4
Last. William W. Seeley (UCSF: University of California, San Francisco)H-Index: 68
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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 fun...
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Cited By4
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Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder characterized by behavioral abnormalities, language impairment, and deficits of executive and motor functions. FTLD has a strong genetic background with about 30%-50% FTLD patients having an autosomal dominant pattern of inheritance with major mutations in the MAPT, GRN and the C9orf72 repeat expansion. These mutations could lead to neurodegeneration years before the onset of clinical symptoms. With potential disease-modify...
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#2Sabrina Sayah (French Institute of Health and Medical Research)H-Index: 1
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Objective To investigate cognitive inhibition in presymptomatic C9orf72 mutation carriers (C9+) and its associated neuroanatomical correlates. Methods Thirty-eight presymptomatic C9orf72 mutation carriers (C9+, mean age 38.2±8.0 years) and 22 C9− controls from the PREV-DEMALS cohort were included in this study. They underwent a cognitive inhibition assessment with the Hayling Sentence Completion Test (HSCT; time to completion (part B−part A); error score in part B) as well as a 3D MRI. Results C...
Source
#1Howie Rosen (UCSF: University of California, San Francisco)H-Index: 62
#2Bradley F. Boeve (Mayo Clinic)H-Index: 121
Last. Adam L. Boxer (UCSF: University of California, San Francisco)H-Index: 49
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#1Qin Chen (Sichuan University)H-Index: 1
#2Bradley F. Boeve (Mayo Clinic)H-Index: 121
Last. Kejal Kantarci (Mayo Clinic)H-Index: 53
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Abstract Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration (FTLD). Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural MRI in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and non-carriers (n...
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#1Qin Chen (Sichuan University)H-Index: 1
#2Bradley F. Boeve (Mayo Clinic)H-Index: 121
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Abstract Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes...
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a ‘dying-back’ disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration...
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#1Qin Chen (Sichuan University)H-Index: 1
#2Bradley F. Boeve (UCSF: University of California, San Francisco)H-Index: 121
Last. Kejal Kantarci (Mayo Clinic)H-Index: 53
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Abstract Introduction The aim of this study was to investigate the rates of lobar atrophy in the asymptomatic microtubule-associated protein tau (MAPT) mutation carriers. Methods MAPT mutation carriers (n = 14; 10 asymptomatic, 4 converters from asymptomatic to symptomatic) and noncarriers (n = 13) underwent structural magnetic resonance imaging and were followed annually with a median of 9.2 years. Longitudinal changes in lobar atrophy were analyzed using the tensor-based morphometry with symme...
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