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Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

ABSTRACT: INTRODUCTION:The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS:We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS:Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes. DISCUSSION:Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

SUBMITTER: Ramos EM

PROVIDER: S-EPMC7199807 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

Ramos Eliana Marisa EM Dokuru Deepika Reddy DR Van Berlo Victoria V Wojta Kevin K Wang Qing Q Huang Alden Y AY Deverasetty Sandeep S Qin Yue Y van Blitterswijk Marka M Jackson Jazmyne J Appleby Brian B Bordelon Yvette Y Brannelly Patrick P Brushaber Danielle E DE Dickerson Bradford B Dickinson Susan S Domoto-Reilly Kimiko K Faber Kelley K Fields Julie J Fong Jamie J Foroud Tatiana T Forsberg Leah K LK Gavrilova Ralitza R Ghoshal Nupur N Goldman Jill J Graff-Radford Jonathan J Graff-Radford Neill N Grant Ian I Grossman Murray M Heuer Hilary W HW Hsiung Ging-Yuek R GR Huey Edward E Irwin David D Kantarci Kejal K Karydas Anna A Kaufer Daniel D Kerwin Diana D Knopman David D Kornak John J Kramer Joel H JH Kremers Walter W Kukull Walter W Litvan Irene I Ljubenkov Peter P Lungu Codrin C Mackenzie Ian I Mendez Mario F MF Miller Bruce L BL Onyike Chiadi C Pantelyat Alexander A Pearlman Rodney R Petrucelli Len L Potter Madeline M Rankin Katherine P KP Rascovsky Katya K Roberson Erik D ED Rogalski Emily E Shaw Leslie L Syrjanen Jeremy J Tartaglia Maria Carmela MC Tatton Nadine N Taylor Joanne J Toga Arthur A Trojanowski John Q JQ Weintraub Sandra S Wong Bonnie B Wszolek Zbigniew Z Rademakers Rosa R Boeve Brad F BF Rosen Howard J HJ Boxer Adam L AL Coppola Giovanni G

Alzheimer's & dementia : the journal of the Alzheimer's Association 20200101 1

<h4>Introduction</h4>The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.<h4>Methods</h4>We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic o ...[more]

PMID: 31914217

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Project description:IntroductionThe possibility to generalize our understandings on treatments and assessments to both familial frontotemporal dementia (f-FTD) and sporadic FTD (s-FTD) is a fundamental perspective for the near future, considering the constant advancement in potential disease-modifying therapies that target particular genetic forms of FTD. We aimed to investigate differences in clinical features, cerebrospinal fluid (CSF), and blood-based biomarkers between f-FTD and s-FTD.MethodsIn this longitudinal cohort study, we evaluated a consecutive sample of symptomatic FTD patients, classified as f-FTD and s-FTD according to Goldman scores (GS). All patients underwent clinical, behavioral, and neuropsychiatric symptom assessment, CSF biomarkers and serum neurofilament light (NfL) analysis, and brain atrophy evaluation with magnetic resonance imaging.ResultsOf 570 patients with FTD, 123 were classified as f-FTD, and 447 as s-FTD. In the f-FTD group, 95 had a pathogenic FTD mutation while 28 were classified as GS = 1 or 2; of the s-FTD group, 133 were classified as GS = 3 and 314 with GS = 4. f-FTD and s-FTD cases showed comparable demographic features, except for younger age at disease onset, age at diagnosis, and higher years of education in the f-FTD group (all P < .05). f-FTD showed worse behavioral disturbances as measured with Frontal Behavioral Inventory (FBI) negative behaviors (14.0 ± 7.6 vs. 11.6 ± 7.4, P = .002), and positive behaviors (20.0 ± 11.0 vs. 17.4 ± 11.8, P = .031). Serum NfL concentrations were higher in patients with f-FTD (70.9 ± 37.9 pg/mL) compared to s-FTD patients (37.3 ± 24.2 pg/mL, P < .001), and f-FTD showed greater brain atrophy in the frontal and temporal regions and basal ganglia. Patients with f-FTD had significantly shorter survival than those with s-FTD (P = .004).Discussionf-FTD and s-FTD are very similar clinical entities, but with different biological mechanisms, and different rates of progression. The parallel characterization of both f-FTD and s-FTD will improve our understanding of the disease, and aid in designing future clinical trials for both genetic and sporadic forms of FTD.HighlightsDo clinical features and biomarkers differ between patients with familial frontotemporal dementia (f-FTD) and sporadic FTD (s-FTD)?In this cohort study of 570 patients with FTD, f-FTD and s-FTD share similar demographic features, but with younger age at disease onset and diagnosis in the f-FTD group.f-FTD showed higher serum neurofilament light concentrations, greater brain damage, and shorter survival, compared to s-FTD.f-FTD and s-FTD are very similar clinical entities, but with different cognitive reserve mechanisms and different rates of progression.

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Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

Publications

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

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