Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis
Jonathan D. Rohrer,Jennifer M. Nicholas,Jennifer M. Nicholas,David M. Cash,John C. van Swieten,Elise G.P. Dopper,Lize C. Jiskoot,Rick van Minkelen,Serge A.R.B. Rombouts,M. Jorge Cardoso,Shona Clegg,Miklos Espak,Simon Mead,David L. Thomas,Enrico De Vita,Mario Masellis,Sandra E. Black,Morris Freedman,Ron Keren,Bradley J. MacIntosh,Ekaterina Rogaeva,David F. Tang-Wai,Maria Carmela Tartaglia,Robert Laforce,Fabrizio Tagliavini,Pietro Tiraboschi,Veronica Redaelli,Sara Prioni,Marina Grisoli,Barbara Borroni,Alessandro Padovani,Daniela Galimberti,Elio Scarpini,Andrea Arighi,Giorgio G. Fumagalli,James B. Rowe,Ian Coyle-Gilchrist,Caroline Graff,Caroline Graff,Marie Fallström,Vesna Jelic,Vesna Jelic,Anne Kinhult Ståhlbom,Anne Kinhult Ståhlbom,Christin Andersson,Christin Andersson,Håkan Thonberg,Håkan Thonberg,Lena Lilius,Giovanni B. Frisoni,Giuliano Binetti,Michela Pievani,Martina Bocchetta,Luisa Benussi,Roberta Ghidoni,Elizabeth Finger,Sandro Sorbi,Benedetta Nacmias,Gemma Lombardi,Cristina Polito,Jason D. Warren,Sebastien Ourselin,Nick C. Fox,Martin N. Rossor +63 more
TLDR
Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia, which could help to define biomarkers that can stage presymPTomatic disease and track disease progression.Abstract:
Summary Background Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin ( GRN ), microtubule-associated protein tau ( MAPT ), or chromosome 9 open reading frame 72 ( C9orf72 ). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. Methods We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT , or C9orf72 , or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Findings Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test −0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all −0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference −0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference −0·2, SE 0·1). Interpretation Structural imaging and cognitive changes can be identified 5–10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Funding Centres of Excellence in Neurodegeneration.read more
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Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria
Michael J. Strong,Sharon Abrahams,Laura H. Goldstein,Susan C. Woolley,Paula M. McLaughlin,Julie S. Snowden,Eneida Mioshi,Angie Roberts-South,Michael Benatar,Tibor Hortobágyi,Jeffrey Rosenfeld,Vincenzo Silani,Paul G. Ince,Martin R Turner +13 more
TL;DR: These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD), which is a re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum.
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Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia
Jonathan D. Rohrer,Ione O.C. Woollacott,Katrina M. Dick,Emilie V. Brotherhood,Elizabeth Gordon,Alexander D. Fellows,Jamie Toombs,Ronald Druyeh,M. Jorge Cardoso,Sebastien Ourselin,Jennifer M. Nicholas,Niklas Norgren,Simon Mead,Ulf Andreasson,Kaj Blennow,Jonathan M. Schott,Nick C. Fox,Jason D. Warren,Henrik Zetterberg +18 more
TL;DR: Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes and show wide variability within each clinical and genetic group.
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Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference
Alexandra L. Young,Razvan V. Marinescu,Neil P. Oxtoby,Martina Bocchetta,Keir Yong,Nicholas C. Firth,David M. Cash,David L. Thomas,Katrina M. Dick,Jorge Cardoso,Jorge Cardoso,John C. van Swieten,Barbara Borroni,Daniela Galimberti,Daniela Galimberti,Mario Masellis,Maria Carmela Tartaglia,James B. Rowe,Caroline Graff,Fabrizio Tagliavini,Giovanni B. Frisoni,Robert Laforce,Elizabeth Finger,Alexandre de Mendonça,Sandro Sorbi,Jason D. Warren,Sebastian J. Crutch,Nick C. Fox,Sebastien Ourselin,Jonathan M. Schott,Jonathan D. Rohrer,Daniel C. Alexander +31 more
TL;DR: A machine-learning technique—Subtype and Stage Inference (SuStaIn)—able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies is introduced, using two neurodegenerative disease cohorts.
Journal ArticleDOI
Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis
Tania D Gendron,Jeannie Chew,Jeannette N. Stankowski,Lindsey R. Hayes,Yong Jie Zhang,Mercedes Prudencio,Yari Carlomagno,Lillian M. Daughrity,Karen Jansen-West,Emilie A. Perkerson,Aliesha D. O’Raw,Casey Cook,Luc Pregent,Veronique V. Belzil,Marka van Blitterswijk,Lilia J. Tabassian,Chris W. Lee,Mei Yue,Jimei Tong,Yuping Song,Monica Castanedes-Casey,Linda Rousseau,Virginia Phillips,Dennis W. Dickson,Rosa Rademakers,John D. Fryer,Beth K. Rush,Otto Pedraza,Ana M. Caputo,Pamela Desaro,Carla Palmucci,Amelia Robertson,Michael G. Heckman,Nancy N. Diehl,Edythe Wiggs,Michael Tierney,Laura Braun,Jennifer Farren,David Lacomis,Shafeeq Ladha,Christina Fournier,Leo McCluskey,Lauren Elman,Jon B. Toledo,Jon B. Toledo,Jennifer D. McBride,Cinzia Tiloca,Claudia Morelli,Barbara Poletti,Federica Solca,Alessandro Prelle,Joanne Wuu,Jennifer Jockel-Balsarotti,Frank Rigo,Christine Ambrose,Abhishek Datta,Weixing Yang,Denitza Raitcheva,Giovanna Antognetti,Alexander McCampbell,John C. van Swieten,Bruce L. Miller,Adam L. Boxer,Robert H. Brown,Robert Bowser,Timothy M. Miller,John Q. Trojanowski,Murray Grossman,James D. Berry,William T. Hu,Antonia Ratti,Bryan J. Traynor,Matthew D. Disney,Michael Benatar,Vincenzo Silani,Jonathan D. Glass,Mary Kay Floeter,Jeffrey D. Rothstein,Kevin B. Boylan,Leonard Petrucelli +79 more
TL;DR: Findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA–based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.
Journal ArticleDOI
An update on genetic frontotemporal dementia.
TL;DR: Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase.
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