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, David M. Cash, John van Swieten, Elise Dopper, Lize Jiskoot, Rick van Minkelen, Serge A. 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 RogaevaDavid 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 Fumagalli, James B. Rowe, Ian Coyle-Gilchrist, Caroline Graff, Marie Fallström, Vesna Jelic, Anne Kinhult Ståhlbom, Christin Andersson, Håkan Thonberg, Lena Lilius, Giovanni B. Frisoni, Giuliano Binetti, Michela Pievani, Martina Bocchetta, Luisa Benussi, Roberta Ghidoni, Elizabeth Finger

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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.
Original languageEnglish
Pages (from-to)253-262
Number of pages10
JournalThe Lancet Neurology
Issue number3
Early online date3 Feb 2015
Publication statusPublished - 1 Mar 2015

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