GENFI – the first published results of the multicentre Genetic FTD Initiative

Approximately one third of patients with frontotemporal dementia have their disease caused by a problem in one of their genes, with these mutations most commonly involving the genes progranulin, microtubule-associated protein tau, or chromosome 9 open reading frame 72 . For many years research has focused on patients once they have developed symptoms, however recently there has been a growing awareness of the need to identify patients who are at risk of developing the disease in order to intervene with potential treatments.

Recently the Lancet Neurology journal published the first results from the GENFI consortium, a group spanning multiple European and Canadian FTD research centres. 220 participants were included who were either known carriers of a genetic mutation who had developed symptoms or were currently healthy people who were at risk of developing FTD because they had a parent or sibling with genetic FTD. In total 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers were included and neuropsychological data and imaging analysed. The main aim of the study was to identify how long prior to expected symptom onset people develop changes, and how these changes may be identified in order to offer treatments before the disease has progressed.

The study found that in currently asymptomatic patients at risk of developing FTD there is shrinkage of particular areas of the brain shown on imaging up to 10 years prior to expected disease onset, with changes seen on tests of cognition up to 5 years prior to disease onset.

The parts of the brain that show shrinkage involve several areas that we know to be involved in patients with FTD including the insula, which has roles in reward and emotion processing and acts as a hub for the networks that control many of the behavioural changes seen in FTD. Other brain structures showing shrinkage included the frontal and temporal cortex and areas deeper in the brain below the cortex, again areas known to be involved in FTD.

On neuropsychology testing participitants at risk of later developing FTD showed changes in tasks involving naming and executive function. Problems with executive function are one of the major hallmarks of FTD, and likely explain patients’ difficulties with planning and problem solving.

These findings provide us with important insights into how FTD progresses and suggest that changes in patients’ brains are occurring well before they develop signs and symptoms. Many of the clinical trials in dementias such as Alzheimer’s disease are believed to have failed due to the fact that treatment has been instigated once the disease is well established. Studies such as this current study in FTD show us that changes can be detected early offering the opportunity to intervene with treatments.

This study will likely be the first in a new aspect of research in FTD, looking for markers that allow us to detect changes before patients exhibit signs and intervene early, offering the greatest hope of changing disease progression and a cure for FTD.

Reference

Rohrer JD, Nicholas JM, Cash DM, van Swieten J, Dopper E, Jiskoot L, van Minkelen R, Rombouts SA, Cardoso MJ, Clegg S, Espak M, Mead S, Thomas DL, De Vita E, Masellis M, Black SE, Freedman M, Keren R, MacIntosh BJ, Rogaeva E, Tang-Wai D, Tartaglia MC, Laforce R Jr, Tagliavini F, Tiraboschi P, Redaelli V, Prioni S, Grisoli M, Borroni B, Padovani A, Galimberti D, Scarpini E, Arighi A, Fumagalli G, Rowe JB, Coyle-Gilchrist I, Graff C, Fallström M, Jelic V, Ståhlbom AK, Andersson C, Thonberg H, Lilius L, Frisoni GB, Pievani M, Bocchetta M, Benussi L, Ghidoni R, Finger E, Sorbi S, Nacmias B, Lombardi G, Polito C, Warren JD, Ourselin S, Fox NC, Rossor MN. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol. 2015 Mar;14(3):253-62.

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