Approximately 50% of patients with FTD have a family history of the disease suggestive of a genetic cause. To date, more than 20 genes carrying mutations are associated with the family forms of DFT (TAU, Progranulin, VCP, CHMP2B...), but some of the family forms (about 15%) are still unexplained, without identified mutations. In genetic forms, clinical manifestations vary greatly from patient to patient, particularly the age of onset of disease. The first symptoms may appear at an early age before the age of 40 or at a very advanced age, or may never appear, depending on the individuals with the same mutation.
The causes of fronto temporal dementia (FTD)
The cause of the sporadic forms (with no family history) has not yet been identified.
Whatever the origin of fronto-temporal dementia, the regions of the brain affected are the same. In 60% of cases, neuronal death is due to protein accumulation in neurons in the frontal and temporal lobe regions. In some patients this is the abnormal accumulation of the TAU protein, which is called “PICK body,” but aggregates of other mutated proteins can be observed with the same consequences.
More rarely, neurons degenerate without specific brain damage.
In all cases of FTD, the symptoms are the consequence of atrophy of the frontal and temporal regions as a result of neuronal death specifically in these brain regions.
Frontal regions are involved in so-called “executive” functions, which include capacities as broad as planning, reasoning and decision-making. They are also important for the control of emotions, social behaviour… Temporal regions are essential for language, the understanding of words and therefore influence speech or writing.
To learn more about these brain regions, read the work of the team “FRONTLAB: Functions and dysfunctions of frontal systems” of Prof. Richard LEVY of Paris Brain Institute:
At Paris Brain Institute
The search for new genes responsible for FTD is part of the research challenges in these pathologies. A study conducted by Dr. Isabelle Le Ber (Team “Fundamental and Translational Neurogenetics” co-led by Prof. Alexandra DURR and Giovanni STEVANIN) has identified a new gene, ataxin2, involved in fronto-temporal degeneration. This discovery represents an advance in the diagnosis of these pathologies and in the genetic counselling of patients' families.
A study conducted by Isabelle Le Ber’s team shows for the first time the influence of genetics on the age of appearance of certain familial forms of fronto-temporal dementia. The precise identification of genetic factors should, in time, make it possible to better predict the age of onset of the disease in a person at risk, which will have a direct impact on genetic counselling and patient management.
Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that may have a common genetic cause, the most common of which is a mutation in the c9orf72 gene. Certain preclinical developments targeting this gene offer encouraging therapeutic prospects. In order to test the efficacy of these potential therapies, it is essential to identify markers to detect the appearance of lesions at an early stage and monitor the progression of the disease.
At the Pitié-Salpêtrière Hospital, AP-HP, the PREVDEMALS cohort includes 80 asymptomatic people with the c9orf72 mutation, who are therefore at risk of developing FTD or ALS in a few years' time. These people were monitored for 36 months (neuropsychological, structural and micro-structural analyses of the brain's white matter, cerebral metabolism, biological and clinical examinations) in order to identify prognostic markers for the onset of the disease at the asymptomatic stage.
Studies carried out on this cohort by several of the Institute's teams have already shown very early changes in brain function and structure before the onset of symptoms in people at risk because they carry the mutation.
