• Rate of change of Frontal Assessment Battery score (/18) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Executive functions changes over time (rate of change in neuropsychological test)
• Rate of change of Trail Making Test B-A time (seconds) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Cognitive flexibility changes over time (rate of change in neuropsychological test)
• Rate of change of Ekman's faces test score (/35) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Emotional assessment changes over time (rate of change in neuropsychological test)
• Rate of change of Faux-pas test score (/35) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Social cognition changes over time (rate of change in neuropsychological test)
• Rate of change of Digit span score [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Short-term memory changes over time (rate of change in neuropsychological test)
• Rate of change of Free and Cued Selective Reminding test, total recall score (/48) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Long-term memory changes over time (rate of change in neuropsychological test)
• Rate of change of Boston Naming test score (/34) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Language changes over time (rate of change in neuropsychological test)
• Rate of change of Gestural Praxis battery score (/168) [ Time Frame: at baseline 0 Months,at 42 Months, at 72 Months ]
  Gestural praxis changes over time (rate of change in neuropsychological test)
• Rate of change of Neuropsychiatric Inventory score (/144) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Behavioral changes over time (rate of change in neuropsychological questionnaire)
• Rate of change of Apathy Evaluation Scale score (/42) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Apathy changes over time (rate of change in neuropsychological questionnaire)
• Change in MRI morphological criteria (brain atrophy by voxel-based morphometry) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
• Change in cerebral metabolism by PET (metabolic markers by Fluoro-DeoxyDGlucose-Positron Emission Tomography (FDG-PET)) [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]

• In symptomatic patients:changes in cognitive and behavioral functions [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Broad neuropsychological assessment (including but no limited to Mini Mental State Assessment,Mattis Dementia Rating Scale,Free and cued selective reminding test) and behavioral scales (including Frontal behavioral inventory, Neuropsychiatric inventory and others).
• Changes in MRI morphological criteria [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Brain structural changes will be evaluated by voxel-based morphometry (SPM12 software) to assess global brain atrophy in one with the evaluation of atypical shape patterns such as cortical thickness (Freesurfer software) and the study of the cortical sulci (BrainVISA/Morphologist software).
• Changes and in cerebral perfusion by SPECT/PET [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Identifying brain metabolic markers by Fluoro Deoxy DGlucose-Positron Emission Tomography (FDG-PET).

• Correlations between cognitive and behavioral scores, MRI morphological criteria, cerebral metabolism by FDG-PET and transcriptome analysis in presymptomatic subjects and in symptomatic patients at early disease stage [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Voxel-based methods using Statistical Parametric Mapping software will be applied to compare different groups or analyze correlations between brain atrophy/metabolism and cognitive deficits.
• Differences in transcriptome analysis between symptomatic patients, asymptomatic carriers and controls. [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Study gene expression and RNA splicing alterations in lymphocytes (RNA sequencing)

• Correlations between cognitive and behavioral score, MRI morphological criteria, cerebral perfusion/ metabolism by SPECT / PET and transcriptome analysis. The investigators will consider the absolute scores of the neuropsychological/behavioral assessment [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Voxel-based methods using Statistical Parametric Mapping software will be applied to compare different groups or analyze correlations between brain atrophy/metabolism and cognitive deficits.
• Predictive factors for disease evolution in symptomatic patients [ Time Frame: at baseline 0 Months, at 42 Months, at 72 Months ]
  The following putative biomarkers will be investigated in the early stage of the disease :

  • Behavioral biomarkers : cross-sectional behavioral scales scores and modifications over time
  • Cognitive biomarkers : cross-sectional neuropsychological assessment scores and modifications over time
  • MRI biomarkers : cross-sectional brain atrophy and progression rate
  • FDG-PET biomarkers : cross-sectional brain hypometabolism and progession rate
• Differences in transcriptome analysis between symptomatic patients, asymptomatic carriers and controls [ Time Frame: at baseline 0 Months,at 42 Months,at 72 Months ]
  Study gene expression and RNA splicing alterations in lymphocytes (RNA sequencing)

The project focuses on the progranulin (PGRN) gene mutation, one of the most frequent genetic forms of frontotemporal dementias (FTD, or frontotemporal lobar degeneration, FTLD). FTD is the second commonest cause of degenerative dementia in presenium after Alzheimer's disease. Behavioral and cognitive impairments progressively lead to dementia. Two major pathological subtypes are now defined in FTD, FTD-TDP and FTD-TAU.

FTD is difficult to detect at an early stage, and no clinical, biological or imaging features can predict the underlying pathology in living patients. Therapeutic perspectives have emerged against tau aggregation, PGRN deficit and C9orf72 expansion. Presymptomatic carriers of genetic FTD would benefit, before onset of symptoms, from these therapeutics that would delay or prevent the disease. At this step, it becomes crucial to develop markers to know how many years before symptoms, the pathological process begins, to treat the patients at the earliest stage of the disease. Markers are also needed to predict the pathology (FTD-TDP/FTD-tau) in patients that will be eligible for trials targeting specific pathological lesion. The main objectives of the project are to identify novel cognitive, brain imaging markers and peripheral biomarkers for early diagnosis of FTLD, and to follow disease progression. Ninety participants including 8 patients and 82 'at-risk' individuals will be recruited and evaluated by clinical partners of the project (Paris, Lille, Rouen, Toulouse, Saint-Etienne, Marseille, Nantes). 'At-risk individuals' are the first- degree relatives of PGRN patients, who have a high a risk (50%) to carry the mutation.

Brain structural changes will be evaluated by voxel-based morphometry (SPM12 software) to assess global brain atrophy in one with the evaluation of atypical shape patterns such as cortical thickness (Freesurfer software) and the study of the cortical sulci (BrainVISA/Morphologist software).

Fluoro Deoxy DGlucose-Positron Emission Tomography (FDG-PET) will allow the identification of brain metabolic markers. Then voxel-based methods using Statistical Parametric Mapping software will be applied to compare different groups or analyze correlations between brain metabolism and cognitive deficits.

The identification of peripheral biomarkers of disease onset and disease progression will take advantage from RNA sequencing, in order to study gene expression and RNA splicing alterations in lymphocytes of patients and 'at risk individuals'.

• Patients with a PGRN gene mutation
  Symptomatic patients with a PGRN gene mutation
  Intervention: Behavioral: Behavioral : Characterization
• Presymptomatic individuals
  Asymptomatic 'At-risk' individuals with a PGRN gene mutation
  Intervention: Behavioral: Behavioral : Characterization
• healthy volunteers
  'At-risk' individuals without a PGRN gene mutation
  Intervention: Behavioral: Behavioral : Characterization

Inclusion Criteria:

Inclusion criteria for symptomatic patients:

• Age ≥ 18
• Signed informed consent for genetic and clinical study
• To be carrier of a PGRN mutation - Diagnosis criteria of FTD
• To be affiliated to the social security scheme

Inclusion criteria for 'at-risk' asymptomatic relatives:

• Age ≥ 18
• To be first degree relative of a person carrying a PGRN mutation or first degree relative of FTD deceased patient whose PGRN mutation as been identified in the family
• Signed informed consent for genetic and clinical study
• To be affiliated to the social security scheme

Exclusion Criteria:

Exclusion criteria for symptomatic patients:

• Presence of one exclusion criteria from Diagnosis criteria of FTD. - Participation to another therapeutic trial. - Contra-indication to perform a brain MRI and/or PET-FDG
• Inability to lie one hour without moving
• Breastfeeding and pregnant women
• Presence of another intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....)

Exclusion criteria for 'at-risk' asymptomatic relatives :

• Presence of neurological or neurodegenerative disease
• Clinical proven signs of FTD, language disorder, praxis disorder, mnemic, of parkinson's syndrome or amyotrophic lateral sclerosis
• Contra-indication to perform a brain MRI and/or PET-FDG
• Inability to lie one hour without moving
• Breastfeeding and pregnant women
• Severe vascular lesion , tumor or infectious brain imaging if an MRI was done previously