NCT04014673

Natural History Characterization in Symptomatic and Asymptomatic Progranuline Gene Mutation Carriers

• Status: Completed
• Phase: N/A
• Study type: Interventional
• Enrollment: 78 (actual)
• Sponsor: Assistance Publique - Hôpitaux de Paris · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Accepted

Summary

The purpose of this study is to investigate whether cognitive deficits, structural and functional changes can be detected before symptom onset in presymptomatic progranuline mutation carriers. 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.

Detailed description

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'.

Conditions

• Frontotemporal Lobar Degeneration

Interventions

Type	Name	Description
BEHAVIORAL	Behavioral : Characterization	Behavioral scales and neuropsychological tests; MRI, SPECT/PET

Timeline

• Start date: 2010-01-19
• Primary completion: 2022-10-06
• Completion: 2022-10-06
• First posted: 2019-07-10
• Last updated: 2024-12-24

Locations

2 sites across 1 country: France