Natural History Characterization in Symptomatic and Asymptomatic Progranuline Gene Mutation Carriers (Predict-PGRN)

Assistance Publique - Hôpitaux de Paris

Status: Completed

Conditions: Frontotemporal Lobar Degeneration

Treatments: Behavioral: Behavioral : Characterization

Study type: Interventional

Funder types: Other

Identifiers

NCT04014673

P071229

Details and patient eligibility

About

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.

Full 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'.

Enrollment: 78 patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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78 participants in 3 patient groups

Patients with a PGRN gene mutation

Other group

Description:

Symptomatic patients with a PGRN gene mutation

Treatment:

Behavioral: Behavioral : Characterization

Presymptomatic individuals

Other group

Description:

Asymptomatic 'At-risk' individuals with a PGRN gene mutation

Treatment:

Behavioral: Behavioral : Characterization

healthy volunteers

Other group

Description:

'At-risk' individuals without a PGRN gene mutation

Treatment:

Behavioral: Behavioral : Characterization