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

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ClinicalTrials.gov Identifier: NCT04014673
Recruitment Status : Recruiting
First Posted : July 10, 2019
Last Update Posted : July 10, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief 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.

Condition or disease Intervention/treatment Phase
Frontotemporal Lobar Degeneration Behavioral: Behavioral : Characterization Not Applicable

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'.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Natural History Characterization in Symptomatic and Asymptomatic Progranuline Gene Mutation Carriers
Actual Study Start Date : January 19, 2010
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2022


Arm Intervention/treatment
Patients with a PGRN gene mutation
Symptomatic patients with a PGRN gene mutation
Behavioral: Behavioral : Characterization
Behavioral scales and neuropsychological tests; MRI, SPECT/PET

Presymptomatic individuals
Asymptomatic 'At-risk' individuals with a PGRN gene mutation
Behavioral: Behavioral : Characterization
Behavioral scales and neuropsychological tests; MRI, SPECT/PET

healthy volunteers
'At-risk' individuals without a PGRN gene mutation
Behavioral: Behavioral : Characterization
Behavioral scales and neuropsychological tests; MRI, SPECT/PET




Primary Outcome Measures :
  1. 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).

  2. 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).

  3. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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

  3. 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04014673


Contacts
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Contact: Isabelle LE BER, MD, PhD 1 57 27 46 79 ext 0033 isabelle.leber@upmc.fr
Contact: Daisy RINALDI, Ph.D 1 57 27 45 52 ext 0033 daisy.rinaldi@aphp.fr

Locations
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France
Groupe Hospitalier Pitié-Salpêtrière - Charles Foix Recruiting
Paris, France, 75013
Contact: Isabelle LE BER, MD, PhD    1 57 27 46 79 ext 0033    isabelle.leber@upmc.fr   
Contact: Daisy RINALDI, PhD    1 57 27 45 52 ext 0033    daisy.rinaldi@aphp.fr   
Pitié Salpetriere Hospital Recruiting
Paris, France, 75013
Contact: Isabelle LE BER         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Isabelle LE BER, MD, PhD Assistance Publique - Hôpitaux de Paris

Publications:
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04014673     History of Changes
Other Study ID Numbers: P071229
First Posted: July 10, 2019    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Frontotemporal Dementia,
biomarkers,
brain Imaging PET

Additional relevant MeSH terms:
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Frontotemporal Lobar Degeneration
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
TDP-43 Proteinopathies
Neurodegenerative Diseases
Proteostasis Deficiencies
Metabolic Diseases
Neurocognitive Disorders
Mental Disorders