Predict to Prevent Frontotemporal Lobar Degeneration (FDT) and Amyotrophic Lateral Sclerosis (ALS) (PREV-DEMALS)

January 15, 2021 updated by: Assistance Publique - Hôpitaux de Paris

Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

The project focuses on C9orf72, the most frequent genetic form of frontotemporal dementias (FTD, or frontotemporal lobar degeneration, FTLD) and amyotrophic lateral sclerosis (ALS). FTD is the second commonest cause of degenerative dementia in presenium after Alzheimer's disease. Behavioural and cognitive impairments progressively lead to dementia. ALS produces progressive muscle weakness leading to the death in 2 to 4 years. Since 2006, major discoveries have linked FTLD and ALS:

  1. TDP-43 aggregates in neurons and
  2. C9orf72 mutations is a major genetic cause in both disorders.

Two major pathological subtypes are now defined in FTD, FTD-TDP and FTD-TAU. C9orf72 mutations (associated to FTD-TDP) are the most frequent genetic causes of FTD (15%), FTD-ALS (65%) and ALS (40%).

FTD is difficult at an early stage; and no clinical, biological or imaging features can predict the underlying pathology in living patients. Therapeutic perspectives emerged against tau aggregation, progranulin deficit and C9orf72 expansion (antisense). Presymptomatic carriers of genetic FTD would benefit, before onset of symptoms, from these therapeutic that would delay or prevent the disease. At this step, it becomes crucial to develop markers to know how many years before symptoms, does the pathological progress begin, to treat the patients at the most early 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This study will investigate whether cognitive deficits, structural and functional changes can be detected before symptom onset in presymptomatic mutation carrier. 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. Methodology

  1. Recruitment and evaluation of participants, neurological, behaviour and cognition evaluations. One hundred participants including 20 C9orf72 patients and 80 'a-risk' individuals will be recruited and evaluated by clinical partners of the project (Paris, Lille, Limoges, Rouen).. 'At-risk individuals' are the first degree relatives of C9ORF72 patients, who have a high a risk (50%) to carry the mutation.
  2. Identifying brain structural markers. Brain structural changes will be evaluated by voxel-based morphometry (SPM12 software) to assess global brain atrophy and evaluation of atypical shape patterns such as cortical thickness (Freesurfer software) and study of the cortical sulci (BrainVISA/Morphologist software).
  3. Identifying brain metabolic markers by Fluoro Deoxy DGlucose-Positron Emission Tomography (FDG-PET). We will apply voxel-based methods using Statistical Parametric Mapping software (SPM8) to compare different groups or analyze correlations between brain metabolism and cognitive deficits.
  4. Identifying peripheral biomarkers of disease onset and disease progression. We propose to use RNA sequencing to study gene expression and RNA splicing alterations in lymphocytes of C9ORF72 patients and 'at risk individuals'.

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75013
        • Groupe Hospitalier Pitié-Salpêtrière - Charles Foix

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18
  • Signed informed consent for genetic and clinical study
  • To be carrier of a C9ORF72 mutation - Diagnosis criteria of FTD or ALS
  • To be French-speaking
  • To be affiliated to the social security scheme
  • Absence of another intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....)

Inclusion criteria for asymptomatic relatives

  • Age ≥ 18
  • To be first degree relative of a person carrying a C9ORF72 mutation OR first degree relative of FTD or ALS deceased patient whose C9ORF72 mutation as been identified in the family
  • Signed informed consent for genetic and clinical study
  • To be French-speaking
  • To be affiliated to the social security scheme
  • Absence of proven neurologic disorders or an intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....)

Exclusion Criteria:

  • Contra-indication to perform a brain MRI (wearing of pacemaker, cardiac valve or incompatible vascular MRI surgical equipment , neurosurgery or surgery vascular equipment, surgical equipment likely to concentrate the radio frequency field, intra ocular or intra cerebral metal foreign body, claustrophobia, wearing a non-compliant radio intrauterine device ),
  • Inability to lie one hour without moving
  • PET-FDG contra-indication
  • Breastfeeding and pregnant women
  • Human chorionic gonadotrophin (Bétâ-HCG) positive determination or Positive urine pregnancy test for women of childbearing age

Exclusion criteria for related asymptomatic :

  • Clinical proven signs of FTD, language disorder, praxis disorder, mnemic, of parkinson's syndrome or amyotrophic lateral sclerosis.
  • Counter-indication to perform a brain MRI (wearing of pacemaker, cardiac valve or incompatible vascular MRI surgical equipment , neurosurgery or surgery vascular equipment, surgical equipment likely to concentrate the radio frequency field, intra ocular or intra cerebral metal foreign body, claustrophobia, wearing a non-compliant radio intrauterine device )
  • Severe chronic alcoholism
  • PET-FDG contre-indication
  • Inability to lie one hour without moving
  • Bétâ-HCG positive determination or Positive urine pregnancy test for women of childbearing age

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Evaluation
Characterization
Behavioral: characterization

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in behavioral assessment (20 scales)
Time Frame: at baseline, 16 weeks and 32weeks
at baseline, 16 weeks and 32weeks
Change in MRI morphological criteria
Time Frame: at baseline, 16 weeks and 32weeks
at baseline, 16 weeks and 32weeks
Change in cerebral perfusion by SPECT / PET
Time Frame: at baseline, 16 weeks and 32weeks
at baseline, 16 weeks and 32weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
correlations between behavioral assessment, MRI morphological criteria, Cerebral perfusion and metabolism by SPECT / PET and transcriptome analysis
Time Frame: 32 weeks
32 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Investigators

  • Principal Investigator: LE BER Isabelle, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 8, 2015

Primary Completion (Actual)

October 27, 2020

Study Completion (Actual)

October 27, 2020

Study Registration Dates

First Submitted

October 5, 2015

First Submitted That Met QC Criteria

October 27, 2015

First Posted (Estimate)

October 29, 2015

Study Record Updates

Last Update Posted (Actual)

January 20, 2021

Last Update Submitted That Met QC Criteria

January 15, 2021

Last Verified

August 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P140705 -
  • IDRCB : 2015-A00856-43 (Other Identifier: ANSM)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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