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

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.

Study Overview

• Status: Completed
• Conditions: Frontotemporal Lobar Degeneration
• Intervention / Treatment: Behavioral: Behavioral : Characterization

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'.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients with a PGRN gene mutation; Symptomatic patients with a PGRN gene mutation	Behavioral: Behavioral : Characterization; Behavioral scales and neuropsychological tests; MRI, SPECT/PET
Other: Presymptomatic individuals; Asymptomatic 'At-risk' individuals with a PGRN gene mutation	Behavioral: Behavioral : Characterization; Behavioral scales and neuropsychological tests; MRI, SPECT/PET
Other: healthy volunteers; 'At-risk' individuals without a PGRN gene mutation	Behavioral: Behavioral : Characterization; Behavioral scales and neuropsychological tests; MRI, SPECT/PET

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	at baseline 0 Months,at 42 Months,at 72 Months
Differences in transcriptome analysis between symptomatic patients, asymptomatic carriers and controls.	Study gene expression and RNA splicing alterations in lymphocytes (RNA sequencing)	at baseline 0 Months,at 42 Months,at 72 Months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Caroppo P, Habert MO, Durrleman S, Funkiewiez A, Perlbarg V, Hahn V, Bertin H, Gaubert M, Routier A, Hannequin D, Deramecourt V, Pasquier F, Rivaud-Pechoux S, Vercelletto M, Edouart G, Valabregue R, Lejeune P, Didic M, Corvol JC, Benali H, Lehericy S, Dubois B, Colliot O, Brice A, Le Ber I; Predict-PGRN study group. Lateral Temporal Lobe: An Early Imaging Marker of the Presymptomatic GRN Disease? J Alzheimers Dis. 2015;47(3):751-9. doi: 10.3233/JAD-150270.
• Saracino D, Dorgham K, Camuzat A, Rinaldi D, Rametti-Lacroux A, Houot M, Clot F, Martin-Hardy P, Jornea L, Azuar C, Migliaccio R, Pasquier F, Couratier P, Auriacombe S, Sauvee M, Boutoleau-Bretonniere C, Pariente J, Didic M, Hannequin D, Wallon D; French Research Network on FTD/FTD-ALS; PREV-DEMALS and Predict-PGRN study groups; Colliot O, Dubois B, Brice A, Levy R, Forlani S, Le Ber I. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications. J Neurol Neurosurg Psychiatry. 2021 Dec;92(12):1278-1288. doi: 10.1136/jnnp-2021-326914. Epub 2021 Aug 4.
• Saracino D, Sellami L, Boniface H, Houot M, Pelegrini-Issac M, Funkiewiez A, Rinaldi D, Locatelli M, Azuar C, Causse-Lemercier V, Jaillard A, Pasquier F, Chastan M, Wallon D, Hitzel A, Pariente J, Pallardy A, Boutoleau-Bretonniere C, Guedj E, Didic M, Migliaccio R, Kas A, Habert MO, Le Ber I; Predict-PGRN. Brain Metabolic Profile in Presymptomatic GRN Carriers Throughout a 5-Year Follow-up. Neurology. 2023 Jan 24;100(4):e396-e407. doi: 10.1212/WNL.0000000000201439. Epub 2022 Oct 18.

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2010
• Primary Completion (Actual): October 6, 2022
• Study Completion (Actual): October 6, 2022

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: July 8, 2019
• First Posted (Actual): July 10, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Frontotemporal Dementia,; biomarkers,; brain Imaging PET
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Metabolic Diseases; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Frontotemporal Lobar Degeneration
• Other Study ID Numbers: P071229

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No