Multimodal Markers of Neurodegenerative Disorders at Presymptomatic Stages (NEUROPREMS)

NeuroPrems is a prospective, monocentric, longitudinal, not relating to a medicinal product for human use, non-randomized, non-controlled research. The study mainly aims to identify longitudinal changes and events in multimodal markers of neurodegeneration and neuroinflammation during the presymptomatic phases of neurodegenerative diseases.

Study Overview

• Status: Not yet recruiting
• Conditions: Neurodegenerative Diseases
• Intervention / Treatment: Radiation: PET; Other: MRI 3T; Other: Oculomotricity assessment; Other: Magnetoencephalography assessment; Other: Body posture and gait assessment; Other: Voice recording; Other: Video-polysomnography; Biological: Blood sampling, skin biopsy, excreta sampling, lumbar puncture

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

• Study Contact: Name: Pierre GEORGES FRANCOIS; Phone Number: 01 57 27 40 00; Email: riph@icm-institute.org

Study Locations

• France
  • Paris, France
    • Pitie Salpetriere Hospital
    • Principal Investigator: Jean-Christophe CORVOL, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study will focus on subjects potentially at high risk of developing a degenerative disease, compared to a control population of healthy volunteers and relatives with no evidence of genetic mutation under study, radiologically isolated syndrome (RIS), Idiopathic rapid eye-movement (REM) sleep behavior disorder (iRBD) and abnormal elevated levels of protein ptau217.

Description

1. Inclusion Criteria :

   1. For all participants :

      • Male or female
      • Age ≥ 18 years
      • Signed Informed consent by the subject
      • Affiliated with a social security system or beneficiary of such a regime
      • Ability to undergo an MRI exam with Gadobutrol

   2. For presymptomatic participants only :

      • Absence of a diagnosis of neurodegenerative disease. And at least one of the criteria :
      • Known carrier or relative of a patient carrying a mutation in a causal or at-risk responsible for a neurodegenerative disease
      • Isolated REM sleep behavioral disorder
      • Radiological isolated syndrome
      • Abnormal brain protein aggregates

   3. For controls only :

      • Absence of symptoms or diagnosis of neurodegenerative disease (or criteria corresponding to at risk group)

2. Exclusion Criteria :

   • Clinical symptoms fulfilling the criteria of a neurodegenerative disease (see table in criteria section)
   • Refusal of blood draw or brain MRI
   • MRI contraindication (see criteria section)
   • Known allergy to gadoteric acid
   • Unwillingness to be informed in case of abnormal MRI (with a significant medical anomaly)
   • Pregnancy or breastfeeding. For women in fertile age a urine pregnancy test will be performed before the MRI.
   • Inability to understand information about the protocol
   • Person deprived of their liberty by judicial or administrative decision
   • Person under legal protection (legal guardianship, tutelage or maintenance of justice)
   • Person without any protection and unable to consent
   • Other medical, neurological, psychiatric, or social conditions that in the investigator's opinion are likely to interfere with study conduct.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
800 presymptomatic participants; Visit interview; Neurological evaluation (NeuroPrems Scale and Self-administered REDCap questionnaires); Psychological evaluation (Motivation, life trajectories and experiencies and semi-structured interview); Cognition and behavior evaluation (Neuropsychological battery and Self-administered REDCap QR); Imaging (MRI 3T and PET DPA-714); Neurophysiology (Eye movement recording, Magnetoencephalography, Body posture and gait recording, voice and language recording); Skin aging (Skin quantitative elasticity assessment); Sleep (Videopolysomnography); Biosampling (Blood draw, lumbar puncture, saliva sampling, skin biopsy, nasal brush and tear fluid collection)	Radiation: PET; [18F]DPA-714 will be injected intravenously as a 1 minute intravenous bolus injection and dynamic PET acquisition will last 90 min. The aim is the quantification of the neuroimmune reaction during neuroinflammation process.; Other: MRI 3T; Brain MRI will aim at providing imaging biomarkers which will allow evaluating brain structure, microstructure, iron load, myelin, neurodegeneration of the substantia nigra and locus coeruleus, functional connectivity, brain perfusion and the glymphatic system.; Other: Oculomotricity assessment; Recording eye movements in a controlled environment (requiring no specific room or area) in binocular vision at a frequency > 500Hz, while retaining infrared video footage of eye movements for high-quality clinical monitoring.; Other: Magnetoencephalography assessment; Recording brain magnetic activity using the Elekta Neuromag® TRIUX Magnetoencephalograph ; The participant will be comfortably seated in an adjustable-height chair. The device is enclosed in a shielded room isolated from external electric and magnetic fields to measure the extremely weak magnetic activities produced by the brain.; Other: Body posture and gait assessment; The acquisition of kinematic gait parameters will be achieved ; markers are positioned on the different segments of members, recognized by a camera system positioned on the walls. Neurophysiologic muscular activity of the lower limbs will also be recorded.; Other: Voice recording; Participants will be recorded during a single session at every visit upon baseline with a professional quality head mounted microphone.; Other: Video-polysomnography; Participants will complete standard sleep questionnaires before the visit and perform neurophysiological tests including cognitive tasks before and after the sleep recording.; Biological: Blood sampling, skin biopsy, excreta sampling, lumbar puncture; Experimental analyses, genetic and multi-OMIC analyses for biomarker research.
200 healthy volunteers; Visit interview; Neurological evaluation (NeuroPrems Scale and Self-administered REDCap questionnaires); Psychological evaluation (Motivation, life trajectories and experiencies and semi-structured interview); Cognition and behavior evaluation (Neuropsychological battery and Self-administered REDCap QR); Imaging (MRI 3T and PET DPA-714); Neurophysiology (Eye movement recording, Magnetoencephalography, Body posture and gait recording, voice and language recording); Skin aging (Skin quantitative elasticity assessment); Sleep (Videopolysomnography); Biosampling (Blood draw, lumbar puncture, saliva sampling, skin biopsy, nasal brush and tear fluid collection)	Radiation: PET; [18F]DPA-714 will be injected intravenously as a 1 minute intravenous bolus injection and dynamic PET acquisition will last 90 min. The aim is the quantification of the neuroimmune reaction during neuroinflammation process.; Other: MRI 3T; Brain MRI will aim at providing imaging biomarkers which will allow evaluating brain structure, microstructure, iron load, myelin, neurodegeneration of the substantia nigra and locus coeruleus, functional connectivity, brain perfusion and the glymphatic system.; Other: Oculomotricity assessment; Recording eye movements in a controlled environment (requiring no specific room or area) in binocular vision at a frequency > 500Hz, while retaining infrared video footage of eye movements for high-quality clinical monitoring.; Other: Magnetoencephalography assessment; Recording brain magnetic activity using the Elekta Neuromag® TRIUX Magnetoencephalograph ; The participant will be comfortably seated in an adjustable-height chair. The device is enclosed in a shielded room isolated from external electric and magnetic fields to measure the extremely weak magnetic activities produced by the brain.; Other: Body posture and gait assessment; The acquisition of kinematic gait parameters will be achieved ; markers are positioned on the different segments of members, recognized by a camera system positioned on the walls. Neurophysiologic muscular activity of the lower limbs will also be recorded.; Other: Voice recording; Participants will be recorded during a single session at every visit upon baseline with a professional quality head mounted microphone.; Other: Video-polysomnography; Participants will complete standard sleep questionnaires before the visit and perform neurophysiological tests including cognitive tasks before and after the sleep recording.; Biological: Blood sampling, skin biopsy, excreta sampling, lumbar puncture; Experimental analyses, genetic and multi-OMIC analyses for biomarker research.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of change of clinical, neurophysiological, anatomical and molecular marker profiles of neurodegenerescence and neuroinflammation in presymptomatic individuals	Clinical markers will be: neurological and neuropsychological testing, and questionnaires; Neurophysiological markers will link functional brain networks and cognitive processes by using MEG, kinematic or eye movement recordings; Anatomical markers will be: cerebral MRI, glymphatic imaging, PET and skin elasticity; Molecular markers will be: blood, CSF, skin cells, iPSC derived biomarkers, transcriptomic, proteomic and metabolomic signatures	Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intra-individual change in trajectory profiles determined by multimodal analysis	Determination by individual parameters form multimodal analysis	Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5
Rate and mean time to symptomatic conversion/progression	Conversion/progression defined according to international criteria for the clinical diagnosis of each disease	Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5
Mean time of onset in genetically presymptomatic individuals	Estimated time to onset in genetic presymptomatic individuals from the average age at diagnosis among affected family members	Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5
Rate of change for each study marker	Period of changes defined (1) as breakpoints in the longitudinal evolution; (2) early, intermediate or late progression for each marker in the whole cohort and for each pathological group	Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5
Rate of change in the self-administered questionnaires	Changes in the self-administered questionnaires on motivation, barriers and psychology	Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5
Rate of change in consumption of information issued from Consultations, hospitalizations and medication prescriptions	Data from SNDS will be extracted during a 10-year period before and 10-year after the cohort entry. This follow-up should allow for a better understanding of when conversion occurs and to compare pathologies which involve a fairly broad spectrum of evolution.	From Year -10 to Year 10 (annual update)
Time to loss of autonomy	Rate of change from baseline of at least 0.1 in the utility index from EQ-5D-51	Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5

Collaborators and Investigators

• Sponsor: Paris Brain Institute (ICM)

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): August 31, 2034
• Study Completion (Estimated): August 31, 2034

Study Registration Dates

• First Submitted: June 6, 2024
• First Submitted That Met QC Criteria: July 17, 2024
• First Posted (Actual): July 23, 2024

Study Record Updates

• Last Update Posted (Actual): July 23, 2024
• Last Update Submitted That Met QC Criteria: July 17, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurodegenerative Diseases
• Other Study ID Numbers: 2024-A00824-43

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