MRI Hippocampal Microstructure and Episodic Memory in Early Multiple Sclerosis (Micro-MS)

Hippocampal Microstructure Assessed by a New MRI Sequence and Episodic Memory at the Early Stage of Multiple Sclerosis: Comparison Between Patients After a Clinically Isolated Syndrome (CIS) and Controls

Clinically isolated syndrome (CIS) can evolve into multiple sclerosis. In CIS patients, episodic memory is frequently impaired. Memory disorders could be preceded by microstructural abnormalities without visible atrophy in hippocampus. A recent MRI imaging of diffusion called NODDI (Neurite Orientation Dispersion and Density Imaging) can measure specifically microstructural abnormalities and map the axons in the white matter (WM) and dendrites in the grey matter (GM). The aim of this study is to evaluate microstructural abnormalities in the dentate gyrus of the hippocampus in CIS patients compared to controls.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Other: Clinical assessment; Other: Neuropsychological evaluation; Other: Psychological evaluation; Device: MRI Evaluation

Detailed Description

Cognitive deficiencies could occur after a first clinical event of the central nervous system suggestive of MS called clinically isolated syndrome (CIS). Cognitive impairment concerned several cognitive domains including episodic memory, attention, working memory and executive functions. It is recognized the negative impact of cognitive impairment on quality of life and vocational status in patients living with MS. Slowness of information processing speed is the main cognitive dysfunction observed in MS seen at the earliest stage of the disease. Recently an international group of MS experts has explain IPS and episodic memory as the minimal cognitive assessment in patients with MS. Visuospatial and verbal episodic memory deficits have been observed in 18 to 28% of patients assessed after a CIS.

Memory disorders could be preceded by microstructural abnormalities without visible atrophy in hippocampus. A recent MRI imaging of diffusion called NODDI (Neurite Orientation Dispersion and Density Imaging) can measure specifically microstructural abnormalities and map the axons in white matter and dendrite in the gray matter. No study has used the NODDI in CIS patients and very few studies have been conducted in MS.

The hypothesis is that the dentate gyrus is the anatomical substrate of early episodic memory dysfunction in patients included after a CIS.

The identification of predictive MRI biomarker of memory impairment would be a useful and clinically relevant prognostic marker at the early stage of MS. This biomarker could contribute to determine the prognosis of the disease and could help for the monitoring of the patients in clinical practice and clinical trials.

• Study Type: Interventional
• Enrollment (Anticipated): 110
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Aurélie RUET, MD, PhD; Phone Number: +33 (0)5 56 79 55 21; Email: aurelie.ruet@chu-bordeaux.fr
• Study Contact Backup: Name: Mathilde DELOIRE, PhD; Phone Number: +33 (0)5 57 82 12 75; Email: mathilde.deloire@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France
    • Recruiting
    • CHU de Bordeaux - Service de neurologie
    • Contact: Aurélie RUET, MD, PhD; Phone Number: +33 (0)5 56 79 55 21; Email: aurelie.ruet@chu-bordeaux.fr
    • Contact: Mathilde DELOIRE, PhD; Phone Number: +33 (0)5 57 82 12 75; Email: mathilde.deloire@chu-bordeaux.fr
    • Principal Investigator: Aurélie RUET, MD, PhD
    • Sub-Investigator: Jean-Christophe OUALLET, MD, PhD
    • Sub-Investigator: Amandine MOROSO, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• - PATIENTS:

  • Men and Women,
  • Age 18-60 years,
  • Native French language,
  • Clinically isolated neurological syndrome (CIS) compatible with a demyelinating inflammatory episode within the central nervous system, potentially beginning multiple sclerosis (MS) whatever the mode of presentation,
  • Between 60 and 180 days from the onset,
  • At least two clinically silent lesions on their T2-weighted brain or spinal MRI scan with a size of least 3 mm, at least one of which being cerebral, ovoid, or periventricular,
  • Willing to participate and to sign informed consent.

• - HEALTHY CONTROLS

  • Men and Women,
  • Age 18-60years,
  • Native French language,
  • Willing to participate and to sign informed consent.

Exclusion Criteria:

• - PATIENTS:

  • Prior documented neurological episode suggestive of MS,
  • History of neurological disease and/or other neurological diseases,
  • Psychiatric diseases,
  • Known chronic systemic diseases as judged by the investigator,
  • Alcohol or other addiction to toxic,
  • Disabling visual or motor problems preventing participation to neuropsychological assessments,
  • Acquisition disorders : Dyslexia, Dysphasia, Dyscalculia and dyspraxia,
  • Dosage change, stop or start of hypnotic or anxiolytic or antidepressive treatment less than 30 days,
  • Contra-indication to MRI (pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body, claustrophobia),
  • Steroid treatment less than one month (be taken orally or by infusion) at the dosage of 500mg daily,
  • Illiteracy, is unable to count or to read,
  • Pregnant or breastfeeding women,
  • Patient concerned by articles L 1121-5 to L 1121-8 (persons deprived of their liberty by a judicial or administrative decision, minors, persons of legal age who are the object of a legal protection measure or unable to express their consent).

• - HEALTHY CONTROLS

  • History of neurological disease and/or neurological diseases,
  • Psychiatric diseases,
  • Known chronic systemic diseases as judged by the investigator,
  • Alcohol or other addiction to toxic,
  • Acquisition disorders: Dyslexia, Dysphasia, Dyscalculia and dyspraxia,
  • Known cognitive impairment or Prior neuropsychological testing with the same tests less than one year,
  • Hypnotic or anxiolytic or antidepressive treatment,
  • Steroid treatment less than one month (be taken orally or by infusion) at the dosage of 500mg daily,
  • Contra-indication to MRI (pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body, claustrophobia) or refusing MRI,
  • Illiteracy, unable to count or to read,
  • Pregnant or breastfeeding women,
  • Patient concerned by articles L 1121-5 to L 1121-8 (persons deprived of their liberty by a judicial or administrative decision, minors, persons of legal age who are the object of a legal protection measure or unable to express their consent).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: CIS patients; Clinically isolated neurological syndrome (CIS) compatible with a demyelinating inflammatory episode within the central nervous system, potentially suggestive of multiple sclerosis (MS) whatever the mode of presentation	Other: Clinical assessment; Expanded Disability Status Scale (EDSS), ambulation test and Multiple Sclerosis functional composite (MSFC). Medications will be recorded.; Other: Neuropsychological evaluation; cognitive tests exploring episodic memories, information processing speed, attention/concentration and working memory.; Other: Psychological evaluation; included questionnaires for depression, anxiety, fatigue, cognitive complaint and reserve; Device: MRI Evaluation; Diffusion including NODDI, 3DT1 with and without gadolinium, 3D-FLAIR before and after gadolinium infusion, 3D White Matter nulled-MPRAGE, 3D Double-Inversion recovery sequences-weighted imaging and Resting state functional MRI
ACTIVE_COMPARATOR: Control; 50 Healthy controls	Other: Neuropsychological evaluation; cognitive tests exploring episodic memories, information processing speed, attention/concentration and working memory.; Other: Psychological evaluation; included questionnaires for depression, anxiety, fatigue, cognitive complaint and reserve; Device: MRI Evaluation; Diffusion including NODDI, 3DT1 with and without gadolinium, 3D-FLAIR before and after gadolinium infusion, 3D White Matter nulled-MPRAGE, 3D Double-Inversion recovery sequences-weighted imaging and Resting state functional MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Index of orientation-dispersion (IOD)	This parameter is measured in the dentate gyrus of hippocampus from NODDI imaging blind to the nature of the patient's group (CIS patients and controls).	At baseline (day 0)
Index of Neurite density (ND)	This parameter is measured in the dentate gyrus of hippocampus from NODDI imaging blind to the nature of the patient's group (CIS patients and controls).	At baseline (day 0)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diffusion parameters : Index of orientation-dispersion	This parameter is measured in thalamus and cerebellum from NODDI imaging blind to the nature of the patient's group (CIS patients and controls).	At baseline (day 0)
Diffusion parameters : Neurite density	This parameter is measured in thalamus and cerebellum from NODDI imaging blind to the nature of the patient's group (CIS patients and controls).	At baseline (day 0)
Diffusion parameters : Fractional Anisotropy	This parameter is measured in dentate gyrus of hippocampus, thalamus and cerebellum from diffusion imaging blind to the nature of the patient's group (CIS patients and controls).	At baseline (day 0)
Diffusion parameters : Mean diffusivity	This parameter is measured in dentate gyrus of hippocampus, thalamus and cerebellum from diffusion imaging blind to the nature of the patient's group (CIS patients and controls).	At baseline (day 0)
Atrophy parameters	Normalized total brain volume and normalized total WM and total GM volumes and in hippocampus, thalamus and cerebellum from 3D-T1, 3D-DIR, 3D-WMn-MPRAGE in CIS patients and controls in double-blind.	At baseline (day 0)
Lesion volume	Normalized volume of lesions double-blind measured by a semi-automatic method based on 3 D Fast Fluid-attenuated inversion-recuperation (3D-FLAIR) and 3 D Double Inversion Recovery (3D-DIR) in whole brain and in the hippocampus, thalamus and cerebellum.	At baseline (day 0)
Inflammatory activity	The inflammatory activity will be the number of T1-gadolinium enhancing lesions in whole brain and in the hippocampus, thalamus and cerebellum.	At baseline (day 0)
Connectivity	The seed-based connectivity is measured between hippocampus and others cerebral regions (Thalamus, cerebellum…) from Diffusion Tensor Imaging (DTI) and resting state functional imaging.	At baseline (day 0)
Verbal episodic memory test	California Verbal Learning Test-Second version (CVLT-II)	At baseline (day 0)
Visual episodic memory score	Brief Visual Memory Test-Revised (BVMT-R) and Memonic Similarity Task (MST) : visuospatial memory tests (2 scores pour BVMT-R, 3 scores pour MST)	At baseline (day 0)
Information processing speed and attention score	Computerized Speed Cognitive Test (CSCT) and TAP	At baseline (day 0)
Working memory score	Paced-Auditory-Serial-Addition-Test (PASAT) and span	At baseline (day 0)

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Aurélie RUET, MD, PhD, CHU Bordeaux; Study Chair: Eric FRISON, MD, PhD, CHU Bordeaux

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 12, 2019
• Primary Completion (ANTICIPATED): February 1, 2023
• Study Completion (ANTICIPATED): February 1, 2023

Study Registration Dates

• First Submitted: August 7, 2018
• First Submitted That Met QC Criteria: October 1, 2018
• First Posted (ACTUAL): October 2, 2018

Study Record Updates

• Last Update Posted (ACTUAL): June 16, 2022
• Last Update Submitted That Met QC Criteria: June 15, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: MRI; Hippocampus; Clinically Isolated Syndrome; dentate gyrus; NODDI; episodic memory function
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: CHUBX 2017/30

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