Stratification of Presymptomatic Amyotrophic Lateral Sclerosis: the Development of Novel Imaging Biomarkers (STRATALS)

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder with no effective disease-modifying therapies at present. The disease is sporadic in 90 % of the ALS patients. Up to 40 % familial ALS cases and up to 25% of familial frontotemporal dementia (FTD) are caused by autosomal dominant GGGGCC hexanucleotide repeat expansions in the C9orf72 gene. The presymptomatic phase of the disease represents a unique opportunity to evaluate mechanisms of disease propagation, characterise patterns of anatomical spread, validate staging systems and appraise the comparative sensitivity profile of emerging imaging modalities. Very few spinal cord imaging studies currently exist in ALS despite their potential to characterise both the lower and upper motor neuron components of the disease. This prospective longitudinal study of asymptomatic and symptomatic c9orf72 hexanucleotide carriers will use a purpose-designed spinal and brain imaging protocol and comprehensive clinical, genetic, electrophysiological and neuropsychological profiling. Newly developed imaging techniques such as spinal cord NODDI, spinal fMRI, quantitative thoracic cord imaging will be implemented in addition to established spinal cord and brain imaging techniques.

Study Overview

• Status: Recruiting
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Other: Neuroimaging and electrophysiology

Detailed Description

The main objective is to study the disease trajectory from the presymptomatic to the symptomatic phase of ALS. We will study a population of asymptomatic subjects carrying an autosomal dominant GGGGCC hexanucleotide repeat expansions in the C9orf72 gene that is the most frequent mutation in familial cases of ALS. The changes will be compared to a population of healthy controls. We have selected two populations of healthy controls to take into account the possible interaction with the genetic background. The first population of controls will consist in subjects sharing the same genetic background than the presymptomatic subjects, e.g. non mutated subjects related to C9 + symptomatic carriers. The second population will consist in healthy individuals coming from the general population. We will compare the presymptomatic changes to changes occurring at the symptomatic phase by studying a group of patients with symptomatic ALS. We will use a multimodal longitudinal approach combing spinal and brain imaging protocol and comprehensive clinical, genetic, electrophysiological and neuropsychological profiling.

Secondary objectives

1. Comparison of the changes in young presymptomatic subjects (less than 40 years) vs older patients
2. Changes over time in ALS patients : MRI metrics, electrophysiological parameters and neuropsychological impairment
3. The development of prognostic indicators based on spinal cord/ brain imaging and electrophysiology to foretell phenotypic manifestation (such as DFT or ALS) and age of onset.
4. The integrative evaluation of brain-cord interactions, comparing the relative detection sensitivity of spinal and cerebral imaging measures.
5. Assessing the imaging evidence for the prevailing 'corticofugal spread' or 'dying-forward' theory based on longitudinal spinal cord and cerebral data.
6. Characterizing associations between imaging and electrophysiology metrics of upper motor neuron (UMN) and LMN (lower motor neuron) integrity; correlation of segmental grey matte metrics to MUNIX; TMS to corticospinal tract measures
7. Assessing whether longitudinal cerebral and spinal cord imaging data are consistent with sequential TDP-43 pathological staging systems.
8. The cross-validation of newly developed cord techniques; NODDI, fMRI, thoracic cord imaging with established structural and diffusion imaging metrics and electrophysiology measures.
9. Correlations between imaging, electrophysiology and neuropsychological metrics

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pierre Francois PRADAT, MD, PH; Phone Number: +33 1.42.16.24.71; Email: pierre-francois.pradat@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Recruiting
    • ICM, GH Pitié-Salpêtrière
    • Contact: Pierre-Francois Pradat, MD; Phone Number: +33 01 42 16 24 71; Email: pierre-francois.pradat@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria shared by all the different cohorts and controls :

• Age more than 18 years.
• Signature of a consent form for clinical, paraclinical and genetic assessment
• Fluent in French
• Affiliated to the French Security Healthcare System ("Sécurité Sociale")
• Absence of neurological comorbidity (stroke, tumor etc)

The inclusion criteria for asymptomatic relatives :

• Being a first-degree to a person carrying a C9orf72 mutation.
• Absence of proven clinical signs of FTD, ALS, language, praxic, memory disorders, Parkinsonian syndrome.

Inclusion criteria for symptomatic ALS patients :

• Patients fulfilling the El Escorial criteria for probable or definite ALS
• Presence of a C9orf72 mutation

Exclusion criteria for participants from all cohorts :

• Contraindication to MRI and TMS
• Impossibility to stay in decubitus during 1 hour,
• For women, childbearing or breastfeeding
• For women of childbearing potential: positive HCG test or positive urine pregnancy test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: participants; Patients fulfilling the El Escorial criteria for probable or definite ALS with a C9orf72 mutation or asymptomatics being a first-degree to a person carrying a C9orf72 mutation or Healthy controls	Other: Neuroimaging and electrophysiology; Brain and spinal cord MRI, transcranial magnetic stimulation; Motor Unit Number Estimation, EEG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional and structural quantitative imaging	Changes in resting state spinal cord MRI (fMRI) signal in presymptomatic and symptomatic ALS patients compared to controls	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electromyography with MUNE	Difference between electrophysiological MUNE between the first and last visit	6 months
TMS	Difference between electrophysiological TMS between the first and last visit	6 months
EEG	Difference between electrophysiological "Resting state (rs-)EEG" ,alpha (7-13 Hz), beta (13-40 Hz) and gamma bands (40-200 Hz) between the first and last visit	6 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2022
• Primary Completion (Estimated): February 21, 2026
• Study Completion (Estimated): February 21, 2026

Study Registration Dates

• First Submitted: February 17, 2022
• First Submitted That Met QC Criteria: May 2, 2022
• First Posted (Actual): May 3, 2022

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: MRI; ALS; FTD; presymptomatic; MUNE; C9orfF72
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: APHP211449; 2022-A00083-40 (Other Identifier: IDRCB)

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