NCT05358431

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

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 120 (estimated)
• Sponsor: Assistance Publique - Hôpitaux de Paris · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Accepted

Summary

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.

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

Conditions

• Amyotrophic Lateral Sclerosis

Interventions

Type	Name	Description
OTHER	Neuroimaging and electrophysiology	Brain and spinal cord MRI, transcranial magnetic stimulation; Motor Unit Number Estimation, EEG

Timeline

• Start date: 2022-07-21
• Primary completion: 2026-02-21
• Completion: 2026-02-21
• First posted: 2022-05-03
• Last updated: 2024-02-20

Locations

1 site across 1 country: France