Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

Abstract

The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.

C9orf72 ALS mutation carriers show extensive cortical and subcortical damage compared to matched wild-type ALS patients

“…These tracts are extensively connected to the regions where we observed reduced cortical thickenss. Besides extensive cortical atrophy, our study emphasizes that thalamic alterations play a crucial role in the C9orf72 genotype as previously reported in neuroimaging studies in both presymptomatic ( Bertrand et al, 2018 , Lee et al, 2017 , Querin et al, 2022 , Rohrer et al, 2015 ) and symptomatic patients ( Bede et al, 2013a , Bede et al, 2013b , Querin et al, 2022 , Westeneng et al, 2016 ). Unquestionably, vertex-wise and subnuclear analyses revealed specific atrophy of the thalamic profile in ALS patients.…”

“…C9orf72 -mediated disease in ALS exhibits a highly precise pattern of cortical and subcortical atrophy. Our results confirm the prevalence of extensive cortical thickness reductions in the posterior regions, encompassing parietal, occipital, and temporal areas, but also extended to frontal regions among ALSC9+ as compared to ALSC9 - patients ( Agosta et al, 2017 , Bede et al, 2013a , Querin et al, 2022 , Westeneng et al, 2016 ). The diffusion studies on the staging of pathology indicate similar white matter impairments in ALSC9+ and ALSC9- patients compared to healthy participants ( Agosta et al, 2017 , Müller et al, 2020 , Müller et al, 2021 , Kassubek et al, 2014 ).…”

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

“…Quantitative measures of motor unit loss, such as Motor Unit Number Index (MUNIX) at EMG, only investigated at the clinical stage so far [101], could represent a promising approach to better define prodromal ALS.…”

Thalamic pathology in frontotemporal dementia: Predilection for specific nuclei, phenotype‐specific signatures, clinical correlates, and practical relevance

“…Presymptomatic insights and the observation that widespread pathological changes can be detected by the time diagnostic criteria are met would suggest that the window for effective pharmacological intervention with true disease‐modifying potential may fall into the presymptomatic or prodromal phase of the disease. The recognition of considerable disease burden around the time of diagnosis should hasten recruitment into clinical trials very early in the course of the disease and may ultimately pave the way for presymptomatic clinical trials in mutation carriers (Querin et al., 2022 ).…”

“…Presymptomatic studies suggest that pathological changes may be detected several years, sometimes decade before symptom onset (Bertrand et al, 2018;Querin et al, 2019). Presymptomatic pave the way for presymptomatic clinical trials in mutation carriers (Querin et al, 2022).…”