JPND: Stratification of presymptomatic amyotrophic lateral sclerosis: the development of novel imaging biomarkers

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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder with no effective disease-modifying therapies at present. The delay between symptom onset and diagnosis by current diagnostic criteria is approximately 12 months worldwide which precludes the timely inclusion of suspected patients into clinical trials. By the time patients are recruited into imaging and pharmacological studies significant pathological changes have already taken place. While the vast majority of existing ALS studies are 'post-symptomatic', 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 consortium proposes to embark on a large, prospective, multicentre, longitudinal study of asymptomatic and symptomatic c9orf72 hexanucleotide carriers using 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. No accurate prognostic indicators currently exist in asymptomatic hexanucleotide mutation carriers to foretell if they will develop ALS or FTD and when symptoms are likely to manifest. Beyond the academic relevance of characterising presymptomatic propagation patterns, the study has a number of pragmatic deliverables such as the development of individualised prognostic indicators, sensitive imaging-based diagnostic protocols and novel monitoring tools which are indispensable for future biomarker-supported clinical trial designs. This proposal endeavours to capitalise on recent technological advances to develop precision imaging tools for academic applications, clinical trials, the clinical care of patients and suspected patients and the support asymptomatic relatives. The ultimate aspiration of this application is the optimisation of novel imaging protocols which will be transferable to other motor neuron diseases, dementia syndromes, and meaningfully contribute to the development of novel disease-modifying therapies.