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

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.

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.

Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive neurodegenerative condition. The average diagnostic delay from symptom onset to definite diagnosis is 12 months, which not only delays neuroprotective treatment, recruitment to pharmaceutical trials and care planning, but misdiagnosis of ALS to other conditions may lead to unnecessary interventions. Factors contributing to diagnostic delay in ALS include disease heterogeneity, insidious symptom onset, and presentation with non-motor symptoms. One of the major challenges of biomarker development in ALS is the significant clinical heterogeneity of the condition. Disease heterogeneity in ALS has multiple dimensions, including genetic origin, site of onset, rate of decline, the presence of cognitive impairment and the relative degree of upper and lower motor neuron involvement.

Imaging studies of ALS suggest that by the time the diagnosis is confirmed using the current diagnostic criteria (El Escorial), significant neurodegenerative changes have already taken place. Participation in clinical trials in the later stages of a neurodegenerative process, when substantive white matter degeneration and cortical atrophy have already developed, hampers the identification of effective disease-modifying or neuroprotective therapies. The majority of existing imaging studies in ALS only evaluate the final, post-symptomatic phase of ALS despite increasing evidence of a long presymptomatic phase. Given the rapid progression rates, development of respiratory weakness and bulbar dysfunction, the majority of patients are unable to tolerate MRI scanning 1-2 years after symptom onset, so even the most robust longitudinal imaging studies are limited to 3-5 timepoints between patients meeting the diagnostic criteria and being unable to tolerate MRI scanning. This 12-24 month period only provides a snapshot of decades of progressive neurodegenerative change. It also clear that recruitment into clinical trials at a stage when considerable cortical atrophy and white matter degeneration can already be readily detected the accurate assessment of proposed neuroprotective medications and disease- modifying agents is contentious.

STRATALS probes the earlier disease stages paving the way for earlier trials and interventions.