Watch Dr Emma Devenney accept the research grant award and hear a bit about the project.
Amyotropic lateral sclerosis (ALS) is a young-onset incurable neurodegenerative disorders1. The search for disease modifying therapies has been hampered by a marked delay to diagnosis. A confirmed diagnosis takes on average 12-18 months for cases with a predominant MND phenotype2. The societal, economic and health burden of delayed diagnosis in these conditions is immense and increasing exponentially in line with the burden of dementia estimated to reach $36.8 billion by 2056 (The National Centre for Social and Economic Modelling NATSEM, 2016). Without a confirmed diagnosis patients and their families are prevented from accessing the right care at the right time in the right place based on their needs with implications for their mental health and disease trajectory. Research by our team has found that the longest diagnostic delay is associated with double the incidence of depression3. Over half of patients initially receive an alternative diagnosis and patients see an average of three physicians before diagnosis is confirmed4, 5. Patients are often misdiagnosed and undergo unnecessary investigations and in some cases interventions adding economic and capacity burden to the health service with implications for safety, quality and efficiency of care. Pilot data by CI Devenney (unpublished) identified a younger age of disease onset was associated with a longer delay to diagnosis. A common statement by families once a diagnosis is confirmed is “we are relieved to finally know what we are dealing with”.
Biomarker development is crucial to address this area of need. Regarding effectiveness of pharmaceutical therapies, there is also a critical need for biomarkers of early disease to facilitate recruitment of patients with early and therefore potentially reversible disease. Current thinking in clinical trials has moved towards stratification of patients according to biomarker profiles and the future for disease modifying therapies will rely heavily on reliable biomarkers. To date, individual biomarkers have shown promise but unfortunately this has not translated to clinical care6. Due to the clinical variability it seems likely that a single biomarker will not capture the specific emergence of this complex disease. Instead we propose that a co-ordinated targeted approach that addresses early symptoms, already identified by our team, using innovative methods offer an alternative and promising approach.
Our team have been at the forefront of research that defined the genetic, clinical and pathological overlap across MND subtypes due to our unique collaborative approach that spans both motor and cognitive research7-14. The delineated behavioural and cognitive profiles are a consequence of progressive degradation of the frontal and temporal lobes due to protein deposition and subsequent cell death that propagates throughout key cortical and subcortical structures. At the time of diagnosis patients may have a degree of behavioural impairment that renders them relatively unperturbed by this devastating diagnosis but changes in personality are often reported by distressed caregivers. The behavioural impairment mirrors that seen in Frontotemporal Dementia (FTD), and ALS is now known to overlap with FTD on clinical, genetic and pathological levels with up to 80% of patients with ALS experiencing a degree of behavioural impairment and approximately 15% satisfying criteria for co-existent FTD. These cognitive and behavioural changes occur early often before the onset of physical symptoms and impact survival – despite this these findings has not translated to reliable biomarkers of early disease nor has it been utilised for patient stratification in clinical trials. This is likely owing in part to the cognitive and motor burden of ALS and multiple confounding variables of conventional neuropsychological assessments.
This project aims to capitilise on the unique experience of our team as experts in the field of cognition, behaviour and neurophysiology to 1) develop a novel behavioural and cognitive diagnostic biomarker for ALS, using advanced statistical modelling techniques, based on our recent work in ALS that identifies loss of empathy as a core early feature of ALS, and 2) to progress the scientific knowledge of underlying mechanisms responsible for the development of ALS. Ultimately this project aims to have direct clinical applicability by improving diagnosis that in turn allows for earlier and appropriate access to care, support and experimental therapeutics.