Title: Biomarkers and modulation of cortical hyperexcitability in ALS
Funder: Dunhill Medical Trust

Abstract: Therapeutic options for the fatal neurodegenerative disorder ALS are urgently needed. Trials rely on blunt outcome measures such as survival because of a lack of objective markers of disease activity and progression. The C9orf72 hexanucleotide repeat expansion (HRE) is associated with 10% of all cases of ALS, bringing the near-future prospect of oligonucleotide therapeutic trials. The development of biomarkers will reduce trial duration and cost by providing more sensitive measures of disease-slowing and/or evidence of target engagement. ALS is consistently associated with cortical hyperexcitability (CE), based on transcranial magnetic paired stimulation (TMS) to induce short-interval cortical inhibition (SICI). This project builds on the potential shown by non-invasive neuroimaging to provide biomarkers in ALS. It will develop functional neuroimaging biomarkers that reflect the phenomenon of CE, including markers of pre-symptomatic pathology. I will also evaluate whether repeated sessions of inhibitory cathodal non-invasive brain stimulation (NIBS) reduces CE. As well as a test of neuroimaging-based outcome measures for future drug trials, it might specifically support this approach as a therapeutic strategy for ALS in the longer-term. I will study affected ALS patients carrying the C9orf72 HRE and a group of asymptomatic carriers. A combined functional MRI (FMRI and MRS) and neurophysiological (MEG) readout will capture the motor system. NIBS will be applied to the motor cortex of affected patients daily for four days followed by a comparative set of scans. This study offers novel non-invasive biomarkers based on a consistent neurophysiological mechanism in ALS to advance therapeutic development.

Lay abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal condition involving degeneration of the motor system – parts of the brain, spinal cord and nerves that control muscles. At least 5000 people in the UK are living with ALS, and many more bear the physical and emotional burden of their care. The average time from first symptoms to death is 3 years. Around 10% of all cases of ALS are caused by a specific abnormality in the affected person’s genetic code. New medications, including revolutionary genetic treatments for ALS, are being actively developed. To show that they are effective in slowing disease, sensitive markers of disease activity (biomarkers) are urgently needed. The motor output of the brain is over-active in ALS, referred to as cortical hyperexcitability. I will use advanced non-invasive brain scanning as a source of biomarkers for cortical hyperexcitability. I will also attempt to reduce the brain’s motor excitability in ALS patients using a technique called non-invasive brain stimulation. I will study a group of affected people carrying the abnormal genetic code, and a group with the same gene who have not yet developed the disease. By comparing the biomarkers in both affected individuals and symptom-free genetic carriers, I hope to identify the earliest changes. Future treatments might then target the disease before a person is aware of weakness. Sensitive biomarkers for those already affected by ALS will help to make clinical trials faster and cheaper, accelerating the prospects for better treatments.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL