7T Imaging Pilot-study in Patients With Motor Neuron Disease to Find Non-Invasive Disease Imaging Biomarkers

Overview

Motor Neuron Disease (MND) is a neurodegenerative disorder, which causes progressive loss of nerve cells controlling the muscles responsible for movement, speech, swallowing and breathing. MND is not actually a single disease, but a range of diseases; some more serious with patients dying within a year, and some less severe cases with a life expectancy of several years. It is often difficult and can take a long time to get a diagnosis of MND, by which time patients are often already very unwell. The aim of this research study is to improve the diagnosis of MND and make it faster. The investigators plan to achieve this goal by using advanced Magnetic Resonance Imaging (MRI) to develop new diagnostic tests for MND. The investigators will use a scanner with a very strong magnetic field of 7 tesla (7T), which provides images of the brain with increased detail compared to standard MRI scanners, which use magnetic field strengths of 1.5T or 3T. The investigators will use the advanced capability of 7T MRI to identify so-called imaging biomarkers, which are features of the scans that are specific to a particular disease, in this case MND and its different subtypes. This is a pilot study with a relatively small number of patients. The preliminary findings from this research will be used to design larger follow-on studies aiming to establish a fast and specific diagnosis for patients living with MND. This would allow patients to enter suitable trials faster and would help patients to receive more tailored treatment.

The purpose of this pilot study is to develop and assess the feasibility of advanced 7 tesla (7T) MRI brain imaging for patients living with motor neuron disease (MND). Motor neuron disease (MND) is a spectrum of neurodegenerative disorders, leading to progressive muscle weakness, paralysis and breathing failure. This is characterised pathologically by loss of motor neurons in the motor cortex and anterior horn cells of the spinal cord. Different subtypes of MND, such as Amyotrophic Lateral Sclerosis (ALS) and Primary Lateral Sclerosis (PLS), have different clinical courses, ALS having a short survival and PLS a much longer survival. The causes for this disease remain unknown; however, there is support from genetic studies for protein misfolding impacting on proteostatic mechanisms, contributing to the development of some cases of MND, ALS in particular. Genetic causes for MND have been identified, most frequently involving the SOD1 and C9orf72 genes (Dharmadasa et al, 2022). There is a need for improved diagnostic approaches to identify MND earlier enabling personalised prognostication, treatment and entry into clinical trials. The development of imaging biomarkers for MND has therefore become more attractive (Zejlon et al, 2022). The different subtypes of MND have variable impacts on patients, with different prognosis and treatment responses. Identification of non-invasive biomarkers, avoiding invasive procedures such as lumbar puncture, could facilitate diagnostic pathways for patients, enable earlier stratification into disease subtypes, and help stratify response to treatment in clinical trials. This study aims to identify an array of 7 tesla (7T) imaging biomarkers in MND to stratify patients according to different disease subtypes, and to establish a new Scottish diagnostic imaging protocol tailored and suitable for patients suffering from MND. This would be a novel imaging approach, which may form the basis for a future MND imaging biomarker database in Scotland. 7T MRI, compared to lower field strength, offers increased signal-to-noise-ratio, allowing for the acquisition of higher resolution images, greater sensitivity to differences in susceptibility effects, and increased spectral resolution (Schick et al, 2005; Keith et al, 2024). These intrinsic properties of 7T make it an ideal tool in establishing imaging biomarkers for MND (De Vries et al, 2024). The integration of 7T imaging technology and of new imaging biomarkers into the current diagnostic pathway for patients with MND would provide distinct advantages over conventional imaging. Identification of microstructural degenerative changes in the motor cortex of patients with this disorder early in the disease process would increase diagnostic certainty. This is particularly important in a disorder such as MND, which has devastating consequences, yet has no definite diagnostic test or specific biomarker. As more expensive biological therapies come into play in treating MND, identifying response by measuring stabilisation of the motor cortex structural integrity will be important. The detailed structural imaging provided by 7T MRI, combined with genetic information, will drive the development of precision medicine in these individuals. There has been much interest in potential biomarkers, including imaging biomarkers, in MND over the recent years. We propose taking this further by establishing an array of specific imaging biomarkers for subtypes of MND, and by developing a tailored diagnostic "Biomarker MND Imaging Protocol" for patients, optimised to benefit from the strength of 7T. This would not only help diagnosis of patients suffering from MND but would allow stratification for treatment purposes and monitoring of the effect of possible new treatments. 7T MRI, compared to lower field strength, offers, increased signal-to-noise-ratio, allowing for the acquisition of higher resolution images, greater sensitivity to differences in susceptibility effects, and increased spectral resolution (Schick et al, 2005). These intrinsic properties of 7T make it an ideal tool in establishing imaging biomarkers for MND. The integration of 7T imaging technology and of new imaging biomarkers into the current diagnostic pathway for patients with MND would provide distinct advantages over conventional imaging. Identification of microstructural degenerative changes in the motor cortex of patients with this disorder early in the disease process would increase diagnostic certainty. This is particularly important in a disorder such as MND, which has devastating consequences, yet has no definite diagnostic test or specific biomarker. As more expensive biological therapies come into play in treating MND, identifying response by measuring stabilisation of the motor cortex structural integrity will be important. The detailed structural imaging provided by 7T MRI, combined with genetic information, will drive the development of precision medicine in these individuals. There is interest in potential biomarkers, including imaging biomarkers, in MND over the recent years. We propose taking this further by establishing an array of specific imaging biomarkers for subtypes of MND, and by developing a tailored diagnostic "Biomarker MND Imaging Protocol" for patients, optimised to benefit from the strength of 7T. This would not only help diagnosis of patients suffering from MND, but would allow stratification for treatment purposes and monitoring of the effect of possible new treatments.