Biomarkers in motor neuron disease - a longitudinal translational neuroimaging and CSF study
Lead Research Organisation:
University of Oxford
Department Name: Clinical Neurosciences
Abstract
Motor Neuron Disease (MND) is a devastating neurodegenerative condition affecting around 5000 people in the UK. Loss of motor neurons produces muscle wasting variably affecting the limbs, swallowing, and ultimately breathing. The average survival from symptom onset is 3-4 years. There is no specific test for MND and diagnosis relies mainly on clinical examination. Many patients wait more than a year from symptom onset to receive a firm diagnosis. Over 75 drugs have failed in clinical trials but it can take many months to establish lack of efficacy with certainty.
This research will study a group of MND patients every six months using magnetic resonance imaging (MRI) of the brain in combination with molecular analysis of the surrounding cerebrospinal fluid (CSF). The Oxford Centre for Functional MRI Brain (FMRIB) has developed techniques highly sensitive to damage within nerve pathways in the brain, and there is local expertise to study the CSF for molecules associated with these changes. In combination it is expected this will provide markers of disease activity to improve the diagnostic process and the way clinical drug trials are monitored, so ineffective drugs can be more quickly discounted. New insights into disease mechanisms may provide novel drug targets.
This research will study a group of MND patients every six months using magnetic resonance imaging (MRI) of the brain in combination with molecular analysis of the surrounding cerebrospinal fluid (CSF). The Oxford Centre for Functional MRI Brain (FMRIB) has developed techniques highly sensitive to damage within nerve pathways in the brain, and there is local expertise to study the CSF for molecules associated with these changes. In combination it is expected this will provide markers of disease activity to improve the diagnostic process and the way clinical drug trials are monitored, so ineffective drugs can be more quickly discounted. New insights into disease mechanisms may provide novel drug targets.
Technical Summary
Aims:
To improve the diagnostic algorithm in Motor Neuron Disease (MND), further understanding of pathogenesis (particularly neuro-inflammation), illuminate phenotype heterogeneity, and optimise patient selection and monitoring in therapeutic trials.
Objectives:
The identification of biomarkers through the longitudinal integration of cerebral magnetic resonance structural and functional imaging (MRI), proteomic and cytokine analysis of cerebrospinal fluid (CSF), with clinical study of patients in a multi-disciplinary MND Care Centre.
Design:
Longitudinal and cross-sectional in vivo pathological study.
Methodology:
Seventy-two MND patients, spanning a full range of phenotypes and progression rates, will undergo serial MRI of the brain and CSF analysis. Studies will be performed at baseline and every six months via The Oxford MND Centre where disease progress can be monitored and patient care optimised. Ten asymptomatic subjects, at risk of MND by virtue of homozygous ‘D90A‘ mutations of the superoxide dismutase-1 gene, 10 symptomatic D90A patients and 25 healthy controls will undergo a single MRI and CSF study. MRI studies will be carried out at the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), involving diffusion tensor, structural and resting state functional MRI (fMRI) sequences at 3 Tesla. Fractional anisotropy (FA) will provide a marker of neuronal integrity in motor and extra-motor regions. Whole-brain unbiased FA analysis will employ FMRIB‘s Tract-based Spatial Statistics (TBSS). Locally-developed Probabalistic Tractography (PT) will visualise neuronal pathways and explore connectivity of motor and extra-motor regions. Voxel-based morphometric analysis of structural MRI will detect changes in grey and white matter volume. Resting state fMRI will be studied speculatively as a marker of extra-motor pathology. CSF samples will undergo proteomic analysis using 2D gel electrophoresis and mass spectrometry to identify proteins associated with disease progression and phenotype. CSF cytokine analysis will specifically explore neuro-inflammatory processes.
Scientific & Medical Opportunities:
The identification of biomarkers in MND will improve the diagnostic pathway and inform prognosis, permitting ineffective drugs to be more quickly discounted in clinical trials. The study of pre-symptomatic patients has the potential to detect the earliest changes in pathogenesis. The exploration of neuro-inflammatory mechanisms may identify novel targets for drug development. Scientific developments anticipated during the study period include pilot studies in MND patients of ultra-small paramagnetic particles of iron oxide administered intravenously, taken up by macrophages and visualised using MRI to further probe cerebral neuro-inflammatory activity. Developments in spinal cord fMRI at FMRIB will permit changes across the entire central nervous system to be integrated.
To improve the diagnostic algorithm in Motor Neuron Disease (MND), further understanding of pathogenesis (particularly neuro-inflammation), illuminate phenotype heterogeneity, and optimise patient selection and monitoring in therapeutic trials.
Objectives:
The identification of biomarkers through the longitudinal integration of cerebral magnetic resonance structural and functional imaging (MRI), proteomic and cytokine analysis of cerebrospinal fluid (CSF), with clinical study of patients in a multi-disciplinary MND Care Centre.
Design:
Longitudinal and cross-sectional in vivo pathological study.
Methodology:
Seventy-two MND patients, spanning a full range of phenotypes and progression rates, will undergo serial MRI of the brain and CSF analysis. Studies will be performed at baseline and every six months via The Oxford MND Centre where disease progress can be monitored and patient care optimised. Ten asymptomatic subjects, at risk of MND by virtue of homozygous ‘D90A‘ mutations of the superoxide dismutase-1 gene, 10 symptomatic D90A patients and 25 healthy controls will undergo a single MRI and CSF study. MRI studies will be carried out at the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), involving diffusion tensor, structural and resting state functional MRI (fMRI) sequences at 3 Tesla. Fractional anisotropy (FA) will provide a marker of neuronal integrity in motor and extra-motor regions. Whole-brain unbiased FA analysis will employ FMRIB‘s Tract-based Spatial Statistics (TBSS). Locally-developed Probabalistic Tractography (PT) will visualise neuronal pathways and explore connectivity of motor and extra-motor regions. Voxel-based morphometric analysis of structural MRI will detect changes in grey and white matter volume. Resting state fMRI will be studied speculatively as a marker of extra-motor pathology. CSF samples will undergo proteomic analysis using 2D gel electrophoresis and mass spectrometry to identify proteins associated with disease progression and phenotype. CSF cytokine analysis will specifically explore neuro-inflammatory processes.
Scientific & Medical Opportunities:
The identification of biomarkers in MND will improve the diagnostic pathway and inform prognosis, permitting ineffective drugs to be more quickly discounted in clinical trials. The study of pre-symptomatic patients has the potential to detect the earliest changes in pathogenesis. The exploration of neuro-inflammatory mechanisms may identify novel targets for drug development. Scientific developments anticipated during the study period include pilot studies in MND patients of ultra-small paramagnetic particles of iron oxide administered intravenously, taken up by macrophages and visualised using MRI to further probe cerebral neuro-inflammatory activity. Developments in spinal cord fMRI at FMRIB will permit changes across the entire central nervous system to be integrated.
