Understanding the Mechanisms of Neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) using Detailed Magnetic Resonance Neuroimaging

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome comprising rapidly progressive weakness, cognitive impairment and death within several years. Non-invasive magnetic resonance imaging (MRI) modalities sensitive to changes in tissue microstructure have been increasingly undertaken to help understand mechanisms of damage within the nervous system, aiming to establish an objective, sensitive and specific biological marker of disease activity for better diagnosis, prognosis and response to potential treatments in vivo. Fractional anisotropy (FA) from diffusion tensor imaging consistently demonstrates changes throughout the corticospinal tract (CST) and corpus callosum (CC) motor pathways compared to controls at group level, although the pathological correlates of FA changes are less certain. Newer MRI modalities including Neurite Orientation Dispersion and Density Imaging (NODDI) and quantitative magnetisation transfer imaging (qMTi) remain relatively unexplored in ALS but their detailed parameters concerning neurite architecture and macromolecular integrity, respectively, hold the potential to broaden understanding of neurodegenerative disease mechanisms. Furthermore, patients who deteriorate fastest possess fewer blood CD4+ CD25+ FoxP3+ Regulatory T Lymphocytes (Tregs) which supports a key role for the immune system in ALS pathogenesis. An ongoing placebo-controlled clinical trial called MIROCALS [Modifying Immune Response and Outcomes in ALS] is testing safety and efficacy of low dose Interleukin-2, to augment Treg numbers, alongside standard treatment with Riluzole in newly-diagnosed patients with ALS. Methods: 23 patients with ALS from MIROCALS and 24 healthy controls underwent 1.5 Tesla MRI brain scans using NODDI and qMTi in this cross-sectional study. Neuroimaging analyses were performed at whole brain and region-of-interest levels, including with a novel modification of the NODDI processing pipeline optimised for grey matter neurite indices, in addition to white matter tract-based spatial statistics (TBSS) for the first time using both MRI modalities. Patients clinical data included the ALS Functional Rating Scale revised (ALSFRS-R), Edinburgh Cognitive and Behavioural ALS Screen (ECAS), disease duration, rate of
disease progression, and blood total CD4 cell count, total Tregs and the Treg:CD4 ratio. Historical cohorts of 23 patients with ALS and 23 healthy controls enabled extended relationships with clinical factors (excluding blood measurements) to be explored. Results: Compared to controls, FA was significantly reduced and the NODDI orientation dispersion index (ODI) increased within the CSTs and CC. Reduced NODDI neurite density index (NDI) in these areas was additionally seen in the historical patients. Significantly reduced kf and increased t2f was demonstrated in the historical patients in the CSTs and CC using qMTi but did not reach significance in the MIROCALS patients. Within the CC, Total blood CD4 count showed a negative association with skeletonised FA, a negative association with the skeletonised qMTi f parameter and a positive association with skeletonised ODI, whereas the Treg:CD4 ratio demonstrated a negative association with NDI within the primary motor cortex. In relation to ALSFRS and disease duration, FA and NODDI neurite density index (NDI) consistently showed positive and negative associations, respectively. Conclusions: The results suggest that disease associated changes in FA within motor pathways of the CSTs and CC in ALS are not solely due to loss of density of neurite processes, but may also be representative of several architectural alterations, including infiltration of glia or breakdown of normal axonmyelin relationships inferred by NODDI, and accompanied by changes to macromolecular integrity inferred by qMTi. For the first time in ALS, biological measures of systemic immune system function, including blood CD4 and the proportion of Treg cells, have shown relationships to quantitative diffusion and magnetisation transfer imaging modalities within areas of the corpus callosum, thereby supporting a role for cross-talk between peripheral and central immune processes in the disease.

Date of Award	Apr 2020
Original language	English
Awarding Institution	University of Brighton
Supervisor	P Nigel Leigh (Supervisor)