Understanding the mechanisms of atrophy associated with spinal cord injury: the application of MRI-based in vivo histology and ex vivo histology

Spinal cord injuries (SCI) are mainly caused by traumatic events such as violence and traffic and sports accidents. Paraplegia (paralysis of the legs) and tetraplegia (paralysis of both legs and arms) permanently, severely and dramatically reduce the quality of life of the affected person as well as their ability to remain a member of the workforce. These negative consequences arise because functional recovery following SCI remains limited and the majority of patients are left with severe impairments in the longer term. While rehabilitative training can improve clinical outcome following SCI, which is a major benefit to the patients' quality of life, the degenerative processes and the mechanisms underpinning any neurological and functional recovery are not well understood. Recent advances in the field of magnetic resonance imaging (MRI) have vastly improved how we can visualize and interrogate the structural organisation and functioning of the central nervous system. Notable among these advances is the emerging ability to investigate "microscopic" changes in the human central nervous system. This includes distinguishing white and grey matter - two fundamental divisions of structure in the spinal cord, brainstem and brain. Using microscopic MRI protocols we have shown that structural changes occur over time following a specific spatial and temporal pattern. In fact these changes occur early after the injury and happen both in the cord and in the brain. However so far, the range of biological changes that may underlie the observed changes cannot be disentangled. By means of in vivo histology using MRI (hMRI) - an emerging field in MRI - we aim to establish the missing link between measured MRI signals and changes in the underlying tissue microstructure, which will help us to explain and better understand the disease processes associated with spinal cord injury.

During the first year after spinal cord injury (SCI), extensive morphometric changes within the central nervous system occur above the level of lesion, with the magnitude of atrophy relating to the degree of clinical impairment. The range of microstructural processes that underlie these observed morphometric changes cannot be disentangled because of the complex dependence of morphometric measures on multiple physical magnetic resonance imaging (MRI) micro-scale properties (e.g. T1, T2* and proton density). This in turn makes it difficult to draw specific conclusions about the underlying cause of the observed volumetric changes. We aim to use in vivo histology based on MRI (hMRI) to establish the missing link between measured MRI signals and the underlying tissue microstructure across the neuroaxis by developing advanced biophysical models to describe this relationship and map tissue properties, e.g. fibre and myelin densities. Methodological developments in the realm of hMRI will provide specific metrics for histological cross-validation and shed light on the mechanisms underpinning morphometric changes in SCI. This will enable us to directly visualize the anatomical evidence for anterograde and retrograde degeneration, repair, and plasticity as well as providing crucial insights over and above the existing clinical descriptors, which are insensitive to subtle treatments effects. These insights will help to improve diagnosis, personalized medicine, stratification and therapy monitoring in neurodegeneration (e.g. by simultaneously measuring myelin and axonal density, we will be able to distinguish between reversible demyelination and irreversible axonal degeneration - key processes of SCI. This potential improvement in diagnosis, stratification and therapy could also help in designing more targeted clinical trials by stratifying patient cohorts making such trials more efficient and less expensive.

This project brings together clinical/neuroscience and imaging/physics expertise from multiple European sites across four countries. It builds on successful collaborations in which innovative research projects have exploited the specific expertise of the group members and led to several highly recognized publications (e.g. Freund et al 2013, Lancet Neurology, Grabher et al 2015, Annals of Neurology). The benefit of quantitative imaging is now well established and has led to its deployment in multi-centre trials examining spinal cord injury (SCI). These trials will greatly benefit from the further development of methods within this project. For example, the proposed project will maximise the sensitivity of SCI studies and ensure that even the smallest effects can still be detected when imaging across varied imaging environments. Most importantly, these efforts will allow findings to be interpreted with greater biological specificity allowing us to increase our understanding of the consequences of SCI.

Our neuroimaging studies have the potential to provide important new insights into the basic disease processes underlying atrophic changes now known to occur in acute and chronic SCI. In vivo histology using MRI (hMRI) has greater specificity to underlying tissue property changes and disease processes. For example, by simultaneously measuring myelin and axonal density it can distinguish between reversible demyelination and irreversible axonal degeneration - key processes in traumatic SCI. This will enable us to directly visualize the anatomical evidence for anterograde and retrograde degeneration, repair, and plasticity. Moreover it promises to provide crucial insights over and above the existing clinical descriptors, which are insensitive to early treatments effects. This potential improvement in diagnosis, stratification and therapy could also help in designing more targeted clinical trials by using these neuroimaging biomarkers to select more homogeneous patient cohorts making such trials more efficient and less expensive. In brief, assessing in-vivo histological makers of the integrity of specific tissue features associated with pathological mechanisms that underlie degeneration and neural repair in SCI, in a temporally and spatially resolved manner, will further elucidate the basic pathological mechanisms underlying atrophic changes consequent to SCI. Importantly, this approach will facilitate the development of novel therapeutic strategies, the stratification of patient groups (personalized medicine) and the identification of surrogate biomarkers that serve as early readouts capturing therapeutic response.

The increased sophistication of the MRI based techniques will allow, for the first time, the detailed analysis of the micro-structural changes which precede and underlie atrophy and which are the potential targets of early therapeutic interventions that would prevent tissue loss and chronic functional impairment. The outcomes will be far reaching providing benefit not only to SCI but also having application for other neurological disorders with spinal cord involvement.