Neuroinflammation and neurodegeneration coexist in multiple sclerosis (MS), although their inter-relation and specific contribution to disability have not been fully elucidated yet. Inflammation mediated by activated microglia and macrophages may persist beyond the acute phase of MS and is associated with disability progression. Magnetic resonance imaging (MRI) allows to evaluate neurodegeneration in MS, as assessed by grey (GM) and white matter (WM) atrophy and specific WM tracts microstructural alterations. On the other hand, 18kDa translocator protein (TSPO) PET imaging with C-11PBR28 can detect chronic innate immune cell activation.
We hypothesize that MR measures of neurodegeneration and PET measures of chronic neuroinflammation are related in MS, that their relation is specific for brain compartments, and that both impact physical and cognitive disability, although at a different extent.
In this international collaborative study, we will analyze MRI and PET images already acquired at Massachusetts General Hospital (Boston) on 50 MS patients and 25 healthy subjects. This novel multimodal imaging approach combines ultra-high field 7T MRI and simultaneous 11C-PBR28 PET-3T MRI brain acquisition. Anonymized images, demographic and clinical data will be transferred to our laboratory. By using advanced methods of data analysis, T13D and diffusion images will be processed to calculate atrophy in both WM and cortical GM, as well as microstructural damage of WM bundles. PET images will be used to assess areas of increased uptake in both cortical and subcortical GM and WM, including WM tracts. Lastly, multivariate analysis will be performed to model the impact of brain structural damage and chronic neuroinflammation on both physical and cognitive disability. Innovative procedures of tractography and PET uptake analysis will provide novel information on the impact of neuroinflammation and neurodegeneration in different brain compartments on disability in MS.
We will use a novel multimodal imaging approach that combines ultra-high field 7T MRI and simultaneous 11C-PBR28 MR-PET brain acquisition to address the main hypothesis that chronic neuroinflammation mediated by activation of microglia and macrophages impact WM bundles and grey matter degeneration, contributing to disease progression in MS. We have the unique opportunity of collaborating with the Multiple Sclerosis Imaging Laboratory at the Athinoula Martinos Center, in Boston, where both ultra-high field 7T MRI and MR-PET images have been already acquired in 50 patients with MS and 25 healthy controls. 11C-PBR28 imaging has been conducted on a high resolution, simultaneous human MR-PET system (BrainPET), a high resolution (
We will use a multimodal approach to analyze a large set of data by using advanced technology. The study of microglia activation will help to elucidate the extent of the inflammatory component along WM tracts within and beyond the focal WM lesions, as well in the cerebral cortex, with the main objective to relate inflammatory changes with well-known degenerative aspects of MS pathology and to assess the relative impact of neuroinflammation and neurodegeneration on physical and cognitive disability.
Data analysis conducted by researchers with specific expertise in the field of MS at the Neuroimaging Laboratory at the Department of Human Neuroscience will consist of cutting-edge data analysis procedures. Specifically, neurodegeneration of the WM will be explored with a probabilistic approach (Tracula software included in Freesurfer pipeline) to extract DTI metrics voxel-based along the WM tract; ultra-high field 7T MRI allows an accurate detection of cortical lesions compared to lower field MRI (Mainero C et al. 2009); the surface-based method to assess the cortical thickness will ensure a fine estimation of neuronal loss compared to a classical volumetric approach. To explore the relation between degeneration and chronic inflammation, PET data will be analyzed with an in-house software which provides a normalization of the values for the NAWM, to obtain unbiased uptake measures in different brain compartments (Herranz et al. 2016).
Although it is known that neurodegeneration is a major determinant of disability progression in MS and emerging data support the detrimental role of the chronic inflammation within the CNS, to the best of our knowledge no studies assessed the inflammation-degeneration interplay in affecting patient clinical status. Building a multivariate model including several imaging features indicative of both neurodegeneration and chronic neuroinflammation, i.e., PET-uptake values, global and regional cortical thickness, and DTI metrics of WM bundles, will help to disentangle the relative impact of different pathophysiological processes on physical and cognitive impairment in MS, paving the way for targeted therapeutic strategies.