Relevance of MRI Biomarkers of Macroscopic and Microscopic Structural Damage to Cognitive Impairment In Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system, representing the most common non-traumatic cause of disability in young adults. Magnetic Resonance Imaging (MRI) in MS represents a fundamental tool for the diagnostic workup, disease monitoring over time and also for treatment response. The focal lesions of cerebral white matter (WM), detected by conventional MRI are distinctive signs of the disease and show a certain relationship with clinical disability, especially in the long term. The involvement of gray matter (GM) is evident from the beginning of the disease and includes focal (i.e., cortical lesions) and diffuse pathology (i.e., atrophy). Both represent an important burden of disease and are associated with physical and cognitive disability. Cognitive impairment (CI) is estimated to affect 40-70% of MS patients. It tends to worsen over time, but might be relevant even at earliest stages and is primarily characterized by reduced information processing speed, visual learning, working and long-term memory and executive functioning. The overall relationship between CI and lesion load was found to be weak-to-moderate, leading to the hypothesis that cannot be adequately explained by conventional MRI, limited to the detection of macroscopic brain damage. In the last years, novel imaging techniques, including diffusor tensor imaging (DTI), have provided further insights into the understanding of CI in people with MS, highlighting the importance of the subtle brain damage in the normal appearing white matter, since the early stage and outside the focal lesions . My PhD research project is divided into three cross-sectional studies, enclosed in the present thesis and conducted from the Novembre 2016 to June 2019 at the Quantitative Neuroimaging Laboratory (QNL), Department of Medicine, Surgery and Neuroscience of University of Siena. Aims of this work were achieved by quantitatively assessing MR-derived brain volumes (Jim 7.0, Xinapse System; Structural Image Evaluation, using Normalization, of Atrophy [SIENAX]) as well as microstructural WM damage (DTI and derived indices such as fractional anisotropy [FA], mean diffusivity [MD], axial [AXD], and radial diffusivity [RD]) in different groups of relapsingremitting MS. More specifically, the first and the second studies are focused on a new DTI-derived MRI marker, named Peak Width of Skeletonized Mean Diffusivity (PSMD) and its role in detecting the diffuse WM microstructural damage in Multiple Sclerosis, taking into account also the correlations between brain structures changes and cognitive measures (assessed through the validated Italian translation of Rao Brief Repeatable Battery [BRB]) and its feasibility in the clinical practice. In the third and last study we reported the preliminary results about the relevance of cognitive reserve (CR) on the association between cognitive impairment and WM microstructural damage in mild disability MS.