Abstract
Focal demyelinated lesions, diffuse white matter (WM) damage, and gray matter (GM) atrophy influence directly the disease progression in patients with multiple sclerosis. The aim of this study was to identify specific characteristics of GM and WM structural networks in subjects with clinically isolated syndrome (CIS) in comparison to patients with early relapsing-remitting multiple sclerosis (RRMS). Twenty patients with CIS, 33 with RRMS, and 40 healthy subjects were investigated using 3 T-MRI. Diffusion tensor imaging was applied, together with probabilistic tractography and fractional anisotropy (FA) maps for WM and cortical thickness correlation analysis for GM, to determine the structural connectivity patterns. A network topology analysis with the aid of graph theoretical approaches was used to characterize the network at different community levels (modularity, clustering coefficient, global, and local efficiencies). Finally, we applied support vector machines (SVM) to automatically discriminate the two groups. In comparison to CIS subjects, patients with RRMS were found to have increased modular connectivity and higher local clustering, highlighting increased local processing in both GM and WM. Both groups presented increased modularity and clustering coefficients in comparison to healthy controls. SVM algorithms achieved 97% accuracy using the clustering coefficient as classifier derived from GM and 65% using WM from probabilistic tractography and 67% from modularity of FA maps to differentiate between CIS and RRMS patients. We demonstrate a clear increase of modular and local connectivity in patients with early RRMS in comparison to CIS and healthy subjects. Based only on a single anatomic scan and without a priori information, we developed an automated and investigator-independent paradigm that can accurately discriminate between patients with these clinically similar disease entities, and could thus complement the current dissemination-in-time criteria for clinical diagnosis.
Highlights
Multiple sclerosis is a neuroinflammatory disease of the central nervous system leading to progressive disability in young adults (Noseworthy et al, 2000; Confavreux and Vukusic, 2006; Alonso and Hernán, 2008)
Patients who do not fulfill these diagnostic criteria after one clinical episode, but whose symptoms are still suggestive of multiple sclerosis, are classified as having clinically-isolated syndrome (CIS; Miller et al, 2005, 2012)
We found that relapsing-remitting multiple sclerosis (RRMS) patients exhibited a stronger modular structure in their white matter networks than patients with CIS, indicating that the nodes in the modules are more densely inter-connected in RRMS but exhibit fewer connections to other modules
Summary
Multiple sclerosis is a neuroinflammatory disease of the central nervous system leading to progressive disability in young adults (Noseworthy et al, 2000; Confavreux and Vukusic, 2006; Alonso and Hernán, 2008). Between 38 and 68% of patients with a first sub-acute neurological event suggestive of multiple sclerosis go on to develop clinically definite relapsing-remitting multiple sclerosis (RRMS; Poser and Poser, 1983; Eriksson et al, 2003; Confavreux and Vukusic, 2006; Fisniku et al, 2008). Patients with CIS can convert to the relapsing-remitting course of multiple sclerosis depending on clinical or MRI markers (Moraal et al, 2009). A rapid transformation from CIS to RRMS is associated with clear progression and a poor long-term outcome (Weinshenker et al, 1989; Achiron and Barak, 2000). Patients experiencing a rapid transformation within 1 year show cortical atrophy in contrast to patients with slower disease progression (Pérez-Miralles et al, 2013)
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