Targeting Cognitive Impairment in Multiple Sclerosis—The Road toward an Imaging-based Biomarker

Abstract

Multiple Sclerosis (MS) is a neuro-degenerative and -inflammatory disease leading to physical and cognitive impairment, pathological fatigue and depression, and affecting patients' quality of life and employment status. The combination of inflammation, demyelination, and neurodegeneration leads to the emergence of MS lesions, reduced white and gray matter brain volumes, a reduced conduction velocity and microstructural changes in the so-called Normal Appearing White Matter (NAWM). Currently, there are very limited options to treat cognitive impairment and its origin is only poorly understood. Therefore, several studies have attempted to relate clinical scores with features calculated either using T1- and/or FLAIR weighted MR images or using neurophysiology. The aim of those studies is not only to provide an improved understanding of the processes that underlie the different symptoms, but also to develop a biomarker—sensitive to therapy induced change—that could be used to speed up therapeutic developments (e.g., cognitive training/drug discovery/…). Here, we provide an overview of studies that have established relationships between either neuro-anatomical or neurophysiological measures and cognitive outcome scores. We discuss different avenues that may help to improve the prediction of cognitive impairment, and how well we can expect them to predict cognitive scores.

Brain dysconnectivity relates to disability and cognitive impairment in multiple sclerosis

“…An important question brought by the analysis of MS‐related rsFC changes and their correlation to cognitive scores, is whether electrophysiological rsFC provides an added value to describe MS‐related CI compared to structural markers that are often used (e.g., brain atrophy, cortical lesions, see e.g., Van Schependom & Nagels, 2017). To address this issue, we focused on cognitive scores that were significantly altered in patients with MS, and we first built for each of them a purely structural regression model with two well‐established markers of neurostructural damage as dependent variables, that is, global lesion load and normalized thalamic volume (see e.g., Barkhof, 2002; Tewarie et al, 2013).…”

“…Specifically, we added as dependent variables all mean network connectivity values (across RSNs and frequency bands, see Figure 2d) exhibiting a significant MS‐related contrast. Given that structural and functional parameters are related (Tewarie et al, 2013; Van Schependom & Nagels, 2017), these rsFC variables were orthogonalized with respect to the structural parameters before being used in the regression. This merely amounts to a reparametrization that emphasizes the independent information brought by rsFC but leaves the R 2 statistic unchanged.…”

Impaired cognition is related to microstructural integrity in relapsing remitting multiple sclerosis

“…A sensitive biomarker to detect risk of cognitive dysfunction and treatment-related cognition improvement is therefore urgently required. 8 MRI is a powerful non-invasive diagnostic and monitoring tool for MS and has great potential to detect cognitive dysfunction. However, recent studies showed only weak associations between traditional MRI measures, such as white matter lesion (WML) load and whole brain atrophy, and cognitive performance.…”

“…9 The development of advanced MRI techniques may allow early detection of cognitive dysfunction. 8,10 White matter (WM), gray matter (GM) and WML were found to account for cognitive dysfunction but the contributions were inconsistent among different studies. 1 Thalamic atrophy, among the subcortical gray matter structures, is most promising to predict cognitive dysfunction.…”

Association between miRNAs expression and cognitive performances of Pediatric Multiple Sclerosis patients: A pilot study

“…However, it is worthy to note that most of our significant results were confirmations of published reports. Among the others, we obtained significant correlations between the overall corpus callosum atrophy and both the executive functions and depression (Benedict, Ramasamy, Munschauer, Weinstock‐Guttman, & Zivadinov, ; Johnson‐Markve, Lee, Loring, & Viner, ; van Schependom & Nagels, ), whereas the right occipital lobe volume was found significantly related to the performances obtained at SDMT (Akbar et al, ).…”