The network collapse in multiple sclerosis: An overview of novel concepts to address disease dynamics

Schoonheim, Menno M.; Broeders, Tommy A.A.; Geurts, Jeroen J. G.

doi:10.1016/j.nicl.2022.103108

Cited by 42 publications

(41 citation statements)

References 125 publications

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“…While it is well-known that several white matter lesions are already visible at the time of diagnosis (which is the basis for the MRI-based criteria of dissemination in space and time after a first clinical episode [2]), we also demonstrate here that several GM structures will exhibit atrophy at this time. This argues for a neurodegenerative component that is very early and probably compensated for before that lesions would reach eloquent areas leading to a first clinical episode and, in turn, to the clinical diagnosis [23].…”

Section: Discussionmentioning

confidence: 99%

Lifespan Neurodegeneration Of The Human Brain In Multiple Sclerosis

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Mansencal

et al. 2023

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Background: Atrophy related to Multiple Sclerosis (MS) has been found at the early stages of the disease. However, the archetype dynamic trajectories of the neurodegenerative process, even prior to clinical diagnosis, remain unknown. Methods: We modeled the volumetric trajectories of brain structures across the entire lifespan using 40944 subjects (38295 healthy controls and 2649 MS patients). Then, we estimated the chronological progression of MS by assessing the divergence of lifespan trajectories between normal brain charts and MS brain charts. Results: Chronologically, the first affected structure was the thalamus, then the putamen and the pallidum (3 years later), followed by the ventral diencephalon (7 years after thalamus) and finally the brainstem (9 years after thalamus). To a lesser extent, the anterior cingulate gyrus, insular cortex, occipital pole, caudate and hippocampus were impacted. Finally, the precuneus and accumbens nuclei exhibited a limited atrophy pattern. Conclusion: Subcortical atrophy was more pronounced than cortical atrophy. The thalamus was the most impacted structure with a very early divergence in life. It paves the way toward utilization of these lifespan models for future preclinical/prodromal prognosis and monitoring of MS.

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Section: Discussionmentioning

confidence: 99%

Lifespan Neurodegeneration Of The Human Brain In Multiple Sclerosis

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Planche

Mansencal

et al. 2023

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“…1 The field of connectomics has now started to bridge this gap, as clinically relevant disruptions to macro-scale brain networks, measured using structural (sMRI), diffusion (dMRI), or resting-state functional (rs-fMRI) MRI, have been extensively demonstrated in people with multiple sclerosis (PwMS), to the point that it has been described as a network disorder. 2,3 Our current understanding points towards abnormal connectivity centred around hubs like the thalamus and the default mode network, evolving along the disease course and representing a possible common mechanism through which cumulative brain damage eventually leads to long-term disability. 2,3 Nevertheless, MRI-based connectivity studies yield conflicting results, somehow failing to identify a unified connectomic hallmark of multiple sclerosis and related disability.…”

Section: Introductionmentioning

confidence: 99%

“…2,3 Our current understanding points towards abnormal connectivity centred around hubs like the thalamus and the default mode network, evolving along the disease course and representing a possible common mechanism through which cumulative brain damage eventually leads to long-term disability. 2,3 Nevertheless, MRI-based connectivity studies yield conflicting results, somehow failing to identify a unified connectomic hallmark of multiple sclerosis and related disability. 4,5 While this is partly explained by multiple sclerosis' intrinsic neurobiological and phenotypic heterogeneity, 6,7 methodological issues may as well play a role, including the disparity of image processing strategies, and the small sample sizes.…”

Section: Introductionmentioning

confidence: 99%

More than the sum of its parts: disrupted core-periphery of multiplex networks in multiple sclerosis

Pontillo

Carrasco

Wink

et al. 2022

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Disruptions to brain networks, measured using either structural (sMRI), diffusion (dMRI), or resting-state functional (rs-fMRI) MRI, have been shown in people with multiple sclerosis (PwMS), highlighting the importance of damage to regions in the core of the connectome. Here, using a multilayer network approach, we aimed to integrate these three modalities to portray an enriched representation of the brain core-periphery organization and explore its alterations in PwMS. In this retrospective cross-sectional study, 1048 PwMS (695F, mean-SD age: 43.3-11.4yr), and 436 healthy controls (250F, mean-SD age: 38.3-11.8yr) with complete multimodal brain MRI acquisitions were selected from 13 European centres within the MAGNIMS network. Clinical variables included the Expanded Disability Status Scale (EDSS) and the Symbol Digit Modalities Test (SDMT), measuring physical disability and cognition, respectively. SMRI, dMRI, and rs-fMRI data were parcellated into 100 cortical (Schaefer atlas) and 14 subcortical (FSL-FIRST) regions to obtain networks of morphological covariance, structural connectivity, and functional connectivity, respectively. Following statistical harmonization and preprocessing, connectivity matrices were merged in a multiplex, from which regional coreness, defined as the probability of a node being part of the multiplex core, and coreness disruption index (kappa), quantifying the global weakening of the core-periphery structure, were computed. The associations of regional coreness and kappa with disease status (PwMS versus healthy controls), clinical phenotype, and physical (EDSS) and cognitive (SDMT z-scores) disability were tested with permutation testing, one-way ANOVA, and Spearman and Pearson correlation, respectively. We used random forest permutation feature importance to assess the relative weights of kappa in the multiplex and single-layer domains, in addition to conventional MRI measures (brain and lesion volumes), for the prediction of disease status, level of physical disability (EDSS≥4 vs EDSS<4), and cognitive impairment (SDMT z-score<-1.5). PwMS showed widespread deviations in regional coreness compared to healthy controls, with a prominent decrease in the thalami (Hedges g>0.90). At the global level, PwMS showed significant disruption of the multiplex core-periphery organization (kappa=-0.19, Hedges g=0.61, p<0.001), correlating with clinical phenotype (F=5.42, p=0.001), EDSS (rho=-0.08, p=0.01) and SDMT (r=0.19, p<0.0001). Multiplex kappa; was the only connectomic measure adding to conventional MRI for the prediction of disease status and cognitive impairment, while physical disability depended also on single-layer contributions. We show that multilayer networks represent a biologically and clinically meaningful framework to model multimodal MRI data, with disruption of the core-periphery structure emerging as a potential novel biomarker for disease severity and cognitive impairment in multiple sclerosis.

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“…It affects people with MS since the earliest phases of the disease, and it can worsen over time like other functional systems, especially in progressive MS. 1 Mechanisms underlying CI are complex, mainly thought to be based on the accumulation of structural disconnection, neurodegeneration and failure of functional reserve capacity. 2 Given this hypothesized complex, slow cascade leading to CI, preserving cognitive functioning might still be in the therapeutic window once a diagnosis of secondary progressive MS (SPMS) is made based on the evidence of progression in other neuronal domains. 3 As more data are accumulating on disease modifying therapies showing an effect on cognition and more trials are being designed, it is now necessary to identify and validate markers useful to stratify patients at risk, monitor and predict the course of CI in MS.…”

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confidence: 99%

“…Earlier work using such batteries has shown a predictive value of MRI in progressive MS, 10 which could be explained by a more severely affected cohort, as CI was relatively mild in this paper. Finally, if the hypothesis of a specific order of events leading to CI is to be proven, that is, starting with acute neuroaxonal damage, then neurodegeneration, finally leading to a ‘network collapse’, 2 larger longitudinal cohorts are now needed, including data from the relapsing remitting stage as well as the transition from relapsing remitting MS towards SPMS.…”

mentioning

confidence: 99%