Networks of microstructural damage predict disability in multiple sclerosis

Abstract

BackgroundNetwork-based measures are emerging MRI markers in multiple sclerosis (MS). We aimed to identify networks of white (WM) and grey matter (GM) damage that predict disability progression and cognitive worsening using data-driven methods.MethodsWe analysed data from 1836 participants with different MS phenotypes (843 in a discovery cohort and 842 in a replication cohort). We calculated standardised T1-weighted/T2-weighted (sT1w/T2w) ratio maps in brain GM and WM, and applied spatial independent component analysis to identify networks of covarying microstructural damage. Clinical outcomes were Expanded Disability Status Scale worsening confirmed at 24 weeks (24-week confirmed disability progression (CDP)) and time to cognitive worsening assessed by the Symbol Digit Modalities Test (SDMT). We used Cox proportional hazard models to calculate predictive value of network measures.ResultsWe identified 8 WM and 7 GM sT1w/T2w networks (of regional covariation in sT1w/T2w measures) in both cohorts. Network loading represents the degree of covariation in regional T1/T2 ratio within a given network. The loading factor in the anterior corona radiata and temporo-parieto-frontal components were associated with higher risks of developing CDP both in the discovery (HR=0.85, p<0.05 and HR=0.83, p<0.05, respectively) and replication cohorts (HR=0.84, p<0.05 and HR=0.80, p<0.005, respectively). The decreasing or increasing loading factor in the arcuate fasciculus, corpus callosum, deep GM, cortico-cerebellar patterns and lesion load were associated with a higher risk of developing SDMT worsening both in the discovery (HR=0.82, p<0.01; HR=0.87, p<0.05; HR=0.75, p<0.001; HR=0.86, p<0.05 and HR=1.27, p<0.0001) and replication cohorts (HR=0.82, p<0.005; HR=0.73, p<0.0001; HR=0.80, p<0.005; HR=0.85, p<0.01 and HR=1.26, p<0.0001).ConclusionsGM and WM networks of microstructural changes predict disability and cognitive worsening in MS. Our approach may be used to identify patients at greater risk of disability worsening and stratify cohorts in treatment trials.

The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis

“…Colato et al recently identified grey and white matter networks of microstructural damage assessed using the sT1w/T2w ratio in patients with multiple sclerosis. 49 Interestingly, they also identified an independent component (WM-IC6) that closely matches the damage pattern in our patients with NMDAR encephalitis. This could potentially indicate that this white matter network covers a specifically vulnerable brain region, or a brain region where multiple sclerosis and NMDAR encephalitis share (downstream) pathophysiological mechanisms.…”

“…47 Moreover, the major SLF component terminates in the dorsolateral prefrontal cortex, a brain region central to working memory that also promotes long-term memory formation. 48 Recent studies have demonstrated that cerebral white matter can also be analysed from a network perspective, both as a structural network 49 and as a functional connectivity network. 42 To estimate the functional implications of the observed white matter changes, we visually assessed overlap with the white matter functional atlas developed by Peer and colleagues.…”

Association of retinal vessel pathology and brain atrophy in relapsing-remitting multiple sclerosis

“…Disability worsening as measured by the EDSS was defined if an increase of the EDSS confirmed at least 3 months after the first documentation occurred during the study follow-up (EDSS increase of ≥ 1.5 if the baseline EDSS was 0, increase of ≥ 1.0 if the baseline EDSS was between 1.0 and 5.0). We defined worsening of the SDMT if a reduction of at least 4 points occurred (confirmed in a second follow-up visit) ( 13 ) and worsening of the T25W and 9HPT if an ≥ 20% increase in test times were recognized (confirmed in a second follow-up visit) ( 14 ). We excluded patients with any relevant eye disease possibly affecting the integrity of the retina and a refractory errors > 6 dioptres.…”