Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging

Rahmanzadeh, Reza; Lu, Po Jui; Baraković, Muhamed; Weigel, Matthias; Maggi, Pietro; Nguyen, Thanh D.; Schiavi, Simona; Daducci, Alessandro; Rosa, Francesco La; Schaedelin, Sabine; Absinta, Martina; Reich, Daniel S.; Sati, Pascal; Wang, Yi; Cuadra, Meritxell Bach; Radüe, Ernst Wilhelm; Kühle, Jens; Kappos, Ludwig; Granziera, Cristina

doi:10.1093/brain/awab088

Cited by 82 publications

(91 citation statements)

References 81 publications

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“…We emailed 14 study investigators to request additional study data or to seek clarification about study methodology, and 7 kindly replied. Not captured by our search were 5 studies that post-dated our literature search [ 20 , 29 – 32 ]. These were subsequently included in our sensitivity analyses.…”

Section: Resultsmentioning

confidence: 99%

The prevalence of paramagnetic rim lesions in multiple sclerosis: A systematic review and meta-analysis

et al. 2021

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Background Recent findings from several studies have shown that paramagnetic rim lesions identified using susceptibility-based MRI could represent potential diagnostic and prognostic biomarkers in multiple sclerosis (MS). Here, we perform a systematic review and meta-analysis of the existing literature to assess their pooled prevalence at lesion-level and patient-level. Methods Both database searching (PubMed and Embase) and handsearching were conducted to identify studies allowing the lesion-level and/or patient-level prevalence of rim lesions or chronic active lesions to be calculated. Pooled prevalence was estimated using the DerSimonian-Laird random-effects model. Subgroup analysis and meta-regression were performed to explore possible sources of heterogeneity. PROSPERO registration: CRD42020192282. Results 29 studies comprising 1230 patients were eligible for analysis. Meta-analysis estimated pooled prevalences of 9.8% (95% CI: 6.6–14.2) and 40.6% (95% CI: 26.2–56.8) for rim lesions at lesion-level and patient-level, respectively. Pooled lesion-level and patient-level prevalences for chronic active lesions were 12.0% (95% CI: 9.0–15.8) and 64.8% (95% CI: 54.3–74.0), respectively. Considerable heterogeneity was observed across studies (I2>75%). Subgroup analysis revealed a significant difference in patient-level prevalence between studies conducted at 3T and 7T (p = 0.0312). Meta-regression analyses also showed significant differences in lesion-level prevalence with respect to age (p = 0.0018, R2 = 0.20) and disease duration (p = 0.0018, R2 = 0.48). Other moderator analyses demonstrated no significant differences according to MRI sequence, gender and expanded disability status scale (EDSS). Conclusion In this study, we show that paramagnetic rim lesions may be present in an important proportion of MS patients, notwithstanding significant variation in their assessment across studies. In view of their possible clinical relevance, we believe that clear guidelines should be introduced to standardise their assessment across research centres to in turn facilitate future analyses.

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Section: Resultsmentioning

confidence: 99%

The prevalence of paramagnetic rim lesions in multiple sclerosis: A systematic review and meta-analysis

et al. 2021

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“…12 studies remained for the eligibility assessment; 5 studies were excluded based on the reasons shown on the PRISMA diagram ( Figure 1 ). A total of 7 studies investigating the brain microstructure in patients with MS using NODDI were included and met the inclusion/exclusion criteria for this meta-analysis [ 20 , 23 , 24 , 25 , 26 , 27 , 29 ]. A total of 202 patients with MS (mean age of 40.1 years) and 172 healthy controls (mean age of 35.1 years) were included.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 202 patients with MS (mean age of 40.1 years) and 172 healthy controls (mean age of 35.1 years) were included. The mean MS duration of all the studies was 8.3 years; however, two studies did not report disease duration [ 26 , 29 ]. There was no significant difference in the age and sex distribution between MS patients and healthy controls, with the caveat that one study did not provide information relating to the sex of participants [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

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Investigating Microstructural Changes in White Matter in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging

et al. 2021

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Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.

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“…The NDI relates to neuroaxonal density and has been found to be reduced in the MS WM and cortex, especially in the progressive disease (16,17,26). In ex vivo studies, NDI has also been found to correlate with myelin content (16,27).…”

Section: Discussionmentioning

confidence: 98%

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis

et al. 2021

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Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T2* and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

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Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging

Cited by 82 publications

References 81 publications

The prevalence of paramagnetic rim lesions in multiple sclerosis: A systematic review and meta-analysis

The prevalence of paramagnetic rim lesions in multiple sclerosis: A systematic review and meta-analysis

Investigating Microstructural Changes in White Matter in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis

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