Relationship between cognition and white matter abnormalities in Multiple Sclerosis as detected by magnetic resonance imaging

Background Multiple sclerosis (MS) is a highly variable disease of the central nervous system with inflammatory and neurodegenerative components, associated with both physical and cognitive disability. Abnormalities are visible on routine magnetic resonance imaging (MRI) of the brain, with 'white matter hyperintensities' (WMHs) representing sites of previous inflammation. Techniques for measuring WMHs have not been standardised, although manual outlining is conventionally taken to be the reference standard, despite its subjective element. WMHs have been found to only partly explain the degree of cognitive impairment, forming part of the 'clinico-radiological paradox'. Research interest has largely moved to advanced imaging techniques, one such technique being diffusion tensor imaging (DTI). Through sensitivity to water molecule movement, DTI reflects the integrity of white matter tracts and thus its measures may be relevant to both the inflammatory and degenerative disease components. Aims The work described in this thesis aims to improve our understanding of the true relationship between measures of white matter damage and cognitive impairment in people with MS, to determine the optimum measurement technique(s) for quantifying WMHs, including developing and testing a novel visual rating scale, and to assess whether information provided by DTI can strengthen the association of imaging and clinical findings. Methods A systematic review of the literature and meta-analysis relating WMHs to cognition was conducted, focussing on image analysis technique. Three separate methods for quantifying WMHs were then investigated. The reproducibility of manual outlining was assessed using scans available from 43 people with secondary progressive MS (SPMS). An automated software method was optimised for the same cohort, based on the results of the manual outlining. A novel semi-quantitative visual rating scale was developed, with validation using the same scans within a larger, more varied cohort. All available information regarding the participants studied was then used to construct a linear regression model predicting cognitive outcomes and determining the utility of the various imaging markers derived from conventional imaging techniques. A non-linear relationship for WMHs was also considered. White matter DTI metrics in the same smaller cohort of 43 people were then investigated, primarily considering tissue outwith WMHs, as well as that within major tracts and the novel diffusion marker `peak width of skeletonised mean diffusivity'. The additional explanatory power of DTI metrics within the linear models developed previously was then determined. Results High variability was found in the literature regarding imaging marker measurement and reporting of technique reproducibility. Manual outlining was found to be associated with considerable measurement error, dependent on observer and cohort factors. It was possible to optimise the automated software for a particular cohort, either for volumetric or spatial outputs. Visual rating of MS imaging features was found to be feasible and measures of WMH burden were closely related to fully quantitative measures. The overall association of WMHs to cognitive function was similar to that found in the published literature, with no additional association following addition of DTI metrics. A trend towards a greater effect of WMH volume at higher levels was found, consistent with a non-linear relationship between imaging metrics and cognitive phenotype. Conclusions Substantial heterogeneity in the reporting of the reproducibility of WMH measurement supports a move towards benchmarking against reference datasets. Poor reliability of the current reference standard, manual segmentation, should be recognised as a key limitation for the field. Rich information can be captured quickly using visual rating of imaging features. The close correlation of visual ratings of WMHs with quantitative measures may represent a practical alternative in the appropriate circumstances. Combining visual rating features provided additional explanatory power, supporting a multidimensional substrate for the cognitive phenotype. Finally, both automated and visual rating analyses support a non-linear relationship between disease burden and cognitive performance in MS

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

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 (I(2)>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, R(2) = 0.20) and disease duration (p = 0.0018, R(2) = 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

Rim lesions are demonstrated in early relapsing–remitting multiple sclerosis using 3 T-based susceptibility-weighted imaging in a multi-institutional setting

PURPOSE: Rim lesions, characterised by a paramagnetic rim on susceptibility-based MRI, have been suggested to reflect chronic inflammatory demyelination in multiple sclerosis (MS) patients. Here, we assess, through susceptibility-weighted imaging (SWI), the prevalence, longitudinal volume evolution and clinical associations of rim lesions in subjects with early relapsing–remitting MS (RRMS). METHODS: Subjects (n = 44) with recently diagnosed RRMS underwent 3 T MRI at baseline (M0) and 1 year (M12) as part of a multi-centre study. SWI was acquired at M12 using a 3D segmented gradient-echo echo-planar imaging sequence. Rim lesions identified on SWI were manually segmented on FLAIR images at both time points for volumetric analysis. RESULTS: Twelve subjects (27%) had at least one rim lesion at M12. A linear mixed-effects model, with ‘subject’ as a random factor, revealed mixed evidence for the difference in longitudinal volume change between rim lesions and non-rim lesions (p = 0.0350 and p = 0.0556 for subjects with and without rim lesions, respectively). All 25 rim lesions identified showed T1-weighted hypointense signal. Subjects with and without rim lesions did not differ significantly with respect to age, disease duration or clinical measures of disability (p > 0.05). CONCLUSION: We demonstrate that rim lesions are detectable in early-stage RRMS on 3 T MRI across multiple centres, although their relationship to lesion enlargement is equivocal in this small cohort. Identification of SWI rims was subjective. Agreed criteria for defining rim lesions and their further validation as a biomarker of chronic inflammation are required for translation of SWI into routine MS clinical practice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00234-021-02768-x

The clinico-radiological paradox of cognitive function and MRI burden of white matter lesions in people with multiple sclerosis: a systematic review and meta-analysis.

Moderate correlation exists between the imaging quantification of brain white matter lesions and cognitive performance in people with multiple sclerosis (MS). This may reflect the greater importance of other features, including subvisible pathology, or methodological limitations of the primary literature.To summarise the cognitive clinico-radiological paradox and explore the potential methodological factors that could influence the assessment of this relationship.Systematic review and meta-analysis of primary research relating cognitive function to white matter lesion burden.Fifty papers met eligibility criteria for review, and meta-analysis of overall results was possible in thirty-two (2050 participants). Aggregate correlation between cognition and T2 lesion burden was r = -0.30 (95% confidence interval: -0.34, -0.26). Wide methodological variability was seen, particularly related to key factors in the cognitive data capture and image analysis techniques.Resolving the persistent clinico-radiological paradox will likely require simultaneous evaluation of multiple components of the complex pathology using optimum measurement techniques for both cognitive and MRI feature quantification. We recommend a consensus initiative to support common standards for image analysis in MS, enabling benchmarking while also supporting ongoing innovation

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p < 0.001). Lesion volume (Spearman’s rho rs= 0.38, p < 0.001) and g-ratio (rs= 0.24 p < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p < 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

Characterisation of tissue-type metabolic content in secondary progressive multiple sclerosis: a magnetic resonance spectroscopic imaging study

Proton magnetic resonance spectroscopy yields metabolic information and has proved to be a useful addition to structural imaging in neurological diseases. We applied short-echo time Spectroscopic Imaging in a cohort of 42 patients with secondary progressive multiple sclerosis (SPMS). Linear modelling with respect to brain tissue type yielded metabolite levels that were significantly different in white matter lesions compared with normal-appearing white matter, suggestive of higher myelin turnover (higher choline), higher metabolic rate (higher creatine) and increased glial activity (higher myo-inositol) within the lesions. These findings suggest that the lesions have ongoing cellular activity that is not consistent with the usual assumption of ‘chronic’ lesions in SPMS, and may represent a target for repair therapies

Forest plot of the individual studies showing their effect sizes as correlation coefficients.

<p>Box sizes are inversely proportional to study variance. Manuscripts reporting “non-significant” results without a point estimate are represented by circles. Aggregate effect size: r = -0.30; 95% confidence interval: -0.34, -0.26.</p

Flowchart showing articles retrieved and considered at each stage of the review process.

<p>Flowchart showing articles retrieved and considered at each stage of the review process.</p

Showing factors relevant to study quality including histograms of a) numbers of participants with MS in individual studies and b) overall quality scores, and c) the reporting of individual factors contributing to the overall quality score.

<p>Showing factors relevant to study quality including histograms of a) numbers of participants with MS in individual studies and b) overall quality scores, and c) the reporting of individual factors contributing to the overall quality score.</p