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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 and neurite orientation dispersion and density imaging diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 versus 0.57, difference 0.036, 95% CI: 0.029–0.043, 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 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., Graphical Abstract Graphical Abstract

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).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.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).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.

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.

Introduction CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke. Methods We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with various degrees of arterial obstruction in different intracranial locations on CTA. To assess inter-observer reliability, seven members of the IST-3 expert image reading panel (>5 years experience reading CTA) and seven radiology trainees (