Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial.

The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

Cognitive processing speed in multiple sclerosis clinical practice: association with patient-reported outcomes, employment and magnetic resonance imaging metrics.

BACKGROUND AND PURPOSE: To analyze the relationship between cognitive processing speed, patient-reported outcome measures (PROMs), employment and magnetic resonance imaging (MRI) metrics in a large multiple sclerosis cohort. METHODS: Cross-sectional clinical data, PROMs, employment and MRI studies within 90 days of completion of the Processing Speed Test (PST), a technology-enabled adaptation of the Symbol Digit Modalities Test, were collected. MRI was analyzed using semi-automated methods. Correlations of PST score with PROMs and MRI metrics were examined using Spearman's rho. Wilcoxon rank sum testing compared MRI metrics across PST score quartiles and linear regression models identified predictors of PST performance. Effects of employment and depression were also investigated. RESULTS: In 721 patients (mean age 47.6 ± 11.4 years), PST scores were significantly correlated with all MRI metrics, including cord atrophy and deep gray matter volumes. Linear regression demonstrated self-reported physical disability, cognitive function, fatigue and social domains (adjusted R2  = 0.44, P < 0.001) as the strongest clinical predictors of PST score, whereas that of MRI variables included T2 lesion volume, whole-brain fraction and cord atrophy (adjusted R2  = 0.42, P < 0.001). An inclusive model identified T2 lesion volume, whole-brain fraction, self-reported upper extremity function, cognition and social participation as the strongest predictors of PST score (adjusted R2  = 0.51, P < 0.001). There was significant effect modification by depression on the relationship between self-reported cognition and PST performance. Employment status was associated with PST scores independent of age and physical disability. CONCLUSION: The PST score correlates with PROMs, MRI measures of focal and diffuse brain injury, and employment. The PST score is a feasible and meaningful measure for routine multiple sclerosis care.

Automated Integration of Multimodal MRI for the Probabilistic Detection of the Central Vein Sign in White Matter Lesions.

BACKGROUND AND PURPOSE: The central vein sign is a promising MR imaging diagnostic biomarker for multiple sclerosis. Recent studies have demonstrated that patients with MS have higher proportions of white matter lesions with the central vein sign compared with those with diseases that mimic MS on MR imaging. However, the clinical application of the central vein sign as a biomarker is limited by interrater differences in the adjudication of the central vein sign as well as the time burden required for the determination of the central vein sign for each lesion in a patient's full MR imaging scan. In this study, we present an automated technique for the detection of the central vein sign in white matter lesions. MATERIALS AND METHODS: Using multimodal MR imaging, the proposed method derives a central vein sign probability, πij, for each lesion, as well as a patient-level central vein sign biomarker, ψi. The method is probabilistic in nature, allows site-specific lesion segmentation methods, and is potentially robust to intersite variability. The proposed algorithm was tested on imaging acquired at the University of Vermont in 16 participants who have MS and 15 participants who do not. RESULTS: By means of the proposed automated technique, participants with MS were found to have significantly higher values of ψ than those without MS (ψMS = 0.55 ± 0.18; ψnon-MS = 0.31 ± 0.12; P < .001). The algorithm was also found to show strong discriminative ability between patients with and without MS, with an area under the curve of 0.88. CONCLUSIONS: The current study presents the first fully automated method for detecting the central vein sign in white matter lesions and demonstrates promising performance in a sample of patients with and without MS.

Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years. MATERIALS AND METHODS: Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis. RESULTS: A significant increase was observed for axial diffusivity (P < .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions (P < .001) and chronic T2 lesions (P = .02) compared with normal-appearing white matter. CONCLUSIONS: An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.

Revisiting the multiple sclerosis functional composite: proceedings from the National Multiple Sclerosis Society (NMSS) Task Force on Clinical Disability Measures.

This article describes proceedings from a meeting of the National Multiple Sclerosis Society (NMSS) Task Force on Clinical Disability Measures (the TF). The TF was appointed by the NMSS Research Programs Advisory Committee with the goal of pooling and analyzing existing datasets to explore the utility of novel disability outcome measures based on the Multiple Sclerosis Functional Composite (MSFC) approach. The TF seeks to determine the suitability of the MSFC approach as a primary clinical outcome measure for registration trials in MS. The TF met in Washington, DC, Dec. 14 and 15, 2011, and provided unanimous support for a collaborative approach involving representatives from academic medicine, the pharmaceutical industry, regulatory agencies, the NMSS and the Critical Path Institute. There was also unanimous agreement that analysis of existing datasets would be useful in making progress toward the objective. The TF placed high value on determining the clinical meaning of individual component measures for the MSFC, and in establishing optimal analysis methods for MSFC so that scores would be more interpretable than the originally recommended z-score method. The background for a collaborative project aimed at developing an improved disability outcome measure is described in this paper.

Measuring myelin repair and axonal loss with diffusion tensor imaging.

BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity and provides an attractive metric for use in neuroprotection clinical trials. The purpose of our study was to use DTI to evaluate the longitudinal changes in brain tissue integrity in a group of patients with MS. MATERIALS AND METHODS: Twenty-one patients with MS starting natalizumab were imaged serially for 12 months. Gadolinium-enhancing lesions and 20 regions of interest from normal-appearing white and gray matter brain tissue were followed longitudinally. Average values within each region of interest were derived for FA, λ(∥), λ(⊥), and MD. New T1 black holes were identified at 12 months. Analysis was performed by using mixed-model regression analysis with slope (ie, DTI change per month) as the dependent variable. RESULTS: During 1 year, FA increased in gadolinium-enhancing lesions but decreased in NABT (P < .0001 for both). Changes in FA within gadolinium-enhancing lesions were driven by decreased λ(⊥) (P < .001), and within NABT, by decreased λ(∥) (P < .0001). A higher λ(⊥) within gadolinium-enhancing lesions at baseline predicted conversion to T1 black holes at 12 months. MD was unchanged in both gadolinium-enhancing lesions and NABT. CONCLUSIONS: We observed changes in DTI measures during 1 year in both gadolinium-enhancing lesions and NABT. The DTI results may represent possible remyelination within acute lesions and chronic axonal degeneration in NAWM. These results support the use of DTI as a measure of tissue integrity for studies of neuroprotective therapies.