Colin Shea

Evolution of the blood–brain barrier in newly forming multiple sclerosis lesions

Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood–brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability.

FLAIR*: A Combined MR Contrast Technique for Visualizing White Matter Lesions and Parenchymal Veins

PURPOSE To evaluate a magnetic resonance (MR) imaging contrast technique, called FLAIR*, that combines the advantages of T2-weighted fluid-attenuated inversion recovery (FLAIR) contrast and T2*-weighted contrast on a single image for assessment of white matter (WM) diseases such as multiple sclerosis (MS). MATERIALS AND METHODS This prospective pilot study was HIPAA compliant and institutional review board approved. Ten patients with clinically definite MS (eight men, two women; mean age, 41 years) provided informed consent and underwent 3.0-T MR imaging. Images from a T2-weighted FLAIR sequence were combined with images from a T2*-weighted segmented echo-planar imaging sequence performed during contrast material injection, yielding high-isotropic-resolution (0.55 × 0.55 × 0.55 mm(3)) FLAIR* images. Qualitative assessment was performed for image quality, lesion conspicuity, and vein conspicuity. Contrast-to-noise ratio (CNR) was calculated to compare normal-appearing WM (NAWM) with cerebrospinal fluid, lesions, and veins. To evaluate the differences in CNR among imaging modalities, a bootstrap procedure clustered on subjects was used, together with paired t tests. RESULTS High-quality FLAIR* images of the brain were produced at 3.0 T, yielding conspicuous lesions and veins. Lesion-to-NAWM and NAWM-to-vein CNR values were significantly higher for FLAIR* images than for T2-weighted FLAIR images (P < .0001). Findings on FLAIR* images included intralesional veins for lesions located throughout the brain and a hypointense rim around some WM lesions. CONCLUSION High-isotropic-resolution FLAIR* images obtained at 3.0 T yield high contrast for WM lesions and parenchymal veins, making it well suited to investigate the relationship between WM abnormalities and veins in a clinical setting.

Quantification of multiple-sclerosis-related brain atrophy in two heterogeneous MRI datasets using mixed-effects modeling

Brain atrophy, measured by MRI, has been proposed as a useful surrogate marker for disease progression in multiple sclerosis (MS). However, it is conventionally assumed that the accurate quantification of brain atrophy is made difficult, if not impossible, by changes in the parameters of the MRI acquisition, which are almost inevitable over the course of a longitudinal study since MRI technology changes rapidly. This state of affairs can negatively affect clinical trial design and limit the use of historical data. Here, we investigate whether we can coherently estimate brain atrophy rates in a heterogeneous MS sample via linear mixed-effects multivariable regression, incorporating three critical assumptions: (1) using age at time of scanning, rather than time since baseline, as the regressor of interest; (2) scanning individuals with a variety of techniques; and (3) introducing a simple additive correction for major differences in MRI protocol. We fit the model to several measures of brain volume as the outcome in two MS populations: 1123 scans from 195 cases acquired for over approximately 7 years in two natural history protocols (Cohort 1), and 1331 scans from 69 cases seen for over 11 years who were primarily treated with two specific MS disease-modifying therapies (Cohort 2). We compared the mixed-effects model with additive correction for MRI acquisition parameters to a model fit without this correction and performed sample-size calculations to provide an estimate of the number of participants in an MS clinical trial that might be required to see a therapeutic effect of treatment using the approach described here. The results show that without the additive correction for T1-weighted protocol parameters, atrophy was underestimated and subject-specific estimates were more narrowly distributed about the population mean. Ventricular CSF is the most consistently estimated brain volume, with a mean of 2.8%/year increase in Cohort 1 and 4.4%/year increase in Cohort 2. An interesting observation was that gray matter volume decreased and white matter volume remained essentially unchanged in both cohorts, suggesting that changes in ventricular CSF volume are a surrogate for changes in gray matter volume. In conclusion, the mixed-effects modeling framework presented here allows effective use of heterogeneously acquired and historical data in the study of brain atrophy in MS, potentially simplifying the design of future single- and multi-site clinical trials and natural history studies.

Clinical 3-tesla FLAIR∗ MRI improves diagnostic accuracy in multiple sclerosis

Objective: To evaluate clinical fluid-attenuated inversion recovery (FLAIR)* 3T magnetic resonance imaging (MRI), which is sensitive to perivenular inflammatory demyelinating lesions, in diagnosing multiple sclerosis (MS). Background: Central veins may be a distinguishing feature of MS lesions. FLAIR*, a combined contrast derived from clinical MRI scans, has not been studied as a clinical tool for diagnosing MS. Methods: Two experienced MS neurologists evaluated 87 scan pairs (T2-FLAIR/FLAIR*), separately and side-by-side, from 68 MS cases, 8 healthy volunteers, and 11 individuals with other neurological diseases. Raters judged cases based on experience, published criteria, and a visual assessment of the “40% rule,” whereby MS is favored if >40% of lesions demonstrate a central vein. Diagnostic accuracy was determined with area under the receiver operating characteristic curve (AUC), and inter-rater reliability was assessed with Cohen’s kappa (κ). Results: Diagnostic accuracy was high: rater 1, AUC 0.94 (95% confidence interval: 0.89, 0.97) for T2-FLAIR, 0.95 (0.92, 0.98) for FLAIR*; rater 2, 0.94 (0.90, 0.98) and 0.90 (0.85, 0.95). AUC improved when images were considered together: rater 1, 0.99 (0.98, 1.00); rater 2, 0.98 (0.96, 0.99). Inter-rater agreement was substantial for T2-FLAIR (κ = 0.68) and FLAIR* (κ = 0.74), despite low agreement on the 40% rule (κ = 0.47) ( p ≪ 0 . 001 in all cases). Conclusions: Joint clinical evaluation of T2-FLAIR and FLAIR* images modestly improves diagnostic accuracy for MS and does not require counting lesions with central veins.

Statistical estimation of T1 relaxation times using conventional magnetic resonance imaging.

Quantitative T1 maps estimate T1 relaxation times and can be used to assess diffuse tissue abnormalities within normal-appearing tissue. T1 maps are popular for studying the progression and treatment of multiple sclerosis (MS). However, their inclusion in standard imaging protocols remains limited due to the additional scanning time and expert calibration required and susceptibility to bias and noise. Here, we propose a new method of estimating T1 maps using four conventional MR images, which are intensity-normalized using cerebellar gray matter as a reference tissue and related to T1 using a smooth regression model. Using cross-validation, we generate statistical T1 maps for 61 subjects with MS. The statistical maps are less noisy than the acquired maps and show similar reproducibility. Tests of group differences in normal-appearing white matter across MS subtypes give similar results using both methods.

Sample-size calculations for short-term proof-of-concept studies of tissue protection and repair in multiple sclerosis lesions via conventional clinical imaging

Background: New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking. Objective: The objective of this paper is to report sample-size calculations for assessment of new lesion recovery. Methods: In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations. Results: In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions ⩾15 mm3, as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20% and statistical power of 90%. Conclusion: Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset.

Slowly eroding lesions in multiple sclerosis

Background: At autopsy, 20%–40% of chronic multiple sclerosis (MS) lesions are labeled “slowly expanding” and feature myelin phagocytosis at the lesion edge. As pathological lesion classification relies on a single, terminal time point, the rate of lesion expansion cannot be directly measured. Objective: To study long-term volume changes in individual MS lesions. Methods: Volumes of individual lesions on proton density magnetic resonance imaging (MRI) acquired between 1992 and 2015 were measured in 22 individuals (one lesion per person). After correction for acquisition protocol, a mixed model evaluated lesion volume changes. Results: The mean (standard deviation) lesion volume at baseline was 142 (82) mL, falling to 74 (51) mL after 16 (3) years. All lesions shrank over time. Change in lesion volume did not correlate with change in supratentorial brain volume (p = 0.33). In simulations, the results could be explained by a process of slow radial expansion superimposed on substantially more rapid resorption of damaged tissue. Conclusion: We noted sustained radiological contraction of MS lesions, a surprising result given that fresh myelin breakdown products within chronic active lesions are observed relatively frequently at autopsy. Therefore, the primary pathological process in chronic lesions, even those described as “slowly expanding,” is likely to be tissue loss.