Reliability of Central Vein Sign Imaging with 3T FLAIR* in a Multicenter Study

Academic Background

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by the formation of white matter lesions (WMLs). Magnetic Resonance Imaging (MRI) is a crucial tool for diagnosing and monitoring MS, particularly T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images, which are commonly used to identify white matter lesions in the brain. However, non-specific white matter lesions are also common in other neurological disorders, which can lead to misdiagnosis of MS.

In recent years, the Central Vein Sign (CVS) has been proposed as a new diagnostic biomarker. CVS refers to the pathological feature of MS lesions forming around small veins, with its MRI manifestation being a hypointense vein at the center of the lesion. High-resolution susceptibility-weighted imaging (such as T2*-weighted imaging) allows for non-invasive detection of CVS at different field strengths. However, susceptibility-weighted imaging has lower sensitivity in detecting CVS and can sometimes struggle to distinguish periventricular lesions from cerebrospinal fluid (CSF). To address these issues, FLAIR* imaging was developed, combining the CSF suppression capability of T2-FLAIR with the vein detection capability of T2*-weighted imaging, providing high sensitivity for both lesions and veins.

Although previous studies have shown that 3T FLAIR* has high accuracy in differentiating MS from other diseases, its reliability in multicenter and multi-MRI scanner settings has not been quantitatively validated. Additionally, whether the use of gadolinium (Gd) contrast agents can improve CVS conspicuity remains unclear. Therefore, this study aimed to evaluate the reliability of CVS imaging with 3T FLAIR* across different imaging centers and MRI scanners and to explore the effect of Gd contrast agents on CVS conspicuity.

Source of the Paper

This paper was co-authored by Melissa Lynne Martin and others from multiple institutions, including the University of Pennsylvania Perelman School of Medicine, Cedars-Sinai Medical Center, and the National Institutes of Health. The paper was published in 2025 in the Journal of Neuroimaging, titled “Reliability of Central Vein Sign Imaging with 3T FLAIR* in a Multicenter Study”.

Research Process

1. Study Design

This study was a cross-sectional, multicenter observational study aimed at evaluating the reliability of CVS imaging with 3T FLAIR* across different imaging centers and MRI scanners. A total of 97 adults suspected of having MS were recruited from 10 North American imaging centers. Ultimately, data from 87 participants were included in the analysis.

2. Image Acquisition

All participants underwent brain imaging on 3T MRI scanners from Siemens Healthineers and Philips Healthcare. The imaging sequences included: - T1-weighted magnetization-prepared rapid gradient-echo (T1-MPRAGE): 1 mm isotropic resolution. - T2-FLAIR: 1 mm isotropic resolution. - T2-weighted 3D segmented echo-planar imaging (T2 3D-EPI): 0.65 mm isotropic resolution, acquired before and after Gd contrast injection.

3. Image Processing

All MRI data were uploaded to the cloud platform Qmenta, Inc. and underwent quality checks. The image processing steps included: 1. Image Alignment: Aligning T2* 3D-EPI images to the Montreal Neurological Institute (MNI) template space. 2. Image Registration: Registering T2-FLAIR images to the aligned T2* 3D-EPI images using a windowed sinc function for interpolation. 3. FLAIR* Image Generation: Generating FLAIR* images by voxel-wise multiplication of the coregistered T2-FLAIR and T2* 3D-EPI images.

4. Lesion and Vein Segmentation

The following processing steps were performed using existing software in the R statistical environment: 1. N4 Bias Correction: Correcting T1-MPRAGE, T2-FLAIR, and T2* 3D-EPI images. 2. Skull Stripping: Removing extracerebral voxels from T1-MPRAGE images using a multi-atlas approach. 3. White Matter Segmentation: Segmenting white matter using multi-atlas joint label fusion. 4. Lesion Segmentation: Segmenting white matter lesions using the MIMOSA method, with manual corrections when necessary. 5. Vein Segmentation: Applying a Frangi vesselness filter to T2* images to segment veins.

5. Data Analysis

The lesion-to-vein contrast-to-noise ratio (CNRlesion-to-vein) was calculated as a quantitative measure of CVS conspicuity. Paired t-tests were used to compare CNRlesion-to-vein values between pre- and post-Gd FLAIR* images, and analysis of variance (ANOVA) was used to compare CNRlesion-to-vein values across different centers and scanners.

Key Findings

1. Consistency of CVS Conspicuity Across Centers

The results showed that CVS was highly conspicuous on 3T FLAIR* images across all centers. There were no significant differences in CNRlesion-to-vein values between centers for both pre- and post-Gd images (p-values of 0.07 and 0.27, respectively), indicating consistency of 3T FLAIR* across different imaging centers.

2. Consistency of CVS Conspicuity Across Scanners

The study also found no significant differences in CNRlesion-to-vein values between Siemens and Philips scanners (p-values of 0.11 and 0.34, respectively), indicating consistency of 3T FLAIR* across different MRI scanners.

3. Effect of Gd Contrast on CVS Conspicuity

Post-Gd FLAIR* images showed significantly improved CVS conspicuity (p-value < 0.001), demonstrating that Gd contrast agents enhance CVS visualization.

Conclusion

This study is the first to quantitatively validate the reliability of 3T FLAIR* for CVS imaging in a multicenter and multi-scanner setting. The results demonstrate that 3T FLAIR* is consistent across different imaging centers and scanners, and that Gd contrast agents significantly improve CVS conspicuity. These findings support the clinical application of 3T FLAIR* for MS diagnosis.

Highlights of the Study

1. Multicenter Validation: First to validate the reliability of 3T FLAIR* for CVS imaging in a multicenter and multi-scanner setting.
2. Role of Gd Contrast: Quantitatively demonstrated that Gd contrast agents significantly improve CVS conspicuity.
3. Clinical Application Value: Provides strong support for the clinical use of 3T FLAIR* in MS diagnosis.

Additional Valuable Information

The limitations of this study include: 1. Limited Sample Size: The small number of participants at each center may affect statistical power. 2. Scanner Limitations: Only two MRI vendors were included; future studies should include more vendors. 3. Complexity of Image Processing: FLAIR* image processing has not yet been implemented for clinical use on all MRI scanners.

Despite these limitations, this study lays the foundation for the widespread application of 3T FLAIR* in MS diagnosis and provides important references for future multicenter studies.