The effect of gadolinium-based contrast-agents on automated brain atrophy measurements by FreeSurfer in patients with multiple sclerosis

Abstract

Objective: To determine whether reliable brain atrophy measures can be obtained from post-contrast 3D T1-weighted images in patients with multiple sclerosis (MS) using FreeSurfer.

Methods: Twenty-two patients with MS were included, in which 3D T1-weighted MR images were obtained during the same scanner visit, with the same acquisition protocol, before and after administration of gadolinium-based contrast agents (GBCAs). Two FreeSurfer versions (v.6.0.1 and v.7.1.1.) were applied to calculate grey matter (GM) and white matter (WM) volumes and global and regional cortical thickness. The consistency between measures obtained in pre- and post-contrast images was assessed by intra-class correlation coefficient (ICC), the difference was investigated by paired t-tests, and the mean percentage increase or decrease was calculated for total WM and GM matter volume, total deep GM and thalamus volume, and mean cortical thickness.

Results: Good to excellent reliability was found between all investigated measures, with ICC ranging from 0.926 to 0.996, all p values < 0.001. GM volumes and cortical thickness measurements were significantly higher in post-contrast images by 3.1 to 17.4%, while total WM volume decreased significantly by 1.7% (all p values < 0.001).

Conclusion: The consistency between values obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable brain atrophy measurements from T1-weighted images acquired after administration of GBCAs, using FreeSurfer. However, absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly. Potential systematic effects, possibly dependent on GBCA dose or the delay time after contrast injection, should be investigated.

Trial registration: Clinical trials.gov. identifier: NCT00360906.

Key points: • The influence of gadolinium-based contrast agents (GBCAs) on atrophy measurements is still largely unknown and challenges the use of a considerable source of historical and prospective real-world data. • In 22 patients with multiple sclerosis, the consistency between brain atrophy measurements obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable atrophy measurements in T1-weighted images acquired after administration of GBCAs, using FreeSurfer. • Absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly, and measurements extracted from certain regions (e.g., the temporal pole) should be interpreted with caution.

Keywords: Atrophy; Gadolinium; Grey matter; Magnetic resonance imaging; Multiple sclerosis.

Conflict of interest statement

I.A. Lie declares no disclosures relevant to the manuscript.

E. Kerklingh declares no disclosures relevant to the manuscript.

K. Wesnes has received unrestricted research grants from Novartis and Biogen, and speaker honoraria from Biogen.

D.R. van Nederpelt declares no disclosures relevant to the manuscript.

I. Brouwer has received research support from Merck KGaA, Novartis, and Teva.

Ø. Torkildsen has received research grants and speaker honoraria from Biogen, Roche, Novartis, Merck, and Sanofi.

K.M. Myhr has received unrestricted research grants to his institution; scientific advisory board, and speaker honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, and Teva; and has participated in clinical trials organised by Biogen, Merck, Novartis, and Roche.

F. Barkhof has received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Teva, Bracco, and IXICO.

L. Bø has received unrestricted research grants to his institution and/or scientific advisory board or speaker’s honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, and Teva; and has participated in clinical trials organised by Biogen, Merck, Novartis, Roche, and Genzyme.

H. Vrenken has received research grants from Pfizer, Merck Serono, Novartis, and Teva, speaker honoraria from Novartis, and consulting fees from Merck Serono; all funds were paid directly to his institution.

© 2021. The Author(s).

Figures

Fig. 1

Post-contrast T1-weighted MRI, showing the border between WM and GM (white surface) (yellow), and the border between GM and CSF (pial surface) (red). a Axial slice showing a moderate pial surface “looping error” (white arrow). b Sagittal slice showing a typical skull stripping failure; a moderate error of the pial surface expanding into the dura and the sagittal sinus (white arrow)

Fig. 2

T1-weighted MRI, showing the segmentation of the left Thalamus in pre- and post-contrast images, in two different patients (subject E3 (a–d) and subject C1 (e–h)). a–d Axial slices demonstrating the typical quality of thalamus segmentations. In post-contrast images (c–d), the medial border of the left Thalamus is slightly overestimated (arrow) compared to pre-contrast images (arrowhead) (a–b), most likely due to hyperintense signal from extraparenchymal structures in the midline. e–h Axial slices demonstrating a more severe overestimation of the medial border of the left Thalamus (arrow) in post-contrast images (g–h) compared to pre-contrast images (arrow head) (e–f). Again, the segmentation of the medial border is overestimated due to inclusion of extraparenchymal hyperintense structures, in this case, the internal cerebral vein)

Fig. 3

Pre-contrast (a–c) and post-contrast (d–f) T1-weighted images obtained from the same patient (subject A3) in the same MRI session. b and e show the white surface, which is the border between white and grey matter as automatically constructed by FreeSurfer (yellow). c and f show the pial surface, which is similarly the automatically constructed border between grey matter and cerebrospinal fluid (red), derived from the white surface. The figure demonstrates a typical failure of moderate degree, where the white surface fails to include parts of the temporal poles in the post-contrast image (e) (arrow), with subsequent mistakes in the pial surface (f) (arrowhead)

Fig. 4

Boxplots of MRI measurements obtained before (yellow) and after (red) GBCA administration, in mL (a, c, d) and mm (b)

Fig. 5

Scatterplots of global (a) and regional (b) MRI measurements obtained before and after GBCA administration. The green lines indicate identity lines

Fig. 6

Heatmaps demonstrating the difference (mm) in cortical thickness in the left (a) and right (b) hemisphere after administration of GBCAs. Brown colours indicate an increase in cortical thickness, and purple colours indicate a decrease in cortical thickness (colour range between -1.6 mm and + 1.6 mm cortical thickness difference). Letters in subject names indicate MRI scanner (a–g)