Mapping myelin in white matter with T1-weighted/T2-weighted maps: discrepancy with histology and other myelin MRI measures

Abstract

The ratio of T1-weighted/T2-weighted magnetic resonance images (T1w/T2w MRI) has been successfully applied at the cortical level since 2011 and is now one of the most used myelin mapping methods. However, no reports have explored the histological validity of T1w/T2w myelin mapping in white matter. Here we compare T1w/T2w with ex vivo postmortem histology and in vivo MRI methods, namely quantitative susceptibility mapping (QSM) and multi-echo T2 myelin water fraction (MWF) mapping techniques. We report a discrepancy between T1w/T2w myelin maps of the human corpus callosum and the histology and analyse the putative causes behind such discrepancy. T1w/T2w does not positively correlate with Luxol Fast Blue (LFB)-Optical Density but shows a weak to moderate, yet significant, negative correlation. On the contrary, MWF is strongly and positively correlated with LFB, whereas T1w/T2w and MWF maps are weakly negatively correlated. The discrepancy between T1w/T2w MRI maps, MWF and histological myelin maps suggests caution in using T1w/T2w as a white matter mapping method at the callosal level. While T1w/T2w imaging may correlate with myelin content at the cortical level, it is not a specific method to map myelin density in white matter.

Keywords: Corpus callosum; Myelin mapping; Myelin water fraction; Neuroanatomy; Neuroimaging; Quantitative susceptibility mapping; Validation.

Fig. 1

T1w/T2w myelin maps at cortical and callosal level. A T1w/T2w myelin maps at the cortical level of 57 healthy participants (aged 21–35) from the Human Connectome Project. T1w/T2w cortical maps show a gradient of T1w/T2w values from the primary motor (M1) and sensory areas (V1, S1, A1), which have higher values, to associative areas. This pattern is consistent with previous reports (Nieuwenhuys ; Van Essen and Glasser ; Nieuwenhuys et al. 2015). Colour scale: purple, low T1w/T2w values; red, high T1w/T2w values. B Left: averaged T1w/T2w maps of the whole brain of healthy participants from HCP (age 21–35, top) and HCP-Lifespan (age 45–75, bottom). The highest intensity signals are located in the red nuclei (RN) and globus pallidus (GP), while moderate and low intensities are in the dentate nucleus (DN) and claustrum (CL). Right: averaged T1w/T2w map of the corpus callosum of the same subjects. The colour-code map shows a heterogeneous distribution of T1w/T2w values in the different callosal subregions, with the highest T1w/T2w values in the rostrum/genu and slightly lower in the isthmus/splenium. Colour scale: purple, low T1w/T2w values; red, high T1w/T2w values

Fig. 2

Histology and ROI sampling. Left, top: one of the four post-mortem brain samples with the corpus callosum in situ. Left, bottom: template of the corpus callosum showing 92 circular regions of interest (ROIs) based on the anatomical subdivision proposed by Witelson (1989). Values were calculated inside the circular ROIs in the centre of each of the 92 squares of the callosal template and then extended to the square surrounding the circle. Centre: Luxol Fast Blue (LFB)-stained midsagittal sections (25 µm thick) of the corpora callosa of subjects 1, 2 and 3. Right: ROI-based, colour-coded maps of the myelin distribution of subjects 1, 2 and 3 along the midsagittal section of the corpus callosum assessed ex vivo via histological myelin staining. The histological myelin distribution pattern of the corpus callosum is different from the T1w/T2w pattern. All three LFB callosal samples have low myelin density in the anterior part (mainly rostrum/genu) and higher myelin density in the posterior part (mainly isthmus/splenium). Colour scale: purple, low values; red, high values

Fig. 3

Myelin mapping of the corpus callosum: LFB-stained midsagittal section of the corpus callosum of a 12-year-old female. Insets: LFB myelin staining at higher magnification shows lower intensity in the anterior corpus callosum (rostrum/genu, left inset) and higher intensity in the posterior part (isthmus, right inset)

Fig. 4

QSM and MWF cortical and myelin mapping. Left, top: average quantitative susceptibility maps (QSM) illustrating iron distribution in the whole brain in 12 healthy subjects (70 ± 5-year-old, 6 females). Higher intensities are localised in the red nuclei (RN) and globus pallidus (GP) as in the T1w/T2w maps. The high QSM intensity in the dentate nucleus (DN) and claustrum (CL) is not matched in the T1w/T2w maps represented in Fig. 1. Left, bottom: Myelin Water Fraction (MWF) maps from (Liu et al. 2019) averaged MWF atlas. Right: averaged QSM and MWF maps of the corpus callosum show different intensity patterns from anterior to posterior regions

Fig. 5

To quantitatively evaluate the correlation between T1w/T2w, MWF and histology, MRI maps were sampled using the same 92-ROI sampling scheme used for histology and correlated with the corresponding average LFB-OD values. Data is displayed on arbitrary units (from 1 to 7) for all methods. A T1w/T2w does not positively correlate with the LFB-Optical Density analysis but, instead, has a significant negative correlation (r² = 0.21 p < 0.001). B MWF presents a strong and significant positive correlation with LFB (r² = 0.52, p < 0.001), suggesting a good agreement between the two modalities. C T1w/T2w and MWF maps do not correlate positively, as they are characterised by a weak negative correlation (r² = 0.13, p < 0.001)