Background

Cortical damage is clinically relevant in multiple sclerosis (MS), however reliable MRI markers for its monitoring are still an unmet need. Ratio of T1-weighted (T1w) and T2-weighted (T2w) sequences (i.e., T1w/T2w-ratio) has been suggested as a feasible MRI measure to assess cortical abnormalities in patients with MS (PwMS), but its histopathological substrate has yet to be definitively elucidated.

Objectives

To define the histopathological substrate of T1w/T2w-ratio in normal-appearing and demyelinated cortices of PwMS by performing a combined post-mortem MRI/histopathology study.

Methods

Fifteen PwMS and ten age- and sex-matched non-neurological controls (nNC) underwent post-mortem in situ 3T MRI with 3D T1w and T2w sequences, followed by brain dissection.

One hundred and five paraffin embedded tissue blocks (49 from PwMS, 56 from nNC) were collected. Tissue regions were matched to T1w/T2w-ratio maps to obtain regional cortical T1w/T2w-ratio. Using immunohistochemistry and silver staining, cortical density of myelin, microglia, neurons, glial cells and neurites were evaluated. Correlates of T1w/T2w-ratio alterations with histological markers were assessed through linear mixed-effects models.

Results

Twenty-six cortical lesions (85% subpial) were found in 24/49 (51%) cortical regions from PwMS. Compared to nNC’s cortex, both PwMS’ normal-appearing and demyelinated cortices had a significantly lower T1w/T2w-ratio (p=0.045 and 0.001). In PwMS, demyelinated cortex showed a significant lower T1w/T2w-ratio compared to normal-appearing cortex (p=0.007). In PwMS, neurite density was significantly lower in both normal-appearing and demyelinated cortices compared to nNC (p=0.041 and 0.001), and in demyelinated vs. normal-appearing cortex (p=0.048). Demyelinated cortex showed also significant lower myelin density compared to normal-appearing cortex in both nNC and PwMS (p<0.001). Regarding the pathological substrate, T1w/T2w-ratio was positively associated with neurite density (β=3.464×10^-2, p=0.004), whereas only a trend for myelin density was found (p=0.082).

Conclusions

Both demyelination and neurite loss were found in the cortex of PwMS. By evaluating several histopathological markers in nNC and PwMS (in normal-appearing and demyelinated cortices), T1w/T2w-ratio was found to be sensitive to MS cortical damage and more specific to neurite than myelin density. T1w/T2w-ratio could be useful to investigate cortical damage in MS.