Neurite density explains cortical T1-weighted/T2-weighted ratio in multiple sclerosis

The ratio between T1-weighted (T1w) and T2-weighted (T2w) sequences (T1w/T2w-ratio) has been proposed to enhance myelin sensitivity and specificity.1 However, studies assessing its histopathological substrates in multiple sclerosis (MS) found contradictory results. One study reported lower T1w/T2w-ratio in demyelinated versus normal-appearing cortex, but neurite density was not investigated.2 In another study, T1w/T2w-ratio correlated with dendrite but not myelin density; however, only normal-appearing cortex was evaluated.3 Both myelin and neurite density could influence T1w/T2w-ratio.4 Since T1w/T2w-ratio is derived from commonly acquired sequences and seems sensitive to cortical damage, its pathological validation is strongly needed before its wider application. In this post-mortem MRI/histopathology study, we evaluated normal-appearing and demyelinated cortices from non-neurological controls (nNC) and patients with MS (PwMS) to define whether myelin and/or neurite density were associated with T1w/T2w-ratio. ### Donors PwMS were collected by the Netherlands Brain Bank (http://www.brainbank.nl/), while nNC by the Normal Aging Brain Collection Amsterdam (http://nabca.eu/). ### MRI The following sequences were acquired during a 3T whole-brain in situ MRI scan: sagittal three-dimensional FLAIR; sagittal three-dimensional T1w fast spoiled gradient echo; axial T2w spin echo. See online supplemental methods for scan geometry. ### Supplementary data [jnnp-2020-324391supp001.pdf] White matter (WM) lesion volume (LV) was automatically quantified on FLAIR.5 T1w/T2w-ratio was obtained with an in-house pipeline adapted from Ganzetti et al 1 (online supplemental figure). Native three-dimensional T1w and T2w sequences underwent bias field correction (SPM12). Unbiased images were calibrated adjusting the intensity histograms using the lowest and highest intensity peaks derived from eye and temporal muscle masks on T1w and T2w images. T2w sequences were coregistered on T1w images and the T1w/T2w-ratio was calculated. From three-dimensional T1w images, grey matter (GM) and WM maps were created (SPM12). GM maps were thresholded at 0.5 to limit partial voluming and masked to include the cortex and remove cerebellum and basal ganglia. ### Histopathology After …