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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.
PwMS were collected by the Netherlands Brain Bank (http://www.brainbank.nl/), while nNC by the Normal Aging Brain Collection Amsterdam (http://nabca.eu/).
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.
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 al1 (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.
Contributors PP: drafting/revising the manuscript, study concept, and acquisition, analysis and interpretation of the data. PMB: drafting/revising the manuscript, study concept, and acquisition and interpretation of the data. SK: drafting/revising the manuscript, and acquisition and interpretation of the data. MDS: drafting/revising the manuscript, and acquisition and interpretation of the data. AM: analysis and interpretation of the data. PJP: drafting/revising the manuscript, and interpretation of the data. MAR: drafting/revising the manuscript, study concept, interpretation of the data and study supervisor. MF: drafting/revising the manuscript, study concept, interpretation of the data and study supervisor. JJGG: drafting/revising the manuscript, study concept, interpretation of the data and study supervisor. LEJ: drafting/revising the manuscript, study concept, acquisition and interpretation of the data and study supervisor.
Funding We thank the VU University MS Centre and the Dutch MS Research Society for their financial support (grant 14-358e MS).
Competing interests PP received speakers honoraria from Biogen Idec, Novartis, Merck-Serono and ExceMED. PMB received research support from the Dutch MS Foundation, grant number 19-1049. SK, MDS, AM and PJP have nothing to disclose. MAR received speakers honoraria from Biogen Idec, Novartis, Genzyme, Teva, Merck Serono, Roche, Celgene and Bayer and receives research support from the Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. MF is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). JJGG reports grants from Biogen, grants from Novartis, grants from Sanofi Genzyme and he is Editor for Europe of Multiple Sclerosis Journal. LEJ reports grants from Alzheimer’s Association and Michael J Fox foundation.
Patient consent for publication Not required.
Ethics approval Institutional review board approval and written informed consent were obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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