Objective To characterise in vivo the microstructural abnormalities of multiple sclerosis (MS) normal-appearing (NA) cortex and cortical lesions (CLs) and their relations with clinical phenotypes and disability using neurite orientation dispersion and density imaging (NODDI).
Methods One hundred and seventy-two patients with MS (101 relapsing–remitting multiple sclerosis (RRMS), 71 progressive multiple sclerosis (PMS)) and 62 healthy controls (HCs) underwent a brain 3T MRI. Brain cortex and CLs were segmented from three-dimensional T1-weighted and double inversion recovery sequences. Using NODDI on diffusion-weighted sequence, intracellular volume fraction (ICV_f) and Orientation Dispersion Index (ODI) were assessed in NA cortex and CLs with default or optimised parallel diffusivity for the cortex (D//=1.7 or 1.2 µm2/ms, respectively).
Results The NA cortex of patients with MS had significantly lower ICV_f versus HCs’ cortex with both D// values (false discovery rate (FDR)-p <0.001). CLs showed significantly decreased ICV_f and ODI versus NA cortex of both HCs and patients with MS with both D// values (FDR-p ≤0.008). Patients with PMS versus RRMS had significantly decreased NA cortex ICV_f and ODI (FDR-p=0.050 and FDR-p=0.032) with only D//=1.7 µm2/ms. No CL microstructural differences were found between MS clinical phenotypes. MS NA cortex ICV_f and ODI were significantly correlated with disease duration, clinical disability, lesion burden and global and regional brain atrophy (r from −0.51 to 0.71, FDR-p from <0.001 to 0.045).
Conclusions A significant neurite loss occurs in MS NA cortex. CLs show a further neurite density reduction and a reduced ODI suggesting a simplification of neurite complexity. NODDI is relevant to investigate in vivo the heterogeneous pathology affecting the MS cortex.
- multiple sclerosis
Data availability statement
Data are available upon reasonable request.
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Contributors PP: drafting/revising the manuscript, study concept, and acquisition, analysis and interpretation of the data. EP: drafting/revising the manuscript, analysis and interpretation of the data. RB: drafting/revising the manuscript, acquisition and interpretation of the data. LC: drafting/revising the manuscript, acquisition and interpretation of the data. AF: drafting/revising the manuscript, acquisition 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; he is responsible for the overall content as guarantor.
Funding PP has been supported by a senior research fellowship from Fondazione Italiana Sclerosi Multipla (cod. 2019/BS/009) and financed or cofinanced with the ‘five per mille’ public funding.
Competing interests Potential conflicts of interest outside the submitted work are as follows: PP received speaker honoraria from Biogen, Novartis, Merck Serono, Bristol Myers Squibb and ExceMED. EP received speaker honoraria from Biogen. RB and AF report no conflicts of interest. LC received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene and Sanofi. MAR received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche and Teva, and received research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. MF is editor-in-chief of the Journal of Neurology, associate editor of Human Brain Mapping, associate editor of Radiology and associate editor of Neurological Sciences; received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda and Teva Pharmaceutical Industries; and received 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).
Provenance and peer review Not commissioned; externally peer reviewed.
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