Relevance of Neurite Orientation and Dispersion Density Imaging to Characterise Microstructural Abnormalities of Multiple Sclerosis Cortex and Cortical Lesions In Vivo: A 3T Study - European Medical Journal

Relevance of Neurite Orientation and Dispersion Density Imaging to Characterise Microstructural Abnormalities of Multiple Sclerosis Cortex and Cortical Lesions In Vivo: A 3T Study

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EMJ Neurology 9.1 2021 Feature Image
Paolo Preziosa,1,2 Elisabetta Pagani,1 Raffaello Bonacchi,1,2 Laura Cacciaguerra,1,2,3 Andrea Falini,3,4 *Massimo Filippi,1-3, 5, 6 Maria A. Rocca1,2,3

Preziosa received speaker honoraria from Biogen Idec, Novartis, Bristol Myers Squibb, Genzyme, and Excemed; was supported by a senior research fellowship (FISM2019/BS/009); and financed or co-financed with the ‘5 per mille’ public funding between 1st March 2020 and 15th June 2021. Cacciaguerra received speaker and consultant honoraria from ACCMED, Roche, BMS Celgene, and Sanofi. Filippi 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 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). Rocca received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva; and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Pagani, Bonacchi, and Falini have declared no conflicts of interest.


The authors would like to thank Associazione Amici del Centro Dino Ferrari for its support.


This study was supported by the Fondazione Italiana Sclerosi Multipla with a senior research fellowship (FISM2019/BS/009), a research grant from (FISM2018/R/16), and financed or co-financed with the ‘5 per mille’ public funding.

EMJ Neurol. ;9[1]:41-43. Abstract Review No. AR4.
Cortex, cortical lesions, grey matter, MRI, multiple sclerosis (MS), neurodegeneration, neurite orientation and dispersion density imaging (NODDI).

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.


Pathology has shown that cortical abnormalities are extensive in multiple sclerosis (MS),1 whereas recent MRI studies have demonstrated that cortical damage is one of the best predictors of clinical disability and cognitive impairment in these patients.1,2 The definition of MRI measures more specifically the pathological processes affecting MS cortex might improve our understanding of the relationship between structural damage and disease clinical manifestations, thus providing novel outcome measures for monitoring MS. Neurite orientation dispersion and density imaging (NODDI) is a promising multi-compartment diffusion model to better evaluate the complexity of brain neuroanatomical microarchitecture.3 The NODDI model allows the evaluation of quantitative measures including the intracellular volume fraction (considered a measure of neurite volume), the extracellular volume fraction (representing the extracellular space), and orientation dispersion index (reflecting neurite orientation variability).3

At present, the investigation of normal-appearing grey matter abnormalities in MS using NODDI has provided conflicting and inconclusive findings.4-9 Accordingly, the application of NODDI in larger cohorts of patients with MS is necessary to provide more consistent pieces of information to better typify cortical damage in MS in vivo and to demonstrate the clinical relevance of NODDI measures.

In this study, the authors used NODDI to characterise the microstructural abnormalities of normal-appearing cortex and cortical lesions and their relations with disease phenotypes and clinical disability in a relatively large cohort of patients with MS.


One hundred and seventy-two patients with MS (101 relapsing-remitting and 71 progressive) and 62 healthy controls underwent a brain 3T acquisition. Brain cortex and cortical lesions were segmented from 3D T1-weighted and double inversion recovery, respectively. Using NODDI, on diffusion-weighted sequence, intracellular volume fraction, extracellular volume fraction, and orientation dispersion index were assessed in normal-appearing cortex and cortical lesions.


The authors found that 117 out of 172 (68%) patients with MS had at least one cortical lesion. Patients with MS with normal-appearing cortex had significantly lower intracellular volume fraction versus the healthy controls’ cortex (false discovery rate [FDR]: p<0.001). Cortical lesions showed significantly increased extracellular volume fractions (FDR: p<0.001) and decreased intracellular volume fraction and orientation dispersion index versus a normal-appearing cortex of both healthy controls and patients with MS (FDR: p≤0.008). Compared with relapsing-remitting, patients with progressive MS had a significantly decreased normal-appearing cortex intracellular volume fraction and orientation dispersion index (FDR: p=0.049 and FDR: p=0.033, respectively). No cortical lesion microstructural differences were found between progressive and relapsing-remitting patients with MS. Multiple sclerosis normal-appearing cortex intracellular volume fraction, extracellular volume fractions, and orientation dispersion index were significantly correlated with disease duration, clinical disability, white matter and cortical lesion burden, and brain, grey matter, and cortical volumes (from -0.51 to 0.71; FDR: from p<0.001 to 0.049).


The authors’ study suggested that a significant neurite loss occurs in multiple sclerosis normal-appearing cortex. Cortical lesions show a further neurite density reduction, an increased extracellular space, possibly reflecting inflammation and cellular loss, and a reduced orientation dispersion index suggesting a simplification of neurites complexity. NODDI is relevant to investigate in vivo the heterogeneous pathology affecting multiple sclerosis cortex.

Figure 1: Comparing healthy control groups to patients with multiple sclerosis.
CL: cortical lesion; FDR: false discovery rate; HC: healthy control; MS: multiple sclerosis; NA: normal-appearing; NODDI: neurite dispersion and density imaging; PMS: progressive multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis.

Filippi M et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 2019;18(2):198-210. Filippi M et al. Diagnosis of progressive multiple sclerosis from the imaging perspective: a review. JAMA Neurol. 2021;78(3):351-64. Zhang H et al. NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage. 2012;61(4):1000-16. De Santis S et al. Characterizing microstructural tissue properties in multiple sclerosis with diffusion MRI at 7T and 3T: the impact of the experimental design. Neuroscience. 2019;403:17-26. Spano B et al. Disruption of neurite morphology parallels MS progression. Neurol Neuroimmunol Neuroinflamm. 2018;5(6):e502. Granberg T et al. In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis. Brain. 2017;140(11):2912-26. Rahmanzadeh R et al. Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging. Brain. 2021;DOI:10.1093/brain/awab088. Collorone S et al. Brain microstructural and metabolic alterations detected in vivo at onset of the first demyelinating event. Brain. 2021;144(5):1409-21. Collorone S et al. Reduced neurite density in the brain and cervical spinal cord in relapsing-remitting multiple sclerosis: a NODDI study. Mult Scler. 2020;26(13):1647-57.

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