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NODDI, diffusion tensor microstructural abnormalities and atrophy of brain white matter and gray matter contribute to cognitive impairment in multiple sclerosis

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Abstract

Background

Pathologically specific MRI measures may elucidate in-vivo the heterogeneous processes contributing to cognitive impairment in multiple sclerosis (MS).

Purpose

Using diffusion tensor and neurite orientation dispersion and density imaging (NODDI), we explored the contribution of focal lesions and normal-appearing (NA) tissue microstructural abnormalities to cognitive impairment in MS.

Methods

One hundred and fifty-two MS patients underwent 3 T brain MRI and a neuropsychological evaluation. Forty-eight healthy controls (HC) were also scanned. Fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICV_f) and orientation dispersion index (ODI) were assessed in cortical and white matter (WM) lesions, thalamus, NA cortex and NAWM. Predictors of cognitive impairment were identified using random forest.

Results

Fifty-two MS patients were cognitively impaired. Compared to cognitively preserved, impaired MS patients had higher WM lesion volume (LV), lower normalized brain volume (NBV), cortical volume (NCV), thalamic volume (NTV), and WM volume (p ≤ 0.021). They also showed lower NAWM FA, higher NAWM, NA cortex and thalamic MD, lower NAWM ICV_f, lower WM lesion ODI, and higher NAWM ODI (false discovery rate-p ≤ 0.026). Cortical lesion number and microstructural abnormalities were not significantly different. The best MRI predictors of cognitive impairment (relative importance) (out-of-bag area under the curve = 0.727) were NAWM FA (100%), NTV (96.0%), NBV (84.7%), thalamic MD (43.4%), NCV (40.6%), NA cortex MD (26.0%), WM LV (23.2%) and WM lesion ODI (17.9%).

Conclusions

Our multiparametric MRI study including NODDI measures suggested that neuro-axonal damage and loss of microarchitecture integrity in focal WM lesions, NAWM, and GM contribute to cognitive impairment in MS.

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Data availability

The dataset used and analyzed during the current study is available from the corresponding Author on reasonable request.

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Funding

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

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Authors and Affiliations

  1. Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy

    Paolo Preziosa, Elisabetta Pagani, Alessandro Meani, Olga Marchesi, Lorenzo Conti, Maria A. Rocca & Massimo Filippi

  2. Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Paolo Preziosa, Maria A. Rocca & Massimo Filippi

  3. Neuroradiology Unit and CERMAC, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Andrea Falini

  4. Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

  5. Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

  6. Vita-Salute San Raffaele University, Milan, Italy

    Paolo Preziosa, Andrea Falini, Maria A. Rocca & Massimo Filippi

Authors
  1. Paolo Preziosa
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  2. Elisabetta Pagani
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  6. Andrea Falini
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  7. Maria A. Rocca
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Corresponding author

Correspondence to Massimo Filippi.

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Conflicts of interest

P. Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb and Genzyme. He has received research support from Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. E. Pagani, A. Meani, O. Marchesi, L. Conti, and A. Falini have nothing to disclose. M.A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Merck Healthcare Germany, Merck Serono SpA, Novartis, Roche, and Teva. She receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. M. Filippi M. 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 from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Ethical approval

Approval was received from the institutional ethical standards committee on human experimentation of IRCCS Ospedale San Raffaele for any experiments using human subjects (Protocol N° 2015–33). Written informed consent was obtained from all subjects prior to study participation according to the Declaration of Helsinki.

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Preziosa, P., Pagani, E., Meani, A. et al. NODDI, diffusion tensor microstructural abnormalities and atrophy of brain white matter and gray matter contribute to cognitive impairment in multiple sclerosis. J Neurol 270, 810–823 (2023). https://doi.org/10.1007/s00415-022-11415-1

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