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The role of cerebellar damage in explaining disability and cognition in multiple sclerosis phenotypes: a multiparametric MRI study

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Abstract

Background

Cerebellar involvement is not comprehensively studied from an MRI point of view in multiple sclerosis (MS). We aimed to quantify cerebellar damage and identify predictors of physical disability and cognitive dysfunction in MS patients, and to characterize patients with cerebellar disability.

Methods

In this prospective study, 164 (89 relapsing–remitting and 75 progressive) MS patients and 53 healthy controls were enrolled. Subjects underwent 3T MRI with sequences for assessing lesions and atrophy in cerebellum, supratentorial brain, brainstem and cervical cord. Cerebellar peduncle diffusion-tensor metrics were also derived. Random forest models identified MRI predictors of Expanded Disability Status Scale (EDSS) score and cognition z-score. Hierarchical clustering was applied on MRI metrics in patients with cerebellar disability.

Results

In MS patients, predictors of higher EDSS score (out-of-bag-R2 = 0.83) were: lower cord grey matter (GM) and global areas, brain volume, GM volume (GMV), cortical GMV, cerebellum lobules I–IV and vermis GMV; and higher cord GM and brainstem lesion volume (LV). Predictors of lower cognition z-score (out-of-bag-R2 = 0.25) were: higher supratentorial and superior cerebellar peduncle LV; and lower brain, thalamus and basal ganglia volumes, GMV, cerebellum lobule VIIIb and Crus II GMV. In patients with cerebellar disability, we found three clusters with homogenous MRI metrics: patients with high brain lesion volumes (including cerebellar peduncles), those with marked cerebellum GM atrophy and patients with severe cord damage.

Conclusions

Damage to cerebellum GM and connecting structures has a relevant role in explaining cognitive dysfunction and physical disability in MS. Data-driven MRI clustering might improve our knowledge of MRI-clinical correlations.

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Abbreviations

MS:

Multiple sclerosis

RRMS:

Relapsing–remitting multiple sclerosis

PMS:

Progressive multiple sclerosis

HC:

Healthy controls

GM:

Grey matter

WM:

White matter

FA:

Fractional anisotropy

MD:

Mean diffusivity

DT:

Diffusion tensor

EDSS:

Expanded Disability Status Scale

EDSS-C:

EDSS cerebellar functional system score

BRB-N:

Brief Repeatable Battery of Neuropsychological tests

T2-LV:

T2-hyperintense lesion volume

pT2-LV:

Percentage T2-hyperintense lesion volume

NBV:

Normalized brain volume

GMV:

Grey matter volume

CSC:

Cervical spinal cord

SD:

Standard deviation

IQR:

Interquartile range

OOB:

Out-of-bag

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Funding

The study received no funding.

Author information

Authors and Affiliations

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

    Raffaello Bonacchi, Alessandro Meani, Elisabetta Pagani, Olga Marchesi, Massimo Filippi & Maria A. Rocca

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

    Raffaello Bonacchi, Massimo Filippi & Maria A. Rocca

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

    Massimo Filippi

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

    Massimo Filippi

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

    Massimo Filippi & Maria A. Rocca

Authors
  1. Raffaello Bonacchi
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  2. Alessandro Meani
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  3. Elisabetta Pagani
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  4. Olga Marchesi
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  5. Massimo Filippi
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  6. Maria A. Rocca
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Contributions

RB contributed to study concept, patient recruitment, MRI data analysis, drafting/revising the manuscript. AM contributed to statistical data analysis and drafting/revising the manuscript. EP contributed to the acquisition and analysis of MRI data and revising the manuscript. OM contributed to analysis of neuropsychological data and drafting/revising the manuscript. MF contributed to study concept, drafting/revising the manuscript and data verification. MAR contributed to study concept, patient recruitment, drafting/revising the manuscript, obtaining funding and data verification, acting as study supervisor. All the authors gave their approval to the current version of the manuscript.

Corresponding author

Correspondence to Maria A. Rocca.

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Conflicts of interest

R. Bonacchi, E. Pagani, and O. Marchesi have nothing to disclose. A. Meani received speaker honoraria from Biogen Idec. M. Filippi is Editor-in-Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services and/or speaking activities from Almiral, Alexion, 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). M.A. 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.

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Bonacchi, R., Meani, A., Pagani, E. et al. The role of cerebellar damage in explaining disability and cognition in multiple sclerosis phenotypes: a multiparametric MRI study. J Neurol 269, 3841–3857 (2022). https://doi.org/10.1007/s00415-022-11021-1

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  • DOI: https://doi.org/10.1007/s00415-022-11021-1

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