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Functional and structural brain MRI changes associated with cognitive worsening in multiple sclerosis: a 3-year longitudinal study

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Abstract

Background

Heterogeneous processes may contribute to cognitive impairment in multiple sclerosis (MS).

Objective

To apply a longitudinal multiparametric MRI approach to identify mechanisms associated with cognitive worsening in MS patients.

Methods

3 T brain functional and structural MRI scans were acquired at baseline and after a median follow-up of 3.4 years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening (reliable change index score < − 1.25 at the Rao’s battery) and longitudinal changes in regional T2-hyperintense white matter (WM) lesions, diffusion tensor microstructural WM damage, gray matter (GM) atrophy and resting state (RS) functional connectivity (FC) were explored.

Results

At follow-up, HC showed no clusters of significant microstructural WM damage progression, GM atrophy or changes in RS FC. At follow-up, 10 MS patients (29%) showed cognitive worsening. Compared to cognitively stable, cognitively worsened MS patients showed more severe GM atrophy of the right anterior cingulate cortex and bilateral supplementary motor area (p < 0.001). Cognitively worsened vs cognitively stable MS patients showed also decreased RS FC in the right hippocampus of the right working memory network and in the right insula of the default mode network. Increased RS FC in the left insula of the executive control network was found in the opposite comparison (p < 0.001). No significant regional accumulation of focal WM lesions nor microstructural WM abnormalities occurred in both patients’ groups.

Conclusions

GM atrophy progression in cognitively relevant brain regions combined with functional impoverishment in networks involved in cognitive functions may represent the substrates underlying cognitive worsening 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

No funding was received for conducting this study.

Author information

Authors and Affiliations

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

    Matteo Azzimonti, Paolo Preziosa, Elisabetta Pagani, Paola Valsasina, Nicolò Tedone, Carmen Vizzino, Maria A. Rocca & Massimo Filippi

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

    Matteo Azzimonti, Paolo Preziosa, Maria A. Rocca & Massimo Filippi

  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

    Paolo Preziosa, Maria A. Rocca & Massimo Filippi

Authors
  1. Matteo Azzimonti
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  2. Paolo Preziosa
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  3. Elisabetta Pagani
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  4. Paola Valsasina
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  5. Nicolò Tedone
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  6. Carmen Vizzino
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  7. Maria A. Rocca
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  8. Massimo Filippi
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Corresponding author

Correspondence to Massimo Filippi.

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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° 2009-74). Written informed consent was obtained from all subjects prior to study participation according to the Declaration of Helsinki.

Conflicts of interest

Matteo Azzimonti has nothing to disclose. Paolo Preziosa received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb and Genzyme; he has received research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. Elisabetta Pagani received speaker honoraria from Biogen Idec. Paola Valsasina received speaker honoraria from Biogen Idec. Nicolò Tedone has nothing to disclose. Carmen Vizzino has nothing to disclose. Maria A. Rocca received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. Massimo Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Map**, Neurological Sciences, and Radiology; 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, and Fondazione Italiana Sclerosi Multipla.

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Azzimonti, M., Preziosa, P., Pagani, E. et al. Functional and structural brain MRI changes associated with cognitive worsening in multiple sclerosis: a 3-year longitudinal study. J Neurol 270, 4296–4308 (2023). https://doi.org/10.1007/s00415-023-11778-z

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