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Multiple sclerosis and cognition: synaptic failure and network dysfunction

Abstract

Cognitive impairment is increasingly recognized to be a core feature of multiple sclerosis (MS), with important implications for the everyday life of individuals with MS and for disease management. Unfortunately, the exact mechanisms that underlie this cognitive impairment are poorly understood and there are no effective therapeutic options for this aspect of the disease. During MS, focal brain inflammatory lesions, together with pathological changes of both CNS grey matter and normal-appearing white matter, can interfere with cognitive functions. Moreover, inflammation may alter the crosstalk between the immune and the nervous systems, modulating the induction of synaptic plasticity and neurotransmission. In this Review, we examine the CNS structures and cognitive domains that are affected by the disease, with a specific focus on hippocampal involvement in MS and experimental autoimmune encephalomyelitis, an experimental model of MS. We also discuss the hypothesis that, during MS, immune-mediated alterations of synapses’ ability to express long-term plastic changes may contribute to the pathogenesis of cognitive impairment by interfering with the dynamics of neuronal networks.

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Fig. 1: Putative mechanisms underlying cognitive impairment in multiple sclerosis.
Fig. 2: Physiological synaptic plasticity and its disruption during neuroinflammation.

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Acknowledgements

M.D.F. and P.C. received funding from Fondazione Italiana Sclerosi Multipla (FISM; project codes 2010/R/10, 2011/R/10 and 2013/R/12). M.D.F. also received support from the Ministero della Salute — Ricerca Finalizzata — Bando Giovani Ricercatori (project code GR-2010-2312924).

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Nature Reviews Neuroscience thanks M. Friese, D. Langdon and B. Weinstock-Guttman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors all researched data for the article, provided substantial contributions to discussion of content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Massimiliano Di Filippo.

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M.D.F. participated on advisory boards for and received speaker or writing honoraria and funding for travelling from Bayer, Biogen Idec, Genzyme, Merck, Novartis, Roche and Teva. E.P. served on scientific advisory boards for Biogen Idec and Merck Serono, received honoraria for speaking and funding for travelling from Biogen, Genzyme, Novartis, Merck and Teva and received research support from Merck Serono. A.M. declares no competing interests. P.C. participated on advisory boards for and received funding for travelling, speaker honoraria and research support from AbbVie, Biogen Idec, Merck, Genzyme, Novartis, Prexton, Teva, UCB and Zambon.

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Glossary

Radiologically isolated syndrome

(RIS). A condition that is characterized by the incidental MRI finding of brain white matter lesions that are highly suggestive of MS and are not explained by another disease process in people without historical accounts of typical MS symptoms. RIS is not considered an MS subtype per se, but patients with RIS can show MRI signs of radiological progression and/or neurological MS symptoms during follow-up.

Clinically isolated syndrome

(CIS). A first clinical episode with features suggestive of MS. It usually occurs in young adults with signs suggesting a lesion in the optic nerve, spinal cord, brainstem or cerebellum or, more rarely, a cerebral hemisphere. CIS develops acutely or subacutely, it lasts more than 24 hours, with or without recovery, and is often the first manifestation of MS.

Expanded Disability Status Scale

(EDSS). A clinical scale aimed at quantifying the neurological disability of patients with MS. The disability score ranges from 0 (normal) to 10 (death due to MS) in half-point increments. The scale measures disability accrual due to MS and takes into account a wide range of neurological functions, particularly ambulation–lower limb function.

T2-weighted images

Specific conventional MRI sequences widely applied to detect MS lesions. Acute and chronic MS lesions appear on T2-weighted images as areas of high signal intensity compared with the adjacent normal regions.

Contrast-enhancing lesions

Intravenously administered contrast agents, such as gadolinium, accumulate in brain regions where the blood–brain barrier is damaged, an early pathological event in inflammatory MS lesions. The presence of a new inflammatory lesion or the recurrence of inflammation in a pre-existing lesion is thus visualized as areas of enhancement on specific MRI images (postcontrast T1-weighted sequences).

Paced Auditory Serial Addition Test

(PASAT). A neuropsychological test developed to assess IPS. Administration of the test involves the oral presentation of a series of single-digit numbers (either every 3 or 2 seconds) in which the two most recent digits must be summed. It is now recognized that other cognitive domains can contribute to PASAT performance, including attention and working memory.

Symbol Digit Modalities Test

(SDMT). A neuropsychological test designed to assess IPS and sustained attention. During the test, the individual is required to rapidly associate symbols and numbers, and the score depends on the number of correct associations performed in a limited time. Other functions (such as learning and visual performance) can influence the execution of the SDMT.

Long-term potentiation

(LTP). LTP is the best-known form of synaptic plasticity, it is expressed by excitatory synapses throughout the brain and it manifests as a persistent increase in the size of the synaptic component of the evoked response following repeated synaptic activation. It represents a compelling cellular model for learning and memory.

Long-term depression

(LTD). The other major form of long-lasting synaptic plasticity in the mammalian brain, characterized by a long-lasting decrease in synaptic strength. Converging evidence supports a key role of LTD in some learning and memory processes.

Homing

The recruitment of circulating immune cells to a specific tissue.

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Di Filippo, M., Portaccio, E., Mancini, A. et al. Multiple sclerosis and cognition: synaptic failure and network dysfunction. Nat Rev Neurosci 19, 599–609 (2018). https://doi.org/10.1038/s41583-018-0053-9

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