Cognitive impairment in multiple sclerosis: from phenomenology to neurobiological mechanisms

Multiple sclerosis (MS) is an autoimmune-mediated disease of the central nervous system characterized by inflammation, demyelination and chronic progressive neurodegeneration. Among its broad and unpredictable range of clinical symptoms, cognitive impairment (CI) is a common and disabling feature greatly affecting the patients' quality of life. Its prevalence is 20% up to 88% with a wide variety depending on the phenotype of MS, with highest frequency and severity in primary progressive MS. Involving different cognitive domains, CI is often associated with depression and other neuropsychiatric symptoms, but usually not correlated with motor and other deficits, suggesting different pathophysiological mechanisms. While no specific neuropathological data for CI in MS are available, modern research has provided evidence that it arises from the disease-specific brain alterations. Multimodal neuroimaging, besides structural changes of cortical and deep subcortical gray and white matter, exhibited dysfunction of fronto-parietal, thalamo-hippocampal, default mode and cognition-related networks, disruption of inter-network connections and involvement of the γ-aminobutyric acid (GABA) system. This provided a conceptual framework to explain how aberrant pathophysiological processes, including oxidative stress, mitochondrial dysfunction, autoimmune reactions and disruption of essential signaling pathways predict/cause specific disorders of cognition. CI in MS is related to multi-regional patterns of cerebral disturbances, although its complex pathogenic mechanisms await further elucidation. This article, based on systematic analysis of PubMed, Google Scholar and Cochrane Library, reviews current epidemiological, clinical, neuroimaging and pathogenetic evidence that could aid early identification of CI in MS and inform about new therapeutic targets and strategies.