Disentangling the molecular mechanisms of multiple sclerosis: The contribution of twin studies.

Twin studies of disease concordance are useful to weight the relative contribution of genetic and environmental factors to the cause of common complex disorders. In multiple sclerosis (MS) different twinning rates from geographic areas at different prevalence suggested that heritable and non-heritable factors contribute in different proportions and ways to MS risk in diverse populations. This concept prompted genome-wide association studies, and the implementation of the co-twin control design, that allows stringent experimental approaches in MS-discordant identical pairs, controlling for genetic influences and many other known and unknown factors. The co-twin control design provided important clues on MS molecular model. These studies will be reviewed, focusing on those showing significant differences between affected and healthy co-twins. In some cases, differences that emerged in non-twin patients compared to matched controls were not confirmed in identical MS-discordant pairs, suggesting an 'MS subclinical trait'. Early patterns of magnetic resonance imaging and predictive biomarkers that characterize 'healthy' co-twins may be useful for the identification of a prodromal reversible phase of the disease.

Intestinal Permeability in Relapsing-Remitting Multiple Sclerosis.

Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care.

Neuropsychological predictors of rapidly progressive Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), the most common cause of dementia, typically shows a slow clinical progression over time. 'Rapidly progressive' AD, a variant of the disease characterized by an aggressive course, exhibits distinct clinical, biological, and neuropathological features. Here, we investigate neuropsychological predictors of rapid decline in a group of mild patients with AD. METHODS: One hundred fifty-three mild patients with AD admitted to a memory disorder clinic and followed for up to 3 years were included in this study. A comprehensive neuropsychological (NP) battery was performed at the time of enrollment. Patients were defined as 'rapidly progressive' if they exhibited a drop of 6 or more points on the Mini Mental State Examination (MMSE) between two consecutive annual visits. This event defined the main outcome in multiple analyses of variance and Cox proportional hazards models that investigated the impact of NP predictors. Categorical principal component analysis (CATPCA) was also employed in order to delineate clusters of NP tests and to test their effect on the outcome. RESULTS: Of 153 subjects, thirty-seven (24%) were classified as 'rapidly progressive'; those subjects showed younger age of symptoms onset compared to slow decliners (68 vs 71.5 years old). Baseline lower performance on a neuropsychological test of naming predicted a rapid decline over the follow-up (P = 0.001). Three clusters of NP were defined by CATPCA: (i) executive/language, (ii) visuospatial memory, and (iii) verbal memory. The executive/language component predicted a rapid decline over the follow-up (P = 0.016). CONCLUSION: Early executive/language impairment is highly predictive of a rapid progression of AD.