Francesca Rossi

Quality of life in multiple sclerosis: the impact of depression, fatigue and disability:

This study deals with the assessment of quality of life and its main clinical and demographical determinants in a clinical series of 103 patients with multiple sclerosis (MS) (37 men; 66 women; mean age 44.89 years; mean disease duration 12.40 years; mean EDSS score 4.07). We used the MSQOL-54 inventory, a disease-specific instrument recently validated in an Italian population. Each patient underwent a complete clinical assessment, including that of disability status (Expanded Disability Status Scale), cognitive function (Mini Mental State Examination), depression (Hamilton Rating Scale for Depression) and fatigue (Fatigue Severity Scale). In terms of Pearsons correlations, there was a moderate inverse relationship between disability level and the MSQOL-54 physical composite score, and a moderate to strong inverse correlation between depression or fatigue severity and both the physical and mental composite scores. In a stepwise linear regression analysis, depression, fatigue and disability level were confirmed to be significant and independent predictors of quality of life. Quality of life instruments can help to provide a broader measure of the disease impact and to develop a care program tailored to the patients needs.

Cognitive reserve and cortical atrophy in multiple sclerosis A longitudinal study

Objective: To test the cognitive reserve (CR) hypothesis in the model of multiple sclerosis (MS) by assessing the interactions among CR, brain atrophy, and cognitive efficiency in patients with relapsing-remitting MS. Methods: A Cognitive Reserve Index was calculated including education, premorbid leisure activities, and IQ. Brain atrophy was assessed through magnetic resonance quantitative parameters of normalized total brain volume and normalized cortical volume. Cognitive function was measured using Raos Brief Repeatable Battery. Results: Fifty-two patients with relapsing-remitting MS were evaluated at baseline and 35 of them were reassessed after a 1.6-year follow-up period. At baseline, higher CR predicted better performance on most of the Brief Repeatable Battery tests, independent of brain atrophy and clinical and demographic characteristics (p ≤ 0.021). An interaction between CRI and normalized cortical volume predicted better cognitive performance on tasks of verbal memory and attention/information processing speed (p < 0.005). However, at the follow-up examination, progressing cortical atrophy (β = 0.45; p = 0.008) and older age (β = −0.33; p = 0.044) were the only predictors of deteriorating cognitive performance. Conclusions: Our findings suggest that higher CR in individuals with MS may mediate between cognitive performance and brain pathology. CR-related compensation may, however, fail with progression of damage. The time window of opportunity for therapeutic approaches aimed at intellectual enhancement most likely lies in the earliest disease stages.

Relevance of Brain Lesion Location to Cognition in Relapsing Multiple Sclerosis

Objective To assess the relationship between cognition and brain white matter (WM) lesion distribution and frequency in patients with relapsing-remitting multiple sclerosis (RR MS). Methods MRI-based T2 lesion probability map (LPM) was used to assess the relevance of brain lesion location for cognitive impairment in a group of 142 consecutive patients with RRMS. Significance of voxelwise analyses was p<0.05, cluster-corrected for multiple comparisons. The Rao Brief Repeatable Battery was administered at the time of brain MRI to categorize the MS population into cognitively preserved (CP) and cognitively impaired (CI). Results Out of 142 RRMS, 106 were classified as CP and 36 as CI. Although the CI group had greater WM lesion volume than the CP group (pu200a=u200a0.001), T2 lesions tended to be less widespread across the WM. The peak of lesion frequency was almost twice higher in CI (61% in the forceps major) than in CP patients (37% in the posterior corona radiata). The voxelwise analysis confirmed that lesion frequency was higher in CI than in CP patients with significant bilateral clusters in the forceps major and in the splenium of the corpus callosum (p<0.05, corrected). Low scores of the Symbol Digit Modalities Test correlated with higher lesion frequency in these WM regions. Conclusions Overall these results suggest that in MS patients, areas relevant for cognition lie mostly in the commissural fiber tracts. This supports the notion of a functional (multiple) disconnection between grey matter structures, secondary to damage located in specific WM areas, as one of the most important mechanisms leading to cognitive impairment in MS.

Improving the Characterization of Radiologically Isolated Syndrome Suggestive of Multiple Sclerosis

Objective To improve the characterization of asymptomatic subjects with brain magnetic resonance imaging (MRI) abnormalities highly suggestive of multiple sclerosis (MS), a condition named as “radiologically isolated syndrome” (RIS). Methods Quantitative MRI metrics such as brain volumes and magnetization transfer (MT) were assessed in 19 subjects previously classified as RIS, 20 demographically-matched relapsing-remitting MS (RRMS) patients and 20 healthy controls (HC). Specific measures were: white matter (WM) lesion volumes (LV), total and regional brain volumes, and MT ratio (MTr) in lesions, normal-appearing WM (NAWM) and cortex. Results LV was similar in RIS and RRMS, without differences in distribution and frequency at lesion mapping. Brain volumes were similarly lower in RRMS and RIS than in HC (p<0.001). Lesional-MTr was lower in RRMS than in RIS (pu200a=u200a0.048); NAWM-MTr and cortical-MTr were similar in RIS and HC and lower (p<0.01) in RRMS. These values were particularly lower in RRMS than in RIS in the sensorimotor and memory networks. A multivariate logistic regression analysis showed that 13/19 RIS had ≥70% probability of being classified as RRMS on the basis of their brain volume and lesional-MTr values. Conclusions Macroscopic brain damage was similar in RIS and RRMS. However, the subtle tissue damage detected by MTr was milder in RIS than in RRMS in clinically relevant brain regions, suggesting an explanation for the lack of clinical manifestations of subjects with RIS. This new approach could be useful for narrowing down the RIS individuals with a high risk of progression to MS.

Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome

Background: The MRI incidental finding in asymptomatic subjects of brain white matter (WM) changes meeting the Barkhof criteria for the diagnosis of multiple sclerosis (MS) has been recently characterized as the radiologically isolated syndrome (RIS). This entity needs to be more specifically defined to allow risk stratification of these subjects. We used brain proton magnetic resonance spectroscopic imaging (1H-MRSI) to assess metabolic changes in an RIS population. Methods: Twenty-three RIS subjects who were classified according to the Okuda Criteria underwent 1H-MRSI examination with a central brain (CB) volume of interest (VOI) to measure levels of N-acetylaspartate (NAA) and choline (Cho) normalized to creatine (Cr) in the whole CB-VOI, in lesional/perilesional and normal-appearing WM regions, and in the cortical gray matter (CGM). The 1H-MRSI data were compared with those of 20 demographically matched healthy controls (HC). Results: NAA/Cr levels were significantly lower in RIS than in HC in all regions (p < 0.005 for all). No differences in Cho/Cr levels were found in either brain region. A single-subject analysis showed that NAA/Cr levels were at least 2 SDs below the HC mean in the 44% of RIS in the normal-appearing WM and in the 61% of RIS in the CGM. Conclusion: Decreased brain NAA/Cr levels in a group of RIS subjects indicates that brain metabolic abnormalities suggestive of axonal damage can be significant even at this early disease stage. This information could be useful for stratifying RIS individuals with a high risk of progression to MS.

Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing–remitting multiple sclerosis: a prospective, non‐randomized pilot study

The development of treatment strategies for cognitive impairment in multiple sclerosis (MS) is still in its infancy. The objective of this prospective, non‐randomized, pilot study was to assess the possible efficacy of treatment with natalizumab in comparison with interferon beta (IFNB) in a group of relapsing–remitting patients with MS.

Relevance of hypointense brain MRI lesions for long-term worsening of clinical disability in relapsing multiple sclerosis

Background: The accrual of brain focal pathology is considered a good substrate of disability in relapsing–remitting multiple sclerosis (RRMS). However, knowledge on long-term lesion evolution and its relationship with disability progression is poor. Objective: The objective of this paper is to evaluate in RRMS the long-term clinical relevance of brain lesion evolution. Methods: In 58 RRMS patients we acquired, using the same scanner and protocol, brain magnetic resonance imaging (MRI) at baseline and 10±0.5 years later. MRI data were correlated with disability changes as measured by the Expanded Disability Status Scale (EDSS). Results: The annualized 10-year lesion volume (LV) growth was +0.25±0.5 cm3 (+6.7±8.7%) for T2-weighted (T2-W) lesions and +0.20±0.31 cm3 (+11.5±12.3%) for T1-weighted (T1-W) lesions. The univariate analysis showed moderate correlations between baseline MRI measures and EDSS at 10 years (p < 0.001). Also, 10-year EDSS worsening correlated with LV growth and the number of new/enlarging lesions measured over the same period (p < 0.005). In the stepwise multiple regression analysis, EDSS worsening over 10 years was best correlated with the combination of baseline T1-W lesion count and increasing T1-W LV (R = 0.61, p < 0.001). Conclusion: In RRMS patients, long-term brain lesion accrual is associated with worsening in clinical disability. This is particularly true for hypointense, destructive lesions.

Automated identification of brain new lesions in multiple sclerosis using subtraction images.

To propose and evaluate a new automated method for the identification of new/enlarging multiple sclerosis (MS) lesions on subtracted images (SI). The subtraction of serially acquired images has shown great potential in assessing new/enlarging brain magnetic resonance imaging (MRI) lesions in MS patients. However, this approach relies on the manual definition of lesions, which is labor‐intensive and subject to operator‐dependent variability.

Appraisal of Brain Connectivity in Radiologically Isolated Syndrome by Modeling Imaging Measures

We hypothesized that appraisal of brain connectivity may shed light on the substrate of the radiologically isolated syndrome (RIS), a term applied to asymptomatic subjects with brain MRI abnormalities highly suggestive of multiple sclerosis. We thus used a multimodal MRI approach on the human brain by modeling measures of microstructural integrity of white matter (WM) tracts with those of functional connectivity (FC) at the level of resting state networks in RIS subjects, demographically matched normal controls (NC), and relapsing-remitting (RR) MS patients, also matched with RIS for brain macrostructural damage (i.e., lesions and atrophy). Compared with NC, in both RIS subjects and MS patients altered integrity of WM tracts was present. However, RIS subjects showed, at a less conservative threshold, lower diffusivities than RRMS patients in distinct cerebral associative, commissural, projection, and cerebellar WM tracts, suggesting a relatively better anatomical connectivity. FC was similar in NC and RIS subjects, even in the presence of important risk factors for MS (spinal cord lesions, oligoclonal bands, and dissemination in time on MRI) and increased in RRMS patients in two clinically relevant networks subserving “processing” (sensorimotor) and “control” (working memory) functions. In RIS, the lack of functional reorganization in key brain networks may represent a model of “functional reserve,” which may become upregulated, with an adaptive or maladaptive role, only at a later stage in case of occurrence of clinical deficit.

Pronounced structural and functional damage in early adult pediatric-onset multiple sclerosis with no or minimal clinical disability

Pediatric-onset multiple sclerosis (POMS) may represent a model of vulnerability to damage occurring during a period of active maturation of the human brain. Whereas adaptive mechanisms seem to take place in the POMS brain in the short-medium term, natural history studies have shown that these patients reach irreversible disability, despite slower progression, at a significantly younger age than adult-onset MS (AOMS) patients. We tested for the first time whether significant brain alterations already occurred in POMS patients in their early adulthood and with no or minimal disability (nu2009=u200915) in comparison with age- and disability-matched AOMS patients (nu2009=u200914) and to normal controls (NC, nu2009=u200920). We used a multimodal MRI approach by modeling, using FSL, voxelwise measures of microstructural integrity of white matter tracts and gray matter volumes with those of intra- and internetwork functional connectivity (FC) (analysis of variance, pu2009≤u20090.01, corrected for multiple comparisons across space). POMS patients showed, when compared with both NC and AOMS patients, altered measures of diffusion tensor imaging (reduced fractional anisotropy and/or increased diffusivities) and higher probability of lesion occurrence in a clinically eloquent region for physical disability such as the posterior corona radiata. In addition, POMS patients showed, compared with the other two groups, reduced long-range FC, assessed from resting functional MRI, between default mode network and secondary visual network, whose interaction subserves important cognitive functions such as spatial attention and visual learning. Overall, this pattern of structural damage and brain connectivity disruption in early adult POMS patients with no or minimal clinical disability might explain their unfavorable clinical outcome in the long term.