Sónia Batista

Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis

Information-processing speed (IPS) slowing is a primary cognitive deficit in multiple sclerosis (MS). Basal ganglia, thalamus and neocortex are thought to have a key role for efficient information-processing, yet the specific relative contribution of these structures for MS-related IPS impairment is poorly understood. To determine if basal ganglia and thalamus atrophy independently contribute to visual and auditory IPS impairment in MS, after controlling for the influence of neocortical volume, we enrolled 86 consecutive MS patients and 25 normal controls undergoing 3T brain MRI and neuropsychological testing. Using Sienax and FIRST software, neocortical and deep gray matter (DGM) volumes were calculated. Neuropsychological testing contributed measures of auditory and visual IPS using the Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT), respectively. MS patients exhibited significantly slower IPS relative to controls and showed reduction in neocortex, caudate, putamen, globus pallidus, thalamus and nucleus accumbens volume. SDMT and PASAT were significantly correlated with all DGM regions. These effects were mitigated by controlling for the effects of neocortical volume, but all DGM volumes remained significantly correlated with SDMT, putamen (rxa0=xa00.409, pxa0<xa00.001) and thalamus (rxa0=xa00.362, pxa0<xa00.001) having the strongest effects, whereas for PASAT, the correlation was significant for putamen (rxa0=xa00.313, pxa0<xa00.01) but not for thalamus. We confirm the significant role of thalamus atrophy in MS-related IPS slowing and find that putamen atrophy is also a significant contributor to this disorder. These DGM structures have independent, significant roles, after controlling for the influence of neocortex atrophy.

Impairment of social cognition in multiple sclerosis: Amygdala atrophy is the main predictor

Background: Patients with multiple sclerosis (MS) frequently reveal social behavior disturbance. Nevertheless, little is known regarding the impact of MS on social cognition, particularly theory of mind (ToM), and its neural basis. Objectives: To explore how ToM is affected in MS and its neural correlates. Methods: Enrolled 60 consecutive MS patients and 60 healthy controls (HC) matched on age, sex, and education. Participants underwent ToM testing (Eyes Test, Videos Test) and 3u2009T brain magnetic resonance imaging (MRI). Using Freesurfer software, cortical and subcortical gray matter (GM) volumes were calculated. Results: MS patients performed worse on Eyes Test (58.7%u2009±u200913.8% vs 81.9%u2009±u200910.4%, pu2009<u20090.001) and Videos Test (75.3%u2009±u20099.3% vs 88.1%u2009±u20097.1%, pu2009<u20090.001). Eyes Test performance in MS was positively correlated with the volume of subcortical structures (amygdala, putamen) and cortical regions (entorhinal cortex, fusiform gyrus, superior temporal gyrus, superior parietal gyrus, supramarginal gyrus, medial orbitofrontal cortex, anterior and posterior cingulate gyrus). In regression analysis, amygdala volume was the single predictor of performance (R2 changeu2009=u20090.064, pu2009=u20090.031), and a mediation analysis indicated that it contributes for the differences observed between MS and HC. Conclusion: Patients with MS have impairment on social cognition. Amygdala atrophy was the main predictor probably due to its central position within the “social brain” network.

Clinical predictors of an optimal response to natalizumab in multiple sclerosis

Despite the high level of effectiveness of natalizumab (NTZ) in the treatment of patients with multiple sclerosis (MS), concerns about its high direct cost and its safety have restricted its use. Our aim was to identify and quantify the clinical factors that predict an optimal response to NTZ. Patients with MS undergoing treatment with NTZ for at least 12 months were classified as optimal responders if, during treatment, they sustained a reduction in their Kurtzke Expanded Disability Status Scale (EDSS) score of 1 point or more or experienced a reduction in annualised relapse rate (ARR) of more than 1. The remaining patients were classified as suboptimal responders and non-responders. Our subject pool included 48 patients. The variables associated with optimal response included: ARR in the previous year of at least 2, an age at first administration of 37.5 years or less, a baseline EDSS score of 4.5 points or less, a disease duration of 9.5 years or less and, in patients with secondary-progressive MS, a progressive-phase duration of 4.5 years or less. The characteristics of the disease at its onset did not affect responsiveness, indicating that patients with highly active disease and low disability are the ideal candidates for NTZ treatment, regardless of previous clinical characteristics.

Anti-JCV antibody serostatus and longitudinal evaluation in a Portuguese Multiple Sclerosis population

Multiple Sclerosis (MS) treatment with natalizumab is associated with Progressive Multifocal Leukoencephalopathy (PML). The risk of PML being related to the anti-JCV antibody index is well established, but there is less known about seroconversion rates in natalizumab-treated patients and longitudinal variation in the anti-JCV antibody index. Our objective was to assess anti-JCV antibody prevalence in an MS population and to evaluate the evolution of the anti-JCV antibody index in natalizumab-treated patients. To assess anti-JCV antibody prevalence, we included all patients who had the anti-JCV antibody test in our consultation, regardless of the treatment. To evaluate the evolution of the anti-JCV antibody index and seroconversion, only natalizumab-treated patients with at least two samples were selected. Demographic characteristics were evaluated. From a total of 371 patients included, 68.19% (n=253) were seropositive for anti-JCV antibodies (JCV+). There was a significant difference in anti-JCV antibody seropositivity concerning gender (male 76.27% vs. female 64.43%, p=0.023), but not age. To evaluate seroconversion, 85 patients who were initially seronegative (JCV-) were selected. The annual rate of seroconversion in the first two years was stable, but after that there was a significant increase with treatment duration (ρ=0.90, p=0.037): in the first year it was 5.88% (n=5/85); in the second, 5.71% (n=4/70); in the third, 6.82% (n=3/44); in the fourth, 10.34% (n=3/29); and in the fifth, 15.0% (n=3/20). The mean index variability was higher in patients who experienced seroconversion (1.16±0.97), followed by JCV+ patients (0.44±0.48), compared to JCV- patients (0.08±0.05). In conclusion, anti-JCV antibody prevalence in our population is comparable to other reported cohorts. The seroconversion rate increased with treatment duration. We found a high fluctuation in the antibody index in JCV+ patients.

Apathy in multiple sclerosis: gender matters

Apathy has been recognized as a frequent symptom in multiple sclerosis (MS) but uncertainty remains about its prevalence and clinical correlates. Therefore, the objective of this work was to assess the prevalence of apathy in patients with MS and to identify clinical and demographic correlates. A case-control study with 30 patients and 30 healthy controls matched for age, gender and education was performed. Apathy diagnosis was established using Robert et al.s criteria. Additionally, apathy was assessed using the 10-item short version of the clinical-rated Apathy Evaluation Scale (AES-C-10). The Beck Depression Inventory (BDI), Modified Fatigue Impact Scale (MFIS), and Montreal Cognitive Assessment (MoCA) were used to evaluate depression, fatigue and cognitive impairment, respectively. Apathy prevalence in MS patients was 43.3%. Patients with MS had higher AES-C-10 scores than controls (13.9 vs. 12.0, p=0.015). Patients with apathy presented a higher proportion of males (53.8% vs. 11.8%, p=0.02), lower educational level (53.8% vs. 11.8% of patients with up to 9years of education), higher scores on cognitive dimension of MFIS (18.0 vs. 8.0, p=0.048) and BDI (13.0 vs. 7.0, p=0.035) and worse performance on MoCA (24.0 vs. 26.0, p=0.028). Gender was the only independent predictor of apathy, with men presenting a higher risk compared to women (OR: 9.62; 95%CI: 1.02-90.61; p=0.048). In conclusion, apathy is a common neuropsychiatric disorder in MS and it is probably underdiagnosed. Male patients seem to have an increased risk of apathy, and this finding may be related to the generally more unfavorable course of MS in men.

Multiple sclerosis: Association of gelatinase B/matrix metalloproteinase-9 with risk and clinical course the disease

BACKGROUNDnMultiple sclerosis (MS) is an autoimmune disease characterized by inflammation and axonal degeneration of the central nervous system and a leading cause of disability in young adults. The matrix metalloproteinases in general and specially gelatinase B/metalloproteinase-9 (MMP-9) plays a role in the pathogenesis of multiple sclerosis.nnnOBJECTIVEnTo investigate the presence of the MMP-9 -1562C/T polymorphism in a Portuguese population of MS patients and assess its impact in susceptibility and course of the disease. The relation of MMP-9 serum levels with the polymorphism and with clinical and therapeutic factors will also be assessed.nnnMETHODSnOur study included 355 Caucasian individuals distributed as MS patients (n=169) and controls (n=186). Samples were genotyped for -1562C/T polymorphism by PCR-RFLP analysis. MMP-9 concentration in serum was analyzed using a commercially available enzyme-linked immunosorbent assay.nnnRESULTSnA significant increase in T-allele frequency was found in female MS patients, but not in the total patient population. No association between the presence of the polymorphism and disease progression was found. MMP-9 serum concentrations were increased in patients, and although not influenced by the -1562C/T polymorphism, were modified by INF-beta therapy.nnnCONCLUSIONnAlthough we did not find an association of this polymorphism with disease susceptibility or prognosis, MMP-9 appears to be a good therapeutic response marker for multiple sclerosis.

Cardiovascular effects of fingolimod: Relevance, detection and approach.

Fingolimod, a structural analogue of sphingosine, is the first oral treatment available for multiple sclerosis. The presence of sphingosine-1-phosphate receptors in the sinus and atrioventricular nodes, myocardial cells, endothelial cells and arterial smooth muscle cells is responsible for fingolimods cardiovascular effects. We provide a comprehensive review of the mechanisms of these effects and characterize their clinical relevance.

The retinal ganglion cell layer predicts normal-appearing white matter tract integrity in multiple sclerosis: A combined diffusion tensor imaging and optical coherence tomography approach

We investigated the relationship between retinal layers and normal‐appearing white matter (WM) integrity in the brain of patients with relapsing‐remitting multiple sclerosis (MS), using a combined diffusion tensor imaging and high resolution optical coherence tomography approach. Fifty patients and 62 controls were recruited. The patients were divided into two groups according to presence (n = 18) or absence (n = 32) of optic neuritis. Diffusion tensor data were analyzed with a voxel‐wise whole brain analysis of diffusion metrics in WM with tract‐based spatial statistics. Thickness measurements were obtained for each individual retinal layer. Partial correlation and multivariate regression analyses were performed, assessing the association between individual retinal layers and diffusion metrics across all groups. Region‐based analysis was performed, by focusing on tracts associated with the visual system. Receiver operating characteristic (ROC) curves were computed to compare the biomarker potential for the diagnosis of MS, using the thickness of each retinal layer and diffusion metrics. In patients without optic neuritis, both ganglion cell layer (GCL) and inner plexiform layer thickness correlated with the diffusion metrics within and outside the visual system. GCL thickness was a significant predictor of diffusion metrics in the whole WM skeleton, unlike other layers. No association was observed for either controls or patients with a history of optic neuritis. ROC analysis showed that the biomarker potential for the diagnosis of MS based on the GCL was high when compared to other layers. We conclude that GCL integrity is a predictor of whole‐brain WM disruption in MS patients without optic neuritis.

Theory of Mind and Executive Functions are Dissociated in Multiple Sclerosis

ObjectivesnTo investigate the relationship of executive functions (EF) and theory of mind (ToM) in multiple sclerosis (MS), clarifing whether ToM impairment in MS is related to EF dysfunction or whether they represent dissociable processes which can be independently impaired in MS.nnnMethodsnWe enrolled 60 consecutive MS patients and 60 healthy controls (HC) matched on age, gender, and education level. All participants underwent ToM testing using the Eyes Test and the Videos Test and neuropsychological testing tapping different EF subdomains. A correlation analysis and a hierarchical cluster analysis were used to determine the similarity between explained variance between EF measures and ToM tests.nnnResultsnMS patients had lower scores on both tasks of ToM compared to HC, i.e., Eyes Test (21.1 ± 5.0 vs. 29.5 ± 3.8, p < .001; Cohens d: 1.9) and Videos Test (19.6 ± 2.4 vs. 22.9 ± 1.8, p < .001; Cohens d: 1.6). They also performed significantly worse on different measures of EF. ToM performance was not significantly correlated with EF tests. The hierarchical cluster analysis showed that ToM measures in MS were clustered separately from the EF measures, revealing three executive clusters (Attention/working memory cluster; Inhibitory control/shifting ability cluster; Verbal Initiative/Abstract reasoning cluster) and one ToM cluster.nnnConclusionnThis study suggests a dissociation of EF and ToM in MS, meaning that the MS-related neurobehavioral symptoms may be associated with a significant impairment in ToM independent of the level of EF performance. Ultimately, this discrimination of ToM deficits in MS may help to identify the appropriate cognitive and behavioral interventions.

Consensus Recommendations of the Multiple Sclerosis Study Group and Portuguese Neuroradiological Society for the Use of the Magnetic Resonance Imaging in Multiple Sclerosis in Clinical Practice: Part 1

INTRODUCTIONnMagnetic resonance imaging is established as a recognizable tool in the diagnosis and monitoring of multiple sclerosis patients. In the present, among multiple sclerosis centers, there are different magnetic resonance imaging sequences and protocols used to study multiple sclerosis that may hamper the optimal use of magnetic resonance imaging in multiple sclerosis. In this context, the Group of Studies of Multiple Sclerosis and the Portuguese Society of Neuroradiology, after a joint discussion, appointed a committee of experts to create recommendations adapted to the national reality on the use of magnetic resonance imaging in multiple sclerosis. The purpose of this document is to publish the first Portuguese consensus recommendations on the use of magnetic resonance imaging in multiple sclerosis in clinical practice.nnnMATERIAL AND METHODSnThe Group of Studies of Multiple Sclerosis and the Portuguese Society of Neuroradiology, after discussion of the topic in national meetings and after a working group meeting held in Figueira da Foz on May 2017, have appointed a committee of experts that have developed by consensus several standard protocols on the use of magnetic resonance imaging in the diagnosis and follow-up of multiple sclerosis. The document obtained was based on the best scientific evidence and expert opinion. Subsequently, the majority of Portuguese multiple sclerosis consultants and departments of neuroradiology scrutinized and reviewed the consensus paper; comments and suggestions were considered. Technical magnetic resonance imaging protocols regarding diagnostic, monitoring and the recommended information to be included in the magnetic resonance imaging report will be published in a separate paper.nnnRESULTSnWe provide some practical guidelines to promote standardized strategies to be applied in the clinical practice setting of Portuguese healthcare professionals regarding the use of magnetic resonance imaging in multiple sclerosis.nnnCONCLUSIONnWe hope that these first Portuguese magnetic resonance imaging guidelines, based in the best available clinical evidence and practices, will serve to optimize multiple sclerosis management and improve multiple sclerosis patient care across Portugal.