[Show abstract][Hide abstract] ABSTRACT: Objective:
To investigate the metabolomic profiles of patients with multiple sclerosis (MS) and to define the metabolic pathways potentially related to MS pathogenesis.
Plasma samples from 73 patients with MS (therapy-free for at least 90 days) and 88 healthy controls (HC) were analyzed by (1)H-NMR spectroscopy. Data analysis was conducted with principal components analysis followed by a supervised analysis (orthogonal partial least squares discriminant analysis [OPLS-DA]). The metabolites were identified and quantified using Chenomx software, and the receiver operating characteristic (ROC) curves were calculated.
The model obtained with the OPLS-DA identified predictive metabolic differences between the patients with MS and HC (R2X = 0.615, R2Y = 0.619, Q2 = 0.476; p < 0.001). The differential metabolites included glucose, 5-OH-tryptophan, and tryptophan, which were lower in the MS group, and 3-OH-butyrate, acetoacetate, acetone, alanine, and choline, which were higher in the MS group. The suitability of the model was evaluated using an external set of samples. The values returned by the model were used to build the corresponding ROC curve (area under the curve of 0.98).
NMR metabolomic analysis was able to discriminate different metabolic profiles in patients with MS compared with HC. With the exception of choline, the main metabolic changes could be connected to 2 different metabolic pathways: tryptophan metabolism and energy metabolism. Metabolomics appears to represent a promising noninvasive approach for the study of MS.
[Show abstract][Hide abstract] ABSTRACT: Background
Recently, a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been developed as an international and standardized brief cognitive test, which is easily performed in everyday clinical practice for neuropsychological assessment in multiple sclerosis (MS). However, we need to gather more information about this tool compared to other neuropsychological batteries. The aim of our study is to compare the performance of BICAMS and Brief Repeatable Battery (BRB) in MS subjects.
Tests of the BRB and BICAMS were administered to MS patients recruited from 11 Italian MS centres. Cognitive impairment (CI) was defined as the failure on at least two tests (scores below the fifth percentile) on the BRB and as the failure on at least one test of the BICAMS. The agreement between the performances on the two batteries was assessed through Cohen’s K statistic. Finally we calculated the effects sizes for each test of the two batteries using Cohen’s d.
The two batteries were administered to 192 MS patients (142 women, 50 men; mean age 41.4 ± 10.8 years, mean education 12.3 ± 3.5 years). Mean scores of patients were lower compared to those of healthy subjects in all the cognitive measures examined. Forty-six MS patients were identified as impaired and 48 as unimpaired on both of the batteries, when the Symbol Digit Modalities Test (SDMT) was included in the analysis. Cohen’s K statistic was 0.46 which corresponds to a moderate accord. If the SDMT was excluded from the BRB, 37 MS patients were identified as impaired and 57 as unimpaired on both of the batteries. Cohen’s K statistic was 0.3 which corresponds to a poor accord. The SDMT, the Paced Auditory Serial Addition Test (PASAT) 3 and 2 yielded higher d values (SDMT 0.83, PASAT 3 0.65, PASAT 2 0.84).
This study confirms the feasibility of BICAMS in everyday clinical practice for the identification of CI and highlights the good psychometric properties of the SDMT.
[Show abstract][Hide abstract] ABSTRACT: Many guidelines are available for the management of lower urinary tract symptoms (LUTSs) in multiple sclerosis (MS) patients, but no agreement exists on the best approach for subjects without LUTSs. The objective of this study was to evaluate whether LUTSs can be detected in MS patients asymptomatic for urinary dysfunction, comparing three different tools [measure of post-void residual volume (PRV), bladder diary (BD), a focused questionnaire (IPSS)], and whether disability, disease duration and signs of pyramidal involvement are linked to their subclinical presence. 178 MS patients (118 women) have been included (mean age 41.2 years, mean disease duration 11.3 years, mean EDSS 2.2), and tested with the above-mentioned tools. PRV was abnormal in 14 subjects (7.8 %), associated to abnormal findings at IPSS in 3 cases, at BD in 2 cases, at both in 1. BD was abnormal in 37 subjects (20.8 %), with concomitant abnormal PRV in 2, abnormal IPSS in 10 cases, abnormal IPSS and BD in 1. IPSS was ≥ 9 in 43 subjects (24.1 %). At least one test was abnormal in 76 patients (42.7 %): 1 in 57 patients (32.0 %), 2 in 17 (9.5 %), and 3 tests in 2 (1.1 %). Patients with at least one abnormal urinary variable, compared to patients without urinary abnormalities, had a more frequent pyramidal involvement (69.5 vs. 16.8 %, χ
2 = 48.6, p < 0.00001), a more frequent occurrence of EDSS ≥2 (83.1 vs. 23.5 %, χ
2 = 56.9, p < 0.00001), and a longer disease duration (15.7 ± 7.3 vs. 9.1 ± 7.1, t = 5.7, p < 0.00001). Asymptomatic LUTS were frequent but none of the tests used permitted to better identify asymptomatic patients.
Full-text · Article · Nov 2015 · Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: We investigated intrafamilial phenotypic variability in carriers of the C9orf72 mutation, analysing clinical, neuropsychological and imaging characteristics of various members from a large Sardinian kindred with FTD or ALS. We compared these with those of C9 + patients in our ALS and FTD cohorts. Results showed that three patients carried the C9orf72 mutation: two with ALS and one with FTD and Parkinsonism. C9 + patients in our bvFTD Sardinian cohort had a higher frequency of Parkinsonism than non-mutated patients (75% vs. 36.3%, p <0.02). Parkinsonism was present in 2.7% of our ALS cohort and 3.3% of the C9 + patients. The prevalence of Parkinsonism in C9 + patients in the bvFTD and ALS cohorts showed a statistically significant difference (p <0.006). In conclusion, Parkinsonism was frequently associated with FTD but not ALS in a large Sardinian family, a finding reflected in the wider C9orf72 associated Sardinian ALS and FTD populations.
[Show abstract][Hide abstract] ABSTRACT: Background:
A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis.
The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis.
This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months.
A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months.
Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis.
Full-text · Article · Oct 2015 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: Background: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. Objective: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. Methods: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerkes R2 and the area under the Receiver Operating Characteristic (ROC) curves. Results: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. Conclusions: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.
No preview · Article · Oct 2015 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: This study analyzes how multiple sclerosis (MS) does affect one of the most common voluntary activities
in life: the gait initiation (GI). The main aim of the work is to characterize the execution of this task by
measuring and comparing relevant parameters based on center of pressure (COP) patterns and to study
the relationship between these and the level of expanded disability status scale (EDSS). To this aim, 95
MS subjects with an average EDSS score of 2.4 and 35 healthy subjects were tested using a force platform
during the transition from standing posture to gait. COP time-series were acquired and processed to
extract a number of parameters related to the trajectory followed by the COP. The statistical analysis
revealed that only a few measurements were statistically different between the two groups and only
these were subsequently correlated with EDSS score. The correlation analysis underlined that a progressive
alteration of the task execution can be directly related with the increase of EDSS score. These
finding suggest that most of the impairment found in people with MS comes from the first part of the
COP pattern, the anticipatory postural adjustments (APAs). The central nervous system performs APAs
before every voluntary movement to minimize balance perturbation due to the movement itself. Gait
Initiation's APAs consist in some ankle muscles contractions that induce a backward COP shift to the
swing limb. The analysis here performed highlighted that MS affected patients have a reduced posterior
COP shift that reveals that the anticipatory mechanism is impaired.
Full-text · Article · Sep 2015 · Multiple Sclerosis and Related Disorders
[Show abstract][Hide abstract] ABSTRACT: Cerebral microbleeds (CMB) might reflect specific underlying vascular pathologies like cerebral amyloid angiopathy (CAA). In the present study we report the gradient-echo MRI pattern of two siblings with P284S PSEN1 mutation. T2* gradient-echo images of the two subjects demonstrated multiple microbleeds in lobar regions. The role and causes of CMB in sporadic Alzheimer's disease (AD) patients have not been clearly established and useful contributions could derive from familial AD studies. Furthermore, since CAA is a potential risk factor for developing adverse events in AD immunization trials, the identification in vivo of CAA through non-invasive MRI methods could be useful to monitoring side effects.
No preview · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
[Show abstract][Hide abstract] ABSTRACT: Purpose
This study proposes to characterize the gait patterns of individuals with Multiple Sclerosis (MS) affected by spasticity using quantitative gait analysis.
Cross-sectional study on 38 individuals with MS, 19 affected by lower limb spasticity and 19 not affected, the latter forming the control group. Both groups were evaluated while walking using three-dimensional gait analysis. Spatio-temporal parameters of gait, kinematic data expressed by means of Gait Profile Score (GPS) and Range of Motion (ROM), as well as muscular activation, were evaluated.
The results show that spasticity originates a peculiar gait pattern characterized by reduced speed, cadence, stride length, swing phase and increased double support time, but they also reveal specific alterations in kinematics and muscular activation. In particular, significantly higher values of GPS, reduced hip and knee flexion-extension ROM and abnormal activation of the rectus femoris were observed in individuals with spasticity.
In people with MS presenting spastic gait, the availability of quantitative data appears crucial in verifying the effectiveness of pharmacologic and rehabilitative treatments, also considering that spasticity scales may not be satisfactory in relating the assessed spasticity with both perception of the patients and the actual body functionalities.
Full-text · Article · Sep 2015 · Journal of the Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: The hexanucleotide repeat expansion GGGGCC in the C9ORF72 gene larger than 30 repeats has been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent papers investigated the possible pathogenic role and associated clinical phenotypes of intermediate C9ORF72 repeat expansion ranging between 20 and 30 repeats. Some studies suggested its pathogenicity for typical Parkinson's disease (PD), atypical parkinsonian syndromes, FTD with/without parkinsonism, and ALS with/without parkinsonism or with/without dementia. In our study, we aimed to screen patients affected by atypical parkinsonian syndromes or PD complicated by psychosis or dementia for the presence of C9ORF72 repeat expansions, and in unrelated age- and sex-matched healthy controls. Consecutive unrelated patients with atypical parkinsonian syndromes and patients with PD complicated by psychosis or dementia were included in this study. Atypical parkinsonian syndromes were further divided into two groups: one with patients who met the criteria for the classic forms of atypical parkinsonism [multiple system atrophy (MSA), Lewy body disease (LBD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)] ;and patients who did not meet the above criteria, named non-classical atypical parkinsonism with or without dementia. Ninety-two unrelated patients (48 men, 44 women) were enrolled. None of the patients was found to be carriers of C9ORF72 repeat expansions with more than 30 repeats. Intermediate 20-30 repeat expansions were detected in four female patients (4.3 %). Three of them presented clinical features of atypical parkinsonian syndromes, two with non-classical atypical parkinsonism and dementia FTD-like, and one with non-classical atypical parkinsonism without dementia. The other patient presented clinical features of typical PD complicated by psychosis. Among 121 control subjects, none presented long or short expansion for the C9ORF72 gene. Our findings seem to support the hypothesis that the hexanucleotide expansions of C9ORF72 gene with intermediate repetitions between 20 and 29 repetitions could be associated with typical PD with psychosis or dementia and atypical parkinsonisms with dementia (non-classical atypical parkinsonism with dementia FTD-like) or without dementia (non-classical atypical parkinsonism upper MND-like), although the causal relationship is still unclear. In these latter patients, parkinsonism, more or less levodopa responsive, constituted the symptomatological central core at onset.
Full-text · Article · Aug 2015 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial–temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled— 9 male and 11 female—with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial–temporal parameters of gait revealed an increased speed (+15 %, p<0.001), cadence (+6 %, p<0.001) and stride length (+10 %, p\0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % (p<0.001): Significant changes involved the pelvic area, hip rotation and knee flexion–extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values.
Full-text · Article · Aug 2015 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and accompanied and followed by neurodegeneration. Missense mutations of the TAR DNA Binding Protein gene (TARDBP) located in the chromosome 1p36.22 region, and the hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are pathogenic in other neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background. Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion. Difference in the frequency of these mutations between MS patients and controls was calculated using the χ 2 test with a standard 2 × 2 table. The Ala382Thr mutation in its heterozygous state was found in 27/1833 patients (1.4%) and 20/1475 controls (1.3%), whereas C9orf72 pathogenic repeat expansion was found in 6/1014 MS patients (0.6%) and 2/333 controls (0.6%). Individuals carrying the mutations did not present with other neurodegenerative conditions and any differences were reported between groups. TARDBP Ala382Thr mutation and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population. Further analyses on larger samples of MS patients from other populations are needed to better define the possible role of these genes in the complex interplay between neuroinflammation and neurodegeneration in MS.
No preview · Article · Aug 2015 · The Italian Journal of Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is a complex autoimmune disease originated from the interplay between genetic and environmental factors. An overlap of clinical and neuroradiological parameters has been described between MS and an adult-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). This syndrome is caused by a trinucleotide premutation expansion of a CGG sequence in the 55-200 repeat range, which is located in the fragile-X mental retardation 1 (FMR1) gene. Female premutation carriers have an increased propensity for immune-mediated disorders. Recently, a case of co-occurrence of MS and FXTAS was reported. Assuming that the premutation expansion may play a role in the MS susceptibility, we evaluated its frequency in a cohort of MS patients from Sardinia, an island characterized by a very high frequency of MS. Nuclear DNA was extracted by standard methods, purified with bisulfite treatment and then amplified twice by PCR with specific primers. Microsatellite analysis was performed and emizogotic subjects were sequenced. Clinical data of patients were also collected. Only 1/755 MS patients exhibited the premutation expansion with a heterozygosis pattern (30/58). No pathogenic repeat expansions (>200 repeats) were found in the entire cohort. Repeats labeled as the gray zone (45-60 repeats) were observed in 15/755 patients. No specific clinical features concerning disease course, disease activity, and disability were reported for these patients. Our results do not support a possible role for premutation or gray zone alleles in MS Sardinian patients. Further studies are needed to better understand the relationship between FXTAS and MS.
No preview · Article · Jul 2015 · Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: Balance training represents a critical part of the rehabilitation process of individuals living with multiple sclerosis (MS) since impaired postural control is a distinctive symptom of the disease. In recent years, the use of the Nintendo Wii system has become widespread among rehabilitation specialists for this purpose, but few studies have verified the effectiveness of such an approach using quantitative measures of balance. In this study, we analyzed the postural sway features of a cohort of twenty-seven individuals with MS before and after 5 weeks of unsupervised home-based balance training with the Wii system. Center of pressure (COP) time-series were recorded using a pressure platform and processed to calculate sway area, COP path length, displacements, and velocities in mediolateral (ML) and anteroposterior (AP) directions. Although the results show a significant reduction in sway area, COP displacements, and velocity, such improvements are essentially restricted to the ML direction, as the Wii platform appears to properly stimulate the postural control system in the frontal plane but not in the sagittal one. Available Wii games, although somewhat beneficial, appear not fully suitable for rehabilitation in MS owing to scarce flexibility and adaptability to MS needs and thus specific software should be developed.
Full-text · Article · Jun 2015 · BioMed Research International