Search

Magnetic resonance imaging (MRI) has been established as the most relevant paraclinical tool for diagnosing and monitoring multiple sclerosis (MS). In this context, counting the number of new enhancing lesions on monthly MRI scans is widely used as a surrogate marker of MS activity when evaluating the effect of treatments. In this study, we investigated whether parametric models based on mixed Poisson distributions (the Negative Binomial (NB) and the Poisson-Inverse Gaussian (P-IG) distributions) were able to provide adequate fitting of new enhancing lesion counts in MS. We found that the NB model gave good approximations in relapsing — remitting and secondary progressive MS patients not selected for baseline MRI activity, whereas the P-IG distribution modelled better new enhancing lesion counts in relapsing – remitting MS patients selected for baseline activity. This study shows that parametric modelling for MS new enhancing lesion counts is feasible. This approach should provide more targeted tools for the design and the analysis of MRI monitored clinical trials in MS. [ABSTRACT FROM AUTHOR]

Introduction: Measurement of brain volume on magnetic resonance imaging (MRI) scans is regarded as an objective marker of multiple sclerosis (MS) severity with the potential to monitor treatment efficacy accurately. This study was performed to assess the variability of brain MRI volume measurements. Patients and methods: We studied nine patients with relapsing-remitting MS, who were imaged on two occasions (separated by an interval of 24 h) using two different MR scanners and fast fluid-attenuated inversion recovery (fast-FLAIR) sequences. The whole brain volume computed from each image was measured three times by three observers using a seed-growing technique based on signal intensity thresholding. Intra-observer, inter-observer and inter-scanner variabilities were expressed as coefficients of variations (COVs). The inter-scanner variability included not only the intra-observer variation but also the repositioning variability and the variation in observed brain volume caused by different scanner hardware and sequence implementations. Results: There was no statistically significant difference in patients' brain volume values between observers (P=0.82) or between scanners (P=0.30). The mean intra-observer COV was 1.2% (s.e.=0.4%), the mean inter-observer COV was 1.8% (s.e.=0.8%) and the mean inter-scanner COV was 2.4% (s.e.=1.2%). The intra-observer variance was not statistically different from those found between observers (P=0.83) or scanners (P=0.44). Conclusion: The intra-observer variability in brain volume measurements found in this study was within the range of intra-observer variability found in previous studies. This study shows that the use of different observers and MR scanners has only a small influence on the measured brain volume and does not affect the reproducibility of this measurement greatly. [ABSTRACT FROM AUTHOR]

In the last few years a number of therapeutical approaches have become available for patients affected by Duchenne muscular dystrophy (DMD). The majority of the approaches proposed so far are specifically targeting distinct group of mutations, such as stop codon point mutations or groups of deletions as in exon skipping studies. Because of this, the number of patients eligible for these studies is limited to those having specific mutations or groups of mutations. This has raised the question of whether natural history data should be used as controls in studies with few eligible patients and, more specifically, whether individual groups of mutations follow the general natural history of boys of DMD or have distinct profiles of progression of functional impairment. The aim of this study was to report 12month longitudinal changes of the 6min walk test (6MWT) in a large cohort of DMD ambulant patients subdivided according to type and site of mutations. 6MWT was performed in 198 DMD ambulant boys, older than 4years at baseline and repeated after 12months. 137 had deletions, 18 had duplications and 43 point mutations. Patients with deletions were further subdivided into subgroups according to whether they had mutations eligible for skipping in different exons, selecting those who were currently or likely to be part of clinical trials, eligible for skipping 44 (n =18), eligible for skipping 45 (n =16), eligible for skipping 51 (n =27), eligible for skipping 53 (n =28). Patients with point mutations were also subdivided identifying those with stop codon mutations. The 6MWD showed 12months changes between −325 and 175 (mean −10)m. There was no significant difference between deletions, duplications and point mutations neither at baseline nor in the 12month changes. When patients were subdivided into different subgroups of deletions according to their eligibility to skip specific exons, there was little difference between the individual subgroups and the patients with the whole cohort. The subgroup eligible for skipping exon 44 however had a trend to perform better at baseline and to show less deterioration than the other subgroups. [Copyright &y& Elsevier]

Abstract: Sequence learning can be investigated by serial reaction-time (SRT) paradigms. Explicit learning occurs when subjects have to recognize a test sequence and has been shown to activate the frontoparietal network in both contralateral and ipsilateral hemispheres. Thus, the left and right superior longitudinal fasciculi (SLF), connecting the intra-hemispheric frontoparietal circuits, could have a role in explicit unimanual visuomotor learning. Also, as both hemispheres are involved, we could hypothesize that the corpus callosum (CC) has a role in this process. Pathological damage in both SLF and CC has been detected in patients with Multiple Sclerosis (PwMS), and microstructural alterations can be quantified by Diffusion Tensor Imaging (DTI). In light of these findings, we inquired whether PwMS with minimal disability showed impairments in explicit visuomotor sequence learning and whether this could be due to loss of white matter integrity in these intra- and inter-hemispheric white matter pathways. Thus, we combined DTI analysis with a modified version of SRT task based on finger opposition movements in a group of PwMS with minimal disability. We found that the performance in explicit sequence learning was significantly reduced in these patients with respect to healthy subjects; the amount of sequence-specific learning was found to be more strongly correlated with fractional anisotropy (FA) in the CC (r=0.93) than in the left (r=0.28) and right SLF (r=0.27) (p for interaction=0.005 and 0.04 respectively). This finding suggests that an inter-hemispheric information exchange between the homologous areas is required to successfully accomplish the task and indirectly supports the role of the right (ipsilateral) hemisphere in explicit visuomotor learning. On the other hand, we found no significant correlation of the FA in the CC and in the SLFs with nonspecific learning (assessed when stimuli are randomly presented), supporting the hypothesis that inter-hemispheric integrity is specifically relevant for explicit sequence learning. [Copyright &y& Elsevier]

Abstract: Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy. [Copyright &y& Elsevier]

The volume of hypointense lesions on T1 weighted brain MRI represents an increasingly used MR endpoint in phase III MS treatment trials. In this study we evaluated the reproducibility of hypointense T1 lesion volume quantification in a cohort of Multiple Sclerosis (MS) patients. The gadolinium enhanced T1 weighted brain MR images of 33 MS patients from three European centers were used in this study. These images were acquired as part of a phase III trial of interferon beta-1 b in secondary progressive MS. The MRI machine manufacturers and imaging parameters varied according to the MRI acquisition center. Three experienced observers used a semi-automated local thresholding technique to quantify the hypointense T1 lesion volume on two occasions, separated by a delay. The intra and inter observer coefficients of variation were 3.7% and 4.9% respectively, with similar values derived for images obtained at all three sites. There was a generally high level of agreement between the lesion volumes obtained by the three raters. However, a modest but significant measurement drift was identified between the first and second sessions for one of the three raters, highlighting the very real possibility of measurement drift even for experienced observers. Our results support the increasing role for T1 hypointense lesion volume as an outcome measure in multicenter phase III MS treatment trials. Multiple Sclerosis (2000) 6, 237–240. [ABSTRACT FROM AUTHOR]

The 6 min walk test (6MWT) has been recently chosen as the primary outcome measure in several international multicenter clinical trials in Duchenne muscular dystrophy (DMD) ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment and with age and 6MWT values at baseline. 96 patients from 11 centers were assessed at baseline and 1, 2 and 3 years after baseline. Three boys (3%) lost the ability to perform the test within 12 months, another 13 between 12 and 24 months (14%) and other 11 between 24 and 36 months (12%). The 6MWT showed an average overall decline of −15.8 (SD 77.3) meters in the first year, of −58.9 (SD 125.7) in the second year and −104.22 (SD 146.2) in the third year. The changes were significantly different in the two baseline age groups and according to the baseline 6MWT values (below and above 350 m) (test for interaction, p < 0.001). The changes were also significantly different according to steroid treatment ( p for interaction = 0.01). These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial. [ABSTRACT FROM AUTHOR]

Abstract: Six minute walk test (6MWT), timed items and North Star Ambulatory Assessment (NSAA) are increasingly used as possible outcome measures in clinical trials in Duchenne Muscular Dystrophy (DMD). Longitudinal data have previously been reported following changes in their scores over a 12month period. The aim of the study was to assess 6MWT and NSAA in a cohort of 119 ambulant DMD boys over 24months in order to establish the spectrum of possible changes over a longer period of time. The study is a longitudinal multicentric cohort study. 119 ambulant DMD patients were assessed using 6MWT, NSAA at baseline 12 and 24months. Clinical data including age and steroid treatment were collected. During the 24months of the study, we observed a progressive decline in both measures that was more obvious in the second year. Not all the DMD boys in our cohort showed a decline as young boys showed some improvement in their 6MWT and NSAA scores up to the age of 7. Fifteen patients (12.6%) lost the ability to walk independently: 2/15 by the end of the first year and the other 13 in the second year. Another 22 patients (21.1%) were still able to walk independently but were unable to get up from supine (8/22 at baseline, 4 at 12months, 10 at 24months). Four children also lost the ability to perform the 6MWT (2 at 12months and the other 2 at 24months). This study provides longitudinal data of NSAA and 6MWT over a 24month period. These data can be useful when designing a clinical trial. [Copyright &y& Elsevier]