Effectiveness of teriflunomide on No Evidence of Disease Activity and cognition in relapsing remitting multiple sclerosis: results of the NEDA3PLUS study.

BACKGROUND: Cognitive impairment (CI) is a prevalent and debilitating manifestation of multiple sclerosis (MS); however, it is not included in the widely used concept of No Evidence of Disease Activity (NEDA-3). We expanded the NEDA-3 concept to NEDA-3 + by encompassing CI assessed through the Symbol Digit Modality Test (SDMT) and evaluated the effect of teriflunomide on NEDA3 + in patients treated in a real-world setting. The value of NEDA-3 + in predicting disability progression was also assessed. METHODS: This 96-weeks observational study enrolled patients already on treatment with teriflunomide for ≥ 24 weeks. The predictiveness of NEDA-3 and NEDA-3 + at 48 weeks on the change in motor disability at 96 weeks was compared through a two-sided McNemar test. RESULTS: The full analysis set (n = 128; 38% treatment naïve) featured relatively low level of disability (baseline EDSS = 1.97 ± 1.33). NEDA-3 and NEDA-3 + statuses were achieved by 82.8% and 64.8% of patients, respectively at 48 weeks vs. baseline, and by 57.0% and 49.2% of patients, respectively at 96 weeks vs. baseline. All patients except one were free of disability progression at Week 96, and NEDA-3 and NEDA-3 + were equally predictive. Most patients were free of relapse (87.5%), disability progression (94.5%) and new MRI activity (67.2%) comparing 96 weeks with baseline. SDMT scores were stable in patients with baseline score ˃35 and improved significantly in those with baseline score ≤ 35. Treatment persistence was high (81.0% at Week 96). CONCLUSION: Teriflunomide confirmed its real-world efficacy and was found to have a potentially beneficial effect on cognition.

REal-World effectIveNess of claDribine for patients with multiple sclerosis: a Sicilian multicentric experience (REWIND study).

BACKGROUND: cladribine tablets is a highly effective option for the treatment of relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: to evaluate the effectiveness of cladribine in a real-world setting. METHODS: this prospective real-world study consecutively screened all RRMS patients from seven different MS centers in Sicily (Italy), who completed the 2-year treatment course of cladribine tablets in the period between 11th March 2019 and 31st October 2021. Data about Expanded Disability Status Scale (EDSS), relapses, previous treatments, adverse events (AEs) and magnetic resonance imaging (MRI) were collected. Patients who were previously treated with other DMTs were further stratified in moderately active treatment (MAT) and highly active treatment (HAT) patients. RESULTS: a total of 217 patients, (70% women, with mean age of 38.4 ± 11.3 years), were enrolled. Fifty patients (23.0%) were naïve to treatment and 167 (77%) switched from another disease modifying therapies. After the second year of treatment, about 80% of were EDSS progression free, 88% remained relapse-free at T24, and 48% of patients were MRI activity-free. Kaplan Meier analyses showed significant differences between MT and HAT in terms of time to first clinical relapse (HR: 2.43, IC 1.02 - 5.76; p=0.04), time to the first new T1-gadolinium enhancing lesion (HR: 3.43, IC 1.35 - 8.70; p= 0.009) and time to MRI worsening (HR: 2.42, IC 1.15 - 5.09; p= 0.02). CONCLUSION: this study confirmed that cladribine is an effective treatment for MS, in particular in naïve patients and in those who have switched from MATs.

Unmet needs and gaps in the identification of secondary progression in multiple sclerosis: a Southern Italy healthcare professionals' perspective.

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing-remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease. METHODS: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition. RESULTS: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed. CONCLUSION: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life.

Radiomics Analysis of Brain [18F]FDG PET/CT to Predict Alzheimer's Disease in Patients with Amyloid PET Positivity: A Preliminary Report on the Application of SPM Cortical Segmentation, Pyradiomics and Machine-Learning Analysis.

BACKGROUND: Early in-vivo diagnosis of Alzheimer's disease (AD) is crucial for accurate management of patients, in particular, to select subjects with mild cognitive impairment (MCI) that may evolve into AD, and to define other types of MCI non-AD patients. The application of artificial intelligence to functional brain [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography(CT) aiming to increase diagnostic accuracy in the diagnosis of AD is still undetermined. In this field, we propose a radiomics analysis on advanced imaging segmentation method Statistical Parametric Mapping (SPM)-based completed with a Machine-Learning (ML) application to predict the diagnosis of AD, also by comparing the results with following Amyloid-PET and final clinical diagnosis. METHODS: From July 2016 to September 2017, 43 patients underwent PET/CT scans with FDG and Florbetaben brain PET/CT and at least 24 months of clinical/instrumental follow-up. Patients were retrospectively evaluated by a multidisciplinary team (MDT = Neurologist, Psychologist, Radiologist, Nuclear Medicine Physician, Laboratory Clinic) at the G. Giglio Institute in Cefalù, Italy. Starting from the cerebral segmentations applied by SPM on the main cortical macro-areas of each patient, Pyradiomics was used for the feature extraction process; subsequently, an innovative descriptive-inferential mixed sequential approach and a machine learning algorithm (i.e., discriminant analysis) were used to obtain the best diagnostic performance in prediction of amyloid deposition and the final diagnosis of AD. RESULTS: A total of 11 radiomics features significantly predictive of cortical beta-amyloid deposition (n = 6) and AD (n = 5) were found. Among them, two higher-order features (original_glcm_Idmn and original_glcm_Id), extracted from the limbic enthorinal cortical area (ROI-1) in the FDG-PET/CT images, predicted the positivity of Amyloid-PET/CT scans with maximum values of sensitivity (SS), specificity (SP), precision (PR) and accuracy (AC) of 84.92%, 75.13%, 73.75%, and 79.56%, respectively. Conversely, for the prediction of the clinical-instrumental final diagnosis of AD, the best performance was obtained by two higher-order features (original_glcm_MCC and original_glcm_Maximum Probability) extracted from ROI-2 (frontal cortex) with a SS, SP, PR and AC of 75.16%, 80.50%, 77.68%, and 78.05%, respectively, and by one higher-order feature (original_glcm_Idmn) extracted from ROI-3 (medial Temporal cortex; SS = 80.88%, SP = 76.85%, PR = 75.63%, AC = 78.76%. CONCLUSIONS: The results obtained in this preliminary study support advanced segmentation of cortical areas typically involved in early AD on FDG PET/CT brain images, and radiomics analysis for the identification of specific high-order features to predict Amyloid deposition and final diagnosis of AD.

PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study.

BACKGROUND: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients. MATERIALS AND METHODS: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other". RESULTS: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04). CONCLUSIONS: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.

Subcutaneous Uptake on [18F]Florbetaben PET/CT: a Case Report of Possible Amyloid-Beta Immune-Reactivity After COVID-19 Vaccination.

Introduction: Large-scale worldwide COVID-19 vaccination programs are being rapidly deployed, and high-risk patients with comorbidity are now receiving the first doses of the vaccine. Physicians should be, therefore, aware of new pitfalls associated with the current pandemic vaccination program, also in the case of [18F]Florbetaben PET/CT.Case PresentationWe described the first image of [18F]Florbetaben PET/CT in the evaluation of a 70-year-old male with suspicious Alzheimer disease and unclear history of heart disease. We detailed the diagnostic imaging PET/CT workup with different findings. Conclusion: In this case, [18F]Florbetaben PET/CT can demonstrate potential beta-amyloid immune-reactivity and deposition associated with the current COVID-19 pandemic vaccination programs.

Multicenter Interventional Phase IV Study for the Assessment of the Effects on Patient's Satisfaction of Peg IFN Beta-1a (Pre-filled Pen) in Subjects With Relapsing-Remitting Multiple Sclerosis Unsatisfied With Other Injectable Subcutaneous Interferons (PLATINUM Study).

Subcutaneous (SC) interferons beta (IFN-beta) are effective therapies for the treatment of relapsing-remitting multiple sclerosis (RRMS). Factors such as dosing schedule, needle intolerance/fatigue, and side effects may impact patient satisfaction with treatment. Improvement of patient satisfaction may increase the adherence to treatment and the patient quality of life. This study was aimed at evaluating the impact of switching to "Peginterferon beta-1a (Peg-IFN beta-1a)" in patients with RRMS unsatisfied with other SC interferons. The multicenter, open-label, phase IV PLATINUM study was conducted in 32 Italian centers. The primary endpoint was changes from baseline in the score of a convenience satisfaction domain of the TSQM-9 questionnaire at 12 weeks. The secondary endpoints were patients' global satisfaction, short-term adherence to treatment, satisfaction with the injection system, effect on fatigue, disease activity, and patient inability score. A total of 193 patients were enrolled and 166 (86%) completed the study, receiving Peg-IFN beta-1a for 24 weeks. Patients switching to Peg-IFN beta-1a from other SC interferons reported a significant improvement (p < 0.001) of Convenience Score and all other scores of the TSQM-9 questionnaire at 12 and 24 weeks (p < 0.001). Peg IFN beta-1a attained very high adherence to the treatment (92 and 86% at 12 and 24 weeks, respectively) with a stable annualized relapse rate (ARR). At 24 weeks, 94% of the participants were relapse free. Adverse events (AEs), recorded on 82 patients (42%), were mild or moderate. The most common AE was flu-like syndrome (29.2%). Patients switching from SC IFN beta therapy to Peg IFN beta-1a showed high treatment satisfaction with a positive safety profile, comparable with that of other currently approved first-line injectable SC interferons. This study suggests that Peg IFN beta-1a might represent a treatment choice to improve adherence in RRMS patients unsatisfied with other SC interferons.

Real world experience with teriflunomide in multiple sclerosis: the TER-Italy study.

OBJECTIVE: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment. METHODS: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment. RESULTS: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007). CONCLUSIONS: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern.

Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis.

INTRODUCTION: Natalizumab (NTZ) is one of the most effective treatment options for multiple sclerosis (MS) treatment. Our study aimed to evaluate the effectiveness of NTZ when administered according to the extended dosing strategy compared with standard 4-weekly administration in a large Italian MS population. MATERIALS AND METHODS: This retrospective multicentre study included patients with relapsing-remitting MS (RR-MS) who received NTZ administrations between the 1 June 2012 and the 15 May 2018 and were followed by the 'Italian MS Register'. All patients with MS were stratified into two groups based on NTZ administration schedule: standard interval dosing (SID) patients who received infusions on average from 28 to 32 days (median 30) and extended interval dosing (EID) including patients who have been infused with interval between 33 and 49 days (median 43). Clinical data were assessed at baseline (before starting NTZ), after 12 (T1) and 24 months (T2) of treatment. RESULTS: Out of 5231 patients with RR-MS screened, 2092 (mean age 43.2±12.0, 60.6% women) were enrolled. A total of 1254 (59.9%) received NTZ according to SID, and 838 (40.1%) according to EID. At 12 and 24 months, no differences in terms of annualised relapse rate and disability status were found between the two groups. Progression index and confirmed disability worsening were similar between the two groups. DISCUSSION: The use of NTZ with an extended interval schedule showed similar effectiveness compared with SID. Unchanged clinical efficacy of EID schedule may raise the question of a possible advantage in terms of tolerability and safety.

Dimethyl fumarate vs Teriflunomide: an Italian time-to-event data analysis.

BACKGROUND: The introduction of oral disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) changed algorithms of RRMS treatment. OBJECTIVES: To compare the effectiveness of treatment with dimethyl fumarate (DMF) and teriflunomide (TRF) in a large multicentre Italian cohort of RRMS patients. MATERIALS AND METHODS: Patients with RRMS who received treatment with DMF and TRF between January 1st, 2012 and December 31st, 2018 from twelve MS centers were identified. The events investigated were "time-to-first-relapse", "time-to-Magnetic-Resonance-Imaging (MRI)-activity" and "time-to-disability-progression". RESULTS: 1445 patients were enrolled (1039 on DMF, 406 on TRF) and followed for a median of 34 months. Patients on TRF were older (43.5 ± 8.6 vs 38.8 ± 9.2 years), with a predominance of men and higher level of disability (p < 0.001 for all). Patients on DMF had a higher number of relapses and radiological activity (p < .05) at baseline. Time-varying Cox-model for the event "time-to-first relapse" revealed that no differences were found between the two groups in the first 38 months of treatment (HRt < 38DMF = 0.73, CI = 0.52 to 1.03, p = 0.079). When the time-on-therapy exceeds 38 months patients on DMF had an approximately 0.3 times lower relapse hazard risk than those who took TRF (HRt>38DMF = 3.83, CI = 1.11 to 13.23, p = 0.033). Both DMTs controlled similarly MRI activity and disability progression. CONCLUSIONS: Patients on DMF had higher relapse-free survival time than TRF group after the first 38 months on therapy.

Pregnancy and the Postpartum Period in Women With Relapsing-Remitting Multiple Sclerosis Treated With Old and New Disease-Modifying Treatments: A Real-World Multicenter Experience.

Introduction: Trends of disease activity during pregnancy, the postpartum period, and until 24 months from the delivery in the era of new drugs for the treatment of relapsing-remitting multiple sclerosis (RRMS) need to be investigated. Methods: In this cross-sectional Italian multicenter study, women with RRMS were included; the disease-modifying treatment (DMT) at the time of conception included were: interferons, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod, and natalizumab. The main outcome of the study was to determine the rate of relapse occurrence during pregnancy and the postpartum period in all women grouped for each DMT. The secondary outcome was to determine the overall disease activity assessed by NEDA 3 (relapse, disability level, and radiological activity) at 24 months from the date of delivery. Results: Completed data were available for 81 pregnancies (in 74 women). Women on interferons and glatiramer had longer disease duration than women on dimethyl fumarate, fingolimod, and natalizumab (p < 0.05). Overall, we recorded 25 relapses during pregnancy (11 in 11 women) and the postpartum period (14 in 14 women). Natalizumab was the most commonly DMT in women (3) who experienced relapses during pregnancy. IFNs were the most commonly prescribed DMT in women (8) who experienced relapses during the postpartum period. At logistic regression analysis, specific treatment per se was not associated with relapse occurrence. No differences among the DMTs groups were recorded about NEDA 3 status at 24 months of follow-up. Conclusions: In our population, there was no difference in terms of relapses occurrence, disability status, and the overall disease activity during a follow up of 24 months.

Incidence of multiple sclerosis in the province of Catania. A geo-epidemiological study.

BACKGROUND: An increasing incidence of MS in the city of Catania was reported during 1975-2004, with a higher incidence along the south-eastern flank of the Mt.Etna. We evaluated the incidence of MS in the entire province of Catania during 2005-2015 and the spatial distribution of MS-cases using a cluster analysis. METHODS: Patients were considered as incident MS-cases if they fulfilled the revised McDonald criteria for MS during 2005-2015 and were residents in the province of Catania at the time of disease onset. Cluster analysis was performed using both LISA and Kulldorff's spatial scan statistic. Residence address at disease onset was considered for each case. Communalities were assessed considering the centroid of their inhabited area. RESULTS: A total of 973 MS-cases were identified. Mean annual incidence risk was 8.2/100,000 person-years (95%CI 7.7-8.7), significantly higher among women (10.5/100,000 versus 5.7/100,000). LISA identified a spatial aggregation of MS-cases in the eastern side of the province of Catania and Kulldorff's statistics confirmed the existence of a statistically significant spatial cluster in this area (SIR 1.23,95%CI 1.08-1.23, p-value 0.04). CONCLUSIONS: Our study confirms a high incidence of MS in the province of Catania and the presence of a spatial cluster along the eastern side of the province. This area is considered the most exposed to volcanogenic ashes due to the prevailing westerly to north-westerly trade winds. Even if such distribution could be related with a greater exposure to volcanogenic metals, further studies are needed to explore possible alternative hypotheses.

Pharmacokinetics and pharmacodynamics of natalizumab in pediatric patients with RRMS.

Objective: This phase I study investigated pharmacokinetic (PK) and pharmacodynamic (PD) profiles of natalizumab in pediatric patients with relapsing-remitting MS (RRMS). Methods: Pediatric patients with RRMS who were prescribed natalizumab 300 mg IV every 4 weeks were enrolled. Blood samples were collected on days 1, 2, 8, 15, and 22 and at weeks 4, 8, 12, and 16 to estimate PK parameters; PD properties were evaluated by measuring α4-integrin saturation and lymphocyte counts over time. Natalizumab's safety profile was also evaluated. Results: PK parameters were similar to those reported in adult patients; natalizumab concentrations peaked approximately 1 day after infusion in most of the participants (Cmax 142.9 µg/mL, AUClast 47389.4 hr*µg/mL), followed by a biphasic decline with a rapid distribution phase and a slow elimination phase, with a terminal half-life of 215.1 hours. In terms of PD, both time course and magnitude of α4-integrin saturation and increase in lymphocyte counts were similar to those observed in adults. During the 16-week study follow-up, 3 adverse events attributed to natalizumab were observed; no unexpected safety events occurred. Conclusions: PK profile, α4-integrin saturation, lymphocyte counts, and safety observed in these pediatric patients are comparable to those reported in adults. Classification of evidence: This study provides Class I evidence that natalizumab PK/PD parameters and safety profile are similar in adults and pediatric patients in the short term. Longer studies, also including a larger number of younger subjects (aged 10-12 years), are required to further inform about long-term PK and PD parameters in pediatric patients with MS.

Comparable efficacy and safety of dimethyl fumarate and teriflunomide treatment in Relapsing-Remitting Multiple Sclerosis: an Italian real-word multicenter experience.

BACKGROUND: The aim of the study was to evaluate the achievement of 'no evidence of disease activity' (NEDA) over a 12-month period in a large multicenter population with relapsing remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) and teriflunomide (TRF) using a propensity-score adjustment. METHODS: A time-to-event method was used to determine the percentages of patients with RRMS (pwRRMS) in both groups achieving NEDA 3 (no relapses, no 12-week confirmed disability progression, and no new T2/gadolinium-enhancing brain lesions). We described the safety profile of the investigated drugs. RESULTS: Of the 587 pwRRMS treated with DMF and the 316 pwRRMS treated with TRF, 468 pwRRMS were successfully paired by propensity score: 234 on DMF and 234 on TRF. The percentages of pwRRMS who achieved NEDA 3 were 80.3% in the DMF group and 77.2% in the TRF group. Serious adverse events occurred in four (1.9%) pwRRMS on DMF and in three (1.3%) pwRRMS on TRF. CONCLUSIONS: DMF and TRF significantly impacted RRMS disease activity in our study. Serious safety concerns were recorded in less than 2% of the studied population.

The Italian Pharmacovigilance Program: An Observational Study of Adverse Effects of Natalizumab in Multiple Sclerosis Therapy.

BACKGROUND This study shows the results of a regional pharmacovigilance program on Natalizumab therapy in relapsing-remitting multiple sclerosis (RR-MS) patients after 3 years of experience. MATERIAL AND METHODS The primary objectives of this study were to estimate the incidence of expected and unexpected adverse effects correlated to Natalizumab therapy in a cohort of 88 RR-MS patients from Sicily, Italy, and to investigate the procedures adopted by the physicians to minimize the risk of developing severe adverse reactions correlated to Natalizumab therapy. Secondary objectives of this study were to evaluate the effectiveness of Natalizumab therapy for a careful examination of the risk/benefit ratio and to assess the actions undertaken in case of adverse reactions. RESULTS Among 88 RR-MS patients, 55.68% did not report any type of adverse reaction, 35.22% showed expected adverse reactions (58.70% slight, 22.58% moderate, and 19.35% severe), and 9.10% showed unexpected adverse effects (62.50% slight, 25.00% moderate, and 12.50% severe). Approximately 4.54% of the patients treated with Natalizumab interrupted the therapy. Overall, among all patients, 56.62% showed ameliorated condition, 32.53% had stable disease condition, and 10.85% worsened. CONCLUSIONS We provide a short overview of evidence, which may be useful to better characterize the efficacy and potential adverse effects correlated to Natalizumab therapy.

Assessment of brain core temperature using MR DWI-thermometry in Alzheimer disease patients compared to healthy subjects.

PURPOSE: To assess the brain core temperature of Alzheimer disease (AD) patients in comparison with healthy volunteers using diffusion-weighted thermometry. MATERIALS AND METHODS: Fourteen AD patients (3 men, 11 women; age range 60-81 years, mean age 73.8 ± 6.1 years) and 14 healthy volunteers, age and sex-matched (mean age 70.1 ± 6.9 years; range 62-84 years; 5 men, 9 women) underwent MR examination between February 2014 and March 2016. MR imaging studies were performed with a 1.5-T MR scanner. Brain core temperature (T: °C) was calculated using the following equation from the diffusion coefficient (D) in the lateral ventricular (LV) cerebrospinal fluid: T = 2256.74/ln (4.39221/D) - 273.15 using a standard DWI single-shot echo-planar pulse sequence (b value 1000 s/mm2). Statistical analysis was performed using a nonparametric Wilcoxon rank-sum test to compare the patient and control groups regarding LV temperatures. RESULTS: There was no significant difference (P = 0.1937) in LV temperature between patients (mean 37.9 ± 1.1 °C, range 35.8-39.2 °C) and control group (38.7 ± 1.4 °C, range 36.9-42.7 °C). CONCLUSIONS: Brain core temperature in AD patients showed no significant alterations compared to healthy volunteers.

Natalizumab in the pediatric MS population: results of the Italian registry.

BACKGROUND: Natalizumab is a promising option for pediatric multiple sclerosis (MS) patients with active evolution and a poor response to Interferon-beta or Glatiramer Acetate. However, no data are available in large cohorts of patients and after a long-term follow up. Our study was planned to shed lights on this topic. METHODS: A registry was established in 2007 in Italy to collect MS cases treated with Natalizumab (NA) before 18 years of age. RESULTS: 101 patients were included (69 females), mean age of MS onset 12.9 ± 2.7 years, mean age at NA initiation 14.7 ± 2.4 years. Mean treatment duration was 34.2 ± 18.3 months. During NA treatment, a total of 15 relapses were recorded in 9 patients, annualized relapse rate was 2.3 ± 1.0 in the year prior to NA and decreased to 0.1 ± 0.3 (p < 0.001) at last NA infusion. Mean Expanded Disability Status Scale (EDSS) decreased from 2.6 ± 1.3 at initiation of NA to 1.8 ± 1.2 at the time of last visit (p < 0.001). At brain MRI, new T2 or Gd enhancing lesions were observed in 10/91 patients after 6 months, 6/87 after 12 months, 2/61 after 18 months, 2/68 after 24 months, 3/62 after 30 months, and 5/43 at longer follow up. At the time of last observation, 58% of patients were free from clinical (relapses/increased EDSS) and/or MRI activity (new T2 or gadolinium-enhancing lesions). No relevant adverse events were recorded. DISCUSSION: NA was safe, well tolerated and very efficacious in the large majority of patients. Our data support the use of this medication in subjects with pediatric MS and an aggressive course. CONCLUSIONS: A relevant reduction of relapse rate and EDSS was observed during NA treatment, compared to pre-treatment period. No evidence of disease activity (NEDA) occurred in 58% of cases.

Trace elements in scalp hair samples from patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Epidemiological studies have suggested a possible role of trace elements (TE) in the etiology of several neurological diseases including Multiple Sclerosis (MS). Hair analysis provides an easy tool to quantify TE in human subjects, including patients with neurodegenerative diseases. OBJECTIVE: To compare TE levels in scalp hair from patients with MS and healthy controls from the same geographic area (Sicily). METHODS: ICP-MS was used to determine the concentrations of 21 elements (Ag, Al, As, Ba, Cd, Co, Cr, Cu, Fe, Li, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, U, V and Zn) in scalp hair of 48 patients with relapsing-remitting Multiple Sclerosis compared with 51 healthy controls. RESULTS: MS patients showed a significantly lower hair concentration of aluminum and rubidium (median values: Al = 3.76 µg/g vs. 4.49 µg/g and Rb = 0.007 µg/g vs. 0.01 µg/g;) and higher hair concentration of U (median values U: 0.014 µg/g vs. 0.007 µg/g) compared to healthy controls. The percentages of MS patients showing hair elemental concentrations greater than the 95th percentile of controls were 20% for Ni, 19% for Ba and U, and 15% for Ag, Mo and Se. Conversely, the percentages of MS patients showing hair elemental concentrations lower than the 5th percentile of healthy controls were 27% for Al, 25% for Rb, 22% for Ag, 19% for Fe, and 16% for Pb. No significant association was found between levels of each TE and age, disease duration or Expanded Disability Status Scale (EDSS) score. After stratification by gender, healthy subjects did not show any significant difference in trace element levels, while MS patients showed significant differences (p<0.01) for the concentrations of Ag, Cr, Fe, Ni and Sr. No significant differences were also found, at p<0.01, in relation to the use of cigarettes, consume of water, vegetables and place of living. CONCLUSION: The different distributions of TE in hair of MS patients compared to controls provides an additional indirect evidence of metabolic imbalance of chemical elements in the pathogenesis of this disease. The increase in U and decrease in Al and Rb levels in MS compared to controls require further assessments as well as the observed different distributions of other elements.

Analysis of thiamine transporter genes in sporadic beriberi.

OBJECTIVE: Thiamine or vitamin B1 deficiency diminishes thiamine-dependent enzymatic activity, alters mitochondrial function, impairs oxidative metabolism, and causes selective neuronal death. We analyzed for the first time, the role of all known mutations within three specific thiamine carrier genes, SLC19 A2, SLC19 A3, and SLC25 A19, in a patient with atrophic beriberi, a multiorgan nutritional disease caused by thiamine deficiency. METHODS: A 44-year-old male alcoholic patient from Morocco developed massive bilateral leg edema, a subacute sensorimotor neuropathy, and incontinence. Despite normal vitamin B1 serum levels, his clinical picture was rapidly reverted by high-dose intramuscular thiamine treatment, suggesting a possible genetic resistance. We used polymerase chain reaction followed by amplicon sequencing to study all the known thiamine-related gene mutations identified within the Human Gene Mutation Database. RESULTS: Thirty-seven mutations were tested: 29 in SLC19 A2, 6 in SLC19 A3, and 2 in SLC25 A19. Mutational analyses showed a wild-type genotype for all sequences investigated. CONCLUSION: This is the first genetic study in beriberi disease. We did not detect any known mutation in any of the three genes in a sporadic dry beriberi patient. We cannot exclude a role for other known or unknown mutations, in the same genes or in other thiamine-associated genes, in the occurrence of this nutritional neuropathy.

A pilot study on the use of interferon beta-1a in early Alzheimer's disease subjects.

Despite the fact that multiple sclerosis (MS) and Alzheimer's disease (AD) share common neuroimmunological features, interferon beta 1a (IFNß1a), the well-established treatment for the prevention of disease progression and cognitive decline in MS patients, has never been used in AD. We evaluated the safety and efficacy of IFNß1a in subjects affected by mild-to-moderate AD in a double-blind, randomized, placebo-controlled, multicenter pilot study. Forty-two early Alzheimer's patients were randomized to receive either a 22 mcg subcutaneous injection of IFNß1a or placebo three times per week. A treatment period of 28 weeks was followed by 24 weeks of observation. IFNß1a was well tolerated and adverse events were infrequent and mild to moderate. Although not statistically significant, a reduction in disease progression during follow-up was measured in IFNß1a-treated patients by the Alzheimer's Disease Assessment Scale cognitive subscale. Interestingly, the treatment group showed significant improvements in the Instrumental Activities of Daily Living and Physical Self-maintenance Scale. This study suggests that IFNß1a is safe and well tolerated in early AD patients, and its possible beneficial role should be further investigated in larger studies.