Functional MR Imaging Correlates of Neuropsychological Impairment in Primary-Progressive Multiple Sclerosis

BACKGROUND AND PURPOSE: Cognitive deficits affect ≤30% of patients with PPMS. We investigated the functional correlates of cognitive network dysfunction in patients with PPMS and their correlation with the extent of structural MR imaging damage. MATERIALS AND METHODS: From 16 right-handed patients with PPMS and 17 matched controls, structural and fMRIs (during the performance of the 2-back task) were acquired. Neuropsychological tests exploring memory, attention, and frontal lobe cognitive domains were administered. T2 LL, NBV, and CC areas were measured. RESULTS: Six patients with PPMS were CI. Structural MR imaging measures did not differ between patients who were CI and those who were CP. Compared with patients who were CI, patients who were CP had increased activations of the left caudate nucleus, PFC, and inferior parietal lobule. Compared with controls and patients who were CP, patients who were CI had increased activations of the SII, cerebellum, and insula. Compared with controls, they also had increased activations of the right precentral gyrus and a reduced recruitment of the left PFC. In patients with PPMS, a decreased composite cognitive score correlated with increased activity of the cerebellum, insula, and SII, as well as decreased PFC activity. T2 LL correlated with decreased PFC recruitment and increased SII recruitment. CONCLUSIONS: In PPMS, an increased recruitment of cognitive-related networks might represent a functional reserve with the potential to limit the severity of cognitive impairment. The accumulation of T2 lesions and the consequent exhaustion of frontal lobe plasticity might contribute to cognitive impairment in PPMS

Long-term management of natalizumab discontinuation in a large monocentric cohort of multiple sclerosis patients

Background Pivotal and post-marketing studies demonstrated the impressive efficacy and the good tolerability profile of natalizumab in Multiple Sclerosis patients. On the other hand long-term safety of natalizumab therapy is burdened by the risk of progressive multifocal leukoencephalopathy, especially in anti-JCV seropositive patients treated for more than two years. Some of these patients must stop the drug at the risk of disease reactivation. Objectives To evaluate the effects of natalizumab discontinuation in a monocentric cohort of multiple sclerosis patients followed for a mean time of 22.4 months. Methods One hundred and ten patients, who stopped therapy after at least 12 infusions, were followed with periodic clinical and magnetic resonance imaging evaluations. One hundred patients started either immunomodulant therapy (n=90) or fingolimod (n=10) while 10 remained without any drug. Results "Disease-activity free" patients were 25% at one year after discontinuation and annualized relapse rate significantly increased from 0.06 to 0.84 (p<0.0001). We found that the risk of reactivation peaked despite alternative treatments between the second and the eighth month after suspension, a so-called "high risk period". During this period the majority of patients showed a return to pre-natalizumab disease activity while 10% of patients presented a "rebound activity". A higher pre-natalizumab disease activity was correlated with an increased risk of reactivation (p=0.004). Conclusions Our data suggest that disease reactivation peaked during a "high risk period" between the second and the eighth month since stopping the drug. During this period no alternative treatments seemed to provide an adequate protection from disease reactivation. Though transient, this phase could be potentially dangerous, therefore we need to develop more effective strategies to deal with this challenge

The ACROSS study : Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis

In chronic diseases such as multiple sclerosis requiring lifelong treatment, studies on long-term outcomes are important. To assess disability and magnetic resonance imaging-related outcomes in relapsing multiple sclerosis patients from a Phase 2 study of fingolimod 10 or more years after randomization and to compare outcomes in patients who had a higher fingolimod exposure versus those with a lower fingolimod exposure. ACROSS was a cross-sectional follow-up study of patients originally enrolled in a Phase 2 fingolimod proof-of-concept study (NCT00333138). Disability and magnetic resonance imaging-related outcomes were assessed in patients grouped according to fingolimod treatment duration, based on an arbitrary cut-off: ≥8 years (high exposure) and <8 years (low exposure). Overall, 175/281 (62%) patients participated in ACROSS; 104 (59%) of these were classified "high exposure." At 10 years, patients in the high-exposure group had smaller increases in Expanded Disability Status Scale (+0.55 vs. +1.21), and lower frequencies of disability progression (34.7% vs. 56.1%), wheelchair use (4.8% vs. 16.9%), or transition to secondary progressive multiple sclerosis (9.6% vs. 22.5%) than those in the low-exposure group. The high-exposure patients also had less progression in most magnetic resonance imaging-related outcomes. After 10 years of fingolimod treatment, disability progression was lower in the high-exposure group than in the low-exposure group

Urea-Doped Calcium Phosphate Nanoparticles as Sustainable Nitrogen Nanofertilizers for Viticulture: Implications on Yield and Quality of Pinot Gris Grapevines

In recent years, the application of nanotechnology for the development of new “smart fertilizers” is regarded as one of the most promising solutions for boosting a more sustainable and modern grapevine cultivation. Despite showing interesting potential benefits over conventional fertilization practices, the use of nanofertilizers in viticulture is still underexplored. In this work, we investigated the effectiveness of non-toxic calcium phosphate nanoparticles (Ca3(PO4)2∙nH2O) doped with urea (U-ACP) as a nitrogen source for grapevine fertilization. Plant tests were performed for two years (2019–2020) on potted adult Pinot gris cv. vines grown under semi-controlled conditions. Four fertilization treatments were compared: N1: commercial granular fertilization (45 kg N ha−1); N2: U-ACP applied in fertigation (36 kg N ha−1); N3: foliar application of U-ACP (36 kg N ha−1); C: control, receiving no N fertilization. Plant nitrogen status (SPAD), yield parameters as well as those of berry quality were analyzed. Results here presented clearly show the capability of vine plants to recognize and use the nitrogen supplied with U-ACP nanoparticles either when applied foliarly or to the soil. Moreover, all of the quali–quantitative parameters measured in vine plants fed with nanoparticles were perfectly comparable to those of plants grown in conventional condition, despite the restrained dosage of nitrogen applied with the nanoparticles. Therefore, these results provide both clear evidence of the efficacy of U-ACP nanoparticles as a nitrogen source and the basis for the development of alternative nitrogen fertilization strategies, optimizing the dosage/benefit ratio and being particularly interesting in a context of a more sustainable and modern viticulture.PSR 2014/2020 Regione Autonoma Friuli Venezia Giulia—Misure 16.1.1, DGR 1313/2018, DC 398/AGFOR 2020—GESOVIT PROJECTFondazione Cariplo, Italy, Grant n. 2016-0648, project: Romancing the stone: size controlled HYdroxyaPATItes for sustainable Agriculture (HYPATIA

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

Objective:to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.Methods:We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.Results:HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10-7) outside the HLA region (65 Mb).Discussion:genetic factors predispose to the development of OCB

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms

A “Candidate-Interactome” Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms