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

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

Effects of Natalizumab and Fingolimod on Clinical, Cognitive, and Magnetic Resonance Imaging Measures in Multiple Sclerosis

Studies comparing the effects of natalizumab and fingolimod in relapsing\u2013remitting multiple sclerosis (RRMS) are limited. We aimed to compare natalizumab and fingolimod effects on clinical, neuropsychological, and MRI measures in RRMS patients after 2 years of treatment. RRMS patients starting natalizumab (n = 30) or fingolimod (n = 25) underwent neurologic, neuropsychological, and brain MRI assessments at baseline, month (M) 6, M12, and M24. Volumes of lesions, brain, gray matter (GM), white matter (WM), and deep GM were measured. Fifteen healthy controls (HC) were also scanned at baseline and M24. Treatment groups were matched for baseline variables. At M24 versus baseline, both drugs reduced the relapse rate (p value < 0.001), stabilized disability, and improved cognitive function (fingolimod: p value = 0.03; natalizumab: p value = 0.01), without between-group differences. The natalizumab group had a higher proportion of freedom from MRI activity (67% vs 36%, p value = 0.02) and no evidence of disease activity-3 (NEDA-3) (57% vs 28%, p value = 0.04). At M24 vs M6, brain ( 12 0.35%, p value = 0.002 [fingolimod]; 12 0.42%, p value < 0.001 [natalizumab]), GM ( 12 0.62%, p value < 0.001 [fingolimod]; 12 0.64%, p value < 0.001 [natalizumab]), and WM ( 12 0.98%, p value < 0.001 [fingolimod]; 12 0.99%, p value < 0.001 [natalizumab]) atrophy progressed at higher rates than in HC, but similarly between treatment groups, whereas only the natalizumab group showed deep GM atrophy ( 12 0.79%, p value = 0.02) (p value vs fingolimod not significant). In both groups, atrophy progression was correlated with lesion accumulation (r from 12 0.49 to 12 0.36, p values from 0.013 to 0.05), whereas no correlation was found between clinical and MRI changes. Natalizumab and fingolimod reduce disease activity and improve cognition in RRMS. Natalizumab seems superior to limit lesion accumulation, whereas both drugs similarly modify atrophy progression

Studies on the novel anti-staphyloccal compound nematophin

A number of analogues of the recently described compound nematophin were prepared and studied for antibacterial activity. The 2-phenyl derivative was found to exhibit exceptional activity against methicillin resistant Staphylococcus aureus (MRSA) whereas the isosteric benzimidazole analogue was much less active

Sensitivity and reproducibility of volume change measurements of different brain portions on magnetic resonance imaging in patients with multiple sclerosis

The course of multiple sclerosis (MS) can be monitored by measuring changes in brain volume, but consensus is still lacking on the best strategy to be adopted. We compared the reproducibility and sensitivity of volume measurements from different brain portions for detecting changes on magnetic resonance imaging (MRI) in patients with MS. T1-weighted MRI of the brain was performed in 50 patients with relapsing-remitting MS at study entry and after an average follow-up of 18.4 months. Using a semiautomated technique for brain parenchyma segmentation, the volumes of the following brain portions were measured: (a) the whole brain (whole-brain volume, WBV), (b) the seven slices rostral to the velum interpositum (seven-slice volume, SSV), (c) the central slice of the image set (central-slice volume, CSV) and (d) the infratentorial regions (infratentorial-brain volume, IBV). All these measurements were carried out by a single observer and were repeated twice on ten randomly selected scans to test the intra-observer reproducibility using the four strategies. At follow-up there was a significant decrease in all the measures of brain volume (P ranged from 0.002 to < 0.001). The univariate correlations between changes in WBV, SSV, CSV and IBV were all statistically significant, with the exception of that between changes in CSV and IBV; r values ranged from 0.34 (for the WBV/IBV correlation) to 0.80 (for the WBV/SSV correlation). The mean intra-observer coefficient of variations were 1.9 % for WBV, 1.5 % for SSV, 2.9 % for CSV and 2.2% for IBV measurements. The measurement of volume on a portion of brain selectively including the regions in which MS pathology is more diffuse is as reliable and sensitive to disease-related changes as that on the whole brain, with significant time saving for processing

Cerebellar contribution to motor and cognitive performance in multiple sclerosis: An MRI sub-regional volumetric analysis

OBJECTIVE: To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients. METHODS: Whole and sub-regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores. RESULTS: Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models. CONCLUSION: Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior-inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level