Latest PUBLICATIONS

  • Neuro-Behçet's disease presenting as an isolated progressive cognitive and behavioral syndrome.
    Publication Date: 25/12/2018, on Neurocase
    by Saracino D, Allegorico L, Barbarulo AM, Pollo B, Giaccone G, D'Amico A, D'Incerti L, Bugiani O, Di Iorio G, Sampaolo S, Melone MAB
    DOI: 10.1080/13554794.2018.1561898

    Behçet's disease is a chronic inflammatory disorder manifesting as a vasculitis that affects arteries and veins of any size. Up to 44% of cases may also present with neurological symptoms, thus defining Neuro-Behçet's disease. We describe a case of Neuro-Behçet's disease characterized by progressive behavioral and cognitive deterioration prevailing over other neurological symptoms, without evident systemic involvement.

  • S29434, a quinone reductase 2 inhibitor: main biochemical and cellular characterization.
    Publication Date: 19/12/2018, on Molecular pharmacology
    by Boutin JA, Bouillaud F, Janda E, Gacsalyi I, Guillaumet G, Hirsch EC, Kane DA, Nepveu F, Reybier K, Dupuis P, Bertrand M, Chhour M, Le Diguarher T, Antoine M, Brebner K, Da Costa H, Ducrot P, Giganti A, Goswami V, Guedouari H, Michel PP, Patel A, Paysant J, Stojko J, Viaud-Massuard MC, Ferry G
    DOI: 10.1124/mol.118.114231

    Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here we present a thorough description of the potent, nanomolar inhibitor S29434 (IC50 = 5 to 16 nM) of QR2 at different organizational levels. We provide full detailed syntheses; describe its co-crystallization with and behavior at QR2 on a millisecond timeline; show that it penetrates cell membranes and inhibits QR2-mediated ROS production within the 100 nM range; and describe its actions in several in vivo models, and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathological conditions including neurodegenerative diseases.

  • Modulating interoception by insula stimulation: A double-blinded tDCS study.
    Publication Date: 17/12/2018, on Neuroscience letters
    by Sagliano L, Magliacano A, Parazzini M, Fiocchi S, Trojano L, Grossi D
    DOI: 10.1016/j.neulet.2018.12.022

    Interoception consists in the perception and processing of internal body signals, such as heartbeat. Previous neuroimaging studies revealed that attention to heartbeat activated bilateral insula and premotor regions. In the present double-blind study, we aimed at testing the role of insula in interoception by means of transcranial direct current stimulation (tDCS) interfering with its activity. Sixteen healthy participants responded to a questionnaire to evaluate the tendency to be internally focused and performed a heartbeat counting task before and after tDCS in three sessions (left insula stimulation, right insula stimulation, sham stimulation). Real and reported heartbeat were recorded and used to calculate the accuracy scores. A significant interaction between stimulation condition and time (pre- and post-stimulation) was found due to a significant improvement of the interoceptive accuracy in the sham condition only. Our results demonstrated that stimulation over the insula reduced the possibility to improve the precision with which individuals detect internal signals.

  • Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression?
    Publication Date: 12/12/2018, on Journal of neuroinflammation
    by Italiani P, Puxeddu I, Napoletano S, Scala E, Melillo D, Manocchio S, Angiolillo A, Migliorini P, Boraschi D, Vitale E, Di Costanzo A
    DOI: 10.1186/s12974-018-1376-1

    Although the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration.

  • Regression-based normative data and equivalent scores for Trail Making Test (TMT): an updated Italian normative study.
    Publication Date: 07/12/2018, on Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
    by Siciliano M, Chiorri C, Battini V, Sant'Elia V, Altieri M, Trojano L, Santangelo G
    DOI: 10.1007/s10072-018-3673-y

    The Trail Making Test (TMT) is widely used to assess psychomotor speed and attentional set-shifting. Since the regression-based norms and equivalent scores (ESs) for the TMT Italian version trace back to more than 20 years ago, we aimed at providing updated normative data for basic (Part A and Part B) and derived (Score B-A and Score B/A) TMT scores collected in a larger sample with an extended age range.

  • Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort).
    Publication Date: 06/12/2018, on Hepatology international
    by Gentile I, Scotto R, Coppola C, Staiano L, Amoruso DC, De Simone T, Portunato F, De Pascalis S, Martini S, Macera M, Viceconte G, Tosone G, Buonomo AR, Borgia G, Coppola N
    DOI: 10.1007/s12072-018-9914-6

    Direct-acting antivirals (DAAs) are safe and effective for the treatment of HCV infection. However, data regarding their efficacy in patients with Child-Pugh B cirrhosis are scarce and their capability in improving liver function is debated. The aim of our study was to assess the clinical benefits of treatment with DAA in subjects with Child-Pugh B cirrhosis.

  • TRIM8-driven transcriptomic profile of neural stem cells identified glioma-related nodal genes and pathways.
    Publication Date: 05/12/2018, on Biochimica et biophysica acta. General subjects
    by Venuto S, Castellana S, Monti M, Appolloni I, Fusilli C, Fusco C, Pucci P, Malatesta P, Mazza T, Merla G, Micale L
    DOI: 10.1016/j.bbagen.2018.12.001

    We recently reported TRIM8, encoding an E3 ubiquitin ligase, as a gene aberrantly expressed in glioblastoma whose expression suppresses cell growth and induces a significant reduction of clonogenic potential in glioblastoma cell lines.

  • Late adult-onset adrenomyeloneuropathy evolving with atypical severe frontal lobe syndrome: Importance of neuroimaging.
    Publication Date: 05/12/2018, on Radiology case reports
    by Dato C, Capaldo G, Terracciano C, Napolitano F, D'Amico A, Pappatà S, Santorelli FM, Di Iorio G, Sampaolo S, Melone MA
    DOI: 10.1016/j.radcr.2018.11.007

    X-linked adrenoleukodystrophy (X-ALD) is a rare inherited metabolic disease affecting the nervous system and the adrenal glands. It is caused by a mutation of the gene, resulting in the impaired degradation of very long-chain fatty acids and their subsequent accumulation in several organs and tissues. X-ALD is notable for its high phenotypical variability, that includes isolated adrenocortical insufficiency, slowly progressive myelopathy with paraparesis, ataxia, and peripheral neuropathy to severe childhood cerebral forms. Here, we describe the case of an X-ALD patient with a p.Gly343Val mutation in gene, who presented in adulthood with a spinal syndrome of mild severity, and later developed a progressive cognitive and behavioral syndrome. Our patient showed a striking correlation between clinical phenotype and neuroimaging, including a brain fluoro-2-deoxy-d-glucose positron emission tomography that displayed an atypical cerebral glucose metabolism.

  • Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.
    Publication Date: 04/12/2018, on Frontiers in neurology
    by D'Amore A, Tessa A, Casali C, Dotti MT, Filla A, Silvestri G, Antenora A, Astrea G, Barghigiani M, Battini R, Battisti C, Bruno I, Cereda C, Dato C, Di Iorio G, Donadio V, Felicori M, Fini N, Fiorillo C, Gallone S, Gemignani F, Gigli GL, Graziano C, Guerrini R, Gurrieri F, Kariminejad A, Lieto M, Marques LourenḈo C, Malandrini A, Mandich P, Marcotulli C, Mari F, Massacesi L, Melone MAB, Mignarri A, Milone R, Musumeci O, Pegoraro E, Perna A, Petrucci A, Pini A, Pochiero F, Pons MR, Ricca I, Rossi S, Seri M, Stanzial F, Tinelli F, Toscano A, Valente M, Federico A, Rubegni A, Santorelli FM
    DOI: 10.3389/fneur.2018.00981

    Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel () comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.

  • Preparation, structure, cytotoxicity and mechanism of action of ferritin-Pt(II) terpyridine compound nanocomposites.
    Publication Date: 03/12/2018, on Nanomedicine (London, England)
    by Ferraro G, Pica A, Petruk G, Pane F, Amoresano A, Cilibrizzi A, Vilar R, Monti DM, Merlino A
    DOI: 10.2217/nnm-2018-0259

    A Pt(II)-terpyridine compound, bearing two piperidine substituents at positions 2 and 2' of the terpyridine ligand (1), is highly cytotoxic and shows a mechanism of action distinct from cisplatin. 1 has been incorporated within the ferritin nanocage (AFt).

  • Bi-cephalic parietal and cerebellar direct current stimulation interferes with early error correction in prism adaptation: Toward a complex view of the neural mechanisms underlying visuomotor control.
    Publication Date: 01/12/2018, on Cortex; a journal devoted to the study of the nervous system and behavior
    by Panico F, Sagliano L, Grossi D, Trojano L
    DOI: 10.1016/j.cortex.2018.09.020

    Prism Adaptation (PA) represents a valid tool to assess short-term visuomotor plasticity. Two adaptive processes are involved during PA: recalibration, contributing to early error compensation, and spatial realignment, contributing to after-effect development. Classical models on PA posit that adaptive mechanisms underlying PA rely on segregated regions in the brain. Indeed, they ascribe recalibration to the activity of the Posterior Parietal Cortex (PPC) and spatial realignment to the activity of the Cerebellum. The present experiment challenges the idea of a clear-cut separation of the role of the brain areas involved in PA, proposing an interpretation in terms of interrelated brain regions. To this purpose we interfered with the activity of the PPC and the Cerebellum by means of complementary protocols of stimulation. Bi-cephalic transcranial Direct Current Stimulation was delivered simultaneously on the PPC and the Cerebellum during PA in two groups of participants receiving real stimulation with opposite polarities (anode on PPC and cathode on Cerebellum or vice-versa) and in a control group (Sham stimulation). Differences in mean errors between groups were analyzed. Results show that the two groups of real stimulation exhibited larger displacements in early error compensation compared to the Sham Group, but they did not differ from each other. No group difference was found in late error compensation and after-effect. In conclusion, the present findings provide the first direct evidence that a brain circuit connecting the PPC and the Cerebellum is involved in early stages of visuomotor adaptation, and pave the way for updating classical models of PA.

  • No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study.
    Publication Date: 01/12/2018, on Journal of neurology
    by Prosperini L, Annovazzi P, Boffa L, Buscarinu MC, Gallo A, Matta M, Moiola L, Musu L, Perini P, Avolio C, Barcella V, Bianco A, Farina D, Ferraro E, Pontecorvo S, Granella F, Grimaldi LME, Laroni A, Lus G, Patti F, Pucci E, Pasca M, Sarchielli P,
    DOI: 10.1007/s00415-018-9070-x

    In this retrospective, multicenter, real-world study we collected clinical and magnetic resonance imaging (MRI) data of all patients (n = 40) with relapsing-remitting multiple sclerosis (RRMS) treated with alemtuzumab according to a "free-of-charge" protocol available before the drug marketing approval in Italy. Almost all (39/40) started alemtuzumab after discontinuing multiple disease-modifying treatments (DMTs) because of either lack of response or safety concerns. We considered the proportion of alemtuzumab-treated patients who had no evidence of disease activity (NEDA-3) and disability improvement over a 36-month follow-up period. NEDA-3 was defined as absence of relapses, disability worsening, and MRI activity. Disability improvement was defined as a sustained reduction of ≥ 1-point in Expanded Disability Status Scale (EDSS) score. At follow-up, 18 (45%) patients achieved NEDA-3, 30 (75%) were relapse-free, 33 (82.5%) were EDSS worsening-free, and 25 (62.5%) were MRI activity-free. Eleven (27.5%) patients had a sustained disability improvement. We found no predictor for the NEDA-3 status, while the interaction of higher EDSS score by higher number of pre-alemtuzumab relapses was associated with a greater chance of disability improvement (odds ratio 1.10, p = 0.049). Our study provides real-world evidence that alemtuzumab can promote clinical and MRI disease remission, as well as disability improvement, in a significant proportion of patients with RRMS despite prior multiple DMT failures. The drug safety profile was consistent with data available from clinical trials.

  • Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts.
    Publication Date: 29/11/2018, on Cancer letters
    by Radhakrishnan R, Ha JH, Jayaraman M, Liu J, Moxley KM, Isidoro C, Sood AK, Song YS, Dhanasekaran DN
    DOI: 10.1016/j.canlet.2018.11.023

    Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.

  • Thrombus aspiration in hyperglycemic ST-elevation myocardial infarction (STEMI) patients: clinical outcomes at 1-year follow-up.
    Publication Date: 29/11/2018, on Cardiovascular diabetology
    by Sardu C, Barbieri M, Balestrieri ML, Siniscalchi M, Paolisso P, Calabrò P, Minicucci F, Signoriello G, Portoghese M, Mone P, D'Andrea D, Gragnano F, Bellis A, Mauro C, Paolisso G, Rizzo MR, Marfella R
    DOI: 10.1186/s12933-018-0795-8

    We evaluate whether the thrombus aspiration (TA) before primary percutaneous coronary intervention (PPCI) may improve STEMI outcomes in hyperglycemic patients.

  • The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21.
    Publication Date: 27/11/2018, on Cell reports
    by Lassot I, Mora S, Lesage S, Zieba BA, Coque E, Condroyer C, Bossowski JP, Mojsa B, Marelli C, Soulet C, Tesson C, Carballo-Carbajal I, Laguna A, Mangone G, Vila M, Brice A, Desagher S
    DOI: 10.1016/j.celrep.2018.11.002

    Although accumulating data indicate that increased α-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, SNCA, are largely unknown. Here, we describe a pathway regulating α-synuclein expression. Our data show that ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is an E3 ubiquitin ligase for ZSCAN21. In contrast, TRIM17 decreases the TRIM41-mediated degradation of ZSCAN21. Silencing of ZSCAN21 and TRIM17 consistently reduces SNCA expression, whereas TRIM41 knockdown increases it. The mRNA levels of TRIM17, ZSCAN21, and SNCA are simultaneously increased in the midbrains of mice following MPTP treatment. In addition, rare genetic variants in ZSCAN21, TRIM17, and TRIM41 genes occur in patients with familial forms of PD. Expression of variants in ZSCAN21 and TRIM41 genes results in the stabilization of the ZSCAN21 protein. Our data thus suggest that deregulation of the TRIM17/TRIM41/ZSCAN21 pathway may be involved in the pathogenesis of PD.