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D'Arco, F., Ugga, L., Caranci, F., Riccio, M.P., Figliuolo, C., Mankad, K., D'Amico, A.
Isolated macrocerebellum: Description of six cases and literature review
(2016) Quantitative Imaging in Medicine and Surgery, 6 (5), pp. 496-503. 
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DOI: 10.21037/qims.2016.06.10
AFFILIATIONS: Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; 
Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy; 
Department of Mental and Physical Health and Preventive Medicine, Child and Adolescent Psychiatry Division, Second University of Naples, Caserta, Italy; 
Section of Pediatrics, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
ABSTRACT: Background: Macrocerebellum is a rare entity described as an isolated and abnormal increase of the cerebellum (CB) size without morphological or signal abnormalities. There have been only eleven patients with macrocerebellum reported in the literature so far. Methods: From December 2011 to March 2014, among 950 paediatric patients that underwent a magnetic resonance scan of the brain in our department, in six subjects an abnormal increase of the cerebellar volume was suspected. A volumetric analysis was performed in all patients on T1-weighted 3D imaging to confirm the diagnosis of macrocerebellum. The ratios between (I) volume of the CB and volume of the supratentorial structures (STB) and (II) volume of the CB and the sum of CB and STB (WB) were calculated in order to normalize the absolute values obtained and compared with the normal values present in literature. Results and Discussion: Quantitative analysis confirmed an increased cerebellar volume relatively to the STB volume ("t": 6.9518; P<0.001) and to the WB ("t": 7.1415; P<0.001) volume in comparison to the normal controls available in literature. Clinical characteristics and other neuroradiological findings of the patients are described. We also describe the differential features between isolated macrocerebellum and other pathological conditions that are characterized by cerebellar enlargement such as Lhermitte-Duclos, Sotos syndrome, Costello syndrome, Williams syndrome, Alexander disease and fucosidosis. Furthermore a detailed literature review is provided. Macrocerebellum is always associated with an abnormal mental and motor development. Conclusion: Macrocerebellum is a neuroradiological entity that can be identified qualitatively and confirmed quantitatively through volumetric analysis. This is the largest cohort of patients with macrocerebellum described so far. The data available in literature on this entity show that macrocerebellum is not a specific disease but an epiphenomenon found in heterogeneous brain disorders. © Quantitative Imaging in Medicine and Surgery. All rights reserved.
CORRESPONDENCE ADDRESS: D'Arco, F.; Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation TrustUnited Kingdom; email: darcofel@gmail.com

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Rengo, G., Pagano, G., Filardi, P.P., Femminella, G.D., Parisi, V., Cannavo, A., Liccardo, D., Komici, K., Gambino, G., D'Amico, M.L., De Lucia, C., Paolillo, S., Trimarco, B., Vitale, D.F., Ferrara, N., Koch, W.J., Leosco, D.
Prognostic value of lymphocyte G protein-coupled receptor kinase-2 protein levels in patients with heart failure
(2016) Circulation Research, 118 (7), pp. 1116-1124. 
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DOI: 10.1161/CIRCRESAHA.115.308207
AFFILIATIONS: Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy; 
Division of Geriatrics, Department of Translational Medical Sciences, University of Naples Federico II, Via S. Pansini, 5, Naples, Italy; 
Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy; 
SDN Foundation IRCCS, Institute of Diagnostic and Nuclear Development, Naples, Italy; 
Department of Pharmacology, Center of Translational Medicine, Temple University School of Medicine, 3500 N Broad St., Philadelphia, PA, United States
ABSTRACT: Rationale: Sympathetic nervous system hyperactivity is associated with poor prognosis in patients with heart failure (HF), yet routine assessment of sympathetic nervous system activation is not recommended for clinical practice. Myocardial G protein-coupled receptor kinase-2 (GRK2) is upregulated in HF patients, causing dysfunctional β-adrenergic receptor signaling. Importantly, myocardial GRK2 levels correlate with levels found in peripheral lymphocytes of HF patients. Objective: The independent prognostic value of blood GRK2 measurements in HF patients has never been investigated; thus, the purpose of this study was to evaluate whether lymphocyte GRK2 levels predict clinical outcome in HF patients. Methods and Results: We prospectively studied 257 HF patients with mean left ventricular ejection fraction of 31.4±8.5%. At the time of enrollment, plasma norepinephrine, serum NT-proBNP, and lymphocyte GRK2 levels, as well as clinical and instrumental variables were measured. The prognostic value of GRK2 to predict cardiovascular (CV) death and all-cause mortality was assessed using the Cox proportional hazard model including demographic, clinical, instrumental, and laboratory data. Over a mean follow-up period of 37.5±20.2 months (range, 3-60 months), there were 102 CV deaths. Age, left ventricular ejection fraction, New York Heart Association class, chronic obstructive pulmonary disease, chronic kidney disease, N-terminal-pro brain natriuretic peptide, and lymphocyte GRK2 protein levels were independent predictors of CV mortality in HF patients. GRK2 levels showed an additional prognostic and clinical value over demographic and clinical variables. The independent prognostic value of lymphocyte GRK2 levels was also confirmed for all-cause mortality. Conclusions: Lymphocyte GRK2 protein levels can independently predict prognosis in patients with HF. © 2016 American Heart Association, Inc.
CORRESPONDENCE ADDRESS: Koch, W.J.; Department of Pharmacology, Center of Translational Medicine, Temple University School of Medicine, 3500 N Broad St., United States; email: walter.koch@temple.edu

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Corbi, G., Conti, V., Davinelli, S., Scapagnini, G., Filippelli, A., Ferrara, N.
Dietary phytochemicals in neuroimmunoaging: A new therapeutic possibility for humans?
(2016) Frontiers in Pharmacology, 7, art. no. 364, . 
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DOI: 10.3389/fphar.2016.00364
AFFILIATIONS: Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy; 
Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy; 
Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy; 
Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese, Telese Terme, Italy
ABSTRACT: Although several efforts have been made in the search for genetic and epigenetic patterns linked to diseases, a comprehensive explanation of the mechanisms underlying pathological phenotypic plasticity is still far from being clarified. Oxidative stress and inflammation are two of the major triggers of the epigenetic alterations occurring in chronic pathologies, such as neurodegenerative diseases. In fact, over the last decade, remarkable progress has been made to realize that chronic, low-grade inflammation is one of the major risk factor underlying brain aging. Accumulated data strongly suggest that phytochemicals from fruits, vegetables, herbs, and spices may exert relevant immunomodulatory and/or anti-inflammatory activities in the context of brain aging. Starting by the evidence that a common denominator of aging and chronic degenerative diseases is represented by inflammation, and that several dietary phytochemicals are able to potentially interfere with and regulate the normal function of cells, in particular neuronal components, aim of this review is to summarize recent studies on neuroinflammaging processes and proofs indicating that specific phytochemicals may act as positive modulators of neuroinflammatory events. In addition, critical pathways involved in mediating phytochemicals effects on neuroinflammaging were discussed, exploring the real impact of these compounds in preserving brain health before the onset of symptoms leading to inflammatory neurodegeneration and cognitive decline.
CORRESPONDENCE ADDRESS: Corbi, G.; Department of Medicine and Health Sciences, University of MoliseItaly; email: graziamaria.corbi@unimol.it

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Buonocore, M., Amarelli, C., Scardone, M., Caiazzo, A., Petrone, G., Majello, L., Santé, P., Nappi, G., Della Corte, A.
Cerebral perfusion issues in acute type A aortic dissection without preoperative malperfusion: How do surgical factors affect outcomes?
(2016) European Journal of Cardio-thoracic Surgery, 50 (4), pp. 652-659. 
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DOI: 10.1093/ejcts/ezw152
AFFILIATIONS: Department of Cardiac Surgery, AZ Sint Jan, Brugge, Belgium; 
Department of Cardiovascular Surgery and Transplants, Monaldi Hospital, Azienda dei Colli, Naples, Italy; 
Department of Cardiothoracic Sciences, Second University of Naples, Naples, Italy; 
Unit of Neurology, Monaldi Hospital, Azienda dei Colli, Naples, Italy
ABSTRACT: OBJECTIVES: Both preoperative (disease-related) and operative (management-related) variables make the assessment of the outcomes of acute type A aortic dissection (ATAAD) surgery a difficult task. Our aim was to evaluate the impact of operative factors, including arterial cannulation site, route of cerebral perfusion and surgeon's specific experience with ATAAD ('aortic surgeon'), on the early results of surgical management, with particular attention to neurological injury. METHODS: Penn classification was used to identify clinically homogeneous risk groups of ATAAD patients undergoing surgery. Between January 2007 and June 2014, 111 of 183 ATAAD patients treated with open surgery in a single centre were in Penn Class Aa (no ischaemic complications at presentation). They were divided in two groups depending on the arterial cannulation site: femoral artery (FemA; 56 patients) or right axillary artery (RAxA; 55 patients). Study outcomes included: 30-day mortality, major adverse cardiac and cerebrovascular events at 30 days, neurological complications and in particular, patterns of stroke as defined by Bamford classification. RESULTS: No significant differences in preoperative variables were observed between cannulation-site groups, except for myocardial ischaemic time (60.9 ± 30.4 min in the RAxA group vs 81.7 ± 52.3 in the FemA group, P = 0.014) and cerebral perfusion time (42.1 ± 25.5 min in the RAxA group vs 52.9 ± 32.6 in the FemA group, P = 0.048). Outcomes in terms of mortality and neurological injury did not differ except for a higher incidence of lacunar cerebral infarction (LACI) in the RAxA group (14.5 vs 3.6%, P = 0.043), mainly but not exclusively explained by a higher incidence of LACI in unilateral (17.2%) than in bilateral cerebral perfusion (6.9%) within the RAxA group. The 'non-aortic surgeon' was associated instead with 30-day mortality and composite outcome in multivariable analysis (respectively, OR 6.40, P = 0.002 and OR 4.68, P = 0.001). CONCLUSIONS: The RAxA cannulation and FemA cannulation are associated with comparable 30-day mortality following surgery for aortic dissection. However, the possible higher risk of LACI-type strokes in the RAxA group, especially when associated with unilateral brain perfusion, should be considered when RAxA cannulation is performed in ATAAD. The hypothesis that more experienced surgeons may produce better earlier outcomes warrants further investigation. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
CORRESPONDENCE ADDRESS: Buonocore, M.; Department of Cardiac Surgery, AZ Sint Jan, Ruddershove 10, Belgium; email: mariannabuonocore@gmail.com

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Makovac, E., Cercignani, M., Serra, L., Torso, M., Spanò, B., Petrucci, S., Ricciardi, L., Ginevrino, M., Caltagirone, C., Bentivoglio, A.R., Valente, E.M., Bozzali, M.
Brain connectivity changes in autosomal recessive Parkinson disease: A model for the sporadic form
(2016) PLoS ONE, 11 (10), art. no. e0163980, . 
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DOI: 10.1371/journal.pone.0163980
AFFILIATIONS: Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy; 
Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Falmer, Brighton, United Kingdom; 
IRCCS Casa Sollievo della Sofferenza, CSS-Mendel laboratory, San Giovanni Rotondo, Italy; 
Dept. of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy; 
Sobell Dept. of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom; 
Dept. of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; 
Dept. of Neuroscience, University of Rome 'Tor Vergata', Rome, Italy; 
Dept. of Neurosciences, Catholic University, Rome, Italy; 
Section of Neurosciences, Dept. of Medicine and Surgery, University of Salerno, Salerno, Italy
ABSTRACT: Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RSfMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients' cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RSfMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms. Copyright © 2016 Makovac et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Krashia, P., Ledonne, A., Nobili, A., Cordella, A., Errico, F., Usiello, A., D'Amelio, M., Mercuri, N.B., Guatteo, E., Carunchio, I.
Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons
(2016) Neuropharmacology, 103, pp. 69-78. 
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DOI: 10.1016/j.neuropharm.2015.12.013
AFFILIATIONS: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; 
Department of Medicine, Unit of Molecular Neurosciences, University Campus-Biomedico, Rome, Italy; 
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 
Ceinge Biotecnologie Avanzate, Naples, Italy; 
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; 
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy
ABSTRACT: Dopamine neurons in the substantia nigra pars compacta regulate not only motor but also cognitive functions. NMDA receptors play a crucial role in modulating the activity of these cells. Considering that the amino-acid D-Aspartate has been recently shown to be an endogenous NMDA receptor agonist, the aim of the present study was to examine the effects of D-Aspartate on the functional properties of nigral dopamine neurons. We compared the electrophysiological actions of D-Aspartate in control and D-aspartate oxidase gene (Ddo-/-) knock-out mice that show a concomitant increase in brain D-Aspartate levels, improved synaptic plasticity and cognition. Finally, we analyzed the effects of L-Aspartate, a known dopamine neuron endogenous agonist in control and Ddo-/- mice. We show that D- and L-Aspartate excite dopamine neurons by activating NMDA, AMPA and metabotropic glutamate receptors. Ddo deletion did not alter the intrinsic properties or dopamine sensitivity of dopamine neurons. However, NMDA-induced currents were enhanced and membrane levels of the NMDA receptor GluN1 and GluN2A subunits were increased. Inhibition of excitatory amino-acid transporters caused a marked potentiation of D-Aspartate, but not L-Aspartate currents, in Ddo-/- neurons. This is the first study to show the actions of D-Aspartate on midbrain dopamine neurons, activating not only NMDA but also non-NMDA receptors. Our data suggest that dopamine neurons, under conditions of high D-Aspartate levels, build a protective uptake mechanism to compensate for increased NMDA receptor numbers and cell hyper-excitation, which could prevent the consequent hyper-dopaminergia in target zones that can lead to neuronal degeneration, motor and cognitive alterations. © 2015 Elsevier Ltd. All rights reserved.
CORRESPONDENCE ADDRESS: Guatteo, E.; Department of Experimental Neurology, IRCCS Santa Lucia FoundationItaly; email: e.guatteo@hsantalucia.it

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Caccavale, S., Bove, D., Bove, R.M., La Montagna, M.
Skin and brain: Itch and psychiatric disorders
(2016) Giornale Italiano di Dermatologia e Venereologia, 151 (5), pp. 525-529. 
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AFFILIATIONS: Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy; 
Fusis Association for Research in Child and Adolescent Neuropsychiatry, Alvignano, Italy; 
Department of Clinical and Experimental Sciences, Section of Psychiatry and Clinical Psychology, University of Foggia, Via Antonio Gramsci, Foggia, Italy
ABSTRACT: Skin diseases (atopic eczema, psoriasis, idiopathic urticaria), systemic diseases (chronic hepatic or renal failure, morbus Hodgkin, diabetes mellitus) and psychiatric disorders (obsessive compulsive disorders, depression, delusions of parasitosis) can occur with itching. The aim of this review is to clarify the link between pruritus and psychiatric morbidity and emphasize the importance of a psychiatric consultation for patients with a chronic itching, without a skin disease. In the last years, there is a growing awareness regarding psychogenic itch, although these types of itch are significantly less studied in comparison to other types of pruritus. Psychogenic pruritus is usually a diagnosis of exclusion. There are not controlled studies about treatment of psychogenic itch, but the same drugs prescribed for neuropathic pain, depression, and anxiety are used. There is a strong association between pruritus and psyche; so, it is important that the dermatologist evaluates psychosomatic dimension. According to the analysis of scientific literature and our clinical experience, pruritus seems to be a rather common phenomenon in patients suffering from depression. Future works should explain the basis of psychopathology of chronic itching thanks to studies of selected groups of patients with a particular type of chronic itching, highlighting the clinical features to establish appropriate and individual targeted care, based on the several types of pruritus. Some questions still unanswered could be clarified in this way. It is really important to decrease the symptoms "itching", because the quality of life of the patient will be improved, but the goal is to identify the underlying mechanisms of itch and establish a targeted therapy, depending on the biological changes and the underlying disease. Copyright © 2016 Edizioni Minerva Medica.
AUTHOR KEYWORDS: Brain;  Mental disorders;  Pruritus;  Skin
CORRESPONDENCE ADDRESS: La Montagna, M.; Department of Clinical and Experimental Sciences, Section of Psychiatry and Clinical Psychology, University of Foggia, Via Antonio Gramsci, Italy; email: maddafly87@libero.it
DOCUMENT TYPE: Review

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Caccavale, S., Bove, D., Bove, R.M., La Montagna, M.
Skin and brain: Itch and psychiatric disorders
(2016) Giornale Italiano di Dermatologia e Venereologia, 151 (5), pp. 525-529. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84988908294&partnerID=40&md5=276651a8dec70d97edb467009baa5ec8

AFFILIATIONS: Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, Naples, Italy; 
Fusis Association for Research in Child and Adolescent Neuropsychiatry, Alvignano, Italy; 
Department of Clinical and Experimental Sciences, Section of Psychiatry and Clinical Psychology, University of Foggia, Via Antonio Gramsci, Foggia, Italy
ABSTRACT: Skin diseases (atopic eczema, psoriasis, idiopathic urticaria), systemic diseases (chronic hepatic or renal failure, morbus Hodgkin, diabetes mellitus) and psychiatric disorders (obsessive compulsive disorders, depression, delusions of parasitosis) can occur with itching. The aim of this review is to clarify the link between pruritus and psychiatric morbidity and emphasize the importance of a psychiatric consultation for patients with a chronic itching, without a skin disease. In the last years, there is a growing awareness regarding psychogenic itch, although these types of itch are significantly less studied in comparison to other types of pruritus. Psychogenic pruritus is usually a diagnosis of exclusion. There are not controlled studies about treatment of psychogenic itch, but the same drugs prescribed for neuropathic pain, depression, and anxiety are used. There is a strong association between pruritus and psyche; so, it is important that the dermatologist evaluates psychosomatic dimension. According to the analysis of scientific literature and our clinical experience, pruritus seems to be a rather common phenomenon in patients suffering from depression. Future works should explain the basis of psychopathology of chronic itching thanks to studies of selected groups of patients with a particular type of chronic itching, highlighting the clinical features to establish appropriate and individual targeted care, based on the several types of pruritus. Some questions still unanswered could be clarified in this way. It is really important to decrease the symptoms "itching", because the quality of life of the patient will be improved, but the goal is to identify the underlying mechanisms of itch and establish a targeted therapy, depending on the biological changes and the underlying disease. Copyright © 2016 Edizioni Minerva Medica.
AUTHOR KEYWORDS: Brain;  Mental disorders;  Pruritus;  Skin
CORRESPONDENCE ADDRESS: La Montagna, M.; Department of Clinical and Experimental Sciences, Section of Psychiatry and Clinical Psychology, University of Foggia, Via Antonio Gramsci, Italy; email: maddafly87@libero.it
DOCUMENT TYPE: Review

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Mucci, A., Dima, D., Soricelli, A., Volpe, U., Bucci, P., Frangou, S., Prinster, A., Salvatore, M., Galderisi, S., Maj, M.
Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback
(2015) Psychological Medicine, 45 (8), pp. 1765-1778. 
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DOI: 10.1017/S0033291714002943
AFFILIATIONS: Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, Naples, Italy; 
Psychosis Research Program, Department of Psychiatry, Icahn School of Medicine, Mount Sinai, NY, United States; 
MRC Social Genetic and Developmental Psychiatry, Institute of Psychiatry, King's College London, United Kingdom; 
University of Naples 'Parthenope', IRCCS Research Institute SDN, Naples, Italy; 
Biostructure and Bioimaging Institute, National Research Council, Naples, Italy; 
Department of Biomorphological and Functional Studies, University of Naples 'Federico II', Naples, Italy
ABSTRACT: Background The neurobiological underpinnings of avolition in schizophrenia remain unclear. Most brain imaging research has focused on reward prediction deficit and on ventral striatum dysfunction, but findings are not consistent. In the light of accumulating evidence that both ventral striatum and dorsal caudate play a key role in motivation, we investigated ventral striatum and dorsal caudate activation during processing of reward or loss in patients with schizophrenia. Method We used functional magnetic resonance imaging to study brain activation during a Monetary Incentive Delay task in patients with schizophrenia, treated with second-generation antipsychotics only, and in healthy controls (HC). We also assessed the relationships of ventral striatum and dorsal caudate activation with measures of hedonic experience and motivation. Results The whole patient group had lower motivation but comparable hedonic experience and striatal activation than HC. Patients with high avolition scores showed lower dorsal caudate activation than both HC and patients with low avolition scores. A lower dorsal caudate activation was also observed in patients with deficit schizophrenia compared to HC and patients with non-deficit schizophrenia. Dorsal caudate activity during reward anticipation was significantly associated with avolition, but not with anhedonia in the patient group. Conclusions These findings suggest that avolition in schizophrenia is linked to dorsal caudate hypoactivation. © Cambridge University Press 2015.
AUTHOR KEYWORDS: Avolition;  deficit schizophrenia;  dorsal caudate;  reward anticipation;  schizophrenia;  ventral striatum
CORRESPONDENCE ADDRESS: Mucci, A.; Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, Italy; email: armida.mucci@gmail.com
DOCUMENT TYPE: Article

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Babiloni, C., Del Percio, C., Caroli, A., Salvatore, E., Nicolai, E., Marzano, N., Lizio, R., Cavedo, E., Landau, S., Chen, K., Jagust, W., Reiman, E., Tedeschi, G., Montella, P., De Stefano, M., Gesualdo, L., Frisoni, G.B., Soricelli, A.
Cortical sources of resting state EEG rhythms are related to brain hypometabolism in subjects with Alzheimer's disease: an EEG-PET study
(2016) Neurobiology of Aging, 48, pp. 122-134. 
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DOI: 10.1016/j.neurobiolaging.2016.08.021
AFFILIATIONS: Department of Human Physiology and Pharmacology “Erspamer”, University of Rome “ La Sapienza”, Rome, Italy; 
Institute for Research and Medical Care, IRCCS San Raffaele Pisana, Rome, Italy; 
Department of Integrated Imaging, IRCCS SDN, Napoli, Italy; 
Medical Imaging Unit, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy; 
Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy; 
LENITEM Laboratory of Epidemiology, Neuroimaging, and Telemedicine, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy; 
Cognition, Neuroimaging and Brain Diseases Laboratory, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épiniére (CRICM-UMRS 975), Université Pierre et Marie Curie-Paris 6, Paris, France; 
Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States; 
Banner Alzheimer's Institute, Phoenix, AZ, United States; 
Department of Neurological Sciences, Second University of Naples, Naples, Italy; 
Dipartimento Emergenza e Trapianti d'Organi (D.E.T.O), University of Bari, Bari, Italy; 
Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland; 
Department of Motor Sciences and Healthiness, University of Naples Parthenope, Naples, Italy
ABSTRACT: Cortical sources of resting state electroencephalographic (EEG) delta (2–4 Hz) and low-frequency alpha (8–10.5 Hz) rhythms show abnormal activity (i.e., current density) in patients with dementia due to Alzheimer's disease (AD). Here, we hypothesized that abnormality of this activity is related to relevant disease processes as revealed by cortical hypometabolism typically observed in AD patients by fluorodeoxyglucose positron emission tomography. Resting state eyes-closed EEG data were recorded in 19 AD patients with dementia and 40 healthy elderly (Nold) subjects. EEG frequency bands of interest were delta and low-frequency alpha. EEG sources were estimated in these bands by low-resolution brain electromagnetic tomography (LORETA). Fluorodeoxyglucose positron emission tomography images were recorded only in the AD patients, and cortical hypometabolism was indexed by the so-called Alzheimer's discrimination analysis tool (PALZ) in the frontal association, ventromedial frontal, temporoparietal association, posterior cingulate, and precuneus areas. Results showed that compared with the Nold group, the AD group pointed to higher activity of delta sources and lower activity of low-frequency alpha sources in a cortical region of interest formed by all cortical areas of the PALZ score. In the AD patients, there was a positive correlation between the PALZ score and the activity of delta sources in the cortical region of interest (p < 0.05). These results suggest a relationship between resting state cortical hypometabolism and synchronization of cortical neurons at delta rhythms in AD patients with dementia. © 2016 Elsevier Inc.
AUTHOR KEYWORDS: Alzheimer's disease (AD);  Brain hypometabolism;  Electroencephalography (EEG);  Fluorodeoxyglucose positron emission tomography (FDG-PET);  Low resolution brain electromagnetic tomography (LORETA)
CORRESPONDENCE ADDRESS: Lizio, R.; Department of Physiology and Pharmacology “V. Erspamer”, University of Rome “La Sapienza”, P.le A. Moro 5, Italy; email: roberta.lizio@uniroma1.it
DOCUMENT TYPE: Article

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Citraro, R., Russo, E., Leo, A., Russo, R., Avagliano, C., Navarra, M., Calignano, A., De Sarro, G.
Pharmacokinetic-pharmacodynamic influence of N-palmitoylethanolamine, arachidonyl-2′-chloroethylamide and WIN 55,212-2 on the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice
(2016) European Journal of Pharmacology, 791, pp. 523-534. 
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DOI: 10.1016/j.ejphar.2016.09.029
AFFILIATIONS: Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University “Magna Graecia” of Catanzaro, Italy; 
Department of Pharmacy, University of Naples “Federico II”Naples, Italy; 
Department of Experimental Pharmacology, University of MessinaMessina, Italy
ABSTRACT: We evaluated the effects of ACEA (selective cannabinoid (CB)1 receptor agonist), WIN 55,212-2 mesylate (WIN; non-selective CB1 and CB2 receptor agonist) and N-palmitoylethanolamine (PEA; an endogenous fatty acid of ethanolamide) in DBA/2 mice, a genetic model of reflex audiogenic epilepsy. PEA, ACEA or WIN intraperitoneal (i.p.) administration decreased the severity of tonic-clonic seizures. We also studied the effects of PEA, WIN or ACEA after co-administration with NIDA-41020 (CB1 receptor antagonist) or GW6471 (PPAR-α antagonist) and compared the effects of WIN, ACEA and PEA in order to clarify their mechanisms of action. PEA has anticonvulsant features in DBA/2 mice mainly through PPAR-α and likely indirectly on CB1 receptors, whereas ACEA and WIN act through CB1 receptors. The co-administration of ineffective doses of ACEA, PEA and WIN with some antiepileptic drugs (AEDs) was examined in order to identify potential pharmacological interactions in DBA/2 mice. We found that PEA, ACEA and WIN co-administration potentiated the efficacy of carbamazepine, diazepam, felbamate, gabapentin, phenobarbital, topiramate and valproate and PEA only also that of oxcarbazepine and lamotrigine whereas, their co-administration with levetiracetam and phenytoin did not have effects. PEA, ACEA or WIN administration did not significantly influence the total plasma and brain levels of AEDs; therefore, it can be concluded that the observed potentiation was only of pharmacodynamic nature. In conclusion, PEA, ACEA and WIN show anticonvulsant effects in DBA/2 mice and potentiate the effects several AEDs suggesting a possible therapeutic relevance of these drugs and their mechanisms of action. © 2016
AUTHOR KEYWORDS: Antiepileptic drugs;  Audiogenic seizure model;  Cannabinoid compounds;  Drug interaction;  PEA;  PPAR-α receptors
CORRESPONDENCE ADDRESS: De Sarro, G.; Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University “Magna Graecia” of CatanzaroItaly; email: desarro@unicz.it
DOCUMENT TYPE: Article

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Coccurello, R., Bisogno, T.
The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases
(2016) Expert Review of Clinical Pharmacology, 9 (10), pp. 1351-1362. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84988531024&partnerID=40&md5=f2b954b1fb46fa7adc30f1273486f327

DOI: 10.1080/17512433.2016.1209111
AFFILIATIONS: Institute of Cell Biology and Neurobiology (IBCN), National Research Council (C.N.R.), Roma, Italy; 
Fondazione S. Lucia (FSL- IRCCS), Neurochemistry of Lipids Lab, Roma, Italy; 
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council (C.N.R.), Pozzuoli, Italy; 
Department of Medicine, Campus Bio-Medico University of Rome, Roma, Italy
ABSTRACT: Introduction: Psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the ‘bright side’ of e cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework. Areas covered: We will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson’s disease and Huntington disease. Expert commentary: Despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network. © 2016 Informa UK Limited, trading as Taylor & Francis Group.
AUTHOR KEYWORDS: cannabinoid-based drugs;  endocannabinoid system;  Huntington disease;  motor diseases;  neuroprotection;  Parkinson’s disease
CORRESPONDENCE ADDRESS: Coccurello, R.; Institute of Cell Biology and Neurobiology (IBCN), National Research Council (C.N.R.), IRCCS Fondazione S. Lucia (FSL), Via del Fosso di Fiorano 64, Italy; email: roberto.coccurello@cnr.it
DOCUMENT TYPE: Review

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Pezzini, A., Grassi, M., Lodigiani, C., Patella, R., Gandolfo, C., Zini, A., Delodovici, M.L., Paciaroni, M., Del Sette, M., Toriello, A., Musolino, R., Calabrò, R.S., Bovi, P., Adami, A., Silvestrelli, G., Sessa, M., Cavallini, A., Marcheselli, S., Marco Bonifati, D., Checcarelli, N., Tancredi, L., Chiti, A., Del Zotto, E., Tomelleri, G., Spalloni, A., Giorli, E., Costa, P., Giacalone, G., Ferrazzi, P., Poli, L., Morotti, A., Piras, V., Rasura, M., Simone, A.M., Gamba, M., Cerrato, P., Zedde, M.L., Micieli, G., Melis, M., Massucco, D., Guido, D., De Giuli, V., Bonaiti, S., D'Amore, C., La Starza, S., Iacoviello, L., Padovani, A.
Propensity Score-Based Analysis of Percutaneous Closure Versus Medical Therapy in Patients with Cryptogenic Stroke and Patent Foramen Ovale: The IPSYS Registry (Italian Project on Stroke in Young Adults)
(2016) Circulation: Cardiovascular Interventions, 9 (9), art. no. e003470, . 
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DOI: 10.1161/CIRCINTERVENTIONS.115.003470
AFFILIATIONS: Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1, Brescia, Italy; 
Dipartimento di Scienze Del Sistema Nervoso e Del Comportamento, Unità di Statistica Medica e Genomica, Università di Pavia, Italy; 
Centro Trombosi, IRCCS Istituto Clinico Humanitas, Rozzano-Milano, Italy; 
Stroke Unit, Azienda Ospedaliera sant'Andrea, Università la Sapienza, Rome, Italy; 
Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genova, Italy; 
Stroke Unit, Clinica Neurologica, Nuovo Ospedale Civile s. Agostino Estense, Modena, Italy; 
Unità di Neurologia, Ospedale di Circolo, Università dell'Insubria, Varese, Italy; 
Stroke Unit, Divisione di Medicina Cardiovascolare, Università di Perugia, Perugia, Italy; 
Unità di Neurologia, Ospedale Galliera, Genova, Italy; 
A.O Universitaria san Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy; 
Dipartimento di Neuroscienze, Scienze Psichiatriche e Anestesiologiche, Clinica Neurologica, Università di Messina, Italy; 
IRCCS, Centro Neurolesi Bonino-Pulejo, Messina, Italy; 
UO Neurologia, Azienda Ospedaliera-Universitaria Borgo Trento, Verona, Italy; 
Stroke Center, Dipartimento di Neurologia, Ospedale Sacro Cuore Negrar, Verona, Italy; 
Stroke Unit, Dipartimento di Neuroscienze, Azienda Ospedaliera Carlo Poma, Mantova, Italy; 
U.O Neurologia, Istituti Ospitalieri, Cremona, Italy; 
Stroke Unit, IRCCS Fondazione Istituto c. Mondino Pavia, Italy; 
Neurologia d'Urgenza e Stroke Unit, IRCCS Istituto Clinico Humanitas, Rozzano-Milano, Italy; 
Stroke Unit, U.O Neurologia, Ospedale s. Chiara, Trento, Italy; 
U.O.C Neurologia, Ospedale Valduce, Como, Italy; 
U.O Neurologia, Azienda Ospedaliera Ospedale sant'Anna, Como, Italy; 
Neurologia, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy; 
U.O Recupero e Rieducazione Funzionale, IRCCS Fondazione Don Gnocchi, Milan, Italy; 
Unità di Neurologia, Ospedale S. Andrea, La Spezia, Italy; 
Clinica Neurologia, IRCCS san Raffaele Milano, Italy; 
Stroke Unit, Azienda Ospedaliera g. Brotzu Cagliari, Italy; 
Stroke Unit, Neurologia Vascolare, Spedali Civili di Brescia, Italy; 
Dipartimento di Neuroscienze, Stroke Unit, Università di Torino, Italy; 
S.C. Neurologia, IRCCS Arcispedale santa Maria Nuova Reggio Emilia, Italy; 
Laboratorio di Epidemiologia Molecolare e Nutrizionale, Dipartimento di Epidemiologia e Prevenzione, IRCCS Istituto Neurologico Mediterraneo, Pozzilli, Italy
ABSTRACT: Background-We sought to compare the benefit of percutaneous closure to that of medical therapy alone for the secondary prevention of embolism in patients with patent foramen ovale (PFO) and otherwise unexplained ischemic stroke, in a propensity scored study. Methods and Results-Between 2000 and 2012, we selected consecutive first-ever ischemic stroke patients aged 18 to 45 years with PFO and no other cause of brain ischemia, as part of the IPSYS registry (Italian Project on Stroke in Young Adults), who underwent either percutaneous PFO closure or medical therapy for comparative analysis. Primary end point was a composite of ischemic stroke, transient ischemic attack, or peripheral embolism. Secondary end point was brain ischemia. Five hundred and twenty-one patients qualified for the analysis. The primary end point occurred in 15 patients treated with percutaneous PFO closure (7.3%) versus 33 patients medically treated (10.5%; hazard ratio, 0.72; 95% confidence interval, 0.39-1.32; P=0.285). The rates of the secondary end point brain ischemia were also similar in the 2 treatment groups (6.3% in the PFO closure group versus 10.2% in the medically treated group; hazard ratio, 0.64; 95% confidence interval, 0.33-1.21; P=0.168). Closure provided a benefit in patients aged 18 to 36 years (hazard ratio, 0.19; 95% confidence interval, 0.04-0.81; P=0.026) and in those with a substantial right-to-left shunt size (hazard ratio, 0.19; 95% confidence interval, 0.05-0.68; P=0.011). Conclusions-PFO closure seems as effective as medical therapy for secondary prevention of cryptogenic ischemic stroke. Whether device treatment might be more effective in selected cases, such as in patients younger than 37 years and in those with a substantial right-to-left shunt size, deserves further investigation. © 2016 American Heart Association, Inc.
AUTHOR KEYWORDS: atrial septum;  follow-up studies;  patent foramen ovale;  secondary prevention;  stroke
CORRESPONDENCE ADDRESS: Pezzini, A.; Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1, Italy; email: ale_pezzini@hotmail.com
DOCUMENT TYPE: Article

Scopus news

Conforti, R., Capasso, R., Galasso, R., Cirillo, M., Taglialatela, G., Galasso, L.
A challenging diagnosis of late-onset tumefactive multiple sclerosis associated to cervicodorsal syringomyelia: Doubtful CT, MRI, and bioptic findings Case report and literature review
(2016) Medicine (United States), 95 (36), art. no. e4585, . 
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DOI: 10.1097/MD.0000000000004585
AFFILIATIONS: Neuroradiology Service, Department of Radiology, Second University of Naples, Naples, Italy; 
Department of Internal Clinical and Experimental Medicine and Surgery, F. Magrassi-A. Lanzara Second University of Naples, Piazza Miraglia, Naples, Italy; 
Neuroradiology Department, San Luca Hospital, Vallo della Lucania, Salerno, Italy
ABSTRACT: Background: Tumefactive multiple sclerosis (MS) is an unusual variant of demyelinating disease characterized by lesions with pseudotumoral appearance on radiological imaging mimicking other space-occupying lesions, such as neoplasms, infections, and infarction. Especially when the patient's medical history is incompatible with MS, the differential diagnosis between these lesions constitutes a diagnostic challenge often requiring histological investigation. An older age at onset makes distinguishing tumefactive demyelinating lesion (TDL) from tumors even more challenging. Methods:We report a case of brain TDL as the initial manifestation of late-onset MS associated with cervico-dorsal syringomyelia. A 66-year-old Caucasian woman with a 15-day history headache was referred to our hospital because of the acute onset of paraphasia. She suffered from noncommunicating syringomyelia associated to basilar impression and she reported a 10-year history of burning dysesthesia of the left side of the chest extended to the internipple line level. Results: Computed tomography (CT) and magnetic resonance imaging (MRI) examinations revealed a left frontal lesion with features suspicious for a tumor. Given the degree of overlap with other pathologic processes, CT and MRI findings failed to provide an unambiguous diagnosis; furthermore, because of the negative cerebrospinal fluid analysis for oligoclonal bands, the absence of other lesions, and the heightened suspicion of neoplasia, the clinicians opted to perform a stereotactic biopsy. Brain specimen analysis did not exclude the possibility of perilesional reactive gliosis and the patient, receiving anitiedemigen therapy, was monthly followed up. In the meanwhile, the second histological opinion of the brain specimen described the absence of pleomorphic glial cells indicating a tumor. These findings were interpreted as destructive inflammatory demyelinating disease and according to the evolution of MRI lesion burden, MS was diagnosed. Conclusion: TDL still remains a problematic entity clinically, radiologically, and sometimes even pathologically. A staged follow-up is necessary, and in our case, it revealed to be the most important attitude to define the nature of the lesion, confirming the classic MS diagnostic criteria of disseminate lesions in time and space. We discuss our findings according to the recent literature. Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All.
AUTHOR KEYWORDS: Brain biopsy;  Magnetic resonance spectroscopy;  Multiple sclerosis;  Syringomyelia;  Tumefactive demyelinating lesion;  Tumefactive multiple sclerosis
CORRESPONDENCE ADDRESS: Capasso, R.; Department of Internal Clinical and Experimental Medicine and Surgery, F. Magrassi-A. Lanzara Second University of Naples, Piazza MiragliaItaly; email: dott.ssacapasso@gmail.com
DOCUMENT TYPE: Article

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Jadhao, A.G., Pinelli, C., D'Aniello, B., Tsutsui, K.
Gonadotropin-inhibitory hormone (GnIH) in the amphibian brain and its relationship with the gonadotropin releasing hormone (GnRH) system: An overview
(2017) General and Comparative Endocrinology, 240, pp. 69-76. 
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DOI: 10.1016/j.ygcen.2016.09.006
AFFILIATIONS: Department of Zoology, RTM Nagpur University Campus, Nagpur, MS, India; 
Department of Environmental, Biological, and Pharmaceutical Sciences & Technologies, Second University of Naples, Caserta, Italy; 
Department of Biology, University of Naples “Federico II”, Napoli, Italy; 
Laboratory of Integrative Brain Sciences, Department of Biology and Centre for Medical Life Science, Waseda University, Tokyo, Japan
ABSTRACT: It is well known that the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) plays an important role as a primary factor regulating gonadotropin secretion in reproductive processes in vertebrates. The discovery of the presence of a gonadotropin-inhibitory hormone (GnIH) in the brains of birds has further contributed to our understanding of the reproduction control by the brain. GnIH plays a key role in inhibition of reproduction and acts on the pituitary gland and GnRH neurons via a novel G protein-coupled receptor (GPR147). GnIH decreases gonadotropin synthesis and release, thus inhibiting gonadal development and maintenance. The GnRH and GnIH neuronal peptidergic systems are well reported in mammals and birds, but limited information is available regarding their presence and localization in the brains of other vertebrate species, such as reptiles, amphibians and fishes. The aim of this review is to compile and update information on the localization of GnRH and GnIH neuronal systems, with a particular focus on amphibians, summarizing the neuroanatomical distribution of GnIH and GnRH and emphasizing the discovery of GnIH based on RFamide peptides and GnIH orthologous peptides found in other vertebrates and their functional significance. © 2016 Elsevier Inc.
CORRESPONDENCE ADDRESS: Jadhao, A.G.; Department of Zoology, RTM Nagpur University Campus, India; email: agj213@hotmail.com
DOCUMENT TYPE: Article

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Birolo, L., Sacchi, S., Smaldone, G., Molla, G., Leo, G., Caldinelli, L., Pirone, L., Eliometri, P., Di Gaetano, S., Orefice, I., Pedone, E., Pucci, P., Pollegioni, L.
Regulating levels of the neuromodulator d-serine in human brain: structural insight into pLG72 and d-amino acid oxidase interaction
(2016) FEBS Journal, pp. 3353-3370. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84987974333&partnerID=40&md5=e4d80b1adf1d88a06d142c226e347d5c
DOI: 10.1111/febs.13809
AFFILIATIONS: Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, Napoli, Italy; 
Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, Varese, Italy; 
Centro Interuniversitario di Ricerca in Biotecnologie Proteiche “The Protein Factory”, Politecnico di Milano and Università degli studi dell'Insubria, Milano, Italy; 
IRCCS SDN, Napoli, Italy; 
Italian Research National Council, Institute of Biostructures and Bioimaging, Napoli, Italy
ABSTRACT: The human flavoenzyme d-amino acid oxidase (hDAAO) degrades the NMDA-receptor modulator d-serine in the brain. Although hDAAO has been extensively characterized, little is known about its main modulator pLG72, a small protein encoded by the primate-specific gene G72 that has been associated with schizophrenia susceptibility. pLG72 interacts with neosynthesized hDAAO, promoting its inactivation and degradation. In this work, we used low-resolution techniques to characterize the surface topology of the hDAAO–pLG72 complex. By using limited proteolysis coupled to mass spectrometry, we could map the exposed regions in the two proteins after complex formation and highlighted an increased sensitivity to proteolysis of hDAAO in complex with pLG72. Cross-linking experiments by using bis(sulfosuccinimidyl)suberate identified the single covalent bond between T182 in hDAAO and K62 in pLG72. In order to validate the designed mode of interaction, three pLG72 variants incrementally truncated at the C terminus, in addition to a form lacking the 71 N-terminal residues, were produced. All variants were dimeric, folded, and interacted with hDAAO. The strongest decrease in affinity for hDAAO (as well as for the hydrophobic drug chlorpromazine) was apparent for the N-terminally deleted pLG7272–153 form, which lacked K62. On the other hand, eliminating the disordered C-terminal tail yielded a more stable pLG72 protein, improved the binding to hDAAO, although giving lower enzyme inhibition. Elucidation of the mode of hDAAO–pLG72 interaction now makes it possible to design novel molecules that, by targeting the protein complex, can be therapeutically advantageous for diseases related to impairment in d-serine metabolism. © 2016 Federation of European Biochemical Societies
CORRESPONDENCE ADDRESS: Pollegioni, L.; Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'InsubriaItaly; email: loredano.pollegioni@uninsubria.it
DOCUMENT TYPE: Article

Scopus news

Sestini, S., Perone, R., Domenichetti, S., Mazzeo, C., Massai, V., Rispoli, A., Barbacci, A., Valtancoli, A., Castagnoli, A., Mansi, L.
Brain network underlying the improvement of social functioning in schizophrenic patients after one-year treatment with social skills training
(2016) Current Radiopharmaceuticals, 9 (2), pp. 150-159. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84986879745&partnerID=40&md5=fda98dac103365e580df13a33230c6a3

DOI: 10.2174/1874471009999160625110759
AFFILIATIONS: Dept. Diagnostic Imaging, Nuclear Medicine Unit, N.O.P. - S. Stefano, U.S.L. 4, Prato, Italy; 
Dept. of Mental Health, Simple Operative Structure for Adult Mental Health 5 (S.O.S. S.M.A.), A.S.L. 10, Florence, Italy; 
Dept. of Mental Health, Functional Unit for Adult Mental Health (U.F. S.M.A), A.S.L. 10, Florence, Italy; 
Dept. uclear Medicine, Second University of Naples, Italy
ABSTRACT: Purpose: To assess changes in social and neuro-cognition and regional cerebral blood flow (rCBF) in schizophrenic patients with psychotic syndrome treated with Social Skill Training (SST). Methods: 17 patients underwent two high resolution rCBF SPECT at rest before and after a one-year treatment with SST. Patients were assessed using a neuropsychological evaluation (W.A.I.S.-R, T.M.T, Verbal Fluency, W.C.S.T.). SPM8 was used to investigate rCBF changes from the pre- to the post-SST condition and the relationship between rCBF and clinical scores used as covariates of interest. Results: All patients presented with an improvement in social perception, ability to deal with abstract social conventions, rules and judgments about people (Comprehension and Picture Completion sub-tests) and some neuro-cognitive functions sustaining the process of socially relevant information. The main effect of SST was to produce rCBF increases in precuneus, PCC, superior parietal lobules, PMC, pre-SMA, precentral gyrus, dmPFC, dlPFC, vmPFC, OFC (p<0.0001 uncorrected). The SPM analysis showed that Comprehension was supported by PMC, dmPFC, OFC and vmPFC, while the Picture Completion was supported by PMC and dmPFC (p<0.0001). Conclusion: SST in schizophrenic patients improves resting neural activity in cortical areas of the amigdala-based and non-amygdala networks of social brain, including dmPFC and vmPFC, and dlPFC, which are known to be part of default mode and task-positive networks and to be implicated in schizophrenia. © 2016 Bentham Science Publishers.
CORRESPONDENCE ADDRESS: Sestini, S.; Nuclear Medicine Unit, N.O.P. - S. Stefano, U.S.L. 4Italy; email: ssestini@uslcentro.toscana.it
DOCUMENT TYPE: Article
SOURCE: Scopus

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Rampino, A., Di Carlo, P., Fazio, L., Ursini, G., Pergola, G., De Virgilio, C., Gadaleta, G., Giordano, G.M., Bertolino, A., Blasi, G.
Association of functional genetic variation in PP2A with prefrontal working memory processing
(2017) Behavioural Brain Research, 316, pp. 125-130. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84986000947&partnerID=40&md5=14c6a6081f3495e61240313db1a66a8f

DOI: 10.1016/j.bbr.2016.08.054
AFFILIATIONS: Department of Basic Medical Science, Neuroscience, Sense Organs – University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, Bari, Italy; 
Psychiatry Unit – Bari University Hospital, Piazza Giulio Cesare 11, Bari, Italy; 
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, (MD), United States; 
Department of Bioscience, Biotechnologies and Biopharmaceutics − − University of Bari ‘Aldo Moro’, Via E. Orabona, 4, Bari, Italy; 
University of Naples SUN, Department of Psychiatry, Largo Madonna delle Grazie 1, Naples, Italy
ABSTRACT: Variation in prefrontal dopaminergic signaling mediated by D2 receptor has been implicated in cognitive phenotypes of schizophrenia, including working memory. Molecular cascades downstream of D2 receptor include a cAMP-dependent- and a cAMP-independent-pathway. Protein-Phosphatase-2A (PP2A) is a key partner of D2 receptor in cAMP-independent signaling. This enzyme comprises a regulatory subunit that is coded by PPP2R2B gene. Given the molecular relationship between PP2A and D2 signaling, we hypothesized genetic variation in PPP2R2B affecting mRNA expression of this gene in prefrontal cortex to be associated with prefrontal processing during working memory. In order to probe such a hypothesis we investigated SNPs associated with PPP2R2B expression in two independent samples of human postmortem prefrontal cortex. Then, we tested SNPs for which association was replicated as predictors of prefrontal activity during WM as probed by functional magnetic resonance (fMRI) in a sample of healthy humans. We found that a SNP associated with PPP2R2B expression (rs959627) predicted prefrontal activity during the N-Back working memory task. In particular, individuals carrying rs959627T allele, a condition associated with lower PPP2R2B expression in postmortem prefrontal cortex, showed greater activity in right inferior frontal gyrus (IFG) during N-Back compared to CC subjects. Furthermore, such an activity was negatively correlated with behavioral performance at the task. Consistently with previous studies, these findings suggest reduced right IFG efficiency during working memory processing in rs959627 T-carriers, as indexed by their greater need to activate this brain region in order to achieve similar levels of behavioral proficiency as compared to CC individuals. © 2016 Elsevier B.V.
CORRESPONDENCE ADDRESS: Blasi, G.; Psychiatry Unit – Bari University Hospital, Piazza Giulio Cesare 11, Italy; email: blasi.seppe@gmail.com
DOCUMENT TYPE: Article

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Motta, M., Tatti, M., Furlan, F., Celato, A., Di Fruscio, G., Polo, G., Manara, R., Nigro, V., Tartaglia, M., Burlina, A., Salvioli, R.
Clinical, biochemical and molecular characterization of prosaposin deficiency
(2016) Clinical Genetics, 90 (3), pp. 220-229. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84983394723&partnerID=40&md5=676dabda308cb3bbda8e40228cffa095

DOI: 10.1111/cge.12753
AFFILIATIONS: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy; 
Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; 
Division of Inherited Metabolic Diseases, University Hospital, Padua, Italy; 
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy; 
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
ABSTRACT: Prosaposin (PSAP) deficiency is an ultra-rare, fatal infantile lysosomal storage disorder (LSD) caused by variants in the PSAP gene, with seven subjects reported so far. Here, we provide the clinical, biochemical and molecular characterization of two additional PSAP deficiency cases. Lysoplex, a targeted resequencing approach was utilized to identify the variant in the first patient, while quantification of plasma lysosphingolipids (lysoSLs), assessed by liquid chromatography mass spectrometry (LC-MS/MS) and brain magnetic resonance imaging (MRI), followed by Sanger sequencing allowed to attain diagnosis in the second case. Functional studies were carried out on patients' fibroblast lines to explore the functional impact of variants. The two patients were homozygous for two different truncating PSAP mutations (c.895G>T, p.Glu299*; c.834_835delGA, p.Glu278Aspfs*27). Both variants led to a complete lack of processed transcript. LC-MS/MS and brain MRI analyses consistently provided a distinctive profile in the two children. Quantification of specific plasma lysoSLs revealed elevated levels of globotriaosylsphingosine (LysoGb3) and glucosylsphingosine (GlSph), and accumulation of autophagosomes, due to a decreased autophagic flux, was observed. This report documents the successful use of plasma lysoSLs profiling in the PSAP deficiency diagnosis, as a reliable and informative tool to obtain a preliminary information in infantile cases with complex traits displaying severe neurological signs and visceral involvement. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
CORRESPONDENCE ADDRESS: Salvioli, R.; Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di SanitàItaly; email: rosa.salvioli@iss.it
DOCUMENT TYPE: Article

Iasevoli, F., Laroøi, F., Buonaguro, E.F., Gebhardt, E., Raballo, A.
Can the "connectomic way" provide a link between molecular neurobiology and phenomenological psychopathology? the case of schizophrenia
(2015) Journal of Psychopathology, 21 (4), pp. 323-331. 
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AFFILIATIONS: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University School of Medicine Federico II, Naples, Italy; 
Outpatient Unit on Treatment Resistant Psychosis, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University School of Medicine Federico II, Naples, Italy; 
Department of Psychology: Cognition and Behaviour, University of Liège, Liège, Belgium; 
Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; 
Neurosciences, Mental Health and Sensory Functions (NESMOS) Department, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy; 
Norwegian Centre for Mental Disorders Research (NORMENT), University of Oslo, Diakonhjemmet Hospital, PB 85 Vinderen, Oslo, Norway
ABSTRACT: Schizophrenia is a severe and complex mental illness whose aetiology remains unknoIasewn. Moreover, changing definitions of the diagnostic criteria of schizophrenia over past decades have not contributed to any substantial progress in terms of deeper pathophysiological understanding of the disease. Nevertheless, to date, significant evidence continues to be accumulated from epidemiologic, genetic and preclinical studies that point to a number of genetic factors that play important roles in the pathophysiology of schizophrenia, especially in terms of disrupted synaptic plasticity molecular processes. Specifically, the most recent approach in human research on schizophrenia is represented by "connectomics" or the study of connectomes, which can be defined as comprehensive maps of connections within an organism's nervous system. Indeed, it has been suggested that schizophrenic pathophysiology might rely on circuit-based dysfunctions that may represent the consequence, on a network scale, of the impairment in synaptic plasticity and neuronal connections that are increasingly found in preclinical molecular research, and that may stem from de novo and/or inherited disease- variants in target genes as well as from aberrant epigenetic mechanisms. On the other hand, circuit-based dysfunctions may underlie the defects in integration of higher-order cognitive functions that characteristically connote schizophrenia patients, and may account for aberrant self-experience which are typically described in phenomenological approaches to the disease. In this paper, we will critically explore the recent advances on molecular, genetic and neuro-imaging research in schizophrenia. Based on these data, we will emphasise the potential of the connectomic framework as an intermediate step between the biological and the phenomenological levels to capture the complexity of schizophrenia manifestations.
CORRESPONDENCE ADDRESS: Raballo, A.; Norwegian Centre for Mental Disorders Research (NORMENT), University of Oslo, Diakonhjemmet Hospital, PB 85 Vinderen, Norway; email: andrea.raballo@medisin.uio.no
DOCUMENT TYPE: Article