IRFMN 38 ACTIVITY OF THE DEPARTMENT The Department of Neuroscience is formed by twelve Laboratories; the activities of research are dedicated to the study of neurological and psychiatric diseases, evaluated by the biological point of view, clinical and epidemiological aspects and the quality of care. In the Department, activities like drug information service, preparation of clinical trial protocols and epidemiological studies are developed not only in the neurological field. Traditionally, part of the Department is devoted to the development of experimental models for the pharmacological, neurochemical and pathogenetic studies in Alzheimer, Parkinson or prion’s diseases, epilepsy, depression and cognitive impairment. More recently, consolidated expertise were established in the studies of amyotrophic lateral sclerosis (ALS) pathogenesis, cerebral stroke, Rett syndrome, trauma and drug abuse. Some of these disor- ders, like epilepsy, ALS and Alzheimer’s disease, are investigated from the clinical and epidemiological points of view to evaluate drug and care efficacy. Genetic investigations and the use of biomaterial tools are the last acquired expertise. A specific sector is dedicated to the elderly with cohort studies in relation to the dementia, but also to the evaluation of quality of services and polytherapies in aging. The activities of the Department are aimed to the integration of the different expertise to develop multidisciplinary approaches. The purpose is to address at different levels, knowledge, therapy and clinical practice to the numerous que- stions, largely unresolved, proposed by the disorders of nervous system. MAIN RESULTS (2017) The studies developed in the Department during the 2017 are related to neuro- degenerative disorders, epilepsy, cerebral stroke and spinal/brain trauma, howe- ver also the analysis of the appropriateness of the therapies in the elderly has been object of various studies Growing evidences show that inflammation is involved in the genesis and the progression of pathological events, acute and chronic. On these basis several laboratories are engaged to develop experimental models useful to identify the- rapeutic approaches based on the inflammatory components of the neurological disorders, in some cases the studies have achieved the appropriate evidence to support the clinical investigations. The use of biomaterials and nanoparticles HEAD OF DEPARTMENT Gianluigi Forloni, Biol.Sci.D. Obtained the Degree of Biological Science at the University of Milan in 1985. After two years of post doc at the Department of Neuroscience and Psychiatry at Johns Hopkins Universi- ty in Baltimore, USA, he came back to the Mario Negri Institute and between 1992 and 1995 he was the head of the Neurobiology of Alzheimer’s disea- se Unit; since 1996 he is the Head of the Biology of Neurodegenerative Di- seases Lab and since 2002 the Head of the Neuroscience Department. He is President of the Italian Associa- tion on Brain Aging Research (AIRIC) and member of the European Aca- demy of Sciences. He is the author of more than 300 peer-reviewed scien- tific articles and about 30 reviews or book chapters. e-mail: [email protected]phone: +39 02 39014462 DEPARTMENT OF NEUROSCIENCE
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IRFMN38
ACTIVITY OF THE DEPARTMENT
The Department of Neuroscience is formed by twelve Laboratories; the activities of research are dedicated to the study of neurological and psychiatric diseases, evaluated by the biological point of view, clinical and epidemiological aspects and the quality of care. In the Department, activities like drug information service, preparation of clinical trial protocols and epidemiological studies are developed not only in the neurological field. Traditionally, part of the Department is devoted to the development of experimental models for the pharmacological, neurochemical and pathogenetic studies in Alzheimer, Parkinson or prion’s diseases, epilepsy, depression and cognitive impairment. More recently, consolidated expertise were established in the studies of amyotrophic lateral sclerosis (ALS) pathogenesis, cerebral stroke, Rett syndrome, trauma and drug abuse. Some of these disor-ders, like epilepsy, ALS and Alzheimer’s disease, are investigated from the clinical and epidemiological points of view to evaluate drug and care efficacy. Genetic investigations and the use of biomaterial tools are the last acquired expertise. A specific sector is dedicated to the elderly with cohort studies in relation to the dementia, but also to the evaluation of quality of services and polytherapies in aging. The activities of the Department are aimed to the integration of the different expertise to develop multidisciplinary approaches. The purpose is to address at different levels, knowledge, therapy and clinical practice to the numerous que-stions, largely unresolved, proposed by the disorders of nervous system.
MAIN RESULTS (2017)
The studies developed in the Department during the 2017 are related to neuro-degenerative disorders, epilepsy, cerebral stroke and spinal/brain trauma, howe-ver also the analysis of the appropriateness of the therapies in the elderly has been object of various studiesGrowing evidences show that inflammation is involved in the genesis and the progression of pathological events, acute and chronic. On these basis several laboratories are engaged to develop experimental models useful to identify the-rapeutic approaches based on the inflammatory components of the neurological disorders, in some cases the studies have achieved the appropriate evidence to support the clinical investigations. The use of biomaterials and nanoparticles
HEAD OF DEPARTMENT
Gianluigi Forloni, Biol.Sci.D.
Obtained the Degree of Biological Science at the University of Milan in 1985.
After two years of post doc at the Department of Neuroscience and Psychiatry at Johns Hopkins Universi-ty in Baltimore, USA, he came back to the Mario Negri Institute and between
1992 and 1995 he was the head of the Neurobiology of Alzheimer’s disea-se Unit; since 1996 he is the Head of the Biology of Neurodegenerative Di-seases Lab and since 2002 the Head of the Neuroscience Department.
He is President of the Italian Associa-tion on Brain Aging Research (AIRIC) and member of the European Aca-demy of Sciences. He is the author of more than 300 peer-reviewed scien-tific articles and about 30 reviews or book chapters.
to pass the blood brain barrier and to guarantee a slow release of the drugs is another aspect treated transversally in the Department. Other experimental projects are devoted to stimulate the regenerative response following the acute spinal/brain traumatic injury. In this contest and in neurodegenerative disorders models, it has been also investigated the use of staminal cells to favour the regenerative response. Another relevant aspect of the experimental research in Alzheimer and Parkinson disease, is focused on the pathogenetic role of the small soluble aggregates, named oligomers, responsible of the neuronal dysfun-ction associated to protein misfolding diseases, it has been coined the term “oligomeropathies” to underline the central role role of these forms. A relevant line of research that involves the Neurological Disorders Lab is the evaluation at the global level the frequency and the trend of the main disorders. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). The group associa-ted to GBD project involved 1700 scientists 120 countries. GBD is coordinated by the Institute for Health Metrics and Evaluation (IHME, Washington University) and it is funded by Bill & Melinda Gates Foundation. The data collected and analyzed by the scientists documented the disabilities and mortality associated to 300 different disorders (including the pathologies associated to drug abuse) in 188 countries distint by sex age since 1990 up to 2015, allowing geographic and time comparisons. The instruments developed by HME to analyze the data can be utilized at global, national and local level, to understand the health trends during the time. The italian scientists involved in the GBD at the moment are 15. Five of them belong to the IRCCS Mario Negri
SELECTED PUBLICATIONS (2017)
Balducci C, Frasca A, Zotti M, La Vitola P, Mhillaj E, Grigoli E, Iacobellis M, Grandi F, Messa M, Colombo L, Molteni M, Trabace L, Rossetti C, Salmona M, Forloni G. Toll-like receptor 4-dependent glial cell activation mediates the impairment in me-
mory establishment induced by b-amyloid oligomers in an acute mouse model of Alzheimer’s disease. Brain Behav Immun 60: 188-197 (2017)
Beghi E New classification of seizures and epilepsies. An advance?.Nat Rev Neurol 13: 324-325 (2017)
Bertani I, Iori V, Trusel M, Maroso M, Foray C, Mantovani S, Tonini R, Vezzani A, Chiesa R Inhibition of
IL-1b signaling normalizes NMDA-dependent neurotransmission and reduces seizure susceptibility in a mouse model of Creutzfeldt-Jakob disease. J Neurosci 37: 10278-10289 (2017)
Buccarello L, Sclip A, Sacchi M, Castaldo A, Bertani I, Re Cecconi A D, Maestroni S, Zerbini G, Nucci P, Borsello T. The c-jun N-terminal kinase plays a key role in ocular degenerative changes in a mouse model of alzheimer disease suggesting a correlation between ocular and brain pathologies. Oncotarget 8: 83038-83051 (2017)
Fumagalli S, Perego C, Zangari R, De Blasio D, Oggioni M, De Nigris F, Snider F, Garred P, Ferrante AM, De Simoni MG. Lectin pathway of complement activation is associated with vulnerability of athe-rosclerotic plaques. Front Immunol 8: 288-296 (2017)
Marcucci M, Franchi C, Nobili A, Mannucci P M, Ardoino I, REPOSI InvestigatorsDefining aging phe-notypes and related outcomes: Clues to recognize frailty in hospitalized older patients. J Gerontol A Biol Sci Med Sci 72: 395-402 (2017)
Pasetto L, Pozzi S, Castelnovo M, Basso M, Estevez A G, Fumagalli S, De Simoni M G, Castellaneta V, Bigini P, Restelli E, Chiesa R, Trojsi F, Monsurru M R, Callea L, Malesevic M, Fischer G, Freschi M, Tortarolo M, Bendotti C, Bonetto V. Targeting extracellular cyclophilin A reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis. J Neurosci 37: 1413-1427 (2017)
BIBLIOMETRICINDICATORS (2017)
118 Publications (with I.F.)
794,50Impact Factor
60H-index
(head of department)
LABORATORIESBiology of Neurodegenerative Disorders
Acute brain injury and therapeutic strategies
Inflammation and Nervous System Diseases
Neurological Disorders
Neuronal Death and Neuroprotection Mechanisms
Molecular Neurobiology
Prion Neurobiology
Neurochemistry and Behavior
Experimental Neurology
Geriatric Neuropsychiatry
Experimental Psychopharmacology
Quality Assessment of GeriatricTherapies and Services
UNITSGenetics of Neurodegenerative Disorders
Acute Spinal Cord Injury and Neuroregeneration
Pharmacology of Cognitive Behaviour
Pathophysiology of glio-neuronal communication
Geriatric Epidemiology
Geriatric Pharmacology
Pharmacotherapy and PrescriptionAppropriateness
Quality of Care and Rights Promotionin Mental Health
Unit of Pharmaco-epidemiologicalResearch in Older People
IRFMN40
RESEARCH ACTIVITIES
The lab studies evaluated the genetic and biological bases of neu-rodegenerative disorders associated to the aging, in particular Al-zheimer’s disease (AD), spongiform encephalopathies (TSE) and Parkinson’s disease (PD), there is also a unit dedicated to spinal injury and regeneration. The genetic studies are focused to identi-fication of causal factors in the familial forms or risk factors in spo-radic ones. In both populations have been studied gene encoding proteins invol-ved in the physiopathology of AD and PD. The role of proteic aggregates in the neurodegenerative pathogenesis has been investigated using in vitro and in vivo models. In the last years it has been shown the pathogenic role of oligomers, small soluble aggregates of b-amyloid and a-synuclein in AD and PD respecti-vely, we coined the term oligomeropathies to indicate the relevance of these for-ms in the neuronal dysfunction that characterized these disorders. The develop of experimental models based on the oligomers activity has demonstrated the role of inflammation in the neurodegenerative processes: The experimental evi-dence of the anti-amyloidogenic activity of doxycycline has been used to develop a protocol to test the preventive effect of the drug to avoid the development of fatal familial insomnia, a genetic form of prion disease in at risk subjectsThe specific objectives of the current research:• Creation of translational models to develop potential therapeutic approaches • Identification of genetic and biological markers of AD and PD• Clarify the therapeutic role of doxycycline in TSE and AD• Development of appropriate techniques to release the drug by nanoparticles and biomaterials • Development of cellular model iPSC and potential cell therapy protocols
MAIN RESULTS (2017)
The oligomers of b-synuclein, essential component of the Lewy bodies, intracel-lualr aggregates that characterized Parkinson’s disease and other neurodegene-rative disorders, injected in the cerebral ventricle has different features from the effect induced by b-oligomers, i.e. is not dependent from the activation of Toll-like 4 receptors Smart delivery tools (nanoparticles) are able to selectively target specific cells of
LABORATORY OF BIOLOGYOF NEURODEGENERATIVE DISORDERS
DEPARTMENTS and LABORATORIES
IRFMN 41
the central nervous system (microglia/macrophages), opening a new therapeutic avenue to counteract the inflammation (single cell therapeutic strategy). Doxycycline, a tetracycline with a good passage of the blood brain barrier, re-duced the formation of bamyloid aggregates and antagonized the inflammatory component induced by the in vivo intracerebral applivation of b-oligomersThe microglial modulation by minocycline induced a long lasting protective effect in an sperimental model of spinal traumatic injury
The conditione medium from mesenchymal cells appropriately stimulated anta-gonized the cognitive decline in a murine model of Alzheimer’s disease
SELECTED PUBLICATIONS (2017)
Balducci C, Frasca A, Zotti M, La Vitola P, Mhillaj E, Grigoli E, Iacobellis M, Grandi F, Messa M, Colombo L, Molteni M, Trabace L, Rossetti C, Salmona M, Forloni G Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by β-amyloid oligomers in an acute mouse model of Alzhei-mer’s disease.Brain Behav Immun 60: 188-197 (2017)
Chierchia A, Chirico N, Boeri L, Raimondi I, Riva G A, Raimondi M T, Tunesi M, Giordano C, Forloni G, Albani D Secretome released from hydrogel-embedded adipose mesenchymal stem cells protects against the Parkinson’s disease related toxin 6-hydroxydopamine. Eur J Pharm Biopharm 121: 113-120 (2017)
Mancini S, Balducci C, Micotti E, Tolomeo D, Forloni G, Masserini M, Re F Multifunctional liposomes delay phenotype progression and prevent memory impairment in a presymptomatic stage mouse model of Alzheimer disease.J Control Release 258: 121-129 (2017)
Vismara I, Papa S, Rossi F, Forloni G, Veglianese P Current options for cell therapy in spinal cord injury.Trends Mol Med 23: 831-849 (2017)
Nathan P J, Lim Y Y, Abbott R, Galluzzi S, Marizzoni M, Babiloni C, Albani D, Bartres-Faz D, Didic M, Farotti L, Parnetti L, Salvadori N, Muller B W, Forloni G, Girtler N, Hensch T, Jovicich J, Leeuwis A, Marra C, Molinuevo J L, Nobili F, Pariente J, Payoux P, Ranjeva J P, Rolandi E, Rossini P M, Schoen-knecht P, Soricelli A, Tsolaki M, Visser P J, Wiltfang J, Richardson J C, Bordet R, Blin O, Frisoni G B, PharmaCog Consortium Association between CSF biomarkers, hippocampal volume and cognitive function in patients with amnestic mild cognitive impairment (MCI).Neurobiol Aging 53: 1-10 (2017)
STAFFGianluigi Forloni, Biol.Sci.D.
Head of Laboratory
Diego Albani, PhD,Head of Genetic of Neurodegenerative
disorders Unit
Pietro Veglianese PhD, Head of Acute Spinal trauma and
Regeneration Unit
IRFMN42
RESEARCH ACTIVITIES
• Incidence, prevalence, risk factors, prognosis and treatment of epilepsy and seizures• Incidence, risk factors, prognosis and treatment of amyotrophic lateral sclerosis• Incidence, prevalence, treatments and rehabilitation of Parkinson disease• Prevalence and treatment of headache• Incidence, course and treatment of acute and chronic inflammatory polyradi-culoneuropathyThe members of the Laboratory of Neurological Disorders have background and experience in the planning and conduction of descriptive, analytic and experi-mental studies in the field of epilepsy, ALS and other acute and chronic neuro-logical disorders. The head of the laboratory has long-lasting clinical experience maturated during pluriennial hospital activities. The clinical background and the need to perform studies in in-and outpatients with neurological disorders fueled collaborations with several Italian and foreign institutes which led to the imple-mentation of collaborative groups and consortia with neurologists, child neurolo-gists and general practitioners in the entire country. The staff of the laboratory has also gained experience in the assessment of administrative records, a valuable source of epidemiological data in large strata of the Italian population, and in the implementation and conduction of randomized clinical trials. Collaborations are also in act between the laboratory and other groups involved in basic science located in the Mario Negri Institute and occasionally also in external institutions.
MAIN RESULTS (2017)
Diabetes mellitus as a risk factor for epilepsy: Diabetes mellitus is an indepen-dent risk factor for seizures in elderly individuals. In diabetic patients, the risk of seizures increases with the number of comorbidities, supporting the role of vascular disease as a cause of seizures. Epilepsy as a risk factor for dementia: Adult-onset epilepsy of undefined cause could thus represent a risk factor for the ongoing neurodegenerative damage, even preceding by years the onset of clinical symptoms of dementia. Diagnosis of epilepsy vs. psychogenic non-epi-leptic seizures (PNES); comparing neurologists and psychiatrists: Psychiatrists,
HEAD OF LABORATORY
Ettore Beghi, M.D.
Neurology specialist. Research Fellow in Medical Statistics and Epidemiolo-gy, Mayo Clinic, Rochester, MN.
Past chair of the Epilepsy Center and the Neurophysiology Unit, University of Milano-Bicocca.
Associate Editor of Neuroepidemiolo-gy and Epilepsia Open. Member of the Editorial Board of Amyotrophic Lateral Sclerosis & Frontotemporal Degene-ration, Clinical Neurology & Neurosur-gery, Clinical Drug Investigation. Refe-ree of 50 journals.
Chair of the European ALS registries. Co-chair of the Epidemiology Panel, European Academy of Neurology.
Author of more than 500 scientific pu-blications (350 in indexed journals).
as a group, are less reliable than neurologists in differentiating seizure types on video but, as individuals, can be quite accurate in making the correct diagnosis because they are more attuned to capture the subtleties of human behavior, of subjective experiences, as the effects of hidden internal conflicts. ALS and trau-ma: Traumatic events leading to functional disability or confined to the head are risk factors for ALS. Traumatic events experienced at age 35-54 years carry the highest risk. Neurological disorders and the global burden of disease: Neurologi-cal disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disor-ders. The number of patients who in need of care for neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.
SELECTED PUBLICATIONS (2017)
Pupillo E, Poloni M, Bianchi E, Giussani G, Logroscino G, Zoccolella S, Chiò A, Calvo A, Corbo M, Lunetta C, Marin B, Mitchell D, Hardiman O, Rooney J, Stevic Z, Bandettini di Poggio M, Filosto M, Cotelli MS, Perini M, Riva N, Tremolizzo L, Vitelli E, Damiani D, Beghi E; EURALS Consortium†.Trauma and amyotrophic lateral sclero-sis: a european population-based case-control study from the EURALS consortium. Amyotroph Lateral Scler Frontotemporal Degener. 2018 Feb;19(1-2):118-125.
Beghi M, Erba G, Cornaggia CM, Giussani G, Bianchi E, Porro G, Russo M, Beghi E. Engaging psychiatrists in the diagnosis of psychogenic nonepileptic seizures. What can they contribute? Seizu-re. 2017 Nov;52:182-187.
Di Francesco JC, Tremolizzo L, Polonia V, Giussani G, Bianchi E, Franchi C, Nobili A, Appollonio I, Beghi E, Ferrarese C. Adult-Onset Epilepsy in Presymptomatic Alzheimer’s Disease: A Retrospective Study.J Alzheimers Dis. 2017;60(4):1267-1274.
GBD 2016 SDG Collaborators. Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016. Lancet. 2017 Sep 16;390(10100):1423-1459.
Rooney JPK, Visser AE, D’Ovidio F, Vermeulen R, Beghi E, Chio A, Veldink JH, Logroscino G, van den Berg LH, Hardiman O; Euro-MOTOR Consortium. A case-control study of hormonal exposures as etiologic factors for ALS in women: Euro-MOTOR. Neurology. 2017 Sep 19;89(12):1283-1290.
Baviera M, Roncaglioni MC, Tettamanti M, Vannini T, Fortino I, Bortolotti A, Merlino L, Beghi E. Diabetes mellitus: a risk factor for seizures in the elderly-a population-based study. Acta Diabetol. 2017 Jun 19. doi: 10.1007/s00592-017-1011-0.
STAFFEttore Beghi, M.D.Head of Laboratory
IRFMN44
RESEARCH ACTIVITIES
The laboratory is mainly engaged in the study of Amyotrophic La-teral Sclerosis (ALS), a rare disease caused by the degeneration of motor neurons that control muscles for movement and breathing causing total paralysis and death within 2-5 years of diagnosis. There is no cure for ALS. Our main interest is to understand, throu-gh the study of transgenic mice carrying the human SOD1 gene mutation, responsible for about 20% of familial ALS, how this disease develops and progresses and how to hinder its evolution . The main laboratory research projects are:• Comparative analysis of two ALS mouse models (transgenic mice for human mutant SOD1 G93A) that despite they carry the same transgene number, show a different onset and duration of the disease. The variability in the onset and course of the disease is also a characteristic of ALS patients. The purpose is to investigate the mechanisms at the basis of this difference in order to identify drug targets for potential therapies that may slow the disease in early stages and for the identification of prognostic biomarkers useful for monitoring the efficacy of experimental treatments.• Study of the role of neuroinflammation and of the immune mechanisms in the development and progression of ALS.• Management of a platform of mouse models of ALS to evaluate the efficacy of innovative therapeutic interventions.
MAIN RESULTS (2017)
• We have observed that TNFa, one of the main factors of inflammation, can play a toxic or protective action on motor neurons depending if it interacts with the TNFR2 or TNFR1 receptor, respectively. TNFa increased in the spinal cord in CSF and in ALS patients, but clinical trials aimed at inhibiting TNFa production were ineffective. Our observation could explain this failure and suggest new, more specific intervention strategies• Human umbilical stem cells injected into the cerebrospinal fluid of mice with SOD1 mutation partially protect spinal motoneurons through the activation of po-tential neuroprotective astrocytes and the stimulation of anti-inflammatory factors. However, this treatment did not prevent denervation of the muscles nor slow
HEAD OF LABORATORY
Caterina Bendotti, Pharm.D.
She got her degree in Pharmacy at the University of Milano in 1984; Research assistant in Neuropharmacology la of the Mario Negri Institute (IRFMN) until 1986.
From 1986 to 1988 post doc at the Genetic developmental Lab, Dept. of Physiology of the Johns Hopkins Uni-versity, Baltimore, USA.
1988 -1992 research fellow in the laboratory of Neuropharmacology and in the 1992, she became head of the Unit and from 1998 of the Lab of Mo-lecular Neurobiology at the IRFMN.
Member of scientific advisory boards( SINS, MND,TLF,AISLA), editorial bo-ard (J.N.C.; CNS & ND-DT),internatio-nal meetings (MND,ENCALS), co-or-ganizer of scientific meetings (2007, 2010, 2014, 2016). Co-author of 160 articles (H index=42)
down the progression of the disease, underlining the growing evidence that the-rapies aimed at protecting only motor neurons are not effective for blocking or at least delaying ALS.• We have shown that while the increased expression of MHCI in the motor neuron in ALS mice is necessary to promote the removal of degenerated motor axons in the nerves and promote collateral reinnervation of the muscles, the in-crease of MHCI in the microglia in concert with the cytotoxic T lymphocytes leads to the degeneration of motor neurons. This counteracting role could explain the lack of efficacy of immunomodulatory treatments in ALS patients.
SELECTED PUBLICATIONS (2017)
Tortarolo M, Lo Coco D, Veglianese P, Vallarola A, Giordana MT, Marcon G, Beghi E, Poloni M, Strong MJ, Iyer AM, Aronica E, Bendotti C.Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFa. Mediators Inflamm. 2017; doi: 10.1155/2017/2985051. Epub 2017 Sep 10. Sironi F, Vallarola A, Violatto MB, Talamini L, Freschi M, De Gioia R, Capelli C, Agostini A, Moscatelli D, Tortarolo M, Bigini P, Introna M, Bendotti C.Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice. Stem Cell Res. 2017, 25: 66-178.
Chiarotto GB*, Nardo G*, Trolese MC, França MC Jr, Bendotti C, Rodrigues de Oliveira AL.The Emer-ging Role of the Major Histocompatibility Complex Class I in Amyotrophic Lateral Sclerosis. Int J Mol Sci. 2017 Nov 1;18(11). pii: E2298. doi: 10.3390/ijms18112298. Review.
Filareti M, Luotti S, Pasetto L, Pignataro M, Paolella K, Messina P, Pupillo E, Filosto M, Lunetta C, Mandrioli J, Fuda G, Calvo A, Chiò A, Corbo M, Bendotti C, Beghi E, Bonetto V.Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis. Front Mol Neurosci. 2017;10:99.
Pasetto L, Pozzi S, Castelnovo M, Basso M, Estevez AG, Fumagalli S, De Simoni MG, Castellaneta V, Bigini P, Restelli E, Chiesa R, Trojsi F, Monsurrò MR, Callea L, Maleševic M, Fischer G, Freschi M, Tortarolo M, Bendotti C, Bonetto V. Targeting Extracellular Cyclophilin A Reduces Neuroinflammation and Extends Survival in a Mouse Model of Amyotrophic Lateral Sclerosis. J Neurosci. 2017; 37:1413-1427.
Patai R, Paizs M, Tortarolo M, Bendotti C, Obàl I, Engelhardt J I, Siklòs LPresymptomatically applied AMPA receptor antagonist prevents calcium increase in vulnerable type of motor axon terminals of mice modeling amyotrophic lateral sclerosisBiochim Biophys Acta Mol Basis Dis 2017 ; 1863 : 1739-1748IF: 5.476
STAFFCaterina Bendotti, Pharm.D.
Head of Laboratory
Amyotrophic lateral sclerosis (ALS) is characterized by an important variability in terms of onset and progres-sion of the disease even in cases affected by the same gene mutation. Such heterogeneity is probably one of the reason for the therapeutic failure Understanding the mechanisms responsible for this variability is essential for identifying therapeutic targets on which act to slow down the disease at an early stage and to identify prognostic biomarkers useful for monitoring the efficacy of clinical treatments.In our laboratory we are studying two models of transgenic mice carrying the same SOD1G93A gene mu-tation C57Bl6-G93A and 129Sv-G93A mice that have an different onset and progression of disease. They represent a useful experimental paradigm from which comparison analyses may emerge potential disease modifiers to be validated later in the clinic.
IRFMN46
RESEARCH ACTIVITIES
The aim of our laboratory is to identify the mechanisms and the key proteins that regulate the intracellular pathways of in both chronic and acute neurodegenerative diseases as well as neurodevelop-ment syndromes. To better identify the protein signaling, we inhibit the action of these proteins with the use of cell penetrating peptides to prevent neurodegeneration. As a strategy against AD synaptic dysfunction, we designed a peptide able to interact with amyloid-b (Ab) protein reducing its aggregation and toxicity, in fat this small peptide Tat-Ab1-6A2V(D) prevents the synaptopathy both in vitro and in vivo. We also characterized the synaptic injury in P301L mice model of tauopathy proving a strong interaction between sex and tau: females are affected more severely than males, showing an increase of agglomerates of P-Tau correlated to a proportional decrease in postsynaptic marker levels (Buccarello et al. 2016). In the same model of tauo-pathy, we also demonstrated how a low fat protein diet induces a neuroprotective effect against synaptopathology and cognitive-locomotor impairments. In Rett syndrome, we demonstrated, for the first time, that JNK is a key molecule that play a pivotal role in this pathology, regulating general wellbeing conditions as well as the biochemical alterations of dendritic spine and the related behavioral impair-ments (i.e., locomotor and exploratory performances) in MeCP2 mice models. The D-JNKI1 treatment induced an improvement of wellbeing and a reduction of behavioral impairment and synaptic injury.
MAIN RESULTS (2017)
Alzheimer disease (AD): the cell permeable peptide Ab1-6A2VTAT(D), which counteracts the Ab oligomers toxic effect, showed a neuroprotective effect pre-venting the synaptopathy both in vitro and in vivo AD model (Cimini et al. 2016).Tauopathy: The P301L model showed a spine injury similar to that detected in AD, with P-tau accumulation in the postsynaptic terminal most marked in females than in males (Buccarello et al. 2016). We found also a neuroprotective effect of a low fat protein diet on synaptopathy, cognitive and locomotor damage in the same mouse model.JNK in the presynaptic compartment: with the Super Resolution and biochemical methods we localized JNK in the presynaptic region and its interaction with the
HEAD OF LABORATORY
Tiziana Borsello, Biol.Sci.D.
She obtained a PhD in Neuroscien-ce at the University of Turin Medical School in 1994.
From 1997 to 1999 she was a Rese-archer at the Institute of Neurobiology, CNR, Rome Italy.
From 1999 to 2003 she was Maitre Assistant and group leader at the Département de Biologie Cellulaire et de Morphologie, Université de Lau-sanne, Switzerland.
Since 2007, she is Group Leader in the “Neuronal Death and Neuropro-tection Laboratory”, Neuroscience Department at the IRCCS Mario Negri Institute of Pharmacological Research, Milano, Italy.
In 2015 she becomes a professor of Human Anatomy at Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Mi-lano, Milano, Italy.
t-SNARE proteins, in particular with Syntaxin-1/2 and SNAP25. Electrophysiolo-gical studies proved the JNK’s action on the modulation of vesicle release in the presynaptic compartment.Rett Syndrome (RTT): we demonstrated for the first time, a role of JNK in this pathology. Treatment with D-JNKI1 in MeCP2y/- mouse model with severe phe-notype leads to: 1) an improvement of wellbeing, 2) a recovery of locomotor impairment, 3) a recovery of synaptic function and 4) a protection of inflammatory state.Angelman syndrome (AS): we detected the JNK activation in AS mouse model that leading to an alteration of dendritic spines; by analogy to RTT we will evaluate the effect of D-JNKI1 peptide in this model.
SELECTED PUBLICATIONS (2017)
Buccarello L, Sclip A, Sacchi M, Castaldo AM, Bertani I, ReCecconi A, Maestroni S, Zerbini G, Nucci P, Borsello T. The c-Jun N-Terminal Kinase plays a key role in ocular degenerative changes in a mouse model of Alzheimer disease suggesting a corre-lation between ocular and brain pathologies. Oncotarget. 2017 Aug doi: 10.18632/oncotarget.19886.
Buccarello L, Grignaschi G, Di Giancamillo A, Domeneghini C, Melcangi RC, Borsello T. Neuro-protective effects of low fat-protein diet in the P301L mouse model of tauopathy. Neuroscience. 2017;354:208-220.
Biggi S, Buccarello L, Sclip A, Lippiello P, Tonna N, Rumio C, Di Marino D, Miniaci MC, Borsello T. Evidence of Presynaptic Localization and Function of the c-Jun N-Terminal Kinase. Neural Plast. 2017;2017:6468356. doi: 10.1155/2017/6468356.
Buccarello L, Grignaschi G, Castaldo AM, Di Giancamillo A, Domeneghini C, Melcangi RC, Borsello T. Sex Impact on Tau-Aggregation and Postsynaptic Protein Levels in the P301L Mouse Model of Tauopathy. J Alzheimers Dis. 2017;56:1279-1292.
Buccarello L, Borsello T. The Tat-Ab1-6A2V(D) peptide against AD synaptopathy. Oncotarget. 2017 Feb 14;8(7):10773-10774. doi: 10.18632/oncotarget.14604. PubMed PMID: 28121622; PubMed Central PMCID: PMC5355218. Ardiles AO, Grabrucker AM, Scholl FG, Rudenko G, Borsello T. Molecular and Cellular Mechanisms of Synaptopathies. Neural Plast. 2017;2017:2643943. doi: 10.1155/2017/2643943. Epub 2017 Apr 30. PubMed PMID: 28540088; PubMed Central PMCID: PMC5429942
STAFFTiziana Borsello, Biol.Sci.D.
Head of Laboratory
IRFMN48
RESEARCH ACTIVITIES
Research FocusResearch interests span the areas of Behavioural Neuroscience and Psychopharmacology.Research projects mainly focus on experimental animal models and their translational application to complex human disorders such as drug abuse, anxiety and depression.Major research areaEffects of recreational drug use in adolescent. This pattern of drug use is growing in number and is becoming an international problem, even without leading to drug addiction and dependence.Behavioural and pharmacological characterization of the so called “New Psycho-active Substances” to establish how they work to produce changes in brain che-mistry and how these changes may reinforce behaviour to induce drug taking and possibly abuse.The transition from initial recreational drug use to addiction, in adolescents and adults may occur through the progressive engagement of different pavlovian and instrumental learning systems in the brain.Investigation of the neural basis of these learning mechanisms underlying addi-ction as well as the molecular and neurochemical basis of drug conditioned cues inducing seeking behaviour.Preclinical efficacy of pharmacological agents in controlling drug seeking and relapse.Technological Equipment and experimental approachesExperimental approaches include behavioural and cognitive testing in rodents, intravenous drug self-administration (cocaine, amphetamine, nicotine, GHB) ope-rant conditioning maintained by sucrose and saccharine, oral drug self-admini-stration (alcohol, alcoholic-beer, near-beer, saccharine solution), unbiased con-ditioned place preference (to evaluate mechanisms underlying the acquisition as well as the expression of drug-induced place conditioning, extinction and reinsta-tement; cocaine, d-amphetamine, morphine, GHB, New Psychoactive Drugs), intra-cerebral and systemic pharmacology, targeted neural and neurochemical brain lesions, immune-histochemistry, pre-clinical magnetic resonance imaging (MRI).
HEAD OF LABORATORY
Luigi Cervo, PhD.
He got the Phd at the Open Uni-versity, Milton Keynes, U. K., since 2006 is the head of the Experimental Psychopharmacology Lab.
From 1978 to 2001 he was a re-search fellow and then chief of the Behavioural Pharmacology Unit in the Laboratory of Neuropharmacology at the “Mario Negri” Institute. Between 1981 and 1983 he spent two years as a research fellow in the Department of Psychiatry at the Chicago Universi-ty, Illinois, U.S.A (Prof. Charles Robert Schuster).
Author and co-author of several pe-er-review articles, author of commu-nications in international meetings, he is reviewer of several international peer-reviewed scientific journals. He is member of the Society for Neuro-science, European Behavioural Phar-macological Society, Italian Society for Neuroscience and Italian Society of Neuropsychopharmacology
Ballerini A, Moro F, Nerini IF, Marzo CM, Di Clemente A, Ferrari M, D’Incalci M, Biondi A, Colombini A, Conter V, Porcu L, Cervo L, Rizzari C, Zucchetti M.Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations. Cancer Chemother Pharmacol. 2017; 79:1267-1271. Lucchetti J, Marzo CM, Passoni A, Di Clemente A, Moro F, Bagnati R, Gobbi M, Cervo L. Brain Dispo-sition of cis-para-Methyl-4-Methylaminorex (cis-4,4’-DMAR) and Its Potential Meta-bolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects. J Pharmacol Exp Ther. 2017; 361:492-500. Lucchetti J, Marzo CM, Di Clemente A, Cervo L, Gobbi M. A validated, sensitive HPLC-MS/MS method for quantification of cis-para-methyl-4-methylaminorex (cis-4,4’-DMAR) in rat and human plasma: application to pharmacokinetic studies in rats. Drug Test Anal. 2017; 9: 870-879.
MAIN RESULTS (2017)
Using experimental models of relapse in drugs of abuse we studied nicotine, the main cause of preventable death for the World Health Organization. We have shown that environmental stimuli associated with nicotine are able to induce experimental relapse in the laboratory rat, even after a long period of abstinence. We have shown that a single administration of N-acetylcysteine, is able to reduce the seeking behavior triggered by the presentation of nicotine associated cues in abstinent rats. This effect appears to be mediated by glutamate mGLU2/3 receptors (Moro et al. , 2017).More recently, always using the laboratory rat, we have shown that 2 new psychoactive substances (NSPs) penetrate the central nervous system and, with a different pharmacological profile [psychostimulant (4,4’-DMAR) vs. analgesic (AH-7921)] induce clear positive motivational effects. In addition, repeated tre-atment with AH-7921 induces tolerance to the analgesic effect while chronic treatment with 4.4’-DMAR induces sensitization of hyper-locomotion, according to their mechanism of action/pharmacological profile. Furthermore, various po-tentially active metabolites of both NPS have been identified (Lucchetti et al., 2017; Lucchetti et al., 2017).
bolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral
STAFFLuigi Cervo, PhD.
Head of Laboratory
IRFMN50
RESEARCH ACTIVITIES
Prion diseases, also known as transmissible spongiform encepha-lopathies, are progressive and invariably fatal degenerative disor-ders of the central nervous system that affect humans and other animals. They result from the conformational change of a cellular protein of unclear function (denominated prion protein, PrP) into a self-propagating pathogenic isoform (prion) that accumulates in the brain of the patients. Three different manifestations of prion diseases are recogni-zed: sporadic, infectious and genetic. Genetic prion diseases display autosomal dominant inheritance and are linked to mutations in the PrP gene, on chromoso-me 20. Different PrP mutations are associated with different disease phenotypes.Specific aims of the program:• To understand the mechanisms of synaptic dysfunction and phenotypic hete-rogeneity in genetic prion diseases. • To develop anti-prion molecoles.• To study prion-like protein spreading in neurodegenerative diseases.
MAIN RESULTS (2017)
CJD patients are prone to seizures and have high brain levels of the inflammatory cytokine IL-1. We have shown that blocking IL-1 receptors with anakinra, the human recombinant form of the endogenous IL-1 receptor antagonist used to treat rheumatoid arthritis, normalizes hippocampal neurotransmission and redu-ces seizure susceptibility in a CJD mouse model (Bertani et al., 2017). These results raise the possibility that targeting IL-1 with clinically available drugs may be beneficial for symptomatic treatment of the disease.We have redefined the antiprion mechanisms of action of chlorpromazine an antipsychotic drug previously shown to inhibit prion replication by binding to PrP (Stincardini et al., 2017), and identified a new small molecule capable of counte-racting prion replication and mutant PrP toxicity (Massignan et al., 2017).We have also contributed to validate cyclophilin A as a potential therapeutic target for amyotrophic lateral sclerosis (Pasetto et al., 2017), and to characterize the role of the c-jun N-terminal kinase in ocular degeneration in a mouse model of Alzheimer’s disease (Bucarello et al., 2017).
HEAD OF LABORATORY
Roberto Chiesa, Dr. Biol.
Graduated in Biological Sciences with major in Genetics at the University of Pavia in 1991, and obtained a Ph.D. in Pharmacology at the Mario Negri Institute for Pharmacological Research in 1994.
From 1996 through 2000 he was Re-search Associate at the Washington University in St. Louis, MO, USA.
In 2001 he moved back to the Mario Negri Institute where he held a Te-lethon Scientist position.
Since 2009 is head of the Laboratory of Prion Neurobiology.
Bertani I, Iori V, Trusel M, Maroso M, Foray C, Mantovani S, Tonini R, Vezzani A, Chiesa R. Inhibition of IL-1b signaling normalizes NMDA-dependent neurotransmission and reduces seizure susceptibility in a mouse model of Creutzfeldt-Jakob disease J Neurosci 37:10278-10289, 2017
Stincardini C, Massignan T, Biggi S, Elezgarai S R, Sangiovanni V, Vanni I, Pancher M, Adami V, Mo-reno J, Stravalaci M, Maietta G, Gobbi M, Negro A, Requena J R, Castilla J, Nonno R, Biasini E. An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein PLoS One 12:e0182589, 2017
Massignan T, Sangiovanni V, Biggi S, Stincardini C, Elezgarai S R, Maietta G, Andreev I A, Ratmanova N K, Belov D S, Lukyanenko E R, Belov G M, Barreca M L, Altieri A, Kurkin A V, Biasini E. A small-molecule inhibitor of prion replication and mutant prion protein toxicity ChemMedChem 12:1286-1292, 2017
Pasetto L, Pozzi S, Castelnovo M, Basso M, Estevez A G, Fumagalli S, De Simoni M G, Castellaneta V, Bigini P, Restelli E, Chiesa R, Trojsi F, Monsurrò M R, Callea L, Malesevic M, Fischer G, Freschi M, Tortarolo M, Bendotti C, Bonetto V. Targeting extracellular cyclophilin A reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis J Neurosci 37:1413-1427, 2017 Buccarello L, Sclip A, Sacchi M, Castaldo A, Bertani I, Re Cecconi A D, Maestroni S, Zerbini G, Nucci P, Borsello T. The c-jun N-terminal kinase plays a key role in ocular degenerative changes in a mouse model of Alzheimer disease suggesting a correlation between ocular and brain pathologies. Oncotar-get 8: 83038-83051, 2017
STAFFRoberto Chiesa, Dr. Biol.
Head of Laboratory
IRFMN52
RESEARCH ACTIVITIES
The Laboratory main scientific interests include the pathogenesis of stroke and of traumatic brain injury and the development of protective strategies. The laboratory has significantly contributed to the knowled-ge of the role of inflammation in brain injury and to the identification of novel therapeutic strategies through manipulation of the inflammatory response. Clinically relevant experimental models of cerebral ischemia and brain trauma, and cellular cultures to reproduce selected aspects of the conditions are available in the lab. Clinical research studies in patients are also performed. Research lines: • The complement system in acute brain injury: early work of the lab has established that complement inhibition by C1-inhibitor or by targeting the lectin pathway of comple-ment activation (LP) provide neuroprotection with a wide therapeutic window; present efforts aim at elucidating the neuroprotective mechanisms. • Immune cells and brain injury: role of microglia and macrophage polarization in injury evolution, relationship between morphology-polarization-phenotype in activated micro-glia, mechanisms of phagocytosis. • Brain endothelium and thromboinflammation: investigations on the vascular even-ts, focusing on hemodynamics by two-photon microscopy and phenotype profiling of activated endothelium in experimental models of stroke and traumatic brain injury; en-dothelial activation in cell cultures following exposure to hypoxic or inflammatory stimuli. The lab research includes also analysis of atherosclerotic plaques in patients, vascular events associated to cardiovascular pathology.
MAIN RESULTS (2017)
• The lectin pathway of complement activation acts as mediator of thromboinflam-matory reactions occurring in stroke by mechanisms which are not fully understood yet. Our studies have been focused on the elucidation of the role of this pathway in atherosclerosis and in the establishment of the vulnerable plaque. We have deter-mined the presence of lectin components in plasma and in atherosclerotic plaques obtained from patients with obstructive carotid stenosis subjected to endoartherec-tomy. We could show that lectin pathway initiators are present within the plaques and their circulating levels change in atherosclerotic patients. In particular, we show that decreased ficolin-2 levels are associated with rupture-prone vulnerable pla-ques, indicating its potential use as marker for cardiovascular risk assessment in
HEAD OF LABORATORY
Maria Grazia De Simoni, Biol.Sci.D.
1978: Honours Doctoral Degree in Biological Sciences, University of Mi-lan; 1981: PhD in Pharmacology, Ma-rio Negri Inst. Milan; 1981-1982 post-doc at INSERM U 171, Lyon, France. Presently: Head of the Laboratory of Inflammation and Nervous System Di-seases, Mario Negri Inst. Milan.
Held about 100 lectures in Italy, United States and Australia. Author of more than 150 scientific papers.
Serves in the Board of Directors and in the Education Committee of the In-ternational Society of Cerebral Blood Flow and Metabolism.
atherosclerotic patients.• Clinical and experimental data indicate that the complement system is implicated in post-injury inflammation and neuropathology after traumatic brain injury. We have reported that targeting mannose-binding lectin, one of the initiator molecules of the lectin pathway of complement activation, by administration of a selective antagonist, selected and characterized by us, improves neurobehavioral outcome, increases hippocampal neurogenesis and protective astrogliosis following murine traumatic brain injury. A further study documented the presence of the lectin pathway compo-nents in human cerebral contused tissue. Once in the brain parenchyma the lectin pathway drives full complement activation which may lead to neuroinflammation and tissue injury. Thus altogether the data show that since the lectin pathway after TBI is associated with injury severity, is persistent and druggable - as indicated by experimental data - this offers an opportunity for the development of pharmacolo-gical interventions.• In acute injury to the brain, including traumatic and ischemic injury, pharmacologi-cal manipulations or stem cell administration induce morphological and phenotypi-cal switch of microglia and recruited macrophages driving protective polarization. This switch can be measured by immunoistochemical marker expression and mor-phological parameters allowing a quantitative assessment of in vivo polarization and information of their function.
SELECTED PUBLICATIONS (2017)
De Blasio D, Fumagalli S, Orsini F, Neglia L, Ortolano F, Zanier E R, Picetti E, Locatelli M, Stocchetti N, Longhi L, Garred P, De Simoni MG. Human brain trauma severity is associated with lectin complement pathway activation. J Cereb Blood Flow Metab, E-pub.
Pilely K, Fumagalli S, Rosbjerg A, Genster N, Skjoedt M-O, Perego C, Ferrante A M R, De Simoni MG, Garred P. C-reactive protein binds to cholesterol crystals and co-localizes with the terminal complement complex in human atherosclerotic plaques. Front Immunol 2017; 8: 1040
De Blasio D, Fumagalli S, Longhi L, Orsini F, Palmioli A, Stravalaci M, Vegliante G, Zanier E R, Bernardi A, Gobbi M, De Simoni MG. Pharmacological inhibition of mannose binding lectin ameliorates neuro-behavioral dysfunction following experimental traumatic brain injury. J Cereb Blood Flow Metab 2017; 37 : 938-950
Fumagalli S, Perego C, Zangari R, De Blasio D, Oggioni M, De Nigris F, Snider F, Garred P, Ferrante A M, De Simoni MG. Lectin pathway of complement activation is associated with vulnerability of athero-sclerotic plaques. Front Immunol 2017; 8 : 288
Pasetto L, Pozzi S, Castelnovo M, Basso M, Estevez AG, Fumagalli S, De Simoni MG, Castellaneta V, Bigini P, Restelli E, Chiesa R, Trojsi F, Monsurrò MR, Callea L, MaleševiC M, Fischer G, Freschi M, Tortarolo M, Bendotti C, Bonetto V. Targeting extracellular cyclophilin A reduces neuroinflammation and extends survival in a mouse model of amyotrophic lateral sclerosis. J Neurosci, 2017; 37:1413-1427.
STAFFMaria Grazia De Simoni,
Biol.Sci.D. Head of Laboratory
Circulating complement initia-tor molecules bind epitopes exposed on the surface of acti-vated endothelial cells. MBL or ficolin/MASP complexes deposited on the endothelium have multiple pro-inflammatory and toxic effects resulting not only in complement activation but also in increased vascular damage, inflammation and co-agulation.
IRFMN54
RESEARCH ACTIVITIES
• Neurobiological basis of psychotropic drug’s action • Neurobiological basis of animal behaviour• Role of brain serotonergic and glutamatergic systems in the ef-fects of psychotropic drugs and in mechanisms controlling cogni-tive processes• Development of novel pharmacological approaches for the tre-atment of Rett syndrome in an experimental model of the pathology, the Mecp2 knockout mice.
MAIN RESULTS (2017)
• Identification of changes in spontaneous motor activity in tryptophan hydroxyla-se-2 knockout mice, which cannot synthetize brain serotonin• Identification of a pharmacological treatment able to abolish motor deficit in a mouse model of Rett syndrome, potentially acting on the primary causes of the disease
HEAD OF LABORATORY
Roberto William Invernizzi, Biol.Sci.D.
Started his career in the laboratory of Neuropharmacology of the Istituto di Ricerche Farmacologiche “Mario Ne-gri” in 1976, where, at present, he he-ads the Laboratory of Neurochemistry and Behavior.
In 1986 he got his degree in Biological Sciences at the Milan State University.
He spent short periods as visiting scientist at the Karolinska Institutet in Stockholm (1988) and Nihon Universi-ty in Tokyo (1995) and in 1996 he was nominated head of the Intracerebral Microdialysis Unit
Pozzer D, Favellato M, Bolis M, Invernizzi RW, Solagna F, Blaauw B, Zito E. Endopla-smic Reticulum Oxidative Stress Triggers Tgf-Beta-Dependent Muscle Dysfunction by Accelerating Ascorbic Acid Turnover. Sci Rep 2017, 7:40993.
DEPARTMENTS and LABORATORIES
IRFMN 55
STAFFRoberto William Invernizzi,
Biol.Sci.D., Head of Laboratory
Mirjana Carli, Ph.D.Head of Pharmacology of Cognitive
Behavior Unit
IRFMN56
RESEARCH ACTIVITIES
Over the last thirty years the investigations of the Laboratory of Ge-riatric Neuropsychiatry have been mainly centered on the study of epidemiology and pharmacology (phase I, II, III trials and observa-tional studies) of dementia and on the assessment of the quality of care and drug use in the elderly population. A large population-ba-sed survey has been conducted to investigate the prevalence, incidence and risk factors of dementia in the oldest old residing in the Varese province (Monzino 80-plus Study). Our research also includes the investigation of the relationship between various pathologies, particularly anemia, and the cli-nical, cognitive and functional condition of elderly subjects using data collected in another large population-based survey in Biella (Anemia and Health Study), and the evaluation of the quality of care of terminally ill patients in hospices (in collaboration with the Hospice “Via di Natale Franco Gallini”). In collaboration with the Geriatric Division of the Ospedali Regionali of Lugano and Mendrisio, Swit-zerland, we evaluate the impact of neuropsychological, functional and mobility variables on heath-related outcomes and disease progression in hospitalized and ambulatory patients (Canton Ticino Study). Our laboratory has always been invol-ved in developing and validating instruments able to reliably assess the different aspects characterising the clinical expression of dementia and Alzheimer’s dise-ase: cognitive deficits, functional disability and behavioural disturbances, as well as global outcomes.
MAIN RESULTS (2017)
In the Monzino 80-plus population-based prospective Study, severe visual and hearing impairments continue to grow also in the very old. Severe hearing im-pairment and measures of cognitive ability or cognitive competence were cross-sectionally associated in the oldest old but not in centenarians. The risk of incident dementia associated with a severe hearing impairment was slightly increased in the oldest old but not in centenarians. No association was instead found between severe visual impairment and dementia.In collaboration with the Department Biomedical Sciences of Humanitas Univer-sity, we have started the study “Aging of hematopietic stem cells - molecular ar-chitecture of marrow dysplasia and clinical contribution of ineffective hematopo-
HEAD OF LABORATORY
Ugo Lucca, MSc.
Over the last thirty years, the focus of his research has been the epidemio-logy of dementia and aging and the clinical pharmacology of antidementia treatments.
He has conducted several clinical trials of antidementia drugs.
He is responsible for two large pro-spective population-based studies in the elderly population (the Monzino 80-plus Study in the province of Vare-se and the Anemia and Health Study in Biella) and for the neuropsycholo-gical part of the Canton Ticino Study, Switzerland.
iesis to frailty in the elderly” aimed at dissecting molecular architecture of marrow dysplasia and the clinical contribution of ineffective hematopoiesis to frailty in the elderly. The definition of molecular architecture of marrow dysplasia would allow us to improve the current diagnosis and classification of anaemia in the elderly and the definition of individual patient’s risk of disease associated morbidity/mor-tality. Finally, in patients with marrow dysplasia sequencing is expected to predict the vulnerability of a particular genotype to specific therapeutic interventions, thus providing a basis for optimizing at individual level timing and modality of therapeu-tic interventions.The mean number of chronic drugs is approximately 3, with about one in four centenarian in polytherapy (five or more drugs). As is the case with “young elder-ly”, the most prevalent drug classes are antithrombotic agents and cardiovascular system drugs. Notable the chronic use in one third of our population of proton pump inhibitors: there is a vast literature on the inappropriate use of this class of drugs.Starting from 2017 a collaboration was started with two clinics of the department of clinical sciences. Cardiologists make a complete cardiologic visit, including echocardiogram, ECG and heart rate variability. Dentist do an objective examination of the oral cavity with oral mucosa brushing for biological studiesIn collaboration with the hospice “Via di Natale” di Aviano, the two research stu-dies in patients with advanced cancer, initiated in 2016 are ongoing. The aim of the first study is to investigate whether the use of a set of clinical variables com-bined with the clinician’s judgement would improve the accuracy in estimate the life expectancy of these patients. In the second study, the nursing staff is involved to monitor the quality of death in the last hours of life on terminally ill oncologic patients in hospice.
SELECTED PUBLICATIONS (2017))
Riva E, Colombo R, Moreo G, Mandelli S, Franchi C, Pasina L, Tettamanti M, Lucca, U, Mannucci PM, Nobili A. Prognostic value of degree and types of anaemia on clini-cal outcomes for hospitalised older patients. Arch Gerontol Geriatr 2017; 69: 21-30.
Chiesa D, Marengoni A, Nobili A, Tettamanti M, Pasina L, Franchi C, Djade C D, Corrao S, Salerno F, Marcucci M, Romanelli G, Mannucci P M, REPOSI InvestigatorsAntipsychotic prescription and mortality in hospitalized older personsPsychogeriatrics 2017; 17: 397-405.
Marzona I, Avanzini F, Lucisano G, Tettamanti M, Baviera M, Nicolucci A, Roncaglioni M C, Risk and Prevention Collaborative GroupAre all people with diabetes and cardiovascular risk factors or microvascular complications at very high risk? Findings from the Risk and Prevention StudyActa Diabetol 2017; 54: 123-131.
Baviera M, Avanzini F, Marzona I, Tettamanti M, Vannini T, Cortesi L, Fortino I, Bortolotti A, Merlino L, Trevisan R, Roncaglioni M CCardiovascular complications and drug prescriptions in subjects with and without diabetes in a Nor-thern region of Italy, in 2002 and 2012Nutr Metab Cardiovasc Dis 2017; 27: 54-62.
Baviera M, Roncaglioni M C, Tettamanti M, Vannini T, Fortino I, Bortolotti A, Merlino L, Beghi EDiabetes mellitus: a risk factor for seizures in the elderly - a population-based studyActa Diabetol 2017; 54: 863-870.
Pasina L, Cortesi L, Tettamanti M, Nobili A, Mannucci P M, REPOSI InvestigatorsUse of non-steroidal anti-inflammatory drugs and analgesics in a cohort of hospitalized elderly patients: results from the REPOSI studyEur J Intern Med 2017; 38: e11-e12.
STAFFUgo Lucca, MSc.
Head of Laboratory
Emma Riva, M.D.Head of Unit
Geriatric Pharmacology Unit
Mauro Tettamanti, Biol.Sci.D.Head of Unit
Geriatric Epidemiology Unit
IRFMN58
RESEARCH ACTIVITIES
The Laboratory and the Units promote and coordinate:• projects on appropriate prescribing in the frail elderly people with multimorbidity and polypharmacy, with particular attention to the ia-trogenic risk, deprescribing and pharmacovigilance;• projects in the field of public health for the study of the quality of assistance and the right advocacy and promotion in mental health;• pharmacoepidemiological investigations based on administrative database, re-cord-linkage and network analysis models for the study of the complexity, frailty and polypharmacy in the elderly;• the REPOSI Registry, a clinical network of more than 80 internal medicine and geriatric wards for the study of multimorbidity and polypharmacy in hospitalized elderly patients;• assessment of the impact of service organization on mental health, frailty and quality of life in different settings of care conducted with Policy makers and care-giver and patient associations;• training and educational intervention on the rational use of drugs and mental health services for health and social workers and citizens.Moreover, they developed INTERCheck-WEB® a computerized support system to optimize drug prescription in older adults that is used in many studies and in many hospitals and long-term care.Finally, the laboratory provide to clinicians and citizens a drug information service.
MAIN RESULTS (2017)
• Bedridden status, severely reduced kidney function, recent hospital admis-sions, severe dementia and hypoalbuminemia were associated with higher risk of three-month mortality in non-oncologic patients after discharge from internal medicine and geriatric hospital wards.• In internal medicine and geriatric wards continuously participating to the REPO-SI register, the proportion of patients with a very low drug use at hospital dischar-ge increased overtime.• In acutely hospitalized older people a high degree of inappropriate prescription among patients prescribed with antiplatelets for primary prevention was found, mainly due to overprescription, and a large proportion of patients with overt car-
HEAD OF LABORATORY
Alessandro Nobili, M.D.
Doctor in Medicine and Master in Bio-techonological and Pharmacoepide-miological Research.
Expert in pharmacoepidemiology, methodology of clinical research and geriatric pharmacology.
Promoter and coordinator of many research projects in the field of eva-luation of appropriateness of drug pre-scribing and assessment of quality of care and services for the elderly.
Author of many scientific publications in international and national journals.
LABORATORY OF QUALITY ASSESSMENTOF GERIATRIC THERAPIES AND SERVICES
DEPARTMENTS and LABORATORIES
IRFMN 59
dio- or cerebrovascular disease were underprescribed in spite of the established benefits of antiplatelet drugs in this context.• Using multiple correspondence analysis among hospitalized elderly, four frailty phenotypes differently associated with adverse events were found. • Mild anaemia predicted hospital re-admission of older in-patients, while three-month mortality risk increased proportionally with anaemia severity. Type and severity of anaemia affected hospital re-admission and mortality, the worst prognosis being associated with normocytic and macrocytic anaemia.• Public health communication about prevention and management of frailty should be founded on a paradigm of resilience, balanced acceptance, and coping. • There is potential for frailty to be managed in a more integrated and person-cen-tred manner, overcoming the challenges associated with niche ownership within the healthcare system. • Physical exercise programs have been shown to be effective for reducing or postponing frailty but only when conducted in groups. • The use of a specific tool and training for the identification of patients at risk of psychosis, in the framework of the integration of child and adolescent mental health and adult mental health services, allowed to intercept a significant number of young people with mental states at risk of psychosis.
SELECTED PUBLICATIONS (2017)
Ardoino I, Rossio R, Di Blanca D, et.al. Appropriateness of antiplatelet therapy for pri-mary and secondary cardio- and cerebrovascular prevention in acutely hospitalized older people. Br J Clin Pharmacol. 2017; 83: 2528-2540.
Barbato A, Civenti G, D’Avanzo B. Community residential facilities in mental health services: A ten-year comparison in Lombardy. Health Policy. 2017; 121: 623-628.
D’Avanzo B, Shaw R, Riva S, et.al. Stakeholders’ views and experiences of care and interventions for addressing frailty and pre-frailty: A meta-synthesis of qualitative evidence. PLoS One. 2017 Jul 19;12(7):e0180127.
Franchi C, Ardoino I, Nobili A, et.al. Pattern of in-hospital changes in drug use in the older people from 2010 to 2016. Pharmacoepidemiol Drug Saf. 2017; 26:1534-1539.
Marcucci M, Franchi C, Nobili A, et.al. Defining Aging Phenotypes and Related Outcomes: Clues to Recognize Frailty in Hospitalized Older Patients. J Gerontol A Biol Sci Med Sci. 2017; 72:395-402.
STAFFAlessandro Nobili, M.D.
Head of Laboratory
Barbara D’Avanzo, Philos.D.Head of Laboratory of Epidemiology
and Social Psychiatry
Carlotta Franchi, Pharm.D. Head of Pharmaco-epidemiological
Research in Older People Unit
Luca Pasina, Pharm.D. Head of Pharmacotherapy and Presciption Appropriateness
IRFMN60
RESEARCH ACTIVITIES
The current research relates to the neurobiology of CNS diseases by covering neuroscience, neuropharmacology and neuroimmuno-logy. More specifically, the laboratory studies with multidisciplinary approaches the molecular, structural, epigenetic and functional modifications in the brain potentially involved in the etiopathoge-nesis of seizures and the associated neurological co-morbidities. The research is focused on neuroactive inflammatory mediators, an hallmark of human epileptogenic brain tissue, and molecules apt to resolve neuroinflam-mation using adult and developmental models of epilepsy. We especially ad-dress acquired or genetic forms of epilepsy using in vivo and in vitro experimental models. Our research programme includes the preclinical discovery and clinical validation of novel predicitive and prognostic biomarkers of epilepsy using nonin-vasive measures such as detection of blood molecules, MRI-based imaging and electrophysiological signatures. Using animal models we are developing novel target-specific disease-modifying drugs with the ultimate scope of translating the laboratory findings to the clinical applications.
MAIN RESULTS (2017)
• We discovered a potential novel molecular and mechanicistic biomarker of epilepsy, namely the infammatory mediator High Mobility group Box 1 (HMGB1), that predicts the therapeutic response to drugs and the development of epilepsy, or seizure relapse, both in in vivo rodent models of acquired epilepsy, and in patients. • We discovered noninvasive imaging (magnetic resonance spectroscopy) and behavioral cognitive deficit features which are predicitive of epilepsy development after experience of an epileptogenic risk factor in animal models.• We identified combinations of antiinflammatory and antioxidant treatments, some of which in medical use, and microRNA-based epigenetic interventions that mediate clinically significant disease-modification effects in animal models of acquired epilepsy. These treatments when transiently applied either before or after disease onset greatly reduced the frequency and blocked the progression of spontaneous drug-resistant seizures, afforded neuroprotection and rescued the cognitive deficits in the animals.
HEAD OF LABORATORY
Annamaria Vezzani, Biol.Sci.D.
PhD in Neuropharmacology. She was visiting scientist at the Univer-sity of Maryland, USA, Univeristy of Stockholm and Karolinska Institute, Sweden, Albert Einstein College of Medicine, NY, USA.
She received the prestigeous Resear-ch Recognition Award for translational research by the American Epilepsy Society.
She has published >160 original pa-pers, several book chapters and re-viewes in peer-reviewed high impact scientific journals (h-index 62). She is member of IMI scientific committe.
• We discovered that Monoacyl-glycerol-lipase (MAGL) is a new target for con-trolling benzodiazepine-resistant status epilepticus, a clinical emergence that can be reproduced in animal models. We also found that the therapeutic effect of MAGL inhibition is synergistic with the ketogenic diet, therefore providing a pro-of-of-concept evidence for the clinical translation of these findings.
SELECTED PUBLICATIONS (2017)
Bertani I, Iori V, Trusel M, Maroso M, Foray C, Mantovani S, Tonini R, Vezzani A, Chie-sa R. Inhibition of IL-1b Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt-Jakob Disease. J Neurosci. 2017 25;37:10278-10289.
Pauletti A, Terrone G, Shekh-Ahmad T, Salamone A, Ravizza T, Rizzi M, Pastore A, Pascente R, Liang LP, Villa BR, Balosso S, Abramov AY, van Vliet EA, Del Giudice E, Aronica E, Antoine DJ, Patel M, Walker MC, Vezzani A. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain. 2017;140:1885-1899.
Walker LE, Frigerio F, Ravizza T, Ricci E, Tse K, Jenkins RE, Sills GJ, Jorgensen A, Porcu L, Thip-peswamy T, Alapirtti T, Peltola J, Brodie MJ, Park BK, Marson AG, Antoine DJ, Vezzani A, Pirmohamed M. Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy.J Clin Invest. 2017; 127:2118-2132.
Milikovsky DZ, Weissberg I, Kamintsky L, Lippmann K, Schefenbauer O, Frigerio F, Rizzi M, Sheintuch L, Zelig D, Ofer J, Vezzani A, Friedman A. Electrocorticographic Dynamics as a Novel Biomarker in Five Models of Epileptogenesis. J Neurosci. 2017; 37:4450-4461. Iori V, Aronica E, Vezzani A.Epigenetic control of epileptogenesis by miR-146a. Oncotarget. 2017; 8: 45040-4504T
STAFFAnnamaria Vezzani, Biol.Sci.D.
Head of Laboratory
Teresa Ravizza, Biol.Sci.D.Head of Physopathology of
glia-neuron communication Unit
Oxidative stress and neuroinflammation: new therapeutic targets and biomarkers for epilepsy. Oxidative stress is ignited in the brain by epileptogenic injuries both in animal models of epilepsy and in humans affected by the disease. It represents a key mechanism for the development of seizures and the cognitive deficits. Our investigations have shown that oxidative stress occurs during epileptogenesis and induces the generation of a molecule named disulfide-HMGB1 which is implicated in the generation of epileptic seizures. Moreover, this molecule is formed in the brain but can also be detected in blood before the animals develop epilepsy and acts as a biomarker which predicts the disease development and the therapeutic response to drugs.
IRFMN62
RESEARCH ACTIVITIES
Acute brain injury can have severe and long-lasting consequences. Pharmacological neuro-protection, both for traumatic brain injury (TBI) or hemorrhagic lesions, is not available, with repeated failu-res of several International trials. There is a gap from successful experimental interventions in animal models and failures in clinical applications. Essential for our research, therefore, is a lively con-nection/interplay between the laboratory and the clinical work. Parallel exploration of mechanisms in the clinical setting (through invasive monitoring and neuro-ima-ging, for instance) and in the lab could refine experimental models and develop neurorestorative treatments.Specific aims of the program:• To understand the mechanisms transforming an initial acute biomechanical injury into a chronic and progressive pathology. • To understand the heterogeneity of TBI and identify biomarkers for acute brain injury• To interfere with injury evolution by reducing toxic events and fostering the en-dogenous reparative response.
MAIN RESULTS (2017)
Traumatic brain injury (TBI) is a risk factor for Alzheimer’s disease (AD) and chro-nic traumatic encephalopathy. The cellular drivers and molecular mechanisms of such progressive cognitive deterioration syndromes are unclear. We have recent-ly found that TBI in wild-type (WT) mice induces a self-propagating tau pathology that progressively spreads in the brain over time and is associated with ongoing inflammation and neurodegeneration (Pischiutta 2017). We will use this injury pla-tform to understand the mechanisms transforming an initial biomechanical injury into a chronic and progressive pathology.We aim at assessing neurorestorative strategies with a specific focus on mesen-chymal stem cells (MSC) and their derivatives. We have shown that MSC im-prove outcome fostering protective and restorative processes after experimental acute brain injury. We have found that MSC released bioactive factors (secreto-me) mediate plasticity and restorative events, indicating the potential for a cell free approach (Sammali et al., 2017).
HEAD OF LABORATORY
Elisa Roncati Zanier, M.D.
Trained in Medicine, Anaesthesia and Intensive Care at the University of Mi-lano.
She was a Post-doctoral fellow at the Neurotrauma Laboratory, University of Los Angeles, California.
She was assistant physician at the Neurosurgical Intensive Care Unit, Fondazione IRCCS Ospedale Mag-giore Policlinico, Milano from 2003-2007.
Since 2007 she has a teaching assi-gnment into postgraduate school of Intensive Care and Anesthesiology, University of Milano.
Since 2008 she is associate resear-cher at the Mario Negri Institute.
LABORATORY OF ACUTE BRAIN INJURY AND THERAPEUTIC STRATEGIES
DEPARTMENTS and LABORATORIES
IRFMN 63
We are planning a first phase I/II clinical study “MATRIx” (MesenchymAl Traumatic bRain Injury) – that aims at evaluating the safety and tolerability of bone marrow MSC infused intravenously in the acute phase after severe TBI. This trial is under evaluation and involves 3 Neurointensive Care Units at San Gerardo H Monza, Policlinico H, Milano and San Raffaele H, and the Verri Laboratory (AIFA certified) that will provide third-party MSC from healthy donors.
SELECTED PUBLICATIONS (2017)
Ercole A, Magnoni S, Vegliante G, Pastorelli R, Surmacki J, Bohndiek SE, Zanier ER. Current and Emerging Technologies for Probing Molecular Signatures of Traumatic Brain Injury. Front Neurol. 2017 Aug 30;8:450.
Zoerle T, Carbonara M, Zanier ER, Ortolano F, Bertani G, Magnoni S, Stocchetti N. Rethinking Neuroprotection in Severe Traumatic Brain Injury: Toward Bedside Neu-roprotection. Front Neurol. 2017 Jul 24;8:354. doi: 10.3389/fneur.2017.00354. eCollection 2017.
Sammali E, Alia C, Vegliante G, Colombo V, Giordano N, Pischiutta F, Boncoraglio GB, Barilani M, Lazzari L, Caleo M, De Simoni MG, Gaipa G, Citerio G, Zanier ER. Intravenous infusion of human bone marrow mesenchymal stromal cells promotes functional recovery and neuroplasticity after ischemic stroke in mice. Sci Rep. 2017 Jul 31;7(1):6962. doi: 10.1038/s41598-017-07274-w.
