27^th Euro-Global Neurologists Meeting July 23 - 25, 2018 Moscow, Russia

Zena Vexler has served as Director of Research at Neonatal Brain Disorders Center, since 2003. She has served on the NIH study sections and chaired Brain 2 and Brain 3 Committees for American Heart Association. She has multi- disciplinary training in chemistry, biochemistry, pharmacology and physiology. For more than 25 years, her research has been centered on the mechanisms of experimental stroke, including cerebrovascular injury and neuro-inflammation.

The major barriers of the brain, the blood-brain barrier (BBB) and the blood-CSF barrier, tightly regulate the transport of molecules, cells and ions between the peripheral circulation and parenchyma. Barrier properties change during brain maturation and aging, affecting susceptibility to and the pathophysiology of various neurodegenerative diseases in age-related manner. Data are emerging that the phenotypic endothelial cell heterogeneity, the more elaborate capillary network in the adult, differences in regional responsiveness of the vessels, pericyte and astrocyte phenotypes and coverage, distinctly modify hemodynamic regulation and BBB integrity after arterial stroke in newborns, children and adults. We will discuss the role of leukocyte-microglial communications in modifying BBB integrity in experimental stroke in three age groups. In particular, we will demonstrate that BBB is strikingly more integrant after perinatal stroke than after adult stroke, in part due to agedependent expression of extracellular matrix proteins and tight junction proteins. We will then discuss our findings that at least a subpopulation of microglial cells protects both BBB integrity and the neonatal brain based on adverse effects of depletion of microglial cells or inhibition of microglial TGFbeta1 signaling on neurovascular integrity in injured brain. We will also discuss how disruption of monocyte and neutrophil signaling affects BBB structure-functional responses in stroke induced in different age groups.

Marina Zueva is a Professor of Pathophysiology. She has completed her Graduation at the Lomonosov Moscow State University and PhD at Moscow Helmholtz Research Institute of Eye Diseases. Currently, she is the Head of the Division of Clinical Physiology of Vision at the Moscow Helmholtz Research Institute of Eye Diseases. She has published over 15 peer-reviewed full-length papers in English and presented near 70 topics at international conferences. Her research topics include “Clinical physiology and electrophysiology of vision, neurophysiology, age-related and neurodegenerative disorders of the visual system and the brain, neurocognitive technologies of the restoration, maintenance and improvement of the brain activity and cognitive functions”

Cognitive decline is characteristic of various pathological conditions including traumatic brain injury (TBI) and can accompany normal aging. Technologies of neurorehabilitation exploiting the structural-functional plasticity of the brain

could promote the forming of new connections to compensate the cognitive deficit. Methods of cognitive rehabilitation include techniques of mental and physical training and different regimens of stimulation therapy such as transcranial magnetic and electrical stimulation, and low-intensity stimulation by sensory stimuli, positive effects of which were shown in many studies.

However, taking into account that in aging and pathology potential of neuroplasticity is reduced, the efficacy of any methods of neurorehabilitation can be objectively restricted. Besides, in the stimulation therapy, optical, audio and other signals with a regular, periodic temporal structure are usually applied. The periodic rhythms can provide some improvement of the cortical

activity in the particular range of EEG. But they cannot restore complex fractal dynamics of the brain's activity typical of a healthy person and improve the cognitive ability of the patient. We suppose that the fractal stimulation by complex-structured optical signals and sound tones will promote activating the structural-functional plasticity and improve cognitive functions in pathological conditions associated with the cognitive decline. Evoked changes in the cortical activity can ensure the impact of stimulation on cognitive functions. Because the fractal stimulation is supposed to increase the potential of neuroplasticity, during the period of enhanced plasticity (against the backdrop of a course of stimulation therapy) an increase in the efficiency of different others neurorehabilitation measures should be expected.

Josef Finsterer received his MD and he is a Prof. of Neurology, from the University of Vienna, Austria. Since his training as a Clinical Neurologist and Electro physiologist at the Neurological Krankenhaus Rosenhuegel and the Ludwig Boltzmann Institute for Epilepsy and Neuromuscular Disorders, he is involved in the management of neuromuscular disorders, particularly muscular dystrophies and metabolic myopathies. In addition to neuromuscular disorders, his research interests focus on genetics, orphan diseases, and cardiac involvement in genetic conditions

Since the central-nervous-system (CNS) is the second most frequently affected organ in mitochondrial disorders (MIDs) and since MIDs are increasingly recognized, it is important to know about the morphological CNS abnormalities on imaging in these patients. The study aims at summarizing and discussing current knowledge and recent advances concerning CNS imaging abnormalities in adult MIDs. The most relevant CNS abnormalities in adult MIDs on imaging include white and grey matter lesions, stroke-like lesions as the morphological equivalent of stroke-like episodes, cerebral atrophy, calcifications, optic atrophy, and lactacidosis. Since these CNS lesions may go along with or without clinical manifestations, it is important to screen all MID patients for cerebral involvement. Some of these lesions may remain unchanged for years whereas others may be dynamic, either in the sense of progression or regress. Typical dynamic lesions are stroke-like lesions and grey matter lesions. Clinically relevant imaging techniques for visualization of CNS abnormalities in MIDs are the computed tomography, magnetic-resonance-imaging, MR-spectroscopy, SPECT, PET, and angiography. CNS imaging in adult MIDs is important for diagnosing and monitoring CNS involvement. It also contributes to the understanding of the underlying pathomechanisms that lead to CNS involvement in MIDs.

Drini Dobi was born in January 27th, 1969, and graduated as PhD in University of Tirana, Albania in 1992, and has done the specialization course in Neurology from1994-1998 in University Hospital Centre Tirana, Albania. After his specialization, he has done some other mini specialization course for neurorehabilitation in Institute Carlo Besta, San Carlo, and Don Carlo Gnocchi Milano, Italy and mini specialization course for neurosonology in UHC & Sestre Milosrdnice, Zagreb, Croatia. He has lot of publications in some medical periodic and has participated in some of AAN Annual Meetings with his works, EFNS and EAN conferences, with his works too, and some other Neurological Conferences abroad. His Masters is in Rehabilitation in Parkinson Disease, in 2005 and PhD in Physical Rehabilitation after stroke in 2015. He is also the Member of EAN Scientific Panel of Neurorehabilitation, Scientific panel of neurotoxicology, and General Neurology.

Statement of the Problem: Presently, there is limited information on stroke care in the very old (80 years and older). Population aging is a summary term to describe shifts in the age distribution of a population toward older ages, most marked in highly developed countries. The number of people aged 80 and above is growing faster than any other age group. In 2006, people aged 80 and over were approximately 19% of the population in developed countries and around 10% in developing countries. The purpose of this study is to evaluate vascular risk factors, stroke subtypes and clinical outcomes in very old patients admitted at our hospital with acute stroke. Methodology & Theoretical Orientation: We included in this study 252 stroke patients admitted to Service of Neurovascular Disorders in University Hospital Centre “Mother Teresa”, Tirana, Albania from February 2015 to December 2016. We assess if there were any significant differences between patients under 80 years old compared with older patients (80 years or older), with regard to vascular risk factors, stroke type and clinical outcome. Findings: Of 252 patients, 189 patients were less than 80 years, 63 were 80 years old and older. Younger patients were more

likely to have diabetes (30.6% versus 16.2%, p<0.001).Older patients were more likely to have ischemic heart disease (38% versus 30.1% p=0.02), or atrial fibrillation (34.5% versus 15.2%, p<0.001).Older patients were more likely to have Total Anterior Circulation Infarcts (TACI) strokes (17.6% versus 11.1%, p<0.009) or Partial Anterior Circulation Infarct strokes (PACI) (30.1% versus 23.5%, p=0. 04)Outcome data, which was available for 91% patients, showed that older patients stayed longer in hospital (median length of stay 23 days versus 18 days, (p=0.008) and had a higher inpatient mortality 14% versus 3.7%, (p<0.001). Conclusion & Significance: Very elderly patients have a different risk factor profile, have more anterior circulation infarcts and have a worse prognosis-with increased mortality and increased length of stay in hospital.

Muhammad Mahajnah is an Assistant Professor of Pediatrics and Pediatric Neurology at the Technion Faculty of Medicine, Israel. He completed his Medical degree at Bruce and Ruth Rappaport Faculty of Medicine, Technion, Israel in 1992 and his PhD degree in 1998. He trained in Pediatrics at Carmel Medical Center and completed fellowship in Pediatric Neurology at Schneider Children Medical Center, Tel Aviv. He has worked with children neurological disorder for about 20 years and has special interest in neurodevelopmental disorders and neuro genetic disorders and devotes his time to both clinical work and research.

About half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. We screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n=618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. We demonstrate that autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified

autosomal recessive and sporadic cases; hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Gjumrakch Aliev is the President of GALLY International Biomedical Research Institute Inc., San Antonio, Texas, USA. He also holds appointment with the University of Atlanta, Georgia, USA as a Professor of Cardiovascular, Neuropathology, Gerontology, Health Science and Healthcare Administration and as a Leading Scientist, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Moscow Region, Chernogolovka, Russian Federation. He completed his MD in 1982 at the Baku Medical University (former USSR) with cum laude. Then he completed his PhD in Cardiovascular Diseases at the prestigious Russian Academy of the Medical Sciences, Moscow, Russia in 1988 with cum laude. He received postdoctoral training with Professor G Burnstock at University College of the London. He is an outstanding teacher, scholar, and a renowned scientist in the area of cellular molecular physiology, and cardiovascular, and neurodegeneration-mediated pathologies including Alzheimer disease (AD). He is nationally and internationally reputed in his area. He is one of the most cited authors in his fields with high impact factors.

Neurodegenerative disorders are characterized by a loss of cognitive function and inappropriate death of nerve cells in areas of the brain that control such functions as memory and language. The trigger for nerve cell death is unknown in the AD, as well as in other neurodegenerative conditions, in which memory decline is a prominent feature. A rapidly growing body of evidence indicates that increased oxidative stress resulting from reactive oxygen radicals is associated with the aging process and agerelated degenerative disorders such as atherosclerosis, ischemia/reperfusion, and arthritis, stroke, and neurodegenerative diseases. Reactive oxygen species (ROS) are generated at sites of inflammation and injury, and at low levels, they can function as signaling intermediates in the regulation of fundamental cell activities such as growth and adaptation responses. At higher concentrations, ROS can cause cell injury and death. The vascular endothelium, which regulates the passage of macromolecules and circulating blood to cells and tissue, is a major target of oxidative stress, playing a critical role in the pathophysiology of vascular diseases. Since the vascular endothelium, neurons, and glia are all able to synthesize, store and release ROS and vascular active substances in response

to certain stimuli, their contribution to the pathophysiology of atherosclerosis, stroke, other non-atherosclerotic cerebrovascular disease and neurodegenerative syndrome such as mild cognitive impairment (MCI) and the AD is extremely important. In addition, abnormalities in cholesterol metabolism, oxidative stress, and vascular lesions are important factors in the pathogenesis of late-onset forms of the AD, forms of mental retardation, stroke and MCI. This idea is based on the positive correlations found between stroke,

MCI, AD and cardiovascular diseases. New evidence indicates that continuous formation of free ROS induces cellular damage and decreases antioxidant defenses. Specifically, oxidative stress increases vascular endothelial permeability and promotes leukocyte adhesion, all of which are coupled with alterations in endothelial signal transduction and redox-regulated transcription factors. We theorize that the cellular and molecular mechanisms, by which cholesterol metabolism abnormalities induce the formation of large amounts of ROS, decrease endothelial barrier function via the overexpression of inducible nitric oxide synthase (iNOS) and promote leukocyte adhesion. Chronic injury stimuli have the action of inducing decompensation and or alterations in normal vascular function, which results in the development of cerebrovascular arterio- and atherosclerosis that further manifest as stroke, MCI and/or AD.

Ling Li has completed her PhD and MD in 2003 at Zhejiang University School of Medicine. She is a Neurologist, Chief Physician, Professor, Supervisor for Doctor,

Director of Pediatric Neurology at Xinhua Hospital Affiliated to Shanghai Jiao tong University School of Medicine, Shanghai, China. She has published more than16 papers in reputed journals. Her main research is about strategies to prevent neuronal damage in pediatric bacterial meningitis

The risk of serious sequelae caused by central nerve system (CNS) infection is 30-60%. Among them, inflammation is one of the critical mechanisms. But how inflammation alters brain function remains unclear. Here, we provide solid evidence about meningitis caused by brain damage reduced host inflammatory response. Neurotrophic factor family plays an important role in neuron development, differentiation and survival. BDNF expression increased in acute S. pneumoniae meningitis, while obviously alleviated after antibiotic treatment. Neonatal meningitis caused long-term BDNF decreases were correlated to adult animal behavioral deficits. Exogenous BDNF can increase neuron survival both in cortex and hippocampus, and reversed brain damage. Meanwhile, it can increase hippocampus neuron stem cells neurogenesis. These findings indicate that BDNF regulatory expression may be parts of host inflammatory response in S. pneumoniae meningitis, and innate immune response could be a double-edged blade. Although the mechanism is still unknown. According to in vivo pneumococcal meningitis experimental models, we investigated BDNF-related signaling effects inflammatory response and hippocampal apoptosis. Before S. pneumoniae intracisternal infection, pretreatment with exogenous BDNF or TrkB inhibitor k252a and assess BDNF/

TrkB-signaling axis activation or inhibition. Administered BDNF in rats reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed inflammatory factors (TNFα, IL-1β and IL-6) expression while increased anti-inflammatory factor IL-10. It also increased TrkB expression, activated downstream PI3K/ protein kinase B (AKT) signaling, and inhibited MyD88/NF-κB-signaling pathway. These results indicated that exogenous BDNF treatment might be a potential therapeutic strategy for inflammatory brain injury. Here is a two-year-old boy with acute necrotizing encephalopathy by infection. After timely treatments with high-dose methylprednisolone and, immunoglobulin therapy, multiple vitamins and nerve growth factor; he had relatively good prognosis and could see neuroregeneration in follow-up brain MRI

Sergei Y Funikov has completed his PhD at Engelhardt Institute of Molecular Biology-Russian Academy of Sciences. His main research focuses on studying the regulation of small non-coding RNAs (in particular, microRNAs and Piwi-interacting RNAs) in stress response as well as investigation of the immune and neuroprotective properties of human recombinant heat shock protein 70 (Hsp70). His study concerns the molecular aspects underlying the progression of motor neurons failure on the model recapitulating the clinical symptoms of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS and TDP-43, implicated in RNA metabolism. Here in, using the in vivo model of FUS-mediated proteinopathy

(ΔFUS1-359 mice) we performed the comprehensive analysis encompassing the onset of the first clinical symptoms inclusions formations as well as changes in gene expression profile in motor neurons and surrounding microglia. The obtained data enable to conclude that FUS-mediated proteinopathy is virtually asymptomatic in terms of both the clinical symptoms and molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days age). From this time point the pathological process develops very rapidly resulting in massive FUS-positive inclusions formation accompanying the transcriptional burst in the spinal cord cells. Specifically, it manifests in activation of pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. Overall, we assume that a highly reproducible course of the pathological process, as well as described accompanying features, make ΔFUS1-359 mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons.

Xiao-Juan Zhu has completed her PhD in Cell Biology from Northeast Normal University, Changchun, China and; Post-doctorate degree from Medical College of Georgia, Augusta, GA, USA. Her research interest includes “Understanding genetic, molecular and cellular basis of brain development”. She is also interested in how the dendritic spines stabilize mature, and how changes in their activities may lead to rapid remodeling of dendritic spines, as well as the defective regulation in dendritic spines that associated with human neuropsychiatric disorders, including autism spectrum. She is using primary culture neuron and genetic modified mice models to study these questions

Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, in reelin null mice, Dab1 tyrosine phosphorylation decreased, but not eliminated, suggesting that Reelin-independent tyrosine phosphorylation of Dab1 may occur. The roles remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with disavled1 (Dab1) specifically. Based on the endogenous DCC and Dab1 expression in the developing neocortex, we demonstrate that DCC physically interacts with Dab1 both in vitro and in cortical neurons, and this interaction depends on the P3 domain of DCC and the PTB domain of Dab1. Netrin 1, a DCC ligand, binding to the DCC induces

Dab1 phosphorylation at Y220 and Y232 through it has no detectably enhancing the DCC-Dab1 interaction. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-tobipolar transition of migrating neurons, as well as migration of newborn neurons toward to the CP, indicating that DCC is required for the proper neuronal migration, particularly for the multipolar-to-bipolar transition. Furthermore, the presence and proper phosphorylation of DCC at tyrosine 1420 is critical for neuronal migration. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation, suggesting that Dab1 is the downstream effector of DCC during neuronal migration. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development. Thus, our finding reveals a cross - talk between reelin and netrin 1 signaling pathways via DCC-Dab1 interaction to illustrate a previously undefined DCC-Dab1 signaling pathway that regulates neuronal migration during neocortical development. 

Aim: The aim of the study was to identify biomarkers for monitoring the effectiveness of Cerebrolysin treatment and to study the long-term prognosis of the therapy in patients with amnestic type mild cognitive impairment (aMCI).

 

Materials & Methods: 19 patients (15 women and 4 men) aging from 56 to 85 years (mean age 72 years), with a diagnosis of amnestic type MCI were included in the study. All patients had a course 20 daily intravenous infusions of Cerebrolysin therapy (the dose was 30 ml in 100 ml of physiological solution once a day with a gradual increase the dose during four days). The

effectiveness of therapy was measured at 0, 4, 10, 26 week of the study on the following scales: CGI, MMSE, MoCA-test, ÐœDRS, FAB, CDT, BNT, test of 10 words Recall, Test of the naming of digits in direct order. Evaluation parameters were measured at the beginning of the study and after 4 and 12 weeks. A fragment 173-193 of the acetylcholine receptor and a fragment of

the receptor 155-164 neurotrophins P75 have been used to study the level of autoantibodies in serums. The autoantibodies to neuronal acetylcholine receptor α7-type and neurotrophins receptor P75 in blood serum of all patients were tested by method of solid-phase enzyme immunoassay at 0, 10 and 26 weeks. 

 

Results: The autoantibodies only to a fragment of 155-164 receptors of neurotrophins P75 (median 0.369) were found in the serum. The level of autoantibodies to fragment 173-193 of acetylcholine receptor in all samples was low or no changes. Statistically significant improvement of cognitive functioning on all scales was revealed immediately after the end of therapy (four weeks). In 10 weeks, the study revealed the preservation of the achieved therapeutic effect on most of the tests. By the end of the study (26 weeks) the therapeutic effect was maintained for four out of nine tests and a slight decrease in estimates for the remaining cognitive tests, but the estimate for seven out of nine cognitive tests remained significantly higher than before treatment. The long-term therapeutic effect predicting of cerebrolysin treatment was found in the study: the age of patients older than 70 years, a higher initial evaluation for the MoCA test, the best initial indicators for the test memory of the scale of Matisse dementia, a high baseline level of autoantibodies to the neurotrophin receptor P75.

Ivanova Natalia Evgenievna, doctor of medical Sciences, Professor, head of the scientific Department of the "Russian Polenov Neurosurgical Institute ", - branch of “National Medical Research Center after V. A. Almazov ", chief neurologist of the Institute, honored doctor of the Russian Federation, Deputy editor-in-chief Of the Russian neurosurgical journal. prof. A. L. Polenov, member of the Board of the Association of neurosurgeons of Russia. The main directions of scientific and practical activity are neurosurgical pathology of brain vessels, neurotrauma, neurorehabilitation and ultrasound diagnostics. Author of 450 scientific works, including 30 patents and three monographs, supervisor of 30 candidates and 4 doctors of Sciences in "nerve diseases" and "neurosurgery".

Introduction: The purpose of early rehabilitation is promoting spontaneous recovery of patients and prevention of secondary complications.

 

Methods: CT, MRT, EEG, ENM, rehabilitation scales.

 

Results: 2000 neurosurgical patients (neurotrauma, neurooncology, vascular neurosurgery, pediatric neurosurgery, vertebrologie, epilepsy, pain and spastic syndromes) received early rehabilitation.

 

Neuroreanimation department neurosurgical and rehabilitational departments: methods used in the acute period can produce paradoxical responses and lead to a breakdown of compensation: the need to find methods of stabilizing stem dysfunction as early as possible, stem dysfunction correction, body-oriented techniques, treatment of bulbar disorders, breathing exercises, passive gymnastics and position treatment with the gradual expansion of the motion mode, early verticalization prevention of bedsores,polymodal sensory stimulation, kinesitherapy. Consequent cognitive impairment that worsen the prognosis of rehabilitation after neurosurgical pathology, a high degree of disability, makes the problem of diagnosis and treatment of cognitive dysfunction socially significant.

 

Conclusions: Early rehabilitation improved the outcome and the long-term quality of life.