Challenges in Parkinson’s Disease Edited by Jolanta Dorszewska and Wojciech Kozubski CHALLENGES IN PARKINSON'S DISEASE Edited by Jolanta Dorszewska and Wojciech Kozubski Challenges in Parkinson’s Disease http://dx.doi.org/10.5772/61880 Edited by Jolanta Dorszewska and Wojciech Kozubski Contributors Patrick Flood, Monika Sharma, Naik Arbabzada, Michelle Hyczy De Siqueira Tosin, Beatriz Oliveira, Massimo Piacentino, Giacomo Beggio, Lorenzo Volpin, Sarat Chandra Yenisetti, Priyanka Modi, Ayajuddin Mohamad, Limamanen Phom, Zevelou Koza, Abhik Das, Rahul Chaurasia, Saikat Samadder, Bovito Achumi, Rajesh Singh Pukhrambam, Muralidhara, Davide Vito Moretti, Anahí Chavarría, Perla Ugalde-MUñiz, Jesús Pérez-H, Satoshi Goto, David Eidelberg, Hideo Mure, Chi-Meng Tzeng, Zhiming Li, Maria Satue, Vicente Polo, Sofia Otin, Jose M. Larrosa, Luis E. Pablo, Elena Garcia-Martin, Javier Obis, Sebastiano Cavallaro, Valentina La Cognata, Francesca Cavalcanti, Velia D’Agata, Iván Galtier, Antonieta Nieto, José Barroso, Fabin Han, Javier Blesa, Ines Trigo-Damas, Ana Quiroga- Varela, Natalia Lopez-Gonzalez Del Rey, Jose A. Obeso, Jasna Saponjic, Jelena Petrovic, Katarina Lazic, Jelena Ciric, Unax Lertxundi, Rafael Hernández, Saioa Domingo-Echaburu, Javier Peral-Aguirregoitia, Juan Medrano, Jolanta Dorszewska, Wojciech Kozubski, Samuel Sw Tay, Meenalochani Sivasubramanian, Thameem Dheen, Keun-A Chang, Seonghan Kim, Susanne Schmid, Andrea R. DiSebastiano, Michael D Staudt, Matthew O. Hebb, Hu Xu, Simon Benoit © The Editor(s) and the Author(s) 2016 The moral rights of the and the author(s) have been asserted. All rights to the book as a whole are reserved by INTECH. The book as a whole (compilation) cannot be reproduced, distributed or used for commercial or non-commercial purposes without INTECH’s written permission. 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No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. First published in Croatia, 2016 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia Legal deposit, Croatia: National and University Library in Zagreb Additional hard and PDF copies can be obtained from orders@intechopen.com Challenges in Parkinson’s Disease Edited by Jolanta Dorszewska and Wojciech Kozubski p. cm. Print ISBN 978-953-51-2463-4 Online ISBN 978-953-51-2464-1 eBook (PDF) ISBN 978-953-51-7291-8 Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI) Interested in publishing with us? Contact book.department@intechopen.com Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com 3,750+ Open access books available 151 Countries delivered to 12.2% Contributors from top 500 universities Our authors are among the Top 1% most cited scientists 115,000+ International authors and editors 119M+ Downloads We are IntechOpen, the world’s leading publisher of Open Access books Built by scientists, for scientists Meet the editors Associate Professor Jolanta Dorszewska is Chief of Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences (PUMS), Poznan, Poland. She graduated from PUMS (M.Sc. Pharmacy, 1987), obtained PhD degree at PUMS (1996) and D.Sc. in Medical Sciences at PUMS (2004). Between the years 1999 and 2000, she worked as a Research Scientist at the Institute for Basic Research in Developmental Disabilities, New York, USA. Associate Professor Dorszewska has authored and co-authored about 100 papers mainly concerning the pathophysiology of Parkinson’s and Alz- heimer’s diseases as well as epilepsy and migraine. She is a co-author and co-editor of books on genetic and biochemical factors in neurological dis- eases. She is a guest editor of two theme issue in Current Genomics (2014, 2013) and a member of editorial board in Advanced Alzheimer’s Disease and Austin Alzheimer’s and Parkinson’s Disease (USA). Prof. Wojciech Kozubski is Head of Chair & Department of Neurology, University of Medical Sciences in Poznan, Poland. Prof. Wojciech Kozubski graduated in Medi- cal School in Lodz, Poland, in 1980. During the years 1980–1983, he was a PhD student in the Department of Neurology, Medical School in Lodz, and next—after his PhD degree—an assistant, adjunct scientific work- er and assistant professor in this department. He was scholarshiped in Academic Unit of Neuroscience of Charing Cross & Westminster Medical School, University of London (1987–1988); Department of Neurology in Sackler School of Medicine, University of Tel-Aviv (1990) and in Depart- ment of Neurology in University of Trondheim, Norway (1990–1991). Prof. Kozubski is an author and co-author of over 290 papers (102 of them are original) concerning mainly the pathophysiology of migraine and related headaches, pathophysiology of stroke, dementia, treatment of headaches and stroke. He is a co-author and co-editor of the Handbook of Clinical Neurology for neurologists, on brain tumors, affective diseases of ner- vous system, therapy in neurology. He is an editor of the Handbook of Treatment in Neurology and co-author and co-editor of the Handbooks of Clinical Neurology for medical students. He is a co-author of the mono- graph on stroke aphasia. During the years 2011–2014, he was the President of Polish Neurological Society; in the years 1999–2001, President of Polish Headache Society. Contents Preface XIII Chapter 1 Introductory Chapter - Genetic and Biochemical Factors in Parkinson’s Disease 1 Jolanta Dorszewska and Wojciech Kozubski Chapter 2 Genetics of Parkinson’s Disease: The Role of Copy Number Variations 7 Valentina La Cognata, Velia D’Agata, Francesca Cavalcanti and Sebastiano Cavallaro Chapter 3 Mechanisms for Neuronal Cell Death in Parkinson’s Disease: Pathological Cross Talks Between Epigenetics and Various Signalling Pathways 39 S Meenalochani, ST Dheen and SSW Tay Chapter 4 Inflammation: Role in Parkinson's Disease and Target for Therapy 57 Patrick Flood, Naik Arbabzada and Monika Sharma Chapter 5 Chronic Inflammation Connects the Development of Parkinson’s Disease and Cancer 89 Zhiming Li and Chi-Meng Tzeng Chapter 6 Is Chronic Systemic Inflammation a Determinant Factor in Developing Parkinson’s Disease? 107 Perla Ugalde-Muñiz, Jesús Pérez-H and Anahí Chavarría Chapter 7 Disorders of Sleep and Motor Control During the Impaired Cholinergic Innervation in Rat – Relevance to Parkinson’s Disease 135 Jasna Saponjic, Jelena Petrovic, Jelena Ciric and Katarina Lazic Chapter 8 Cognitive Impairment in Parkinson’s Disease: Historical Review, Past, and Present 155 Ivan Galtier, Antonieta Nieto and Jose Barroso Chapter 9 Brain Network Metabolic Changes in Patients with Parkinsonian Tremors 181 Hideo Mure, David Eidelberg and Satoshi Goto Chapter 10 Animal Models of Parkinson’s Disease 195 Javier Blesa, Ines Trigo‐Damas, Ana Quiroga‐Varela and Natalia Lopez‐Gonzalez del Rey Chapter 11 Understanding Pathophysiology of Sporadic Parkinson's Disease in Drosophila Model: Potential Opportunities and Notable Limitations 217 Priyanka Modi, Ayajuddin Mohamad, Limamanen Phom, Zevelou Koza, Abhik Das, Rahul Chaurasia, Saikat Samadder, Bovito Achumi, Muralidhara, Rajesh Singh Pukhrambam and Sarat Chandra Yenisetti Chapter 12 Pharmacotherapeutic Challenges in Parkinson’s Disease Inpatients 245 Unax Lertxundi, Rafael Hernández, Saioa Domingo-Echaburu, Javier Peral-Aguirregoitia and Juan Medrano Chapter 13 Clinical and Experimental Cell Therapy in Parkinson’s Disease 257 Keun-A Chang and Seonghan Kim Chapter 14 Cell-Based Therapies for Parkinson’s Disease: Preclinical and Clinical Perspectives 273 Andrea R. Di Sebastiano, Michael D. Staudt, Simon M. Benoit, Hu Xu, Matthew O. Hebb and Susanne Schmid Chapter 15 Stem Cell Therapy for Parkinson's Disease 293 Fabin Han Chapter 16 Surgical Therapy of Parkinson's Disease 317 Massimo Piacentino, Giacomo Beggio and Lorenzo Volpin Contents X Chapter 17 Neuro-Ophthalmologic Evaluation as a Biomarker for Diagnosis and Progression in Parkinson Disease 335 María Satue, Vicente Polo, Sofía Otin, Jose M. Larrosa, Javier Obis and Elena Garcia-Martin Chapter 18 Possible Treatments of Atypical Parkinsonism 353 Moretti Davide Vito Chapter 19 The Role of Nurses in Parkinson's Disease 365 Michelle Hyczy de Siqueira Tosin and Beatriz Guitton Renaud Baptista de Oliveira XI Contents Preface Despite being discovered almost 200 years ago, Parkinson’s disease is still not fully under‐ stood. Current state of knowledge concerning Parkinson’s disease and other movement dis‐ orders is growing rapidly. This development is related to numerous discoveries in the field of genetics and significant improvement in neuroimaging techniques and surgical protocols, especially deep brain stimulation treatment. There is also a continuing search for markers of early diagnosis and the establishment of effective pharmacotherapy. This publication is a sum up of knowledge on the genetic factors and neuronal death mecha‐ nisms induced by excitotoxic and inflammatory agents. We summarize the pathophysiology observed both in patients with Parkinson’s disease and in experimental models. The book also contains the latest views on drug therapy used in the treatment of parkinsonism and other therapeutic approaches for Parkinson’s disease. We hope that this book may help in understanding the complex mechanisms behind Parkin‐ son’s disease pathogenesis and guide clinicians to right diagnosis and therapy. Associate Professor Jolanta Dorszewska, MDs, PhD Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poland Professor Wojciech Kozubski, MD, PhD Chair and Department of Neurology, Poznan University of Medical Sciences, Poland Chapter 1 Introductory Chapter - Genetic and Biochemical Factors in Parkinson’s Disease Jolanta Dorszewska and Wojciech Kozubski Additional information is available at the end of the chapter http://dx.doi.org/10.5772/64216 1. Introduction Worldwide increased life expectancy, which was seen in the second half of the twentieth century, has contributed to an increased number of cases of diseases typical of old age, including Parkinson's disease (PD). At present, PD is one of the most common degenerative diseases of the central nervous system (CNS) and affects nearly 2% of the population over the age of 65 and 5% over the age of 85. Moreover, the estimates show that in the face of population aging, the number of patients with this neurodegenerative disease will maintain an upward trend. Although PD was first described nearly 200 years ago, it is still an incurable disease and its cause is not fully understood. It is known that disturbances in the structure of two pathological proteins of PD, alpha-synuclein (ASN) and Parkin, may lead to the formation of Lewy bodies (LB), which lead to damage of dopaminergic neurons and decreased levels of dopamine (DA). The disturbances in the structure of ASN and Parkin are due to both genetic and environmental factors. Despite numerous reports in the literature concerning the molecular basis of this disease, little is known about the interactions occurring between the individual genes respon‐ sible for encoding these proteins and the pathological manifestation of PD [1–8]. As a result of the lack of knowledge of PD pathomechanism, it is also not possible to have early, potentially intravital, diagnosis of this disease. Currently, the diagnosis of PD is based on clinical criteria, supported with neuroimaging, and is only a probable diagnosis of this disease. Reliable detection of PD is only possible after testing for the presence of neuropatho‐ logical changes in the brain that is typical for this disease and is carried out postmortem . It is known that lack of early and definite diagnosis of PD may make it difficult to provide effective therapy to slow down the progression of the disease and can decrease the quality of life of patients [9]. © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PD belongs to the disorders of the extrapyramidal system (EPS), in which we observe symp‐ toms in a number of nonmotor (NMS) symptoms, such as dementia, hallucinations, depres‐ sion, and orthostatic hypotension, in addition to motor disorders [9–12]. Many studies are currently being conducted on the pathogenesis of PD in many research centers around the world, and knowledge of this disease is growing rapidly. In the last two decades, new genes associated with PD (PARK1-PARK18) were discovered, and there was a remarkable progress of surgical treatment techniques using deep brain stimulation (DBS) of selected brain structures [6]. 2. Genes important for pathogenesis of Parkinson’s disease The causes of PD are both genetic and environmental. To date, a number of genes associated with the presence of PD have been described within distinct patient families (familial PD, FPD) and/or corresponding locations of genes identified as PARK (PARK1-PARK16) as described in [5]. It is believed that genetic factors include mutations of the SNCA gene (PARK1, PARK4), encoding the ASN protein, may also be responsible for increased susceptibility in sporadic PD (SPD) [6,7]. It has been shown that approximately 5–10% of all known PD patients are people with FPD, a monogenic condition that is classically inherited in a recessive or dominant manner. The molecular mechanisms responsible for RPD also play an important role in the pathogenesis of SPD. Moreover, SPD occurs due to the influence of various factors, including signal transduction, vesicular transport, the process of autophagy, and mitochondrial dysfunction. It is also suggested that the clinical heterogeneity of PD, including SPD, may involve interactions not only in genetic and environmental factors, as well as in the reactions between genes, such as SNCA, PRKN, LRRK2, PINK1 , and their protein products: ASN, Parkin, LRRK2, and PINK1, respectively [1–8]. 3. Oxidative damage and hyperhomocysteinemia and biogenic amines in Parkinson’s disease It is known that the degenerative process in PD occurs for many years before the manifestation of clinical symptoms. There are several hypotheses to explain the pathological processes in PD. One of them indicates the participation of oxidative stress in the damage that occurs to dopaminergic neurons [13–15]. In oxidative neuron damage, it is possible that impaired metabolism of homocysteine (Hcy) and other biothiols, such as methionine (Met), cysteine (Cys), and glutathione (GSH), may be involved. Moreover, Hcy, or its oxidative product homocysteine acid, may increase prooxidative activity, most probably through its direct interaction with NMDA receptors (as agonist of NMDA receptor). Many of the literature reports indicate that pathogenesis of PD is associated with increased apoptosis [13,15–18]. Challenges in Parkinson's Disease 2 Homocysteine in physiological condition is converted to Met and Cys, depending on the activity of enzymes MTHFR, MTR, MTHFD1, and CBS, encoded by genes MTHFR, MTR, MTHFD1 , and CBS , respectively [13]. Activity of these enzymes depends on the genotype of the gene encoding a given enzyme. As also shown in [13], the following genotypes are included in the pathogenesis of PD, for Hcy metabolites, Met [MTR, AA (A2756G)], Cys [MTR, AG (A2756G)], and Met/Hcy [MTHFR: CC, CT (C677T), and AA (A1298C), and GG (G1793A); MTHFD1 AA (G1958A); MTR AA (A2756G)] and Hcy [MTHFR: CT (C677T) and GG (G1793A); MTR, AG (A2756G)]. Biogenic amines are also involved in the generation of oxidative stress in the course of PD and include catecholamines such as norepinephrine (NE), epinephrine (E), DA and serotonin (5- HT). Catecholamines are subject to nonenzymatic autoxidation and form highly reactive derivatives. Increased endogenous neurotoxin levels may lead to the formation of ubiquitin and ASN-positive cytoplasmic inclusions (LB) [10–12]. Regulation of plasma biogenic amine levels in PD affects both coding by genes the enzymes responsible for metabolism ( COMT, MAO-A and MAO-B ), and the amines’ transport and reuptake ( NET, DAT, SERT ). Polymorphisms in genes related to trading of biogenic amines may influence the manifestation of this disease, especially NET GA (c.1287G>A) and NET AA (c.1287G>A) [12]. 4. L-Dopa therapy effects in Parkinson’s disease The strategy of therapy of patients with movement disorders, particularly PD, is based essentially on the strengthening of dopaminergic transmission with exogenous L-dihydroxy‐ phenylalanine (L-dopa) and DA agonists [9]. It has been shown that long-term treatment of PD patients with L-dopa improves their motor functions by increasing the level of central DA. At the same time, it has been shown that increasing dopaminergic neuronal damage in PD may reduce the effectiveness of L-dopa and DA agonist therapy. Moreover, in patients with PD, due to the loss of dopaminergic neurons in the striatum , L-dopa may penetrate other dopaminergic neurons, especially the mesolimbic, and lead to emotional and neuropsychiat‐ ric disorders in these patients. L-Dopa therapy in PD may also induce cardiovascular disease and stroke by increasing the plasma levels of risk factors for vascular diseases, such as asymmetric dimethylarginine (ADMA) and Hcy. Moreover, L-dopa leads to increased levels of 8-oxo-2’-deoxyguanosine (8- oxo2dG), a parameter of oxidative stress, and changes levels of biogenic amines and pro‐ teins involved in apoptosis [9,15,19–21]. 5. Summary Although PD has been known and studied since the early nineteenth century, the cause of death of dopaminergic neurons remains unknown and the treatment of this disease focuses on treating symptoms. Introductory Chapter - Genetic and Biochemical Factors in Parkinson’s Disease http://dx.doi.org/10.5772/64216 3 In PD, as in other neurodegenerative diseases, research seeks to determine biomarkers to enable early definite diagnosis of this disease and the development of effective neuroprotec‐ tive or modulatory disease drugs. PD patients who do not respond to conventional drug treatment are currently treated using one of the new surgical techniques, including DBS. Currently, research in PD is looking for a therapy that can ensure effective antiparkinsonian treatment, eliminate dyskinesia, and slow or stop the progression of this disease. Author details Jolanta Dorszewska 1* and Wojciech Kozubski 2 *Address all correspondence to: dorszewskaj@yahoo.com 1 Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland 2 Chair and Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland References [1] Polrolniczak A, Dorszewska J, Florczak J, Owecki M, Rozycka A, Rubis B, Jagodziń‐ ski PP, Kozubski W. Analysis of SNCA and PARK2 mutations in sporadic Parkinson’s disease. In: 10th International Conference on Alzheimer’s and Parkinson’s Diseases; 9– 13 March 2011; Barcelona, Spain. Neurodegenerative Diseases. 2011; 8(Supp. 1):P1. [2] Dorszewska J. Genetic factors in Parkinson's disease. Current Genomics. 2013;14:485. doi: 10.2174/138920291408140206113810 [3] Oczkowska A, Kozubski W, Lianeri M, Dorszewska J. Mutations in PRKN and SNCA genes important for the progress of Parkinson's disease. Current Genomics. 2013;14:502–517. doi: 10.2174/1389202914666131210205839 [4] Oczkowska A, Lianeri M, Kozubski W, Dorszewska J. Mutations of PARK genes and alpha-synuclein, and parkin levels. In: Abdul Qayyum Rana, editor. A Synopsis of Parkinson’s Disease. InTech, Rijeka, Croatia; 2014. pp. 1–38. [5] Oczkowska A, Kozubski W, Lianeri M, Dorszewska J. Genetic variants in diseases of the extrapyramidal system. Current Genomics. 2014;15:18–27. doi: 10.2174/1389202914666131210213327 [6] Dorszewska J. Genetics of Parkinson’s disease and other diseases of the extrapyrami‐ dal system. Current Genomics. 2014;15:1. doi: 10.2174/138920291501140306110937 Challenges in Parkinson's Disease 4 [7] Oczkowska A, Kozubski W, Dorszewska J. Alpha-synuclein in Parkinson's disease. (Alfa-synukleina w chorobie Parkinsona). Przeglad Lekarski. 2014;71:26–32. Polish. [8] Oczkowska A, Florczak-Wyspianska J, Permoda-Osip A, Owecki M, Lianeri M, Kozubski W, Dorszewska J. 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Influence of L-dopa treatment on the level of oxidative damage to DNA, and the concentration of thiol compounds in patients with Parkinson's disease. (Wplyw dlugosci leczenia preparatami L-dopy na poziom oksydacyjnych uszkodzen DNA i stezenie zwiazów tiolowych u pacjentów z choro‐ ba Parkinsona). Neurologia i Neurochirurgia Polska. 2008;42(Suppl. 1):36–44. Polish. [21] Dorszewska J, Florczak J, Kozubski W. Asymmetric dimethylarginine in the plasma of patients with Alzheimer's and Parkinson's diseases. In: Alzheimer's and Parkinson's Diseases: Advances, Concepts and New Challenges. 9th International Conference AD/ PD, 11–15 March 2009; Prague, Czech Republic. Neurodegenerative Diseases. 2009;6:548. Challenges in Parkinson's Disease 6