Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"5313",leadTitle:null,fullTitle:"Update on Dementia",title:"Update on Dementia",subtitle:null,reviewType:"peer-reviewed",abstract:"The dementia challenge is the largest health effort of the times we live in. The whole society has to move to a realization of the significance of prioritization to make an attempt in the direction of mental health promotion and dementia risk reduction. New priorities for research are needed to go far beyond the usual goal of constructing a disease course-modifying medication. Moreover, a full empowerment and engagement of men and women living with dementia and their caregivers, overcoming stigma and discrimination should be promoted. The common efforts and the final aim will have to be the progress of a ''dementia-constructive'' world, where people with dementia can take advantage of equal opportunities.",isbn:"978-953-51-2655-3",printIsbn:"978-953-51-2654-6",pdfIsbn:"978-953-51-4178-5",doi:"10.5772/61983",price:159,priceEur:175,priceUsd:205,slug:"update-on-dementia",numberOfPages:558,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:"6b264ef130a59fe71274c3811750e6c3",bookSignature:"Davide Vito Moretti",publishedDate:"September 28th 2016",coverURL:"https://cdn.intechopen.com/books/images_new/5313.jpg",numberOfDownloads:46998,numberOfWosCitations:63,numberOfCrossrefCitations:45,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:95,numberOfDimensionsCitationsByBook:3,hasAltmetrics:1,numberOfTotalCitations:203,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 19th 2015",dateEndSecondStepPublish:"December 10th 2015",dateEndThirdStepPublish:"March 29th 2016",dateEndFourthStepPublish:"June 27th 2016",dateEndFifthStepPublish:"July 27th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,8,9",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"147154",title:"Dr.",name:"Davide",middleName:"Vito",surname:"Moretti",slug:"davide-moretti",fullName:"Davide Moretti",profilePictureURL:"https://mts.intechopen.com/storage/users/147154/images/4806_n.jpg",biography:"Dr. Davide Vito Moretti is a consultant neurologist and senior researcher at the National Institute of Research and Cure for Mental Disorders and Dementia, St. John of God Institute, Brescia, Italy. Since 2014, he is a professor of Neurophysiology at the UniLudes University in Lugano. He received his medical degree from the Catholic University in Rome and completed his residency in neurology and fellowship in movement disorders at the State University in Trieste. Moreover, he received his PhD in Neurophysiology at the Sapienza University of Rome.\nDr. Moretti is currently involved in research and care of subjects with Alzheimer’s disease and dementia in the Memory Clinic/Alzheimer Operative Unit of the St. John of God Institute. Moreover, he is the chief of the clinical neurophysiology unit and of the Alzheimer’s disease rehabilitation operative unit. Since March 2015, he is also the head of the whole rehabilitation in dementia line research in the St. John of God Institute.\nHis research is primarily concerned about Alzheimer’s disease both in prodromic and in clinically evident phase of the disease, Parkinson’s disease, movement disorders, and clinical neurophysiology.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Centro San Giovanni di Dio Fatebenefratelli",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1171",title:"Developmental Cognitive Neuroscience",slug:"developmental-cognitive-neuroscience"}],chapters:[{id:"52167",title:"Alternative Splicing and Alzheimer’s Disease",doi:"10.5772/64513",slug:"alternative-splicing-and-alzheimer-s-disease",totalDownloads:1902,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Alzheimer’s disease is a neurodegenerative process whose origin is unknown. It has been associated with this process at least two important proteins: the first is the β-amyloid forming amyloid plaques and the second protein is Tau, which has been determined to precipitates inside the neuron because hyperphosphorylation, causing instability in the axon. Tau microtubule-associated protein (MAP) is essential for the development of neuronal cell polarity. Tau protein is preferentially localized in the axons, whereas MAP2, another neuronal specific microtubule-associated protein, is localized in the somatodendritic domain. Previous studies have demonstrated that the localization of these proteins depends, at least in part, on messenger RNA (mRNA) subcellular localization, that is, Tau mRNA into the axon and MAP2 mRNA into the dendrite. Tau protein has an essential role in the pathology of Alzheimer’s disease, and hyperphosphorylated Tau promotes destabilization of microtubules. Tau alternative splicing generates six isoforms in the adult human brain due to the inclusion or exclusion of exons 2, 3, and 10. The failure in the splicing process of exon 10 generates a tauopathy, which can be carried out by the amyloid peptide; however, the splicing of other exons is less studied. The impact of amyloid peptide on the alternative splicing of exons 2, 3, and 6 caused formed cell processes to retract in differentiated cells and altered the expression of exons 2/3 in cell culture. Expression of exon 6 was repressed under β-amyloid treatment. The molecular mechanism for this amyloid-Tau interaction remains to be determined, but may have potential implications for the understanding of the underlying neuropathological processes in Alzheimer’s disease.",signatures:"Gonzalo Emiliano Aranda Abreu, Sonia Lilia Mestizo Gutiérrez,\nMaría Elena Hernández Aguilar and Fausto Rojas Durán",downloadPdfUrl:"/chapter/pdf-download/52167",previewPdfUrl:"/chapter/pdf-preview/52167",authors:[{id:"72314",title:"Dr.",name:"Gonzalo Emiliano",surname:"Aranda Abreu",slug:"gonzalo-emiliano-aranda-abreu",fullName:"Gonzalo Emiliano Aranda Abreu"},{id:"186065",title:"Dr.",name:"Sonia Lilia",surname:"Mestizo Gutiérrez",slug:"sonia-lilia-mestizo-gutierrez",fullName:"Sonia Lilia Mestizo Gutiérrez"},{id:"186066",title:"Dr.",name:"María Elena",surname:"Hernández Aguilar",slug:"maria-elena-hernandez-aguilar",fullName:"María Elena Hernández Aguilar"},{id:"186067",title:"Dr.",name:"Fausto",surname:"Rojas Durán",slug:"fausto-rojas-duran",fullName:"Fausto Rojas Durán"}],corrections:null},{id:"51676",title:"Neuroinflammation and Neurodegeneration",doi:"10.5772/64545",slug:"neuroinflammation-and-neurodegeneration",totalDownloads:3482,totalCrossrefCites:6,totalDimensionsCites:12,hasAltmetrics:0,abstract:"Pathophysiological processes of neurodegenerative diseases are not clearly defined. However, an important body of evidence points toward the role of various inflammatory processes. The microglial cell is the main representative of the immune system in the central nervous system (CNS). This cell type can sense foreign or harmful pathogens and trigger its own activation and the generation of neuroinflammatory processes through phagocytosis and the release of cytokines, in order to maintain the cellular microenvironment. However, after maintaining a permanent state of activation due to sustained stimulation over time, microglial cells may generate a focus of persistent inflammation that in some cases precedes or enhances the neurodegenerative process. Thus, neuroinflammatory microenvironment becomes toxic and harmful for the neuronal cell, which degenerates and releases various factors that in turn activate the inflammatory response of microglia, potentiating the neurodegenerative cycle. In this chapter, we discuss the evidence on the role of microglial cell activation in neurodegenerative conditions and the association between neuroinflammatory processes and age-related neurological diseases. Finally, we outline how this new approach can help us to find new ways to understand neurodegenerative processes and to orientate the search for new therapies.",signatures:"Inelia Morales, Gonzalo A. Farías, Nicole Cortes and Ricardo B.\nMaccioni",downloadPdfUrl:"/chapter/pdf-download/51676",previewPdfUrl:"/chapter/pdf-preview/51676",authors:[{id:"137002",title:"Dr.",name:"Gonzalo",surname:"Farias",slug:"gonzalo-farias",fullName:"Gonzalo Farias"},{id:"183194",title:"Dr.",name:"Ricardo",surname:"Maccioni",slug:"ricardo-maccioni",fullName:"Ricardo Maccioni"},{id:"183196",title:"MSc.",name:"Inelia",surname:"Morales",slug:"inelia-morales",fullName:"Inelia Morales"},{id:"183197",title:"MSc.",name:"Nicole",surname:"Cortes",slug:"nicole-cortes",fullName:"Nicole Cortes"}],corrections:null},{id:"51651",title:"High-Fat and Cholesterol Intake Affects Brain Homeostasis and Could Accelerate the Development of Dementia: A Systemic View",doi:"10.5772/64357",slug:"high-fat-and-cholesterol-intake-affects-brain-homeostasis-and-could-accelerate-the-development-of-de",totalDownloads:1898,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:'Alzheimer’s disease is the most common type of dementia in occidental countries. The majority of the cases develop the disease for no genetic reasons; therefore, it is crucial to establish which environmental factors trigger the development of the disease. It has been proposed that nutritional habits, especially main components of Western countries’ diet such as saturated fat or cholesterol, increase the risk for development of Alzheimer’s disease (AD) and/or accelerate the onset of the disease, which is a big concern in countries where obesity is a public health problem. It is crucial to understand the links between alimentary habits and the development of AD and other types of dementia. A possible mechanism is the disruption of blood–brain barrier (BBB), which is the protection of the brain from circulating blood. Such disruptions can result from consuming high-fat diet (HFD) or high-cholesterol diet (HCD) and inflammation produced by alteration in brain vasculature resulted for chronic consumption of such type of diets. What has named a "Systemic view" comprises the idea that; what happens outside of the brain environment does affect brain functioning and the modifications experienced in the brain environment resulted from the influence of external factors will affect the entire body. In the current chapter, we will review the state of the art in the studies of the impact of a diet rich in fat or cholesterol on the brain and how the alterations induced in other organs can impact brain functioning increasing the susceptibility of development of dementia.',signatures:"Marco Antonio Meraz-Ríos and Perla Leal-Galicia",downloadPdfUrl:"/chapter/pdf-download/51651",previewPdfUrl:"/chapter/pdf-preview/51651",authors:[{id:"114746",title:"Dr.",name:"Marco",surname:"Meraz-Ríos",slug:"marco-meraz-rios",fullName:"Marco Meraz-Ríos"},{id:"187600",title:"Dr.",name:"Perla",surname:"Leal-Galicia",slug:"perla-leal-galicia",fullName:"Perla Leal-Galicia"}],corrections:null},{id:"51637",title:"Plasma Biomarkers in Alzheimer’s Disease",doi:"10.5772/64512",slug:"plasma-biomarkers-in-alzheimer-s-disease",totalDownloads:1921,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Biomarker study on dementia has developed widely. In applying biomarkers, there seems to be several utilizations such as presymptomatic- and early-stage detection, differential diagnosis, and evaluation of treatment effect. Currently, most reliable fluid markers are amyloid peptide (Aβ) with microtubule-associated protein tau (TAU) and phosphorylated TAU (P-TAU) detected in cerebrospinal fluid (CSF). Aβ42 correlates with plaque pathology, TAU reflects the intensity of neuroaxonal degeneration, and P-TAU may correlate with neurofibrillary tangle (NFT) pathology. An attenuation of the level of Aβ42 and elevation in the ratio of Aβ42 relative to the shorter major species of Aβ42 peptide with 40 amino acid residues (Aβ40) has been identified as significant events in the early stage of Alzheimer’s disease (AD) pathology. In addition, there is great interest in blood-based markers of AD since blood extraction is much less invasive. Moreover, plasma biomarkers can be measured at relatively low expense once a standard system of measurement is established. Although there is not yet an established or validated diagnostic test for plasma biomarkers, there is great interest in blood-based markers. We will summarize reported biomarkers, describe our novel potential plasma biomarker for AD (annexin A5), offering a strategy for selecting candidates, and show our results and evaluation.",signatures:"Hitoshi Sohma and Yasuo Kokai",downloadPdfUrl:"/chapter/pdf-download/51637",previewPdfUrl:"/chapter/pdf-preview/51637",authors:[{id:"179340",title:"Prof.",name:"Hitoshi",surname:"Sohma",slug:"hitoshi-sohma",fullName:"Hitoshi Sohma"},{id:"180263",title:"Prof.",name:"Yasuo",surname:"Kokai",slug:"yasuo-kokai",fullName:"Yasuo Kokai"}],corrections:null},{id:"51964",title:"Alzheimer’s-Related Amyloid Beta Peptide Aggregates in the Ageing Retina: Implications for Sight Loss and Dementia",doi:"10.5772/64790",slug:"alzheimer-s-related-amyloid-beta-peptide-aggregates-in-the-ageing-retina-implications-for-sight-loss",totalDownloads:1917,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Although visual problems are reported by patients with Alzheimer’s disease and dementia, studies into this particular aspect of neuropathology are scarce. The growing awareness of complex pathological processes in the ageing retina and brain, however, enables us to consider this from a new perspective. Here we discuss the latest findings on the wide-ranging visual defects experienced by those suffering from Alzheimer’s disease and dementia. We propose that events leading to chronic degeneration of the retina and the brain in fact share many striking similarities. In particular, we discuss the role of the Alzheimer’s-related amyloid beta (Aβ) group of peptides that has been shown to accumulate in senescent retinas, correlated with increased risk of retinal degeneration. The high photo-oxidative retinal environment creates ideal conditions for Aβ aggregation, evidenced by high Aβ loads reported in aged and donor eyes from patients with age-related macular degeneration. Consequently, longitudinal and non-invasive retinal assessments may provide invaluable information on incipient pathology and disease progression in the retina as well as the senescent brain. Such insights may not only lead to identifying new pathogenic mechanisms in the retina with implications for understanding Alzheimer’s disease but reveal the underlying causes of visual abnormalities reported in patients with dementia.",signatures:"J. Arjuna Ratnayaka and Savannah Lynn",downloadPdfUrl:"/chapter/pdf-download/51964",previewPdfUrl:"/chapter/pdf-preview/51964",authors:[{id:"183572",title:"Dr.",name:"J Arjuna",surname:"Ratnayaka",slug:"j-arjuna-ratnayaka",fullName:"J Arjuna Ratnayaka"},{id:"183847",title:"Ms.",name:"Savannah A.",surname:"Lynn",slug:"savannah-a.-lynn",fullName:"Savannah A. Lynn"}],corrections:null},{id:"51804",title:"Proteomic Study of Degenerative Protein Modifications in the Molecular Pathology of Neurodegeneration and Dementia",doi:"10.5772/64693",slug:"proteomic-study-of-degenerative-protein-modifications-in-the-molecular-pathology-of-neurodegeneratio",totalDownloads:1654,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Dementia is a major public health burden, and the World Health Organization has identified this disorder as a major public health priority. There are limited treatment options due to poor understanding of key mechanism of dementia pathogenesis. Dementia has been regarded as a proteinopathy in which alterations of brain protein structure and function are the key features of the disorder. Proteinopathy can be triggered by degenerative protein modifications (DPMs), misfolding, aggregation, and deposition of the malformed proteins. Despite the clinical significance of alteration in protein abundances, DPMs, protein misfolding, and aggregation, the molecular mechanism that promotes these changes remains inadequately understood, mostly due to technical challenges. Proteomic is a powerful, sensitive, and advanced tool to study the progressive brain tissue damage that critically dysregulates key enzymes, accumulates modified proteins, and causes protein misfolding and aggregation, resulting in cognitive decline and dementia. The proteomic profiling of protein abundances and correlating DPMs with protein misfolding and aggregation have potential to elucidate underlying molecular mechanism of the disease. This chapter summarizes the recent proteomic developments for studying brain proteome, DPMs, and protein aggregation mechanism that may lead to dementia. We attempted to correlate DPMs and its impact on protein aggregation and deposition in brain tissues.",signatures:"Sunil S. Adav and Siu Kwan Sze",downloadPdfUrl:"/chapter/pdf-download/51804",previewPdfUrl:"/chapter/pdf-preview/51804",authors:[{id:"184065",title:"Dr.",name:"Siu Kwan",surname:"Sze",slug:"siu-kwan-sze",fullName:"Siu Kwan Sze"},{id:"187076",title:"Dr.",name:"Sunil S",surname:"Adav",slug:"sunil-s-adav",fullName:"Sunil S Adav"}],corrections:null},{id:"52003",title:"Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease",doi:"10.5772/64757",slug:"brain-lipids-in-the-pathophysiology-and-treatment-of-alzheimer-s-disease",totalDownloads:2147,totalCrossrefCites:2,totalDimensionsCites:13,hasAltmetrics:1,abstract:"Alzheimer’s disease (AD) is a neurodegenerative disorder that causes severe and progressive cognitive impairment. The discovery of specific mutations related to AD supported the amyloid cascade hypothesis, which postulates that the accumulation of the amyloid-β (Aβ) peptide triggers neuronal death and dementia. However, most drugs that aim to prevent Aβ accumulation or tau phosphorylation have consistently failed in clinical trials. This would suggest that the amyloid pathology lies downstream of (an)other cellular event(s) that is/are responsible for AD pathogenesis. In this context, several lipid alterations have been described in the brain and in peripheral fluids of patients with AD, suggesting the involvement of lipids in the etiology of this condition. Indeed, the central nervous system (CNS) has the highest lipid content in the body, next to adipose tissue, and it is thought that normalization of brain membrane lipid levels would revert AD-related pathogenic events. In this sense, novel hydroxylated derivatives of docosahexaenoic acid (DHA) such as natural resolvins or synthetic hydroxy-DHA (HDHA, DHALifort) can modulate membrane lipid composition and show remarkable beneficial effects on AD hallmarks, such as prevention of amyloid production and tau phosphorylation, and cognitive restoration in animal models. Therefore, normalization of the neuronal lipid environment by hydroxyl-DHA and/or other lipids may constitute a promising therapy for AD treatment, memory loss and, possibly, other types of dementia.",signatures:"Manuel Torres, Xavier Busquets and Pablo V. Escribá",downloadPdfUrl:"/chapter/pdf-download/52003",previewPdfUrl:"/chapter/pdf-preview/52003",authors:[{id:"184164",title:"Prof.",name:"Pablo",surname:"Escribá",slug:"pablo-escriba",fullName:"Pablo Escribá"},{id:"191108",title:"Prof.",name:"Xavier",surname:"Busquets",slug:"xavier-busquets",fullName:"Xavier Busquets"},{id:"191260",title:"Dr.",name:"Manuel",surname:"Torres",slug:"manuel-torres",fullName:"Manuel Torres"}],corrections:null},{id:"52048",title:"Beta Amyloid Peptides: Extracellular and Intracellular Mechanisms of Clearance in Alzheimer’s Disease",doi:"10.5772/64744",slug:"beta-amyloid-peptides-extracellular-and-intracellular-mechanisms-of-clearance-in-alzheimer-s-disease",totalDownloads:2246,totalCrossrefCites:4,totalDimensionsCites:8,hasAltmetrics:0,abstract:"Alzheimer’s disease (AD) is a neurodegenerative disease and the most common form of dementia, characterized by the overproduction and accumulation of different amyloid-β peptide peptides (Aβ) within different areas in the brain conducting to memory loss and dementia. The Aβ cascade hypothesis of AD was originally proposed by Selkoe in 1991 by the theory that accumulation of Aβ42 is the initial trigger for neurodegeneration. The Aβ cascade hypothesis assumes that changes in the production or accumulation of Aβ are responsible for AD pathology. Different Aβ clearance mechanisms are also affected by AD pathology. Studies from the past years have revealed that the blocking of Aβ production is not effective for reducing the brain Aβ levels. However, the relevance of Aβ clearance in AD, especially in late-onset sporadic AD (LOAD), has been heightened, and the study of the Aβ clearance mechanisms has elucidated new possible therapeutic targets. This chapter summarizes recent data underlying the idea of the reduced Aβ clearance and subsequent Aβ spread in AD. We discuss the Aβ clearance mechanisms altered in AD, and the Aβ clearance through autophagy in more detail, a more recent mechanism proposed, and the new strategies to eliminate Aβ42 inducing autophagy.",signatures:"Luis F. Hernández-Zimbrón, Elisa Gorostieta-Salas, Mei-Li Díaz-\nHung, Roxanna Pérez-Garmendia, Gohar Gevorkian and Hugo\nQuiroz-Mercado",downloadPdfUrl:"/chapter/pdf-download/52048",previewPdfUrl:"/chapter/pdf-preview/52048",authors:[{id:"75951",title:"BSc.",name:"Hugo",surname:"Quiroz-Mercado",slug:"hugo-quiroz-mercado",fullName:"Hugo Quiroz-Mercado"},{id:"181180",title:"Dr.",name:"Luis Fernando",surname:"Hernandez-Zimbron",slug:"luis-fernando-hernandez-zimbron",fullName:"Luis Fernando Hernandez-Zimbron"},{id:"181277",title:"Dr.",name:"Roxanna",surname:"Pérez-Garmendia",slug:"roxanna-perez-garmendia",fullName:"Roxanna Pérez-Garmendia"},{id:"181278",title:"BSc.",name:"Elisa",surname:"Gorostieta-Salas",slug:"elisa-gorostieta-salas",fullName:"Elisa Gorostieta-Salas"},{id:"181279",title:"MSc.",name:"Mei-Li",surname:"Díaz-Hung",slug:"mei-li-diaz-hung",fullName:"Mei-Li Díaz-Hung"},{id:"190226",title:"Dr.",name:"Gohar",surname:"Gevorkian-Markosian",slug:"gohar-gevorkian-markosian",fullName:"Gohar Gevorkian-Markosian"}],corrections:null},{id:"52062",title:"Alzheimer's Disease: From Animal Models to the Human Syndrome",doi:"10.5772/64619",slug:"alzheimer-s-disease-from-animal-models-to-the-human-syndrome",totalDownloads:2312,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Some animal models, genetically modified (such as murine) and sporadic (as others species), enable the study of the origin of specific lesions observed in human neurodegenerative diseases. In particular, Alzheimer's disease (AD) models have been designed to test the hypothesis that certain lesions are associated with functional and morphological changes beginning with memory loss and impairment in activities of daily life. This review compares and evaluates the phenotypes of different AD animal models, on the basis of the specific objectives of each study, with the purpose of encompassing their contributions to the comprehension of the AD signs and symptoms in humans. All these models contribute to the comprehension of the human AD mechanisms regarding the heterogeneity of AD phenotypes: the overlap between AD and age‐related changes, the variability of AD onset (early or late), the probable reactiveness of amyloid‐β and tau proteins, the scarcity of senile plaques and/or neurofibrillary tangles in some AD cases, the spatial correlation of the pathology and cerebral blood vessels, and the immunological responses (microglial aging) and synaptopathy. Altogether, these considerations may contribute to find therapies to treat and prevent this disease.",signatures:"Erika Orta‐Salazar, Isaac Vargas‐Rodríguez, Susana A Castro‐\nChavira, Alfredo I. Feria‐Velasco and Sofía Díaz‐Cintra",downloadPdfUrl:"/chapter/pdf-download/52062",previewPdfUrl:"/chapter/pdf-preview/52062",authors:[{id:"184728",title:"Dr.",name:"Erika Maria",surname:"Orta Salazar",slug:"erika-maria-orta-salazar",fullName:"Erika Maria Orta Salazar"},{id:"185118",title:"Ph.D. Student",name:"Isaac",surname:"Vargas-Rodríguez",slug:"isaac-vargas-rodriguez",fullName:"Isaac Vargas-Rodríguez"},{id:"185119",title:"Ph.D. Student",name:"Susana Angelica",surname:"Castro-Chavira",slug:"susana-angelica-castro-chavira",fullName:"Susana Angelica Castro-Chavira"},{id:"185120",title:"Ph.D.",name:"Alfredo I",surname:"Feria-Velasco",slug:"alfredo-i-feria-velasco",fullName:"Alfredo I Feria-Velasco"},{id:"185121",title:"Ph.D.",name:"Sofia",surname:"Diaz-Cintra",slug:"sofia-diaz-cintra",fullName:"Sofia Diaz-Cintra"}],corrections:null},{id:"51441",title:"Risk Factors for Alzheimer’s Disease",doi:"10.5772/64270",slug:"risk-factors-for-alzheimer-s-disease",totalDownloads:1770,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Currently there is no effective treatment available. Senile plaques and neurofibrillary tangles are hallmarks of AD pathology, and patients demonstrate cognitive complaints with deficits in various neuropsychological domains. Familial AD (FAD) accounts for 0.5% of all AD cases and usually presents before the age of 65 years. Approximately 50% of the FAD patients carry mutations in one of the following genes: APP, PSEN1, and PSEN2. Inheriting any of these genetic mutations increases Aβ42 production, which has been linked to AD pathogenesis. Late-onset AD represents the majority of AD cases, with evidence suggesting impaired Aβ clearance. However, the etiology of late-onset AD is more complex. Several findings suggest that multiple risk genes and factors may contribute to the pathogenesis of LOAD. In this chapter, we elaborate some of these factors and their involvements in the development of AD.",signatures:"Dongming Cai and Farida El Gaamouch",downloadPdfUrl:"/chapter/pdf-download/51441",previewPdfUrl:"/chapter/pdf-preview/51441",authors:[{id:"183531",title:"Prof.",name:"Dongming",surname:"Cai",slug:"dongming-cai",fullName:"Dongming Cai"},{id:"183867",title:"Dr.",name:"Farida",surname:"El Gaamouch",slug:"farida-el-gaamouch",fullName:"Farida El Gaamouch"}],corrections:null},{id:"51355",title:"Normal Aging and Dementia",doi:"10.5772/64203",slug:"normal-aging-and-dementia",totalDownloads:1880,totalCrossrefCites:6,totalDimensionsCites:8,hasAltmetrics:0,abstract:"Normal aging begins after 60 years of age. According to Harman, the accumulation of free radicals, which results from weakening of repair and protective mechanisms, takes place in the aging brain. It is believed that especially in the population of the most elderly there is increased incidence of both dementia and depression. The causes of these central nervous system disorders in the aging human body are changes at the molecular level, such as changes in the biochemical parameters, the accumulation of mutations in nuclear and mitochondrial DNA, and epigenetic changes. Biomarkers associated with aging of the brain include accumulated deposits of β-amyloid (Aβ), disturbed cholesterol homeostasis, altered neuroimaging parameters, and impaired glucose metabolism. Genetic factors are also responsible for normal aging, for example, SIRT1, AKT1, and CDKN1A, and among them the longevity genes, such as FOXO3A and CETP. Dementia as well as cognitive decline may be modified by poly-T variants of TOMM40 and APOE alleles via influencing the level of apolipoprotein E (apoE) in the brain and in the plasma as well as by its ability of Aβ clearance.",signatures:"Michał Prendecki, Jolanta Florczak-Wyspianska, Marta Kowalska,\nMargarita Lianeri, Wojciech Kozubski and Jolanta Dorszewska",downloadPdfUrl:"/chapter/pdf-download/51355",previewPdfUrl:"/chapter/pdf-preview/51355",authors:[{id:"31962",title:"Dr.",name:"Jolanta",surname:"Dorszewska",slug:"jolanta-dorszewska",fullName:"Jolanta Dorszewska"},{id:"83372",title:"Prof.",name:"Wojciech",surname:"Kozubski",slug:"wojciech-kozubski",fullName:"Wojciech Kozubski"},{id:"183236",title:"Dr.",name:"Jolanta",surname:"Florczak-Wyspianska",slug:"jolanta-florczak-wyspianska",fullName:"Jolanta Florczak-Wyspianska"},{id:"186409",title:"MSc.",name:"Michal",surname:"Prendecki",slug:"michal-prendecki",fullName:"Michal Prendecki"},{id:"186528",title:"MSc.",name:"Marta",surname:"Kowalska",slug:"marta-kowalska",fullName:"Marta Kowalska"},{id:"186529",title:"Dr.",name:"Margarita",surname:"Lianeri",slug:"margarita-lianeri",fullName:"Margarita Lianeri"}],corrections:null},{id:"52137",title:"Changes in Visual Cortex in Healthy Aging and Dementia",doi:"10.5772/64562",slug:"changes-in-visual-cortex-in-healthy-aging-and-dementia",totalDownloads:1722,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"This chapter reviews the differences in specific structural and functional characteristics of human visual cortex among young adults, healthy aging adults, and patients with dementia, with a primary focus on those with Alzheimer’s disease (AD). Such visual cortex changes have been shown to underlie many of the behavioral deficits that develop in healthy aging and AD. Measurements of disordered visual cortex in dementia patients may be possible early in the course of neurodegeneration and thus may be useful for improving early diagnosis of these devastating diseases.",signatures:"Alyssa A. Brewer and Brian Barton",downloadPdfUrl:"/chapter/pdf-download/52137",previewPdfUrl:"/chapter/pdf-preview/52137",authors:[{id:"115304",title:"Dr.",name:"Alyssa",surname:"Brewer",slug:"alyssa-brewer",fullName:"Alyssa Brewer"},{id:"149246",title:"Dr.",name:"Brian",surname:"Barton",slug:"brian-barton",fullName:"Brian Barton"}],corrections:null},{id:"52368",title:"Clusterin (APOJ) in Alzheimer’s Disease: An Old Molecule with a New Role",doi:"10.5772/64233",slug:"clusterin-apoj-in-alzheimer-s-disease-an-old-molecule-with-a-new-role",totalDownloads:2246,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:0,abstract:"Clusterin (CLU), initially identified in 1983 as a “clustering factor” in ram rete testis fluid, is a multifaceted protein that was re-discovered and subsequently renamed eight times from 1983 to 1992. CLU exists as multiple protein isoforms including the 80 kDa glycosylated mature/secreted form of CLU (mCLU) and the smaller non-modified nuclear and intracellular forms of CLU (nCLU and icCLU, respectively). These isoforms, which are expressed at the highest levels in the brain, are suggested to play distinct roles in various disease processes such as those involving inflammation and apoptosis. Currently, CLU, also known as apolipoprotein J (APOJ) which belongs to the same protein family as apolipoprotein E (APOE), is the third most significant genetic risk factor for the development of late-onset Alzheimer’s disease (LOAD); however, an extensive gap exists in the literature in understanding the physiological roles of CLU in normal brain and the pathogenic mechanisms conferred by CLU polymorphisms in the onset of LOAD. In this chapter, we discuss the status of the current knowledge regarding the generation and regulation of CLU protein isoforms, the clinical evidence and possible mechanisms involved in LOAD, and provide our perspectives for future studies.",signatures:"Sarah K. Woody and Liqin Zhao",downloadPdfUrl:"/chapter/pdf-download/52368",previewPdfUrl:"/chapter/pdf-preview/52368",authors:[{id:"182716",title:"Prof.",name:"Liqin",surname:"Zhao",slug:"liqin-zhao",fullName:"Liqin Zhao"},{id:"187597",title:"Ms.",name:"Sarah",surname:"Woody",slug:"sarah-woody",fullName:"Sarah Woody"}],corrections:null},{id:"51440",title:"New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach",doi:"10.5772/64327",slug:"new-targets-for-diagnosis-and-treatment-against-alzheimer-s-disease-the-mitochondrial-approach",totalDownloads:2116,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia. AD is characterized by brain presence of senile plaques, which are formed by aggregates of Aβ peptide and neurofibrillary tangles (NFTs), formed by pathological forms of tau protein. Evidence suggests that these elements affect neurons compromising energy supply, antioxidant response and synaptic activity. AD principally affects the memory and cognitive functions of the patients, and currently, successful strategies for diagnosis and early treatment are lacking. In this scenario, accumulative evidence suggests that mitochondrial dysfunction precedes the establishment of tau and Aβ pathology and contributes to synaptic degeneration observed in AD. Therefore, reducing mitochondrial injury may have beneficial effects for neuronal dysfunction and cognitive decline observed in AD patients. Interestingly, the examination of peripheral cells from AD patients also presents mitochondrial dysfunction, suggesting that tracking these mitochondrial defects in peripheral cells could be a potential mechanism of early diagnosis of AD. In this chapter, we analyse current evidence that suggests that mitochondrial injury is an important factor in the pathogenesis of AD and how studying this process could reveal new strategies to mitigate neurodegeneration and to develop new diagnostic methods for an early detection of AD.",signatures:"María José Pérez, Claudia Jara, Ernesto Muñoz‐Urrutia and Rodrigo\nA. Quintanilla",downloadPdfUrl:"/chapter/pdf-download/51440",previewPdfUrl:"/chapter/pdf-preview/51440",authors:[{id:"182849",title:"Dr.",name:"Rodrigo",surname:"Quintanilla",slug:"rodrigo-quintanilla",fullName:"Rodrigo Quintanilla"},{id:"183872",title:"MSc.",name:"María José",surname:"Pérez",slug:"maria-jose-perez",fullName:"María José Pérez"},{id:"183873",title:"Dr.",name:"Claudia",surname:"Jara",slug:"claudia-jara",fullName:"Claudia Jara"},{id:"183874",title:"MSc.",name:"Ernesto",surname:"Muñoz",slug:"ernesto-munoz",fullName:"Ernesto Muñoz"}],corrections:null},{id:"51819",title:"The Impact of the Eye in Dementia: The Eye and its Role in Diagnosis and Follow‐up",doi:"10.5772/64490",slug:"the-impact-of-the-eye-in-dementia-the-eye-and-its-role-in-diagnosis-and-follow-up",totalDownloads:2974,totalCrossrefCites:4,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Over the last few decades, the importance of ophthalmic examination in neurodegenerative diseases of the CNS has reportedly increased. The retina is an extension of the CNS and thus should not be surprising to find abnormal results in both the test exploring visual processing and those examining the retina of patients with CNS degeneration. Current in vivo imaging techniques are allowing ophthalmologists to detect and quantify data consistent with the histopathological findings described in the retinas of Alzheimer’s disease (AD) patients and may help to reveal unsuspected retinal and optic‐nerve repercussions of other CNS diseases. In this chapter, we perform an analysis of the physiological changes in ocular and cerebral ageing. We analyse the ocular manifestations in CNS disorders such as stroke, AD and Parkinson’s disease. In addition, the pathophysiology of both the eye and the visual pathway in AD are described. The value of the visual psychophysical tests in AD diagnosis is reviewed as well as the main findings of the optical coherence tomography as a contribution to the diagnosis and monitoring of the disease. Finally, we examine the association of two neurodegenerative diseases, AD and glaucoma, as mere coincidence or possible role in the progression of the neurodegeneration.",signatures:"Elena Salobrar‐García, Ana I. Ramírez, Rosa de Hoz, Pilar Rojas, Juan\nJ. Salazar, Blanca Rojas, Raquel Yubero, Pedro Gil, Alberto Triviño\nand José M. Ramírez",downloadPdfUrl:"/chapter/pdf-download/51819",previewPdfUrl:"/chapter/pdf-preview/51819",authors:[{id:"142707",title:"Prof.",name:"José M.",surname:"Ramírez",slug:"jose-m.-ramirez",fullName:"José M. Ramírez"},{id:"142864",title:"Prof.",name:"Alberto",surname:"Triviño",slug:"alberto-trivino",fullName:"Alberto Triviño"},{id:"145761",title:"Prof.",name:"Juan J",surname:"Salazar",slug:"juan-j-salazar",fullName:"Juan J Salazar"},{id:"145765",title:"Prof.",name:"Rosa",surname:"De Hoz",slug:"rosa-de-hoz",fullName:"Rosa De Hoz"},{id:"145766",title:"Prof.",name:"Blanca",surname:"Rojas",slug:"blanca-rojas",fullName:"Blanca Rojas"},{id:"145767",title:"Prof.",name:"Ana I.",surname:"Ramírez",slug:"ana-i.-ramirez",fullName:"Ana I. Ramírez"},{id:"183853",title:"MSc.",name:"Elena",surname:"Salobrar-García",slug:"elena-salobrar-garcia",fullName:"Elena Salobrar-García"},{id:"183854",title:"MSc.",name:"Pilar",surname:"Rojas",slug:"pilar-rojas",fullName:"Pilar Rojas"},{id:"183858",title:"Dr.",name:"Pedro",surname:"Gil",slug:"pedro-gil",fullName:"Pedro Gil"},{id:"183859",title:"Dr.",name:"Raquel",surname:"Yubero",slug:"raquel-yubero",fullName:"Raquel Yubero"}],corrections:null},{id:"52006",title:"Caring for Individuals with Dementia on a Continuum: An Interdisciplinary Approach Between Music Therapy and Nursing",doi:"10.5772/64663",slug:"caring-for-individuals-with-dementia-on-a-continuum-an-interdisciplinary-approach-between-music-ther",totalDownloads:3880,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Background: Music has long been used to ease symptoms of dementia. Several studies have shown the therapeutic benefits of music therapy to decrease symptoms of agitation in people with dementia (PWD). Other research has demonstrated that the use of music during caregiving can ease agitated behaviors. However, few studies have shown the clinical benefits of using translational research in practice between music therapists and certified nursing assistants.",signatures:"Kendra Ray, Ayelet Dassa, Jan Maier, Renita Davis and Olayinka\nOgunlade",downloadPdfUrl:"/chapter/pdf-download/52006",previewPdfUrl:"/chapter/pdf-preview/52006",authors:[{id:"183246",title:"Dr.",name:"Kendra",surname:"Ray",slug:"kendra-ray",fullName:"Kendra Ray"},{id:"183915",title:"Prof.",name:"Renita",surname:"Davis",slug:"renita-davis",fullName:"Renita Davis"},{id:"183916",title:"Ms.",name:"Jan",surname:"Maier",slug:"jan-maier",fullName:"Jan Maier"},{id:"184382",title:"Dr.",name:"Ayelet",surname:"Dassa",slug:"ayelet-dassa",fullName:"Ayelet Dassa"},{id:"184383",title:"Mr.",name:"Olayinka",surname:"Ogunlade",slug:"olayinka-ogunlade",fullName:"Olayinka Ogunlade"}],corrections:null},{id:"52128",title:"Behavior and Emotion in Dementia",doi:"10.5772/64681",slug:"behavior-and-emotion-in-dementia",totalDownloads:1840,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:1,abstract:"During the course of disease, the patient and caregiver face emotional and behavioral problems that may occur. Therefore, it is important to knowing how emotions and the perception of them are modified and thus to know the impact they have on mood and behavior of the patient and caregiver. Publicizing the type of pathology, both emotional and behavioral levels, in a patient with dementia can help in the development of nonpharmacological interventions that could slow the symptoms and improve the quality of life of patients.",signatures:"Teresa Mayordomo Rodríguez, Alicia Sales Galán, Rita Redondo\nFlores, Marta Torres Jordán and Javier Bendicho Montes",downloadPdfUrl:"/chapter/pdf-download/52128",previewPdfUrl:"/chapter/pdf-preview/52128",authors:[{id:"184060",title:"Dr.",name:"Teresa",surname:"Mayordomo Rodríguez",slug:"teresa-mayordomo-rodriguez",fullName:"Teresa Mayordomo Rodríguez"},{id:"370127",title:"Dr.",name:"Alicia Sales",surname:"Galán",slug:"alicia-sales-galan",fullName:"Alicia Sales Galán"},{id:"370128",title:"Dr.",name:"Rita Redondo",surname:"Flores",slug:"rita-redondo-flores",fullName:"Rita Redondo Flores"},{id:"370129",title:"Dr.",name:"Marta Torres",surname:"Jordán",slug:"marta-torres-jordan",fullName:"Marta Torres Jordán"},{id:"370130",title:"Dr.",name:"Javier Bendicho",surname:"Montes",slug:"javier-bendicho-montes",fullName:"Javier Bendicho Montes"}],corrections:null},{id:"51705",title:"Non-Pharmacological Approaches in the Treatment of Dementia",doi:"10.5772/64232",slug:"non-pharmacological-approaches-in-the-treatment-of-dementia",totalDownloads:2778,totalCrossrefCites:3,totalDimensionsCites:11,hasAltmetrics:0,abstract:"Currently, a pharmacological disease-modifying treatment for dementia is not available, but different non-pharmacological approaches appear to be useful. In this chapter, we describe traditional treatments such as cognitive and emotion-oriented interventions, sensory and multi-sensory stimulation interventions and also potentially alternative interesting options such as behavioural therapy, animal-assisted therapy, home-adaptation therapy and assistive technologies to support patient with dementia. Many non-pharmacological treatments have reported benefits in multiple research studies, but there is a need for further Randomized controlled trials (RCTs) with an adequate sample size to improve the strength of evidence in order to apply these approaches.",signatures:"Grazia D’Onofrio, Daniele Sancarlo, Davide Seripa, Francesco\nRicciardi, Francesco Giuliani, Francesco Panza and Antonio Greco",downloadPdfUrl:"/chapter/pdf-download/51705",previewPdfUrl:"/chapter/pdf-preview/51705",authors:[{id:"184079",title:"Dr.",name:"Daniele",surname:"Sancarlo",slug:"daniele-sancarlo",fullName:"Daniele Sancarlo"},{id:"184081",title:"Dr.",name:"Antonio",surname:"Greco",slug:"antonio-greco",fullName:"Antonio Greco"},{id:"272620",title:"Dr.",name:"Davide",surname:"Seripa",slug:"davide-seripa",fullName:"Davide Seripa"},{id:"272628",title:"Dr.",name:"Grazia",surname:"D'Onofrio",slug:"grazia-d'onofrio",fullName:"Grazia D'Onofrio"},{id:"368922",title:"Dr.",name:"Francesco",surname:"Ricciardi",slug:"francesco-ricciardi",fullName:"Francesco Ricciardi"},{id:"368923",title:"Dr.",name:"Francesco",surname:"Giuliani",slug:"francesco-giuliani",fullName:"Francesco Giuliani"},{id:"368924",title:"Dr.",name:"Francesco",surname:"Panza",slug:"francesco-panza",fullName:"Francesco Panza"}],corrections:null},{id:"52095",title:"Medication Management for People Living with Dementia: Development and Evaluation of a Multilingual Information Resource for Family Caregivers of People Living with Dementia",doi:"10.5772/64661",slug:"medication-management-for-people-living-with-dementia-development-and-evaluation-of-a-multilingual-i",totalDownloads:1760,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The aim of this chapter is to describe the development and evaluation of an online multilingual information resource focused on medication management, targeting people living with dementia and their family caregivers. Maintaining effective medication management is important to allow ongoing quality of life within the community setting and avoiding medication-related preventable hospitalisations for the person living with dementia. Family caregivers are likely to assume the role of medication management on behalf of the person in their care as dementia progresses. Little training or information is available to family caregivers to assist them with this role. A pilot online information resource was developed and evaluated. Responding to the evaluation, this resource was improved, and a more extensive evaluation process was undertaken. The development and evaluation process are outlined with a view to guiding the development of similar resources, especially those targeting linguistically diverse family caregivers and those with dementia. This is especially important given that many older adults will migrate during their lifetime, often to a country where they are not familiar with the language or health services. Extra support is needed to assist older immigrants who are themselves at risk or are caring for someone with dementia.",signatures:"Robyn Gillespie, Pippa Burns, Lindsey Harrison, Amanda Baker, Khin\nWin, Victoria Traynor and Judy Mullan",downloadPdfUrl:"/chapter/pdf-download/52095",previewPdfUrl:"/chapter/pdf-preview/52095",authors:[{id:"183243",title:"Mrs.",name:"Robyn",surname:"Gillespie",slug:"robyn-gillespie",fullName:"Robyn Gillespie"},{id:"190390",title:"Dr.",name:"Pippa",surname:"Burns",slug:"pippa-burns",fullName:"Pippa Burns"},{id:"190391",title:"Dr.",name:"Judy",surname:"Mullan",slug:"judy-mullan",fullName:"Judy Mullan"},{id:"190392",title:"Dr.",name:"Lindsey",surname:"Harrison",slug:"lindsey-harrison",fullName:"Lindsey Harrison"},{id:"190393",title:"Dr.",name:"Amanda",surname:"Baker",slug:"amanda-baker",fullName:"Amanda Baker"},{id:"190394",title:"Dr.",name:"Khin",surname:"Win",slug:"khin-win",fullName:"Khin Win"},{id:"190395",title:"Dr.",name:"Victoria",surname:"Traynor",slug:"victoria-traynor",fullName:"Victoria Traynor"}],corrections:null},{id:"52044",title:"Diabetes Mellitus and Depression as Risk Factors for Dementia: SADEM Study",doi:"10.5772/64678",slug:"diabetes-mellitus-and-depression-as-risk-factors-for-dementia-sadem-study",totalDownloads:1541,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Aim: 3Evidence indicates that the comorbidity of dementia with diabetes and depression may affect most cognitive functions. Our chief interest was to examine the patterns of cognitive functioning in individuals diagnosed with dementia, diabetes, and depression as compared with dementia plus diabetes (DDM), or dementia plus depression (DD) and healthy controls.",signatures:"Juárez‐Cedillo Teresa, Hsiung Ging‐Yuek, Sepehry A. Amir, Beattie\nB. Lynn, Jacova Claudia and Escobedo de la Peña Jorge",downloadPdfUrl:"/chapter/pdf-download/52044",previewPdfUrl:"/chapter/pdf-preview/52044",authors:[{id:"183147",title:"Dr.",name:"Teresa",surname:"Juarez-Cedillo",slug:"teresa-juarez-cedillo",fullName:"Teresa Juarez-Cedillo"},{id:"187568",title:"Dr.",name:"Ging-Yuek",surname:"Hsiung",slug:"ging-yuek-hsiung",fullName:"Ging-Yuek Hsiung"},{id:"187569",title:"Dr.",name:"Amir",surname:"Sepehry",slug:"amir-sepehry",fullName:"Amir Sepehry"},{id:"187570",title:"MSc.",name:"B. Lynn",surname:"Beattie",slug:"b.-lynn-beattie",fullName:"B. Lynn Beattie"},{id:"187571",title:"Dr.",name:"Claudia",surname:"Jacova",slug:"claudia-jacova",fullName:"Claudia Jacova"},{id:"187572",title:"Dr.",name:"Jorge",surname:"Escobedo De La Peña",slug:"jorge-escobedo-de-la-pena",fullName:"Jorge Escobedo De La Peña"}],corrections:null},{id:"51311",title:"Idiopathic Normal Pressure Hydrocephalus: An Overview of Pathophysiology, Clinical Features, Diagnosis and Treatment",doi:"10.5772/64198",slug:"idiopathic-normal-pressure-hydrocephalus-an-overview-of-pathophysiology-clinical-features-diagnosis-",totalDownloads:3015,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Normal pressure hydrocephalus is characterised by the triad of gait disturbance, dementia and urinary incontinence. Although our understanding of the condition has considerably improved since it was initially described over 50 years ago, its pathophysiology is still a matter of debate. We provide an overview of the current concepts in pathophysiology and discuss the clinical features, diagnosis and treatment of this cause of dementia.",signatures:"Rubesh Gooriah and Ashok Raman",downloadPdfUrl:"/chapter/pdf-download/51311",previewPdfUrl:"/chapter/pdf-preview/51311",authors:[{id:"183615",title:"Dr.",name:"Rubesh",surname:"Gooriah",slug:"rubesh-gooriah",fullName:"Rubesh Gooriah"},{id:"367770",title:"Dr.",name:"Ashok",surname:"Raman",slug:"ashok-raman",fullName:"Ashok Raman"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"2646",title:"Visual Cortex",subtitle:"Current Status and Perspectives",isOpenForSubmission:!1,hash:"8a5632344dfe9b3f0153eeee84a6ea83",slug:"visual-cortex-current-status-and-perspectives",bookSignature:"Stephane Molotchnikoff and Jean Rouat",coverURL:"https://cdn.intechopen.com/books/images_new/2646.jpg",editedByType:"Edited by",editors:[{id:"145800",title:"Prof.",name:"Stephane",surname:"Molotchnikoff",slug:"stephane-molotchnikoff",fullName:"Stephane Molotchnikoff"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"673",title:"Dyslexia",subtitle:"A Comprehensive and International Approach",isOpenForSubmission:!1,hash:"9a88d127d035ab53de96a00f9ed407ba",slug:"dyslexia-a-comprehensive-and-international-approach",bookSignature:"Taeko N. Wydell and Liory Fern-Pollak",coverURL:"https://cdn.intechopen.com/books/images_new/673.jpg",editedByType:"Edited by",editors:[{id:"87489",title:"Prof.",name:"Taeko",surname:"Wydell",slug:"taeko-wydell",fullName:"Taeko Wydell"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5947",title:"Mechanisms of Neuroinflammation",subtitle:null,isOpenForSubmission:!1,hash:"e4ade830cd06a3aebc5eae0dae96aff2",slug:"mechanisms-of-neuroinflammation",bookSignature:"Gonzalo Emiliano Aranda Abreu",coverURL:"https://cdn.intechopen.com/books/images_new/5947.jpg",editedByType:"Edited by",editors:[{id:"72314",title:"Dr.",name:"Gonzalo Emiliano",surname:"Aranda Abreu",slug:"gonzalo-emiliano-aranda-abreu",fullName:"Gonzalo Emiliano Aranda Abreu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2599",title:"The Amygdala",subtitle:"A Discrete Multitasking Manager",isOpenForSubmission:!1,hash:"429fa5522790c0837406fd1fed1280bd",slug:"the-amygdala-a-discrete-multitasking-manager",bookSignature:"Barbara Ferry",coverURL:"https://cdn.intechopen.com/books/images_new/2599.jpg",editedByType:"Edited by",editors:[{id:"139945",title:"Dr.",name:"Barbara",surname:"Ferry",slug:"barbara-ferry",fullName:"Barbara Ferry"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2604",title:"Basal Ganglia",subtitle:"An Integrative View",isOpenForSubmission:!1,hash:"76d19f809182eea657ce36eb4817c5b8",slug:"basal-ganglia-an-integrative-view",bookSignature:"Fernando A. 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1. Introduction
Acute exacerbations of Idiopathic Pulmonary fibrosis (AE-IPF) represent important milestone in the disease course of IPF, which is the most common disease among the group of Idiopathic interstitial pneumonia (IIP). The IPF is more common among males and in the elderly age group [1]. Although the exact etiology of AE-IPF is unknown, there are many important risk factors as well as triggers that have been identified. There is associated accelerated decline in lung function which leads to poor prognosis [1]. It is estimated that about 35 to 46% of deaths in IPF are caused by AE-IPF [2]. In hospital mortality is more than 50% and follow up after hospitalization shows a mortality up to 73% at the end of 90 days [2, 3]. Although treatment with high dose Gluco corticoids have been used extensively, there is lack of controlled well designed trials to support its use and in fact survival has been shown to be decreased with steroids and or other immune suppressants [4, 5]. Some newer anti-fibrotic agents like Pirfenidone and Nintedanib may improve survival, the latter may be helpful in preventing AE-IPF [1, 6, 7].
2. Criteria for diagnosis of AE-IPF
Acute exacerbation of IPF is recognized with the help of a set of criteria laid out by the International IPF Working group network which is as follows [2, 4, 8, 9, 10, 11, 12].
“An acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality”.
The following four diagnostic criteria have to be met as shown in Table 1.
A known or concurrent diagnosis of IPF
Clinical respiratory deterioration noted “typically” in the preceding 30 days.
Presence of typical UIP pattern on CT chest including bilateral basilar reticular changes with honeycombing and traction bronchiectasis. Superimposed ground glass attenuation and /or consolidation is necessary in exacerbation. When possible specific UIP pattern may be combined with histopathological information to make a more robust diagnosis.
Absence of heart failure, Pulmonary embolism, fluid overload or any other differential pathology.
Note that endotracheal aspirate is not necessary as per new diagnostic criteria.
The 30-day time limit of clinical deterioration is not strictly enforced.
Exclude other causes of Interstitial Lung disease such as drug toxicity, connective tissue disease, hypersensitivity pneumonitis, etc.
Table 1.
Criteria for diagnosing IPF exacerbation as per working group idiopathic pulmonary fibrosis network (IPF net).
The guidelines also provided certain clarifications that help in making a diagnosis [11].
Events that are clinically considered to meet the definition of acute exacerbation of IPF but fail to meet all four diagnostic criteria owing to missing computed tomography data are to be termed “suspected acute exacerbations.” For example, if CT scan shows unilateral ground glass attenuation or data available is incomplete [2].
If the diagnosis of IPF is not previously established, this criterion can be met by the presence of radiologic and/or histopathologic changes consistent with usual interstitial pneumonia pattern on the current evaluation [11].
It is to be noted that the term “idiopathic” was removed from the older definition, as it was seen to be restrictive [11]. Making a distinction between idiopathic and non-idiopathic respiratory events is not easy as there are not well defined clinical or biological criteria [11]. So, although the acute deterioration could be due to an infectious etiology and it is not necessary to rule this out for the purpose of definition, at a practical level infection needs to be diagnosed and treated empirically or definitely as it does have a definite therapeutic recourse [11, 13]. It also follows from this that Broncho alveolar lavage (BAL) is not needed for diagnosis and hence it will help capture more of such events, but at the expense of specificity [11, 13]. BAL may not be needed when HRCT pattern is consistent with UIP, but when the Usual interstitial pneumonia (UIP) pattern is indeterminate or suspect then BAL can be useful [12]. Similarly, surgical lung biopsy (SLB) is recommended only when UIP is indeterminate or suspect [12]. However there is considerable morbidity and mortality associated with BAL or surgical biopsy in the context of AE and hence such procedures are to be generally avoided [11].
Similar to Acute lung injury in non-IPF lungs precipitated by triggers such as aspiration, post-operative, medication etc., exacerbation in IPF can be sub-categorized as either “triggered” when a known precipitating etiology is documented or “Idiopathic” when no such etiology is apparent [11].
The new definition also replaced the 30-day time restriction for the acute deterioration to “typically or generally of less than one-month duration” [11]. The phrase “typically less than 1 month” was included to provide precision but allow for the inclusion of exceptions that clinicians believe represent acute exacerbations [11]. A more flexible time interval may lead to “heterogeneity” among clinicians and clinical trial endpoint definitions for acute exacerbation [11].
3. Epidemiology
The incidence of acute exacerbations is variably reported in literature. This is because exacerbations could be more common in certain populations like more elderly people who are also likely to have severe disease, inconsistent definitions and its use, statistical design, follow up time and other factors [2, 9]. Exacerbations are less common in mild to moderate disease compared to severe disease [3, 14]. Reporting can vary depending on the type of study as well. Prospective trials may lack sufficient data to report all exacerbations [2, 4, 8],typically include younger patients with less comorbidities, with mild to moderate disease and therefore may under report incidence [15]. Retrospective studies may over report depending on the criteria used, by including events with pulmonary embolism, heart failure etc. [2, 13, 16].
Suspected exacerbations, which may not satisfy the definition of definitive AE-IPF are also important as they are associated with poor outcomes [4].
A meta-analysis analyzed six trials and reported acute exacerbation rate of 41 acute exacerbations per 1000 patient/years [14]. Rate of acute exacerbations were much lower in trials that included only mild to moderate disease [14].
In a retrospective study from Korea, which included 461 patients with IPF of which 269 cases were biopsy-proven and the median follows up period was 22.9 months, acute exacerbation occurred in 96 (20.8%) patients, and 17 (17.7%) of those acute exacerbation patients experienced multiple episodes of acute exacerbations (range 2–3 episodes). The incidence of acute exacerbation was noted to be 14.2, 18.8 and 20.7 percent at the end of 1, 2 and 3 years respectively [17].
It is to be noted that exacerbation of IPF may even occur in individuals with limited fibrosis and well-preserved lung function [2]. In the STEP-IPF trail, definite AE-IPF was reported as 40 per 1000 patient-years. However, the combined definite and suspected AE-IPF increased the exacerbation rate to 200 per 1000 patient-year [2, 4, 8, 13].
There have been reports of increased rate of AE-IPF in people of Asian descent in the far east such as Japan and Korea, however this has not been proven by randomized control trials [7, 8, 18].
4. Risk factors and pathophysiology
There are many risk factors for acute exacerbation. However, the most important risk factor is advanced disease [2, 14]. Other factors described in literature include low Forced vital capacity [8, 17], recent decline in FVC [19, 20], Low diffusion capacity for carbon monoxide [4], low 6 min walk test [4], pulmonary hypertension [21], poor baseline oxygenation [4, 22], increased dyspnea score [4], younger age group [2], presence of concurrent coronary artery disease [4], higher body mass index [22], previous history of acute exacerbation of IPF [19, 23].
Some important triggers for acute exacerbation have been described.
4.1 Infection
Infections are very common causes of respiratory deterioration. Exacerbations are more common in winter and spring season [24] and in those who are immunosuppressed [2, 25]. Postmortem analysis, multiplex polymerase chain reaction (PCR), pan viral micro array, high output cDNA sequencing and other techniques have demonstrated that infectious etiology is incriminated in many but not all acute exacerbations [23]. Based on the cumulative evidence which demonstrates infection to be causing some but not all acute exacerbations, it is thought to be an important but not exclusive trigger for precipitating acute exacerbations.
4.2 Silent aspiration of gastric contents
Aspiration of gastric contents has been postulated to be a causative factor for IPF and exacerbations in IPF.
In a case control study involving 24 acute exacerbations and 30 controls, Pepsin level in Broncho alveolar lavage (BAL) was found to be fairly commonly present, suggestive of gastric aspiration being fairly common in IPF.8 of the 24 acute exacerbation IPF patients had very high levels of Pepsin suggesting that aspiration of gastric contents could be a contributor for acute exacerbation [26].
In a study involving 32 patients with asymmetric idiopathic pulmonary fibrosis (AIPF) compared with 64 matched controls with symmetrical IPF, Gastro esophageal reflux disease (GERD) and AE-IPF was significantly higher in patients with AIPF with the left side being less commonly involved [27].
On the contrary, in a post hoc analysis of the two Phase III randomized placebo-controlled INPULSIS trials of Nintedanib in patients with IPF, the rate of decline of FVC in the placebo group was much higher in patients who were taking an antacid (Proton pump inhibitor or H2-receptor antagonists) at baseline when compared to those who were not [difference of − 47.5 mL/year (95% CI: −105.1, 10.1); p = 0.1057] [28].
The data as it is apparent, that although gastro esophageal reflex has been widely debated to be causative, is not very definitive. Therefore, it can be likely that the aspiration of gastro esophageal contents can trigger acute exacerbations like infections but is not the sole causative factor.
4.3 Surgery and other interventions
Many surgical procedures like bronchoscopy and BAL, lung biopsy, lung resection, non-thoracic surgery and others can precipitate acute exacerbation [24, 29, 30, 31, 32]. The mechanism of action is unclear but could be related to stress like volutrauma, barotrauma, free oxygen radicals, or intra operative fluid balance.
4.4 Air pollution
Air pollution can be a cause for interstitial lung disease. In a retrospective south Korean longitudinal cohort, out of 505 IPF patients 436 patients were included in the final analysis.75 patients experienced at least one exacerbation. There were 89 acute exacerbation events occurring over 1699 patient-years, for an incidence rate of 5.2 exacerbations per 100 patient-years. [23].
Air pollution data for each of the five pollutants Ozone (O3),Nitrogen di oxide (NO2), particles with a 50% cut-off aerodynamic diameter of <10 μm (PM10), sulfur dioxide (SO2) and carbon monoxide (CO) were measured prospectively at Tele-Monitoring-Systems (TMS) situated throughout Korea. Each TMS recorded hourly measurements of each pollutant during the study period. Mean and maximum exposures of all these 5 pollutants were recorded over the 42-day period prior to the exacerbation period. Acute exacerbation of IPF was significantly associated with important measurement metrics of O3 and NO2 during the exposure period. Mean Ozone and Nitrogen dioxide levels were weakly correlated; however, both were statistically significant independent predictors of AE-IPF [23].
4.5 Medications
Medications can provoke respiratory deterioration in interstitial pneumonia which closely resembles acute exacerbation. Such drugs include everolimus, interferon-gamma and others [33, 34]. Drugs and surgery used to treat Lung cancer patients with interstitial pneumonia did not appear to cause more exacerbations compared to best supportive care and hence should not be withheld when treating Lung cancer with interstitial pneumonia patients [35].
As noted, there have been many triggers associated with acute exacerbation of IPF. However currently the most accepted theory is that exacerbation is thought to be “an acceleration of the underlying inflammatory fibro proliferative disease process”.
This theory is supported by markers of cell injury as well as genetic expressions.
In one study by Collard et al., 47 patients with acute exacerbation of IPF, 20 patients with stable IPF and 20 patients with acute lung injury were studied. Plasma from these patients were collected and measured for biomarkers of cell activity/injury-receptor for advanced glycation end (RAGE) products, surfactant protein D, KL-6, von Willebrand factor; systemic inflammation-Interleukin-6; and biomarkers of coagulation/fibrinolysis-protein C, thrombomodulin, plasminogen activator inhibitor-1. Plasma from patients with AE-IPF showed higher levels of markers of type II alveolar epithelial cell injury/proliferation, endothelial cell injury, and coagulation/fibrinolysis very much like stable IPF but the response was much more exaggerated. This biomarker profile was different from patients with acute lung injury which was consistent with type I alveolar epithelial injury [36].
In another study, RNA was extracted from 23 stable IPF lungs, 8 IPF lungs with acute exacerbation of IPF and 15 control lungs. The gene expressions were studied. Results indicated that 579 genes were differentially expressed between stable IPF and acute exacerbation of IPF. Functional analysis of these genes was not suggestive of infectious or inflammatory etiology. Gene expression patterns in acute exacerbations of IPF and IPF samples were quite similar and different from the control lung arm [37].
Other immunological theories have also been proposed. Annexin 1 is an antigen found in human body which is increased in patients who have AE of IPF [38]. This antigen can induce both humoral and cell mediated immune responses and certain parts of this antigen have been implicated in the pathogenesis of AE of IPF [38]. Certain molecular studies have also been performed. Heat shock protein 47 (HSP47), has been studied and found to be a good bio marker for collagen production and secretion [39]. In studies comparing stable and AE-IPF patients, serum HSP47 were significantly elevated in AE-IPF patients in comparison to stable IPF patients [39]. Ironically patients who have anti-HSP70 autoantibodies in smaller studies have much poor prognosis due to AE of IPF when compared to controls or even those patients who have IPF but negative anti-HSP70 autoantibodies [40, 41].
Epithelial damage and impaired healing by abundance fibrosis has been an important theory that tries to explain the pathologic damage in IPF patients. When compared to IPF patients, patients with AE of IPF have higher bio markers of neutrophilic damage such as Alpha-defensins which are produced by activated neutrophils [37, 42] and also increased levels of Fibrocytes have been noted which have been found to be associated with worser outcomes in patients with AE of IPF [42, 43].
5. Clinical features
Patients present with worsening respiratory symptoms generally which are less than 30 days in duration. It consists of cough, worsening dyspnea especially on exertion, fever, malaise, and other flu like symptoms. Criteria for diagnosis include PaO2/FiO2 ratio < 225 or a decrease in PaO2 of ≥10 mmHg over time [8, 16].
Physical examination is consistent with IPF including bibasilar crackles on auscultation, but with increased respiratory rate [37].
Laboratory testing and imaging are directed to rule out other differentials like congestive heart failure, Myocardial infarction, pulmonary embolism, pulmonary hypertension, pulmonary infections etc. [2, 8]. Accordingly, complete blood count, B-type natriuretic peptide, C-reactive protein, chemistry profile including Blood urea nitrogen and serum creatinine can be performed along with highly sensitive troponins. Laboratory values are consistent with an infectious or inflammatory process but there is no evidence of infection on Blood culture, Urine antigen tests or Broncho alveolar lavage (BAL) if these tests are undertaken [8]. BAL if performed typically shows neutrophilic predominance [8]. BNP is typically elevated in heart failure and pulmonary hypertension [44]. Echo may be beneficial in heart failure and pulmonary hypertension [44]. CRP is typically elevated in infections and inflammation [44]. Pro calcitonin can guide when infection is suspected and even helping with limiting duration of antibiotic use [45]. D-dimer and CT pulmonary angiogram can help with ruling in or ruling out Pulmonary embolism [44].
High resolution computed tomography (HRCT) reveals bilateral ground glass or consolidative opacities superimposed on a background of typical HRCT features of IPF which includes bibasilar reticular opacities, honeycomb changes, and traction bronchiectasis [2].
Acute exacerbation of IPF is essentially a clinical diagnosis aided by predominantly noninvasive test. Although surgical biopsy can be performed for diagnosis which may show diffuse alveolar damage, the mortality and morbidity in the acute situation appear to be prohibitively high and not recommended [46].
6. Treatment and prognosis
Treatment is primarily supportive in nature.
Supplemental oxygen consisting of low flow and high flow oxygen can be used to keep Oxygen saturation (Spo2) more than 92%. Noninvasive ventilation mechanical ventilation (NIMV) and Mechanical ventilation (MV) is used as needed.
In a retrospective review of 19 hospitalized patients with IPF and AE, 1/3rd of patients had an infectious etiology, the percentage of patients who were discharged alive was 37% and only 14.8% of patients were alive at 1 year [47]. Patients with IPF experience AE very commonly. In IPF, about 40% of patients may die due to AE [48, 49]. In another observational study of 112 patients, 56 patients (42.9%) died due to AE [48]. The five-year survival rate of all patients with IPF was 38.3% and the Median survival time was 3.1 years post diagnosis. However, in patients who had an AE, the five-year survival rate was 10.7% and median survival time was 0.6 years [48].
In a pooled data consisting of nine studies, including 135 patients who were intubated for AE of IPF the cumulative mortality was 118 (87%) and short-term mortality (within 3 months of discharge) was 127 (94%) [50]. Therefore AE of IPF is not only common, but also a very poor predictor of survival. Based on these observations, the 2011 IPF guidelines discouraged MV in the vast majority and recommended its use in a selective minority of patients after careful weighing of risks and benefits [11]. However, this data pertains to a time period before 2007. In a study that reported US national data of 1703 patients who received Mechanical ventilation (MV)and 778 patients who received Noninvasive mechanical ventilation (NIMV),mortality was about 50% in those who received MV compared to 30% for those who received NIMV. The mortality of IPF patients treated with MV improved from 58.4% in 2006 to 49.3% in 2012 which was significant [51]. Overall this is suggestive that survival of patients treated with MV has seen a marginal improvement which could be due to various factors such as relative changes in diagnostic criteria and their use, difference in variables used and study design, differences in the severity of disease (patients with decreased FVC have poorer prognosis), judicious selection of patients who were placed on MV and widespread adoption and use of lung protective ventilation strategies [52]. Hence it is imperative that well informed discussions relating to advance care directives are made at the time of diagnosis and re visited when hospitalized [50]. In patients who are candidates for Lung transplant, the use of mechanical ventilation and extra corporeal membrane oxygenation, can be effective and lifesaving [11, 52, 53, 54, 55].
Ventilator induced lung injury (VILI) secondary to use of MV results in lung damage and poor prognosis [52]. In IPF, the lungs are fibrotic and non-compliant. Lower PEEP may be more beneficial and protective along with low tidal volume ventilation, hence minimizing both volutrauma and barotrauma [52, 56]. NIMV and high flow oxygen are being increasingly used and may be beneficial [56, 57]. Both NIMV and High flow Oxygen could be beneficial in patients who are not appropriate or choose to forego intubation, the survival may be the same with both modalities [57, 58],with high flow nasal oxygen being better tolerated, allowing patients to even eat and drink [57, 58, 59]. Hence they could be very effective means for palliative care [57, 58].
In patients who undergo thoracic surgery, VILI may be a potential etiological mechanism and can be minimized by the aforementioned lung protective ventilation including reducing lung volume, low PEEP, low partial pressure of inspired oxygen (Fio2), and less invasive surgical techniques [52, 56, 60, 61].
Symptoms such as dyspnea are treated with a palliative intent [8, 11]. Oxygen and opioids can also be given for symptom control [8, 11].
In IPF, a combination of inflammation, epithelial cell injury, fibro proliferative repair, and tissue remodeling which interact with the coagulation system help characterize IPF as a procoagulant state [62]. The use of therapeutic anticoagulation such as Warfarin or Alfa-Thrombomodulin has proven to be either harmful or non-beneficial in well conducted studies [63, 64, 65]. There is no evidence supporting therapeutic anticoagulation in patients experiencing acute exacerbation [63]. Nevertheless, patients with IPF have almost twice the risk of venous thromboembolism compared to general population and hence pharmacological venous thromboprophylaxis should be routinely used in hospitalized patients [66, 67].
There is not enough evidence of protective role from the use of antacids, but patients who are already using them can continue with their use [68, 69]. Evidence is often contradictory if antacids protect or may potentiate or worsen AE of IPF [70, 71].
Corticosteroids have been used extensively but the practice is driven by expert opinion and anecdotal reports and not driven by good data. Expert guidelines give a weak recommendation to the use of steroids [2, 6]. Acute IPF is characterized by high degree of inflammation with areas of diffuse alveolar damage secondary to Acute Lung injury and organizing pneumonia [9]. Therefore, the use of high dose steroids is intuitively thought to be beneficial [9, 72, 73, 74], in spite of absence of good data from randomized control trials [9]. Dosage and duration are also not well defined in literature, although it is typical to use initially high dose corticosteroids followed by a rapid tapering course, as longer duration of steroids may be harmful in IPF [9, 62]. In EXAFIP, a randomized control trial comparing Cyclophosphamide with corticosteroids against placebo with corticosteroids in AE of IPF, the steroid regimen used in all patients was Methylprednisolone 10 mg/kg per day for 3 days followed by a progressive taper to 10 mg per day for patients above 65 kg and 7·5 mg per day for patients below 65 kg at the end of 6 months [75]. Similarly in a RCT involving 77 patients in Japan, Alpha-Thrombomodulin (ART-123) was compared against placebo. All patients received glucocorticoids in two courses of pulse Methylprednisolone (500–1000 mg/day) for 3 days followed by Prednisolone 0.5–1.0 mg/kg/day for 4 days followed by gradual taper [64]. Smaller retrospective studies have shown that using high dose of glucocorticoids used in first 30 days prevent recurrence of exacerbation when compared to lower doses in the same duration or after 30 days but this has not been substantiated by other studies [76, 77]. The use of high dose steroids has been noted to increase survival in non-IPF exacerbation of Interstitial lung disease [76]. It is noteworthy that some studies and even guidelines recommend using no immunosuppressives in select patients, as mortality was no better in the immunosuppressed group when compared to the non-immunosuppressed, with higher incidence of infection in the immune suppressed group, especially in severe disease [11, 14].
Concomitant Immunosuppressive therapy with steroids have also been used and the evidence base for this practice is also not very sound [2, 48]. While treatments such as Alfa-Thrombomodulin and Cyclophosphamide along with concomitant glucocorticoids have been subjected to randomized control trials and have not been shown to improve outcomes [64, 75], others do not have much evidence as they were too small, were uncontrolled, used historical data as control or had no control arm [2]. The latter studies have used medications like Tacrolimus, Cyclosporin-A, Rituximab combined with plasma exchange, Intravenous Immunoglobulin, and polymyxin B-immobilized fiber column (PMX) [6]. Other medications that have been used include Acetylcysteine as standalone therapy, sildenafil, bosentan, interferon-gamma 1b, warfarin, ambrisentan, and imatinib [8].
In a small retrospective study consisting of 11 patients in each group, Corticosteroids alone were compared with Cyclosporin-A and Corticosteroids. The mortality was similar in each group but the Cyclosporin-A group appeared to have longer survival [78]. However in a larger retrospective review with 384 patients in Cyclosporin-A and high dose Corticosteroids and 7605 patients treated with high dose Corticosteroids alone in Japan, no change in survival was noted [79].
Other considerations include empiric treatment of a course of antibiotics since infectious etiology can be treated but cannot be ruled out conclusively in the vast majority of cases [2]. Procalcitonin has been used in clinical trials and can reduce the duration of antibiotics (8.7 ± 6.6 compared to 14.2 ± 5.2 days in the routine treatment group), without any effect on treatment success, mortality rate, days of hospitalization and ventilation therapy [45]. Tacrolimus, an immunosuppressive drug used widely in solid organ transplant patients including Lung transplant was found to have beneficial survival effects and protection against future exacerbations in small retrospective studies, with lack of data from better designed controlled studies [80]. Direct hemoperfusion with Polymyxin B immobilized fiber column (PMX-DHP) has been used in AE of IPF to absorb endotoxins and reactive oxygen species, among other toxic substances, as well as selectively remove activated neutrophils and preventing activation of monocytes with a goal to limit endothelial damage [81, 82]. PMX-DHP may act by adsorbing harmful cytokines such as vascular endothelial growth factor and may have anti-fibrotic effect [83, 84]. The adsorption of proinflammatory, profibrotic and proangiogenic cytokines is postulated to be an important mechanistic action of PMX-DHP [83]. The use of PMX-DHP along with Corticosteroids has demonstrated improvement in oxygenation, with possible improvement in survival in a multicentric Japanese retrospective study with 73 patient who had AE of IPF [82]. There is a prevailing hypothesis that auto antibodies may have a role in IPF progression. Removal of these auto antibodies by plasma exchange and Rituximab followed by IVIG subsequently may be beneficial in AE-IPF [62, 85]. A small pilot study involving 11 patients has shown the safety and possible efficacy, paving way for a Phase 3 randomized control trial [85].
Interestingly in a retrospective study, patients who were not on any immunosuppression had better survival than those who were on immunosuppression [5].
7. Prognostic score
There has been considerable interest in developing prognostication scores for AE of IPF. A number of markers have been used in different studies and Forced vital capacity %, Diffusion capacity for Carbon monoxide, Pao2/Fio2 (P/F) ratio, HRCT patterns, Acute Physiology and Chronic Health Evaluation II score (APACHE II), Glasgow prognostic score and serum biomarkers like C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6) have all been considered [86]. In a retrospective study of 108 patients, a lower FVC % at baseline (1 year before AE) and P/F ratio on AE presentation were predictive of mortality [86]. In another study of 103 AE-IPF cases, a combination of P/F ratio less than 250 (P), CRP ≥ 5.5 (C), and diffuse HRCT pattern (radiological) (R), together called as PCR index was used to stratify and predict mortality at the end of 3 months [87]. In a systematic review and meta-analysis, 37 studies and 31 prognostic factors were analyzed [88]. Five independent variables after multivariate analysis were found to be helpful with prognostication namely APACHE II score, P/F ratio, LDH level, white blood cell (WBC) count, and oxygen therapy before AE [88]. Interestingly the latter did not find use of FVC or imaging scores to be helpful in terms of prognostication [88]. Prognostication scores and models are certainly good research tools but not commonly used in clinical practise as no intervention other than good supportive care has been found to be useful.
8. Prevention
Prevention of exacerbation in IPF is the most effective strategy as we do not seem to have very effective therapies once the exacerbation gets underway. Avoidance of air pollutants [23], preventing infections like Streptococcal pneumonia and Influenza by vaccination [26, 61], general hygiene measures like handwashing again to prevent infections [52], and judicious use of antacids may be helpful strategies [68, 69].
Many medications have been tested, using prevention of acute exacerbation as an end point. Acetylcysteine monotherapy, bosentan, interferon-gamma,sildenafil, showed no effect [8]. Others like imatinib, ambrisentan, triple therapy (prednisone, azathioprine, acetylcysteine combination) and warfarin showed increased risk of exacerbation [8].
Azuma et al. studied 107 IPF patients in a phase 2 Randomized placebo-controlled trial comparing Pirfenidone and placebo. Although there were no acute exacerbations noted in the Pirfenidone arm compared to placebo [89], the same results could not be reproduced in a phase 3 RCT with 275 patients, showing no difference between the intervention and control arm [18]. In the large phase 3 RCT’s, CAPACITY and ASCEND which compared Pirfenidone with placebo yet again, unfortunately AE of IPF as an end point was not studied [90, 91]. Nevertheless, a pooled analysis of the CAPACITY and ASCEND trial did reveal a reduction in non-elective respiratory related hospitalization favoring Pirfenidone [92]. Interestingly Pirfenidone in small studies has proven to be safe and effective in preventing exacerbations in peri operative period in patients who were given 2–4 weeks of medication prior to surgery and continued post operatively when compared against historical controls [93, 94]. Larger RCTs need to be performed for this promising intervention [94].
Another antifibrotic agent Nintedanib was studied after Pirfenidone, which showed a favorable effect against placebo for preventing AE of IPF in the phase 2 TOMORROW trial and phase 3 INPULSIS-2 trial, but no such effect was seen in the phase 3 INPULSIS-1 trial [95, 96]. However the pooled analysis of patients from TOMORROW and INPULSIS trials [6],consisting of 1231 patients (Nintedanib n = 723, placebo n = 508), the hazard ratio for time to first acute exacerbation was 0.53 (95% CI: 0.34, 0.83; p = 0.0047) favoring Nintedanib. The proportion of patients with ≥1 acute exacerbation was 4.6% in the Nintedanib group and 8.7% in the placebo group [6]. Nintedanib can be added after recovering from an exacerbation or continued if it was previously being used.
In a systematic review and meta-analysis, 12,956 patients were included comparing the use of anti fibrotics (Pirfenidone or Nintedanib) vs. nonuse of antifibrotics, which showed that the use of antifibrotics decreased all-cause mortality, RR 0.55 (95% CI, 0.45–0.66). The same review included seven studies involving 2002 treated and 1323 non-treated patients, and showed a decrease in AE, which was statistically significant for Nintedanib (RR 0.62 [95% CI, 0.43–0.89) but only non-significant decrease for Pirfenidone, RR of 0.57 (95% CI, 0.29–1.12) [1].
Overall, the evidence favors Nintedanib over Pirfenidone in terms of preventing AE of IPF. However, there are no head to head comparisons between these two approved medications and real world data could produce results to the contrary [97]. Hence it would be prudent to plan design and conduct appropriate RCT that would give an unambiguous answer to this very important question.
9. Conclusion
Episodes of Acute exacerbation are important events in the disease course of IPF. Up to 40% of deaths in IPF are caused by acute exacerbations. After the initial diagnosis, the median survival of patients with acute exacerbation was much shorter (15.5 months) than that of patients without respiratory deterioration (60.6 months). The 5 year rate of survival of patients with acute exacerbation was 18.4%, whereas 50.0% of patients without respiratory deterioration survived.
While medications like Nintedanib can slow down progression of disease and prevent exacerbations, once diagnosed it has no known effective treatment. Hence more research is needed to alter the disease course of IPF as well as prevent the occurrence of these exacerbations which invariably is an indicator of poor prognosis.
\n',keywords:"acute exacerbation of IPF, idiopathic pulmonary fibrosis, acute exacerbation, drug therapy, treatment, clinical trials, nintedanib, pirfenidone, respiratory failure",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81614.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81614.xml",downloadPdfUrl:"/chapter/pdf-download/81614",previewPdfUrl:"/chapter/pdf-preview/81614",totalDownloads:33,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 24th 2021",dateReviewed:"March 22nd 2022",datePrePublished:"May 11th 2022",datePublished:null,dateFinished:"May 2nd 2022",readingETA:"0",abstract:"Episodes of Acute exacerbation (AE) of Idiopathic Pulmonary fibrosis (IPF) are important events in the disease trajectory of IPF, associated with punctuated decline in lung function with significant mortality and morbidity associated with it. These episodes are idiosyncratic, and often unpredictable and may have triggers. Our diagnostic criteria for these events, etiology, pathogenesis, risk factors and management continue to evolve over the years, with limited availability of qualitative research data to help guide management. Outcome in general is poor with no well-defined therapy but prevention may be possible with use of Nintedanib. Our chapter aims to explore the contemporary knowledge of the key aspects of this disease entity.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81614",risUrl:"/chapter/ris/81614",signatures:"Nitesh Kumar Jain, Shikha Jain, Hisham Ahmed Mushtaq, Anwar Khedr, Thoyaja Koritala, Aysun Tekin, Ramesh Adhikari, Anupam Sule, Samir Gautam, Vishwanath Pattan, Vikas Bansal, Ali Rabaan, Kovid Trivedi, Amos Lal, Brian Bartlett, Abbas Jama, Aishwarya Reddy Korsapati, Mohamed Hassan, Simon Zec, Adham Mohsen, Amit Munshi Sharma, Ibtisam Rauf, Mikael Mir, Lia Nandi, Mool Chand, Hariprasad Reddy Korsapati, Rahul Kashyap, Salim Surani and Syed Anjum Khan",book:{id:"9816",type:"book",title:"Idiopathic Pulmonary Fibrosis",subtitle:null,fullTitle:"Idiopathic Pulmonary Fibrosis",slug:null,publishedDate:null,bookSignature:" Salim Surani and Dr. Venkat Rajasurya",coverURL:"https://cdn.intechopen.com/books/images_new/9816.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83969-240-6",printIsbn:"978-1-83969-239-0",pdfIsbn:"978-1-83969-241-3",isAvailableForWebshopOrdering:!0,editors:[{id:"15654",title:null,name:"Salim",middleName:null,surname:"Surani",slug:"salim-surani",fullName:"Salim Surani"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Criteria for diagnosis of AE-IPF",level:"1"},{id:"sec_3",title:"3. Epidemiology",level:"1"},{id:"sec_4",title:"4. Risk factors and pathophysiology",level:"1"},{id:"sec_4_2",title:"4.1 Infection",level:"2"},{id:"sec_5_2",title:"4.2 Silent aspiration of gastric contents",level:"2"},{id:"sec_6_2",title:"4.3 Surgery and other interventions",level:"2"},{id:"sec_7_2",title:"4.4 Air pollution",level:"2"},{id:"sec_8_2",title:"4.5 Medications",level:"2"},{id:"sec_10",title:"5. Clinical features",level:"1"},{id:"sec_11",title:"6. Treatment and prognosis",level:"1"},{id:"sec_12",title:"7. Prognostic score",level:"1"},{id:"sec_13",title:"8. Prevention",level:"1"},{id:"sec_14",title:"9. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Petnak T, Lertjitbanjong P, Thongprayoon C, Moua T. Impact of Antifibrotic therapy on mortality and acute exacerbation in idiopathic pulmonary fibrosis: A systematic review and Meta-analysis. 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Internal Medicine. 2011;50:189-195. DOI: 10.2169/internalmedicine.50.4327'},{id:"B81",body:'Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: The EUPHAS randomized controlled trial. Journal of the American Medical Association. 2009;301:2445-2452. DOI: 10.1001/jama.2009.856'},{id:"B82",body:'Abe S, Azuma A, Mukae H, Ogura T, Taniguchi H, Bando M, et al. Polymyxin B-immobilized fiber column (PMX) treatment for idiopathic pulmonary fibrosis with acute exacerbation: A multicenter retrospective analysis. Internal Medicine. 2012;51:1487-1491. DOI: 10.2169/internalmedicine.51.6965'},{id:"B83",body:'Oishi K, Mimura-Kimura Y, Miyasho T, Aoe K, Ogata Y, Katayama H, et al. Association between cytokine removal by polymyxin B hemoperfusion and improved pulmonary oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis. Cytokine. 2013;61:84-89. DOI: 10.1016/j.cyto.2012.08.032'},{id:"B84",body:'Tachibana K, Inoue Y, Nishiyama A, Sugimoto C, Matsumuro A, Hirose M, et al. Polymyxin-B hemoperfusion for acute exacerbation of idiopathic pulmonary fibrosis: Serum IL-7 as a prognostic marker. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 2011;28:113-122'},{id:"B85",body:'Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, et al. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS One. 2015;10:e0127771. DOI: 10.1371/journal.pone.0127771'},{id:"B86",body:'Suzuki T, Hozumi H, Miyashita K, Kono M, Suzuki Y, Karayama M, et al. Prognostic classification in acute exacerbation of idiopathic pulmonary fibrosis: A multicentre retrospective cohort study. Scientific Reports. 2021;11:9120. DOI: 10.1038/s41598-021-88718-2'},{id:"B87",body:'Sakamoto S, Shimizu H, Isshiki T, Nakamura Y, Usui Y, Kurosaki A. 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DOI: 10.1056/NEJMoa1402582'},{id:"B91",body:'Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials. Lancet. 2011;377:1760-1769. DOI: 10.1016/s0140-6736 (11)60405-4'},{id:"B92",body:'Ley B, Swigris J, Day BM, Stauffer JL, Raimundo K, Chou W, et al. Pirfenidone reduces respiratory-related hospitalizations in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine. 2017;196:756-761. DOI: 10.1164/rccm.201701-0091OC'},{id:"B93",body:'Iwata T, Yoshino I, Yoshida S, Ikeda N, Tsuboi M, Asato Y, et al. West Japan oncology G: A phase II trial evaluating the efficacy and safety of perioperative pirfenidone for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan oncology group 6711 L (PEOPLE study). Respiratory Research. 2016;17:90-90. DOI: 10.1186/s12931-016-0398-4'},{id:"B94",body:'Iwata T, Yoshida S, Fujiwara T, Wada H, Nakajima T, Suzuki H, et al. Effect of perioperative Pirfenidone treatment in lung cancer patients with idiopathic pulmonary fibrosis. The Annals of Thoracic Surgery. 2016;102:1905-1910. DOI: 10.1016/j.athoracsur.2016.05.094'},{id:"B95",body:'Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. The New England Journal of Medicine. 2011;365:1079-1087. DOI: 10.1056/NEJMoa1103690'},{id:"B96",body:'Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of Nintedanib in idiopathic pulmonary fibrosis. New England Journal of Medicine. 2014;370:2071-2082. DOI: 10.1056/NEJMoa1402584'},{id:"B97",body:'Isshiki T, Sakamoto S, Yamasaki A, Shimizu H, Miyoshi S, Nakamura Y, et al. 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IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\\n\\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\\n\\n
\\n\\t
Does your institution already have a budget for covering Open Access publication costs?
\\n\\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\\n
\\n\\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\\n\\n
Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at funders@intechopen.com
\\n\\n
Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
\n\n
Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at funders@intechopen.com
\n\n
Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. 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He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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One of the most suitable examples of nanoparticles used for this purpose are quantum dots, a type of colloidal fluorescent semiconducting nanocrystalline material that has the possibility, due to its unique optical and electronic properties, to be used in numerous technological applications such as biosensing, in vivo imaging techniques, photovoltaics, nanomedicine, molecular pathology, and drug delivery. Thus, there are almost endless possibilities for quantum dots materials. In spite of the fast advance in the search of quantum dots with better nanomaterial performance, environmentally benign and sustainable production is still lacking. Although the use of these materials is developing promptly, there is increasing concern that these materials might pose potential risks to human health. Herein, we discuss principal properties of quantum dots, including their functional architecture and toxicity, and review the main studies about “green” quantum dots synthesis to be aligned with green nanotechnology approach for nontoxic, cleaner, safer, and more responsible processes. The organometallic colloidal synthesis and the aqueous colloidal synthesis, as well as their drawbacks and benefits, are conferred. Recent advances in technological and biological quantum dots–based applications are also discussed in this chapter.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Carlos A. Martínez Bonilla and Vladimir V. Kouznetsov",authors:[{id:"105180",title:"Prof.",name:"Vladimir V.",middleName:"V.",surname:"Kouznetsov",slug:"vladimir-v.-kouznetsov",fullName:"Vladimir V. Kouznetsov"},{id:"179817",title:"M.Sc.",name:"Carlos A.",middleName:"Andrés",surname:"Martínez Bonilla",slug:"carlos-a.-martinez-bonilla",fullName:"Carlos A. Martínez Bonilla"}]},{id:"50214",doi:"10.5772/62620",title:"TiO2 Nanostructures and Nanocomposites for Sustainable Photocatalytic Water Purification",slug:"tio2-nanostructures-and-nanocomposites-for-sustainable-photocatalytic-water-purification",totalDownloads:2299,totalCrossrefCites:3,totalDimensionsCites:12,abstract:"Water, together with energy and food, has been addressed as one of the main urgent problems of humanity. The conventional wastewater treatments suffer some limitations related to the effectiveness in decontamination (mechanical filtration), in the heavy use of chemicals (chlorination), or in elevation of operational costs and energy requirements (desalination and reverse osmosis). In this sense, new materials such as nanocomposites may overcome these issues taking advantage of the peculiar properties of materials at nanoscale. Research on novel nanotechnologies must bring advances in order to contrast and prevent water scarcity and pollution. In order to be effective, these nanotechnologies should run at low operational cost, even in places unequipped by strong infrastructures and in concert with conventional cheap methodologies.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Giuseppe Cacciato, Massimo Zimbone, Francesco Ruffino and Maria\nGrazia Grimaldi",authors:[{id:"178880",title:"Ph.D.",name:"Francesco",middleName:null,surname:"Ruffino",slug:"francesco-ruffino",fullName:"Francesco Ruffino"},{id:"180334",title:"Dr.",name:"Giuseppe",middleName:null,surname:"Cacciato",slug:"giuseppe-cacciato",fullName:"Giuseppe Cacciato"},{id:"180335",title:"Dr.",name:"Massimo",middleName:null,surname:"Zimbone",slug:"massimo-zimbone",fullName:"Massimo Zimbone"},{id:"180336",title:"Prof.",name:"Maria Grazia",middleName:null,surname:"Grimaldi",slug:"maria-grazia-grimaldi",fullName:"Maria Grazia Grimaldi"}]},{id:"50705",doi:"10.5772/63314",title:"Metal Nanoparticles as Emerging Green Catalysts",slug:"metal-nanoparticles-as-emerging-green-catalysts",totalDownloads:3314,totalCrossrefCites:2,totalDimensionsCites:8,abstract:"Green nanotechnology is defined as the technology applied for building clean technology by which one can reduce the potential risks of environment and also improve human health conditions. It is linked with the implementation of products of nanotechnology and its process of manufacturing. Green nanotechnology synthesizes new nanoproducts with improved properties in such a way that they can substitute some of the existing low‐quality products. The main motive of developing new nanoproducts is to enhance sustainability and also to make them more environment friendly. In particular, nanoscale materials (e.g., nanoparticles) can be defined as those having characteristic length scale lying within the nanometric range, that is, in the range between one and several hundreds of nanometers. Within this length scale, the properties of matter are sufficiently different from individual atoms/molecules or from bulk materials. The primary objective of this chapter is to provide comprehensive overview about metal nanoparticles (MNPs) and its application as emerging green catalysts. This chapter contains six sections in total. Section 1 starts with a general introduction, recent progress, and brief summary of the application of MNPs as green catalyst. Section 2 reviews the preparation and characterization of supported metal nanoparticles for a wide range of catalytic applications. Section 3 presents the catalytic properties of supported metal nanoparticles. Section 4 describes briefly some of the most commonly reported supported MNPs in different green catalytic applications. Section 5 concentrates on our own results that related to the application of supported MNPs in catalysis. In this section, the oxidation of benzyl alcohol to benzaldehyde, the production of adipic acid from cyclohexane, the photodegradation of dyes using green route will be discussed. Finally, Section 6 describes the summary of main points and also presents an outlook of the application of MNPs in green chemistry.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Ahmad Alshammari, V. Narayana Kalevaru and Andreas Martin",authors:[{id:"178547",title:"Dr.",name:"Ahmad",middleName:null,surname:"Alshammari",slug:"ahmad-alshammari",fullName:"Ahmad Alshammari"},{id:"180753",title:"Dr.",name:"V. Narayana",middleName:null,surname:"Kalevaru",slug:"v.-narayana-kalevaru",fullName:"V. Narayana Kalevaru"},{id:"180804",title:"Dr.",name:"Andreas",middleName:null,surname:"Martin",slug:"andreas-martin",fullName:"Andreas Martin"}]},{id:"50074",doi:"10.5772/62316",title:"Nanostructured TiO2 Layers for Photovoltaic and Gas Sensing Applications",slug:"nanostructured-tio2-layers-for-photovoltaic-and-gas-sensing-applications",totalDownloads:2136,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Titanium dioxide (TiO2) has been an important material for decades, combining numerous attractive properties in terms of economy (low price, large availability) or ecology (non-toxic), as well as broad physical and chemical possibilities. In the last few years, the development of nanotechnologies offered new opportunities, not only in an academic perspective but also with a view to many applications with particular reference to the environment. This chapter focuses on the many ways that allow to tailor and organize TiO2 crystallites at the nanometre scale to make the most of this amazing material in the field of photovoltaics and gas sensing.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"André Decroly, Arnaud Krumpmann, Marc Debliquy and Driss\nLahem",authors:[{id:"108357",title:"Dr.",name:"Marc",middleName:null,surname:"Debliquy",slug:"marc-debliquy",fullName:"Marc Debliquy"},{id:"156323",title:"Dr.",name:"Driss",middleName:null,surname:"Lahem",slug:"driss-lahem",fullName:"Driss Lahem"},{id:"179585",title:"Associate Prof.",name:"André",middleName:null,surname:"Decroly",slug:"andre-decroly",fullName:"André Decroly"},{id:"179653",title:"MSc.",name:"Arnaud",middleName:null,surname:"Krumpmann",slug:"arnaud-krumpmann",fullName:"Arnaud Krumpmann"}]},{id:"50087",doi:"10.5772/62240",title:"Friccohesity and Tentropy: New Models of Molecular Sciences",slug:"friccohesity-and-tentropy-new-models-of-molecular-sciences",totalDownloads:1767,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Understanding and developing new molecules in chemical sciences have been great thrust areas of research, not only to develop new synthetic methods or reaction mechanisms of new and greener experimental conditions but also to know what are the new molecule science and what are the new models which can track their new role in chemical processes and also their applications in allied interdisciplinary sciences. The SAR (structure-activity relationship) and STAR (structure-thermodynamics activity relationship) have been the most intimate theories in understanding and finding unique applications of the new molecules. Initially, simple molecules are the focus; however, proteins, hemoglobin, starch, and certain metallic complexes are also in the focus but as natural chemicals; but for past few decades, a lot of focus has been on synthesizing new complex molecules to make them suitable for varieties of applications such as solar, catalysts, biosensors, and others. Hence, it has been essential for focusing on structural sciences of the chemical substances. Dendrimers have been the invention of 1990s in the areas of biocomplexes, biomaterials which are hot thrust areas in molecular interaction engineering to focus on intramolecular potential for industrial applications. Thus, the molecule’s internal structure signifies the various scientific components for playing or making their best use in materials sciences, semiconductor, spintronics, photonics, electronics, etc. Therefore, the molecule’s interacting response with other molecules becomes cohesive or kinetic in nature or whether it induces structuredness or weakens the binding forces and allows more and more kinetic movement or the motion is noted or defined by friccohesity as it is expressed as frictional and cohesive forces. Thus, the friccohesity is a dual forces theory which deals with frictional and cohesive forces together and determined with Survismeter using Mansingh equation molecules [1–3].",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Man Singh",authors:[{id:"24553",title:"Prof.",name:"Man",middleName:null,surname:"Singh",slug:"man-singh",fullName:"Man Singh"}]}],mostDownloadedChaptersLast30Days:[{id:"50106",title:"“Green” Quantum Dots: Basics, Green Synthesis, and Nanotechnological Applications",slug:"-green-quantum-dots-basics-green-synthesis-and-nanotechnological-applications",totalDownloads:3843,totalCrossrefCites:9,totalDimensionsCites:19,abstract:"Nanotechnological development of new materials involves the discovery or design of materials at small length scales with controlled physical and chemical properties than can be tuned or modified in function of their applications. One of the most suitable examples of nanoparticles used for this purpose are quantum dots, a type of colloidal fluorescent semiconducting nanocrystalline material that has the possibility, due to its unique optical and electronic properties, to be used in numerous technological applications such as biosensing, in vivo imaging techniques, photovoltaics, nanomedicine, molecular pathology, and drug delivery. Thus, there are almost endless possibilities for quantum dots materials. In spite of the fast advance in the search of quantum dots with better nanomaterial performance, environmentally benign and sustainable production is still lacking. Although the use of these materials is developing promptly, there is increasing concern that these materials might pose potential risks to human health. Herein, we discuss principal properties of quantum dots, including their functional architecture and toxicity, and review the main studies about “green” quantum dots synthesis to be aligned with green nanotechnology approach for nontoxic, cleaner, safer, and more responsible processes. The organometallic colloidal synthesis and the aqueous colloidal synthesis, as well as their drawbacks and benefits, are conferred. Recent advances in technological and biological quantum dots–based applications are also discussed in this chapter.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Carlos A. Martínez Bonilla and Vladimir V. Kouznetsov",authors:[{id:"105180",title:"Prof.",name:"Vladimir V.",middleName:"V.",surname:"Kouznetsov",slug:"vladimir-v.-kouznetsov",fullName:"Vladimir V. Kouznetsov"},{id:"179817",title:"M.Sc.",name:"Carlos A.",middleName:"Andrés",surname:"Martínez Bonilla",slug:"carlos-a.-martinez-bonilla",fullName:"Carlos A. Martínez Bonilla"}]},{id:"50705",title:"Metal Nanoparticles as Emerging Green Catalysts",slug:"metal-nanoparticles-as-emerging-green-catalysts",totalDownloads:3314,totalCrossrefCites:2,totalDimensionsCites:8,abstract:"Green nanotechnology is defined as the technology applied for building clean technology by which one can reduce the potential risks of environment and also improve human health conditions. It is linked with the implementation of products of nanotechnology and its process of manufacturing. Green nanotechnology synthesizes new nanoproducts with improved properties in such a way that they can substitute some of the existing low‐quality products. The main motive of developing new nanoproducts is to enhance sustainability and also to make them more environment friendly. In particular, nanoscale materials (e.g., nanoparticles) can be defined as those having characteristic length scale lying within the nanometric range, that is, in the range between one and several hundreds of nanometers. Within this length scale, the properties of matter are sufficiently different from individual atoms/molecules or from bulk materials. The primary objective of this chapter is to provide comprehensive overview about metal nanoparticles (MNPs) and its application as emerging green catalysts. This chapter contains six sections in total. Section 1 starts with a general introduction, recent progress, and brief summary of the application of MNPs as green catalyst. Section 2 reviews the preparation and characterization of supported metal nanoparticles for a wide range of catalytic applications. Section 3 presents the catalytic properties of supported metal nanoparticles. Section 4 describes briefly some of the most commonly reported supported MNPs in different green catalytic applications. Section 5 concentrates on our own results that related to the application of supported MNPs in catalysis. In this section, the oxidation of benzyl alcohol to benzaldehyde, the production of adipic acid from cyclohexane, the photodegradation of dyes using green route will be discussed. Finally, Section 6 describes the summary of main points and also presents an outlook of the application of MNPs in green chemistry.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Ahmad Alshammari, V. Narayana Kalevaru and Andreas Martin",authors:[{id:"178547",title:"Dr.",name:"Ahmad",middleName:null,surname:"Alshammari",slug:"ahmad-alshammari",fullName:"Ahmad Alshammari"},{id:"180753",title:"Dr.",name:"V. Narayana",middleName:null,surname:"Kalevaru",slug:"v.-narayana-kalevaru",fullName:"V. Narayana Kalevaru"},{id:"180804",title:"Dr.",name:"Andreas",middleName:null,surname:"Martin",slug:"andreas-martin",fullName:"Andreas Martin"}]},{id:"49331",title:"Metal Complexes Immobilized on Magnetic Nanoparticles",slug:"metal-complexes-immobilized-on-magnetic-nanoparticles",totalDownloads:2136,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The reusability of valuable catalysts in organic reaction without change in properties is known as an important feature in the evolution of green processes. The imobilization of metal catalysts on magnetic nanoparticles makes them recoverable and can be used as building blocks for the fabrication of various functional systems, which are applied in several fields such as catalysis, environmental remediation magnetic resonance imaging, data storage, and biotechnology. Applying magnetic nanoparticles in organic reaction as a scaffold for the immobilization of metal complexes is reviewed as well as the improvement of the methods of production and applying catalysts with magnetic properties in organic reaction.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Seyed Mohsen Sadeghzadeh and Mehdi Mogharabi",authors:[{id:"175879",title:"Dr.",name:"Seyed Mohsen",middleName:null,surname:"Sadeghzadeh",slug:"seyed-mohsen-sadeghzadeh",fullName:"Seyed Mohsen Sadeghzadeh"},{id:"191799",title:"Dr.",name:"Mehdi",middleName:null,surname:"Mogharabi",slug:"mehdi-mogharabi",fullName:"Mehdi Mogharabi"}]},{id:"50132",title:"Recent Highlights in Green Oxidative Chemical Processes Applied to Steroid Chemistry",slug:"recent-highlights-in-green-oxidative-chemical-processes-applied-to-steroid-chemistry",totalDownloads:2413,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Steroids and their oxidation products are widely distributed in living organisms and are important intermediates for the synthesis of many biologically active molecules. Due to their pharmacological and synthetic relevance, several oxidative chemical processes for the functionalization of the steroid nucleus have been developed. Green chemistry principles have been incorporated in some oxidative transformations of steroids, allowing significant advances in synthetic chemistry applied to these compounds. This chapter presents a selection of relevant applications of pharmaceutical green chemistry to steroid’s oxidative processes. Special emphasis is given to catalytic processes encompassing heterogeneous nanocatalysts, whose application in this context is increasing over the past years. This chapter is organized according to the reaction type that includes alcohol oxidation, epoxidation of alkenes, and allylic oxidation of alkenes to enones, among other relevant oxidative transformations. Biocatalytic oxidative methods applied to steroid synthesis are not included in this review.",book:{id:"5170",slug:"green-nanotechnology-overview-and-further-prospects",title:"Green Nanotechnology",fullTitle:"Green Nanotechnology - Overview and Further Prospects"},signatures:"Samuel M. Silvestre, M. Manuel C. Silva and Jorge A. R. Salvador",authors:[{id:"69976",title:"Prof.",name:"Jorge António Ribeiro",middleName:null,surname:"Salvador",slug:"jorge-antonio-ribeiro-salvador",fullName:"Jorge António Ribeiro Salvador"},{id:"157541",title:"Prof.",name:"Samuel",middleName:null,surname:"Silvestre",slug:"samuel-silvestre",fullName:"Samuel Silvestre"},{id:"185027",title:"Prof.",name:"Maria Manuel Cruz",middleName:null,surname:"Silva",slug:"maria-manuel-cruz-silva",fullName:"Maria Manuel Cruz Silva"}]},{id:"50074",title:"Nanostructured TiO2 Layers for Photovoltaic and Gas Sensing Applications",slug:"nanostructured-tio2-layers-for-photovoltaic-and-gas-sensing-applications",totalDownloads:2136,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Titanium dioxide (TiO2) has been an important material for decades, combining numerous attractive properties in terms of economy (low price, large availability) or ecology (non-toxic), as well as broad physical and chemical possibilities. In the last few years, the development of nanotechnologies offered new opportunities, not only in an academic perspective but also with a view to many applications with particular reference to the environment. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:"2753-6580",scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
\r\n
\r\n\t
\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
\r\n\t
\r\n
\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
\r\n
\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n
\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. 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