Book Volume 5
Page: 3-40 (38)
Author: Paul David Dash
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The question of possible benefits of physicians screening for dementia in elderly patients in the outpatient setting remains open. Although no controlled studies have thus far been able to conclusively demonstrate that doing so is in fact beneficial, the end points of such studies, such as mortality, are rather crude. Increasingly, there are arguments that harder to track end points need to be examined in more detail, and that earlier recognition of cognitive impairment can potentially have a significant impact on a number of clinical matters. These include, for example, recognition of potential problems with medication compliance, driving risk, predicting post-operative delirium, and allowing more time for patient and family planning of finances and living arrangements, as well as recommending life style changes in diet and exercise habits that may help retard the progression of early cognitive impairment. In this article we will discuss evidence regarding these points, and also give a brief outline of the pros and cons of some of the numerous brief cognitive screens that can be utilized for screening purposes.
Endothelial Dysfunction and Chronic Low-Grade Inflammation as Potential Therapeutic Targets in Dementia Disorders
Page: 41-82 (42)
Author: Asija Zaciragic, Nesina Avdagic, Nermina Babic, Amela Devisevic, Amina Valjevac, Almir Fajkic, Jasminko Huskic, Almira Hadzovic-Dzuvo and Orhan Lepara
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The inability of drugs based on the amyloid-clearing strategies to provide benefits for Alzheimer’s disease (AD) patients has led to widely accepted notion that the paradigm in dementia research should be broaden beyond amyloid deposition and clearance. In recent years significant overlap between cardio-metabolic risk factors and cognitive decline has been reported. Consistent with these observations, the importance of endothelial dysfunction in the development of AD has been highlighted. According to newly proposed “vascular hypothesis” for AD development, vascular risk factors lead to blood–brain barrier (BBB) dysfunction and a reduction in the cerebral blood flow. These two detrimental vascular changes result in the reduction of amyloid-β clearance as well as in its increased production leading to consequent amyloid- β accumulation. The increase in amyloid-β leads to neuronal dysfunction and injury causing cognitive dysfunction and neurodegeneration with consequent dementia. Furthermore, a growing body of evidence also suggest that the impaired structure and function of cerebral blood vessels and cells in AD patients is mediated by vascular oxidative stress as well as by chronic low-grade inflammation. The importance of inflammatory changes in many age-related diseases including dementia has led to coining and use of the term “inflammaging” to indicate that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses.
The aim of this chapter is to provide a comprehensive insight into currently available evidence on molecular pathways and players implicated in the above mechanisms. Furthermore, chapter summarizes findings from ongoing clinical trials and results from studies using novel pharmacological therapeutics targeting endothelial dysfunction and chronic low-grade inflammation as pathophysiological events that contribute to the onset and development of dementia disorders.
Page: 83-143 (61)
Author: Xin Yi Choo and Alexandra Grubman
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Alzheimer’s disease is the most common neurodegenerative disease. Despite intensive research, promising therapies have failed to translate to the clinic. This chapter will review the prevailing mechanistic hypotheses to explain AD pathogenesis, including the cholinergic, amyloid-cascade, inflammatory and metal dyshomeostasis theories, present an update on the clinical developments in therapies targeting each of the hypotheses, and highlight promising areas requiring further research.
Recent Perspective About the Amyloid Cascade Hypothesis and Stem Cell-Based Therapy in the Treatment of Alzheimer's Disease
Page: 144-174 (31)
Author: Hany E. Marei, Asmaa Althani, Jaana Suhonen, Mohamed E. El Zowalaty, Mohammad A. Albanna, Carlo Cenciarelli, Tengfei Wang and Thomas Caceci
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Alzheimer's disease (AD) is a complex neurodegenerative condition that is clinically characterized by impaired cognitive functions. The major morphologically observed lesion of AD encompasses the accumulation of extracellular amyloid aggregates (plaques) formed of amyloid-β (Aβ) protein and of intracellular neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein. According to the currently accepted amyloid cascade hypothesis, the major induction factor underlying the loss of cholinergic neurons in the cortex and hippocampus is the pathological accumulation of a smaller protein fragments known as amyloid-β which in turn is derived from a larger membrane protein called amyloid precursor protein (APP). Based on this hypothesis, several diagnostic and drug-based therapeutic interventions were suggested, mostly targeting amyloid-β and hyperphosphorylated Tau proteins. Several data have emerged that might indicate the inconsistency of the amyloid cascade hypothesis. Moreover, due to the purely palliative nature of AD drugs used so far, new stem cell-based therapy has been suggested as a promising potential therapeutic approach. Several cell sources have been used, such as embryonic stem cells, neural stem cells, mesenchymal stem cells, and induced pluripotent stem cells. While this suite of cell-based trials has shown promising results in preclinical paradigms, stumbling blocks still exist in the current treatment regimens. The present review highlights the recent perspective that argues against the long standing amyloid cascade hypothesis as well as the major efforts in the experimental application of stem cellbased therapies used as treatment options for AD, and discusses the major impediments against their successful translation into clinical.
Page: 175-213 (39)
Author: Vida Demarin, Zlatko Trkanjec, Marijana Bosnar Puretić, Sandra Morović and Anton Glasnović
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Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaque and neurofibrillary tangles formation in the brain tissue. It is a progressive disease with death as the final outcome. In 2012 there were 35.6 million affected people worldwide and this number is constantly increasing. The main risk factor is age and life expectancy after the diagnosis is approximately ten years. The most important diagnostic procedures are neurocognitive tests, which are used to assess behavior and thinking abilities, while neuroimaging is used to exclude other brain pathologies and confirm the specific atrophic changes. Although a large number of studies have investigated this issue, no effective treatment for AD has been found. Most frequently used medications are ACh esterase inhibitors, mainly donepezil, rivastigmin and galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, but they are mostly used to relieve the symptoms. Therefore, the emphasis should be put on early disease detection and delaying cognitive impairment through lifestyle modifications, such as increased physical activity, healthy nutrition, and mental training. The disease influences not only the patients’ quality of life, but also that of the caregivers, and represents a heavy financial burden for the society as a whole.
Page: 214-302 (89)
Author: Andreia Corciova, Daniela Matei, Calin Corciova and Bianca Ivănescu
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Alzheimer’s disease is a common form of dementia. Drugs currently available for treatment of Alzheimer’s disease are only symptomatic and act by augmenting the level of acetylcholine. These drugs do not stop or delay the evolution of disease and manifest specific adverse effects that limit their use. In this context, it is crucial the development of new drugs that will target the causal agent of disease. Such compounds that intervene at different levels in the pathogenesis of Alzheimer’s disease were identified in plant extracts.
In this chapter, we propose an overview of some compounds that have anti amyloidogenic activity of which the most important are: curcuminoids, ellagic acid, gallic acid, salvianolic acid B, resveratrol and epicagallocatechin-3-gallate. Besides the mechanism and biological actions, this chapter will present the vegetal products from which the active compounds are extracted, methods of extraction, identification and quantification. Selected techniques will be compared in terms of optimal conditions for extraction. Moreover, methods for identification and quantification will be described in terms of analytical conditions. Nature remains an important resource of active molecules and a hope in treating Alzheimer’s disease.
Frontiers in Clinical Drug Research - Alzheimer Disorders is an e-Book series which covers recent topics related to understanding Alzheimer's disease (AD) that causes dementia and has a neurodegenerative effect on the brain. The disease affects memory, thought process, and language of affected individuals. Chapters in each volume focus on (Alzheimer Disorders) drug research with special emphasis on clinical trials, research on drugs in advanced stages of development and cure for Alzheimer’s disease and related disorders. Frontiers in Clinical Drug Research - Alzheimer Disorders will be of particular interest to readers interested in drug therapy of this specific neurodegenerative condition and related brain disorders as the series provides relevant reviews written by experts in field of Alzheimer’s Disease research. The fifth volume of this series features chapters covering critical discussions on AD management and new therapies. The topics reviewed in this volume include: - Current concepts in management of AD - The amyloid cascade hypothesis and stem cell-based AD therapy - Phytochemicals targeting AD - Dementia screening in primary clinical care settings - Updates in dementia / AD clinical research and drug development