Pub Date : 2018-07-18DOI: 10.5772/INTECHOPEN.75509
M. Janelidze, N. Botchorishvili
Mild cognitive impairment (MCI) refers to cognitive decline from a previous level of functioning, both subjectively and by objective evidence. MCI is an intermediate stage of cognitive impairment between the normal cognitive aging and dementia. The concept of mild cognitive impairment originally evolved with an intention to characterize the pre-dementia phase of cognitive impairment. MCI is a known risk factor for dementia. Patients with MCI may represent an optimal target population for pharmacological and non-pharmacological interventions. The following chapter provides an overview of the concept of mild cognitive impairment, epidemiological data, current diagnostic criteria, clinical approach and management of MCI.
{"title":"Mild Cognitive Impairment","authors":"M. Janelidze, N. Botchorishvili","doi":"10.5772/INTECHOPEN.75509","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.75509","url":null,"abstract":"Mild cognitive impairment (MCI) refers to cognitive decline from a previous level of functioning, both subjectively and by objective evidence. MCI is an intermediate stage of cognitive impairment between the normal cognitive aging and dementia. The concept of mild cognitive impairment originally evolved with an intention to characterize the pre-dementia phase of cognitive impairment. MCI is a known risk factor for dementia. Patients with MCI may represent an optimal target population for pharmacological and non-pharmacological interventions. The following chapter provides an overview of the concept of mild cognitive impairment, epidemiological data, current diagnostic criteria, clinical approach and management of MCI.","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130081419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-07-18DOI: 10.5772/INTECHOPEN.75510
A. Verma, M. Zabel
This chapter describes the various systems beyond the central nervous system that are associated with Alzheimer’s disease (AD). There is strong evidence to believe that while AD has symptoms of memory and cognitive impairment—undoubtedly domains of the central nervous system—the primary insult that causes this condition may arise systemi-cally. We describe associations with the immune system, gut microbiome, and endocrine abnormalities that may be at play. Our goal is to incorporate a multi-system approach to understand the pathogenesis of AD. Our body does not function as soloed organ sys- tems, and we hypothesize that the mechanisms described herein are similarly contribut-ing to the progression of cognitive impairment in AD.
{"title":"Alzheimer’s Disease: Beyond the Neuron","authors":"A. Verma, M. Zabel","doi":"10.5772/INTECHOPEN.75510","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.75510","url":null,"abstract":"This chapter describes the various systems beyond the central nervous system that are associated with Alzheimer’s disease (AD). There is strong evidence to believe that while AD has symptoms of memory and cognitive impairment—undoubtedly domains of the central nervous system—the primary insult that causes this condition may arise systemi-cally. We describe associations with the immune system, gut microbiome, and endocrine abnormalities that may be at play. Our goal is to incorporate a multi-system approach to understand the pathogenesis of AD. Our body does not function as soloed organ sys- tems, and we hypothesize that the mechanisms described herein are similarly contribut-ing to the progression of cognitive impairment in AD.","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"187 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128653217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-07-18DOI: 10.5772/INTECHOPEN.76299
P. Dolan, W. Zago
The development of therapeutics for the treatment of Alzheimer’s disease (AD) has been challenged with a myriad of obstacles: an evolving and incomplete understanding of disease etiology and progression, challenges with early diagnosis, multifactorial genetic and environmental factors that contribute to patient variability, and the cost of conducting lengthy clinical trials. One approach that has garnered a significant amount of attention and resources for its potential as a disease modifying approach is passive immunotherapy directed at clearing amyloid-β (Aβ) species, a pathological hallmark of Alzheimer’s disease. While passive immunotherapeutic trials directed at Aβ have not yet demonstrated clinical benefit, they have prompted important advances in the application and understanding of biomarkers, patient selection, novel functional readouts, and safety monitoring. Application of these lessons has enabled more recent clinical trials to incorporate better trial designs and refine inclusion criteria to optimize patient population enrollment. In addition, new passive immunotherapy targets emerging in the clinic have emerged, as well as novel technologies to enhance future antibody therapeutics. Taken together, the advances in research and clinical science have prepared the passive immunotherapy field to advance emerging promising disease modifying treatments in AD.
阿尔茨海默病(AD)治疗方法的发展面临着无数障碍的挑战:对疾病病因和进展的不断发展和不完整的理解，早期诊断的挑战，导致患者变异的多因素遗传和环境因素，以及进行冗长临床试验的成本。作为一种潜在的疾病修饰方法，一种已经获得了大量关注和资源的方法是针对清除淀粉样蛋白-β (a β)物种的被动免疫疗法，这是阿尔茨海默病的病理标志。虽然针对Aβ的被动免疫治疗试验尚未显示出临床益处，但它们在生物标志物的应用和理解、患者选择、新的功能读数和安全性监测方面取得了重要进展。这些经验的应用使最近的临床试验能够纳入更好的试验设计和完善纳入标准，以优化患者人群入组。此外，新的被动免疫治疗靶点已经出现在临床，以及新技术，以加强未来的抗体治疗。综上所述，研究和临床科学的进步为被动免疫治疗领域推进新出现的有前景的AD疾病修饰治疗做好了准备。
{"title":"Passive Immunotherapy in Alzheimer’s Disease","authors":"P. Dolan, W. Zago","doi":"10.5772/INTECHOPEN.76299","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.76299","url":null,"abstract":"The development of therapeutics for the treatment of Alzheimer’s disease (AD) has been challenged with a myriad of obstacles: an evolving and incomplete understanding of disease etiology and progression, challenges with early diagnosis, multifactorial genetic and environmental factors that contribute to patient variability, and the cost of conducting lengthy clinical trials. One approach that has garnered a significant amount of attention and resources for its potential as a disease modifying approach is passive immunotherapy directed at clearing amyloid-β (Aβ) species, a pathological hallmark of Alzheimer’s disease. While passive immunotherapeutic trials directed at Aβ have not yet demonstrated clinical benefit, they have prompted important advances in the application and understanding of biomarkers, patient selection, novel functional readouts, and safety monitoring. Application of these lessons has enabled more recent clinical trials to incorporate better trial designs and refine inclusion criteria to optimize patient population enrollment. In addition, new passive immunotherapy targets emerging in the clinic have emerged, as well as novel technologies to enhance future antibody therapeutics. Taken together, the advances in research and clinical science have prepared the passive immunotherapy field to advance emerging promising disease modifying treatments in AD.","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"425 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126717340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-07-18DOI: 10.5772/intechopen.74239
J. Rybakowski
Alzheimer’s disease (AD) represents one of the greatest health-care challenges of the twenty-first century. Besides known pathologies such as intracellular accumulation of neurofibrillary tangles and extracellular deposition of amyloid-beta plaques, other factors, such as dysregulated GSK-3 activity, mitochondrial dysfunction, inflammation, and oxidative stress, have been shown to play a role in the pathogenesis of AD. Over the last two decades, the evidence accumulated for a neuroprotective effect of lithium, as an important mechanism of this ion in mood disorders, reflected by an increase in cerebral gray matter volume in lithium-treated subjects. Neurobiological mechanisms of lithium neuroprotective actions may also be relevant to the pathogenesis and treatment of AD, and they will be delineated. In most epidemiological studies, a negative association between lithium use and dementia has been shown, including two most recent papers regarding a concentration of lithium in drinking water. In this article, the results of initial studies using lithium in the treatment of dementia and showing some promise will also be presented. Therefore, considering the current paucity of treatments for the AD, further testing of lithium as a disease-modifying treatment in this illness may be warranted.
{"title":"Lithium and Alzheimer’s Disease: Experimental, Epidemiological, and Clinical Findings","authors":"J. Rybakowski","doi":"10.5772/intechopen.74239","DOIUrl":"https://doi.org/10.5772/intechopen.74239","url":null,"abstract":"Alzheimer’s disease (AD) represents one of the greatest health-care challenges of the twenty-first century. Besides known pathologies such as intracellular accumulation of neurofibrillary tangles and extracellular deposition of amyloid-beta plaques, other factors, such as dysregulated GSK-3 activity, mitochondrial dysfunction, inflammation, and oxidative stress, have been shown to play a role in the pathogenesis of AD. Over the last two decades, the evidence accumulated for a neuroprotective effect of lithium, as an important mechanism of this ion in mood disorders, reflected by an increase in cerebral gray matter volume in lithium-treated subjects. Neurobiological mechanisms of lithium neuroprotective actions may also be relevant to the pathogenesis and treatment of AD, and they will be delineated. In most epidemiological studies, a negative association between lithium use and dementia has been shown, including two most recent papers regarding a concentration of lithium in drinking water. In this article, the results of initial studies using lithium in the treatment of dementia and showing some promise will also be presented. Therefore, considering the current paucity of treatments for the AD, further testing of lithium as a disease-modifying treatment in this illness may be warranted.","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"22 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125146160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-07-18DOI: 10.5772/INTECHOPEN.75511
D. Walker, L. Lue
The concept of activated microglia being associated with neurodegenerative pathological structures in aging and Alzheimer’s disease (AD) has been well established, but questions remain about how well are we defining “what are microglia actually doing” when we look at diseased or aged brains? Most studies of microglia in human AD brains have employed a limited set of antigenic markers, particularly the major histocompatibility complex protein HLA-DR and ionized calcium-binding adaptor molecule IBA-1, along with cellular morphological criteria, but in recent years, it has been appreciated that microglial responses are very heterogeneous depending on their surrounding environment—every microglia might be different. Initial observations on human brain microglia associated with plaques and tangles suggested that microglial inhibition with broad spectrum anti-inflammatory drugs should slow down AD pathology, but clinical trials did not show this approach to be effective. In this article, we will consider the needs, challenges and benefits for refining how microglia are defined as they associate with pathological proteins. This may aid in defining which ones are accelerating neurotoxicity and which ones are performing reparative/phagocytic functions. More complete definition of microglial phenotypes offers the potential of developing targeted anti-inflammatory approaches for this disease.
{"title":"Defining Microglial Phenotypes in Alzheimer’s Disease","authors":"D. Walker, L. Lue","doi":"10.5772/INTECHOPEN.75511","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.75511","url":null,"abstract":"The concept of activated microglia being associated with neurodegenerative pathological structures in aging and Alzheimer’s disease (AD) has been well established, but questions remain about how well are we defining “what are microglia actually doing” when we look at diseased or aged brains? Most studies of microglia in human AD brains have employed a limited set of antigenic markers, particularly the major histocompatibility complex protein HLA-DR and ionized calcium-binding adaptor molecule IBA-1, along with cellular morphological criteria, but in recent years, it has been appreciated that microglial responses are very heterogeneous depending on their surrounding environment—every microglia might be different. Initial observations on human brain microglia associated with plaques and tangles suggested that microglial inhibition with broad spectrum anti-inflammatory drugs should slow down AD pathology, but clinical trials did not show this approach to be effective. In this article, we will consider the needs, challenges and benefits for refining how microglia are defined as they associate with pathological proteins. This may aid in defining which ones are accelerating neurotoxicity and which ones are performing reparative/phagocytic functions. More complete definition of microglial phenotypes offers the potential of developing targeted anti-inflammatory approaches for this disease.","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"75 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131709888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-03-23DOI: 10.5772/INTECHOPEN.75306
N. Apaijai, Wasana Pratchayasakul, N. Chattipakorn, S. Chattipakorn
There is much evidence to demonstrate that the presence of the metabolic syndrome (MetS) is associated with an increase in the incidence of pre-Alzheimer’s disease. The possible underlying mechanisms linking pre-Alzheimer’s disease and MetS are still unclear. This study summarizes and discusses the potential mechanisms involved in pre-Alzheimer’s disease under MetS conditions, including an increased brain oxidative stress, brain inflammation, brain mitochondrial dysfunction, hyper-phosphorylated tau protein, and amyloid beta production. This report focuses on brain mitochondrial altera- tions in cases of pre-Alzheimer’s disease where MetS is also extant. The data from in vitro , in vivo, and clinical studies are included. In addition, potential interventions against pre-Alzheimer’s disease in conjunction with MetS are summarized and discussed.
{"title":"Mitochondrial Link Between Metabolic Syndrome and Pre-Alzheimer’s Disease","authors":"N. Apaijai, Wasana Pratchayasakul, N. Chattipakorn, S. Chattipakorn","doi":"10.5772/INTECHOPEN.75306","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.75306","url":null,"abstract":"There is much evidence to demonstrate that the presence of the metabolic syndrome (MetS) is associated with an increase in the incidence of pre-Alzheimer’s disease. The possible underlying mechanisms linking pre-Alzheimer’s disease and MetS are still unclear. This study summarizes and discusses the potential mechanisms involved in pre-Alzheimer’s disease under MetS conditions, including an increased brain oxidative stress, brain inflammation, brain mitochondrial dysfunction, hyper-phosphorylated tau protein, and amyloid beta production. This report focuses on brain mitochondrial altera- tions in cases of pre-Alzheimer’s disease where MetS is also extant. The data from in vitro , in vivo, and clinical studies are included. In addition, potential interventions against pre-Alzheimer’s disease in conjunction with MetS are summarized and discussed.","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"26 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134366653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-03-14DOI: 10.5772/INTECHOPEN.75629
J. Korábečný, K. Spilovska, O. Soukup, R. Doležal, K. Kuča
The amyloid cascade hypothesis poses one possible explanation for the onset and progres- sion of Alzheimer’s disease (AD). With this respect, neurotoxic effect is attributed to soluble and diffusive amyloid-β (Aβ) oligomers. Aβ peptides are produced by proteolytic cleavage of the hydrophobic transmembrane portion of the amyloid precursor protein (APP) by suc-cessive action of β- and γ-secretases. Aβ peptides are generated in several isoforms, out of which the most pronounced are Aβ40 and Aβ42 being the major constituents of amyloid plaques found in AD patients’ brains. Since the indisputable evidence pointed out to Aβ oligomers as toxic agents, several pathways to modulate or control the aggregation have been inspected . Given all these aspects, inhibitors of the β- and γ-secretases have gained the most attention. This chapter presents amyloid cascade hypothesis with current progress in the development of β- and γ-secretase modulators to counteract the Aβ burden. BACE-2 knockout (−/−) mice showed the same phenotype. Double-knockout mice, that is, mice with deactivated genes for BACE-1 (−/−) as well as for BACE-2 (−/−), are not phenotypically very different from mice without the gene for the BACE-1, with the exception of an increased num ber of dying mice freshly after birth. The results of this study therefore assume that nonselective inhibitors of both subtypes of the enzyme BACE may be well tolerated at least from the perspec tive of the inhibition of BACE-2. The latest research has shown that BACE-2 is expressed in the pancreatic β cells and BACE-2 knockout mice exhibit an improved glycemic regulation due to the increased production of insulin. These findings imply the possible use of BACE-2 inhibitors for the treatment of diabetes mellitus of type 2 [ 15].
{"title":"Amyloid Beta Hypothesis: Attention to β- and γ-Secretase Modulators","authors":"J. Korábečný, K. Spilovska, O. Soukup, R. Doležal, K. Kuča","doi":"10.5772/INTECHOPEN.75629","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.75629","url":null,"abstract":"The amyloid cascade hypothesis poses one possible explanation for the onset and progres- sion of Alzheimer’s disease (AD). With this respect, neurotoxic effect is attributed to soluble and diffusive amyloid-β (Aβ) oligomers. Aβ peptides are produced by proteolytic cleavage of the hydrophobic transmembrane portion of the amyloid precursor protein (APP) by suc-cessive action of β- and γ-secretases. Aβ peptides are generated in several isoforms, out of which the most pronounced are Aβ40 and Aβ42 being the major constituents of amyloid plaques found in AD patients’ brains. Since the indisputable evidence pointed out to Aβ oligomers as toxic agents, several pathways to modulate or control the aggregation have been inspected . Given all these aspects, inhibitors of the β- and γ-secretases have gained the most attention. This chapter presents amyloid cascade hypothesis with current progress in the development of β- and γ-secretase modulators to counteract the Aβ burden. BACE-2 knockout (−/−) mice showed the same phenotype. Double-knockout mice, that is, mice with deactivated genes for BACE-1 (−/−) as well as for BACE-2 (−/−), are not phenotypically very different from mice without the gene for the BACE-1, with the exception of an increased num ber of dying mice freshly after birth. The results of this study therefore assume that nonselective inhibitors of both subtypes of the enzyme BACE may be well tolerated at least from the perspec tive of the inhibition of BACE-2. The latest research has shown that BACE-2 is expressed in the pancreatic β cells and BACE-2 knockout mice exhibit an improved glycemic regulation due to the increased production of insulin. These findings imply the possible use of BACE-2 inhibitors for the treatment of diabetes mellitus of type 2 [ 15].","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130865034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-12-20DOI: 10.5772/INTECHOPEN.72866
Kevin T Ong
Alzheimer’s and other neurodegenerative diseases are generally incurable and often difficult to diagnose accurately. Yet early and accurate diagnosis of a neurodegenerative disease can potentially contribute to more effective treatment. Hence research efforts are moving towards early identification of high risk subjects and prevention of disease progression with biomarkers. Unfortunately dementia and biomarker studies are hampered by variables such as drop outs, challenges in comparing data sets, discordant biomarker sets, availability of histopathological confirmation at death, validity of cognitive testing, and nonlinear fluctuations in cognitive domains as disease progresses in vivo in subjects. This chapter is an assessment of the challenges in the early diagnosis of dementia, as well as a presentation of the issues faced in conducting dementia and biomarker studies.
{"title":"Challenges in Dementia Studies","authors":"Kevin T Ong","doi":"10.5772/INTECHOPEN.72866","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.72866","url":null,"abstract":"Alzheimer’s and other neurodegenerative diseases are generally incurable and often difficult to diagnose accurately. Yet early and accurate diagnosis of a neurodegenerative disease can potentially contribute to more effective treatment. Hence research efforts are moving towards early identification of high risk subjects and prevention of disease progression with biomarkers. Unfortunately dementia and biomarker studies are hampered by variables such as drop outs, challenges in comparing data sets, discordant biomarker sets, availability of histopathological confirmation at death, validity of cognitive testing, and nonlinear fluctuations in cognitive domains as disease progresses in vivo in subjects. This chapter is an assessment of the challenges in the early diagnosis of dementia, as well as a presentation of the issues faced in conducting dementia and biomarker studies.","PeriodicalId":437558,"journal":{"name":"Alzheimer's Disease - The 21st Century Challenge","volume":"152 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2017-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132636311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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