Page: viii-xiii (5)
Author: Debomoy K. Lahiri
Page: 3-32 (30)
Author: Céline Souchay and Chris J.A. Moulin
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Human memory can be split into familiarity and recollection processes which contribute to different aspects of memory function. These separate processes result in different experiential states. In this review, we examine how this dominant theoretical framework can explain the subjective experience of people with Alzheimer’s disease, the profile of their memory impairments and their inability to reflect on their performance metacognitively. We conclude with a brief overview of the brain regions supporting conscious experience of memory, and propose that the memory and awareness deficits seen in Alzheimer’s disease could be primarily conceived of as a deficit in autonoetic consciousness. We briefly introduce how these these robust constructs are being incorporated into research programmes examining rehabilitation and pharmacological intervention.
Page: 33-57 (25)
Author: Maria I. Behrens, Daniela P. Ponce, Catherine M. Roe and Felipe Salech
Epidemiological studies show an inverse association between Alzheimer’s disease (AD) and cancer, such that the risk of developing cancer is significantly lower in patients with AD, while participants with a history of cancer in the past have a lower risk of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death. Here we discuss the possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders. Mechanisms that induce changes in the activity of molecules with key roles in determining the decision to “repair and live”- or “die” could play a role in the pathogenesis of the two disorders. As examples, the roles of p53, PARP-1, the Wnt signaling pathway, and the process of adult neurogenesis are discussed as potential candidates that, speculatively, may explain an inverse association between AD and cancer.
Page: 58-99 (42)
Author: Massimo Stefani and Gianfranco Liguri
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The role of cholesterol as a susceptibility factor or a protective agent in neurodegeneration and, more generally, in amyloid-induced cytotoxicity is still controversial. Epidemiological studies on the hypercholesterolemia-AD risk relation and some reports indicating a beneficial effect of statin therapy suggest cholesterol as a susceptibility factor in AD. The ApoE4 genotype as a prevalent genetic risk factor for AD and the function of ApoE as main cholesterol carrier in the brain also underlie a close cholesterol load-AD risk relation. Finally, cell biology evidences support a critical involvement of lipid raft cholesterol in the modulation of β- and γ-cleavage of APP with altered Aβ production.
However, little exchange does exist between circulating and brain cholesterol, the latter arising from endogenous synthesis. In addition, increasing evidence supports the idea that amyloid cytotoxicity in most cases is initiated by oligomer recruitment at the cell membrane with oligomer nucleation, loss of membrane integrity, Ca2+ ingress into the cell, oxidative stress and apoptosis. In such a scenario, increased membrane cholesterol seems to be protective by disfavouring aggregate binding to the membrane. Recent findings also point at a key role performed by lipid rafts and their proteins and indicate that a reduction of cellular cholesterol favours co-localization of BACE1 and APP in non-raft membrane domains and hinders generation of plasmin, an Aβ-degrading enzyme. Finally, recent researches on Seladin-1, involved in cholesterol biosynthesis, show that modulation of membrane cholesterol affects Aβ generation and cell resistance against Aβ oligomer toxicity. These data confirm previous findings indicating a reduction of the cholesterol/phospholipid ratio in aged and AD brains.
The aim of this review is to critically discuss some of the main results reported in the recent years in this field supporting a role of cholesterol either as a susceptibility factor or as a protective agent in AD.
Page: 100-147 (48)
Author: Silvia Morante and Giancarlo Rossi
Alzheimer disease is a pathology causing severe problems with memory, thinking and behavior. It accounts for the majority of dementia cases and is the sixth leading cause of death in developed countries. Unfortunately a real cure is still missing and the drug treatments today available can only reduce symptoms. It belongs to a large class of diseases, called amyloidosis, in which endogenous proteins or peptides undergo a misfolding process switching from the physiological soluble configuration to a pathological fibrillar insoluble state. An important, but not yet fully elucidated, rôle appears to be played in these processes by transition metals (mainly copper and zinc) that have been observed to be present in fairly large amounts in patient's neurological plaques. In this review we will show that the challenging problem of understanding the physico-chemical basis of protein misfolding and aggregation can be successfully investigated with a combination of modern spectroscopic techniques and advanced first principle numerical simulations. In particular, it will be shown that different metals can rival in peptide binding thus adding support to the hypothesis that metal dyshomeostasis may be relevant in the Alzheimer disease development.
Increased CRMP-2 Phosphorylation is Observed in Alzheimer’s Disease: Does This Tell Anything about Disease Development?
Page: 148-170 (23)
Author: Marc P.M. Soutar, Paul Thornhill, Adam R. Cole and Calum Sutherland
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Collapsin response mediator protein-2 (CRMP-2) is a physiological substrate for GSK3 and Cdk5, two protein kinases suggested to exhibit greater activity in Alzheimer’s disease (AD). Indeed, phosphorylation of CRMP-2, at the residues targeted by GSK3 and Cdk5, is relatively high in cortex isolated from human AD brain, as well as in the brains of animal models of AD, while phospho-CRMP-2 is found in neurofibrillary tangles. In mouse models of AD, increased phosphorylation occurs prior to pathology, and abnormal phosphorylation is not seen in other forms of human dementia. Although CRMP-2 has no known enzymatic activity, a great deal of information is appearing on its importance in neuronal development and polarity, as well as in axon growth and guidance. In this mini-review, we examine what is known about CRMP-2 function, how that is controlled by phosphorylation, what alterations in molecular mechanisms could lead to the abnormally high CRMP-2 phosphorylation in AD, and whether this is likely to be specific to AD or occur in other forms of neurodegeneration. This will include discussion of the evidence for increased GSK3 or Cdk5 activity, for decreased phosphatase activity, or the upregulation of other CRMP-2 protein kinases in AD. Importantly, we will compare the processes that may contribute to increased CRMP-2 phosphorylation with those known to increase tau hyperphosphorylation in AD, and whether these are likely to be part of disease development or a useful early marker for AD.
N200 Latency and CSF Cytochrome C Levels as Biomarkers for Early Detection of Progression to Alzheimer’s Disease in Mild Cognitive Impairment Patients
Page: 171-186 (16)
Author: Vasileios T. Papaliagkas, Georgios A. Anogianakis, Magda N. Tsolaki and Vasileios K. Kimiskidis
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The role of CSF cytochrome c levels and auditory event-related potentials (AERPs) in the progress of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) is investigated. A study sample that consisted of fifty one MCI patients and fourteen healthy individuals that underwent lumbar puncture at baseline was used and their CSF cytochrome c levels were determined. CSF cytochrome c levels were reexamined in 20 patients after a time period of 11 months. During this period five patients progressed to AD. All patients underwent AERP examinations both at baseline and follow-up. MCI patients were found to have significantly higher cytochrome c levels compared to healthy controls (Mann-Whitney test, Z=-2.110, p=0.018). ADconverters, had a higher increase over time in cytochrome c levels (Mann-Whitney test, p=0.002; effect size r=0.63) and significantly prolonged N200 latency (Mann-Whitney test, p<0.001; effect size r=0.50) compared to MCI stable patients. Amongst the ERP wave characteristics that were studied, only N200 amplitude was significantly correlated with CSF cytochrome c levels (rs=0.310, p=0.03). Both parameters could discriminate AD converters from MCI stable patients, with sensitivity and specificity >75%. When both N200 latency and cytochrome c increase were applied, the prediction of the MCI patients who converted to AD was 100%.
Our results suggest that MCI to AD conversion is associated with a marked elevated N200 latency at baseline and a high increase in cytochrome c levels during a relatively short period of time, and that both parameters could be possibly considered as candidate markers for the discrimination between AD converters and MCI stable patients.
Page: 187-213 (27)
Author: Giancarlo Pepeu and Maria G. Giovannini
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Cholinesterase inhibitors (ChEIs) were introduced in the therapy of Alzheimer Disease (AD) in the nineties with great expectations. The hopes and large interest raised by these drugs are well demonstrated by 12,000 references listed by PubMed under ChEI for 1995-2007. The list is reduced to 2500 if we confine ourselves to ChEIs and dementia. Of them about 500 were published in the last two years. Whereas an increase in brain acetylcholine and an improvement of cognitive deficits have been consistently demonstrated in animal models of AD, from aging rats to transgenic mice, ChEIs clinical effectiveness has been and is still a matter of contrasting opinions. These range from the negative conclusions of the AD2000 trial on donepezil, claiming that it is no cost effective, with benefits below minimally relevant threshold, to the NICE appraisal of 2007 declaring that donepezil, rivastigmine, galantamine are efficacious for mild to moderate AD, irrespective of their different selectivity for AChE and BuChE. The possibility that ChEIs may exert their effects through mechanisms beyond cholinesterase inhibition has been envisaged. However, according to the information presented in this review, the “classical” ChEIs, donepezil, rivastigmine and galantamine, show no pharmacological actions beyond cholinesterase inhibition which may play an important role in their therapeutic efficacy. The diverging opinions on clinical efficacy do not discourage from developing new ChEIs, and the so called multifunctional ChEIs. They represent the future of the cholinergic therapy for AD but other indications for these drugs may be considered, including vascular dementia, mild cognitive impairment, and the ethically sensitive improvement of memory and learning in healthy subjects.
An update of this review carried out four years after its first publication reveals a persistent interest for ChEIs, as demonstrated by the publication of more than 3500 preclinical and clinical papers since 2010. However, no substantial development in the field has come about, namely no novel ChEI effects have been detected beside those caused by inhibition of cholinesterases and the ensuing acetylcholine increase. The only novel indication is the extension of rivastigmine to the treatment of dementia with Lewy bodies and Parkinson’ disease dementia, in some countries.
Page: 214-229 (16)
Author: Hyman M. Schipper, Ajay Gupta and Walter A. Szarek
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The mechanisms responsible for oxidative damage, pathological brain iron deposition and mitochondrial insufficiency in Alzheimer disease (AD) remain enigmatic. Heme oxygenase-1 (HO-1) is a 32 kDa stress protein that catabolizes heme to biliverdin, free iron and carbon other tissues in various models of disease and trauma. Our laboratory demonstrated that 1) HO-1 protein is significantly over-expressed in AD-affected temporal cortex and hippocampus relative to neurohistologically-normal control preparations, 2) in cultured astrocytes, HO-1 up-regulation by transient transfection of the human ho-1 gene, or stimulation of endogenous HO-1 expression by exposure to β-amyloid, TNFα or IL-1β, promotes intracellular oxidative stress, opening of the mitochondrial permeability transition pore and accumulation of non-transferrin iron in the mitochondrial compartment, and 3) the glial iron sequestration renders cocultured neuron-like PC12 cells prone to oxidative injury (reviewed in Schipper HM. J Neurochem 110: 469-85, 2009). Induction of the astroglial ho-1 gene may constitute a ‘common pathway’ leading to pathological brain iron deposition, intracellular oxidative damage and bioenergetic failure in AD and other human CNS disorders. Hypothesis: Targeted suppression of glial HO-1 hyperactivity may prove to be a rational and effective neurotherapeutic intervention in AD and related neurodegenerative disorders. To begin testing this hypothesis, studies have been initiated to determine whether systemic administration of a novel, selective and brain-permeable inhibitor of HO-1 activity ameliorates cognitive dysfunction and neuropathology in a transgenic mouse model of AD.
Page: 230-254 (25)
Author: Alfredo Raglio and Maria V. Gianelli
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This contribution focuses on the definition of music therapy as a specific applicative context to be seen as distinct from the generic use of music in a variety of pathologies. Music therapy is presented as a discipline grounded upon both relationship and the theoretical-methodological principles peculiar to each applicative model. The therapeutic nature proper to music therapy is highlighted with specific reference to the domain of the dementias. Music therapy facilitates expression, communication and relationship in the non-verbal context. Such an opportunity allows persons with dementia to establish contact, to express, and even contrive an organisation/regulation of their emotions, through the sonorous-musical relationship with the music therapist. With reference to a brief analysis of the relevant literature, attention is drawn to the importance of both evidence–based clinical practice and music therapy evaluations, aimed at proving the effectiveness of music therapy, while promoting its correct application.
Page: 255-274 (20)
Author: Manuel Sarasa and Pedro Pesini
The most common animal models currently used for Alzheimer disease (AD) research are transgenic mice that express a mutant form of human Aβ precursor protein (APP) and/or some of the enzymes implicated in their metabolic processing. However, these transgenic mice carry their own APP and APP-processing enzymes, which may interfere in the production of different amyloid-beta (Aβ) peptides encoded by the human transgenes. Additionally, the genetic backgrounds of the different transgenic mice are a possible confounding factor with regard to crucial aspects of AD that they may (or may not) reproduce. Thus, although the usefulness of transgenic mice is undisputed, we hypothesized that additional relevant information on the physiopathology of AD could be obtained from other natural non-transgenic models. We have analyzed the chick embryo and the dog, which may be better experimental models because their enzymatic machinery for processing APP is almost identical to that of humans. The chick embryo is extremely easy to access and manipulate. It could be an advantageous natural model in which to study the cell biology and developmental function of APP and a potential assay system for drugs that regulate APP processing. The dog suffers from an age-related syndrome of cognitive dysfunction that naturally reproduces key aspects of AD including Aβ cortical pathology, neuronal degeneration and learning and memory disabilities. However, dense core neuritic plaques and neurofibrillary tangles have not been consistently demonstrated in the dog. Thus, these species may be natural models with which to study the biology of AD, and could also serve as assay systems for Aβ-targeted drugs or new therapeutic strategies against this devastating disease.
Detection and Quantitation of Amyloid-β Aggregates in Body Fluids may be Suitable for Early Diagnosis of Alzheimer’s Disease
Page: 275-290 (16)
Author: Susanne A. Funke, Eva Birkmann and Dieter Willbold
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The post mortem identification of amyloid plaques, consisting of the amyloid-β (Aβ) peptide, and neurofibrillary tangles in the brains of patients still leads to the most reliable diagnosis for Alzheimer’s disease (AD). Substantial efforts have been made to identify reliable biomarkers for AD that can be used for early diagnosis of AD. Body fluids of AD patients have been investigated for their content of total or soluble Aβ(1-40) or Aβ(1-42), either using classical ELISA procedures, or non-classical assays with more innovative read-out signals, or a combination of both. The concentration of total soluble Aβ(1-42) in cerebrospinal fluid (CSF) is reduced by 40 to 50 % in AD patients compared to age-matched healthy controls, as confirmed in more than 30 studies, with both sensitivity and specificity exceeding 80 to 90 %. Thus, it was suggested that detection of low levels of Aβ(1-42) in CSF might help preclinical diagnosis. The achievable sensitivity using such CSF biomarkers, however, is 85 % or less. Therefore, these assays cannot deliver any increase in the diagnostic outcome as compared to existing algorithms based on neuropsychological and imaging modalities. Regarding the amyloid cascade hypothesis, Aβ oligomers and aggregates are directly involved in the pathologic process. The presence of Aβ aggregates in CSF could thus be the most direct and most reliable biomarker for AD and increasing efforts are undertaken to develop methods that are suitable to quantify and characterize Aβ aggregate species present in body fluids, especially in CSF. Here, we present an overview of the current status of the development of methods for Aβ aggregate specific detection and quantitation, which is an update of a previous review.
Methods for Studying and Structure–Function Relationships of Non-Fibrillar Protein Assemblies in Alzheimer's Disease and Related Disorders
Page: 291-374 (84)
Author: Farid Rahimi and Gal Bitan
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Several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and prion diseases, are characterized by intra- and/or extracellular deposition of fibrillar proteinaceous aggregates, and by extensive, neuron loss. Related non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes, also are characterized by deposition of aggregated proteins. It is debated whether these hallmark lesions are causative. Substantial evidence suggests that the aggregates are the end state of protein misfolding whereas the actual culprits likely are transient, non-fibrillar assemblies preceding the aggregates. The non-fibrillar, oligomeric assemblies are believed to initiate pathogenesis, leading to synaptic dysfunction, neuron loss, and pathognomonic brain atrophy. It is hypothesized that nonfibrillar assemblies or fibril-derived fragments may promote anatomical progression of pathology, or even disease transmissibility, akin to misfolded prions.
Amyloid β-protein (Aβ), which is believed to cause Alzheimer's disease, is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Aβ assemblies. However, the dynamic and metastable nature of Aβ oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting.
In this chapter we review structural, functional, and biological experiments used to produce and study non-fibrillar Aβ assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary researchers are facing and future research prospects in this demanding, yet highly important, field.
Page: 375-394 (20)
Author: Christian Tackenberg, Adnan Ghori and Roland Brandt
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Since their first description by Ramon y Cajal at the end of the 19th century, dendritic spines have been proposed as important sites of neuronal contacts and it has been suggested that changes in the activity of neurons directly affect spine morphology. In fact, since then it has been shown that about 90% of excitatory synapses end on spines. Data indicate that spines are highly dynamic structures and that spine shape correlates with the strength of synaptic transmission. Several mental disorders including Alzheimer's disease (AD) are associated with spine pathology suggesting that spine alterations play a central role in mental deficits. The aim of this review is to provide an overview about the current knowledge on spine morphology and function as well as about different experimental models to analyze spine changes and dynamics. The second part concentrates on disease-relevant factors that are associated with AD and which lead to spine alterations. In particular, data that provide evidence that Aβ oligomers influence spine morphology and function will be presented and the contribution of tau pathology will be discussed. The review ends with the discussion of potential mechanisms how disease-relevant factors influence dendritic spines and whether and how spine changes could be therapeutically suppressed or reversed.
Planum Temporale Analysis Via a New Volumetric Method in Autoptic Brains of Demented and Psychotic Patients
Page: 395-413 (19)
Author: Petr Zach, Zdena Krištofiková, Jana Mrzílková, Emerich Majer, Pavel Selinger, Filip Španiel, Daniela Řípová, Martina Kutová and Jana Kenney
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Investigations of alterations in brain asymmetry often focus on the planum temporale of patients with schizophrenia. Data also suggest changes in laterality of demented patients associated with a more marked impairment of the left hemisphere. Our study was performed on autoptic brain tissue of 84 patients, out of which there were 25 nondemented nonpsychotic controls, 50 demented patients (34 Alzheimer disease, 9 multi - infarct dementia and 7 mixed-type dementia patients) and 9 people with schizophrenia. The plana temporalia were evaluated via a new volumetric method using dental resin matter. Areas, cortical thickness and volumes of the right and left planum temporale were evaluated without normalization to brain weight in 60 patients and with normalization in 24 people. In controls, a mild right/left laterality of areas, cortical thickness and volumes was found. Moreover, in control women the areas of the left planum temporale were smaller than those observed in control men. The shifts to left/right laterality of areas and volumes were found in all demented groups. In the more numerous Alzheimer group, the change in laterality of an area was associated with a mild decrease on the right and a mild increase on the left side. In contrast, marked but only bilateral area shrinkage as well as reduced cortical thickness and brain volumes were observed in schizophrenic patients.
Page: 414-432 (19)
Author: Yueh-Feng Y. Lu and Joan E. Haase
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To describe commonalities of the lived experience of being a spouse caregiver of a person with mild cognitive impairment (MCI).
Design and Methods: The Colaizzi method of empirical phenomenology was used for interviewing and analyzing data obtained from 10 spouse caregivers of persons with MCI.
Results: Four major themes were found and labeled: (a) Putting the Puzzle Pieces Together-There Really is Something Wrong; (b) A Downward Spiral into a World of Silence; (c) Consequences to Caregivers of Living in a World of Silence; (d) Taking Charge of Care.
Implications: The findings of this study provided data rich in implications for interventions to help caregivers to gain awareness, information, and skills to more effectively deal with and adjust to the caregiving of their spouse with MCI over the long-term.
Alzheimer’s disease (AD) is currently recognized as an untreatable, progressive, degenerative and terminal disease that is global – afflicting over 36 million people worldwide, with the number growing in an unabated and frightening manner. The goal of the series Advances in Alzheimer’s Research , with Volumes 1 and 2, is to provide an integrated approach to AD from basic and clinical research and to highlight the valuable information in order to unravel the origin, pathogenesis and prevention of AD. The aim of this book is to both capture and discuss improvements toward the diagnosis and potential treatment of AD by both established and novel strategies. This book series, including the Volume 2, provides an important mechanism to bring under the same roof a variety of scientific interests and expertise to specifically focus on AD and related dementias. The fullest attempt has been made to disseminate the most current knowledge on recent advances in potential therapy of AD.