Journal of Alzheimer's Disease - Volume 33, issue s1

Authors: Hodges, John R.

Article Type: Review Article

Abstract: This review focuses on six key papers published in the mid 2000 s based on work conducted in Cambridge. The first two relate to clinico-pathological studies which established that Alzheimer's disease (AD) is a relatively common cause of focal cortical syndromes, notably progressive aphasia (largely nonfluent), progressive apraxia, and posterior cortical atrophy with complex visual symptoms. Building on these findings, criteria for the progressive aphasias have been developed which define the variant associated with AD (progressive logopenic aphasia). Memory in the dementias has been a major area of interest and one paper discussed here explored the neural basis for episodic …and semantic memory failure in AD and semantic dementia. Despite very different memory profiles, the two disorders both cause severe hippocampal hypometabolism and atrophy but differ in the degree of involvement of other memory related structures. This work drew attention to the role of pathology in non-hippocampal structures early in AD. The next two articles deal with the behavioral variant frontotemporal dementia (bvFTD) which we have shown is associated with breakdown in theory of mind, social reasoning, empathy, and emotion processing and contributed to work on the neural basis of social cognition. We also identified a subgroup of bvFTD who fail to progress over many years, termed phenocopy cases, who are differentiated by their lack of atrophy on MRI. The final paper described the application of the Addenbrooke's Cognitive Examination-Revised, which has proven a useful brief assessment tool for the early detection of a range of neurodegenerative disorders including AD and FTD. It also appears to be helpful in predicting those with mild cognitive impairment who will progress to frank dementia. Show more

Keywords: Addenbrooke's cognitive examination, Alzheimer's disease, episodic memory, frontotemporal dementia, Papez circuit, progressive aphasia, semantic dementia

DOI: 10.3233/JAD-2012-129038

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S211-S217, 2013

Authors: Beach, Thomas G.

Article Type: Review Article

Abstract: Medical science is currently perceived as underperforming. This is because of the relatively slow recent rate of development of new disease treatments. This has been blamed on cultural, regulatory, and economic factors that generate a so-called “Valley of Death”, hindering new drug candidates from being moved into clinical trials and eventually approved for use. We propose, however, that for neurodegenerative diseases, a relative decline of human brain tissue research is also a contributor. The present pharmacological agents for treating Alzheimer's disease (AD) were identified through direct examination of postmortem human brain tissue more than 30 years ago. Since that time …the percentage of research grants awarded to human brain tissue-using projects has dropped precipitously and publication rates have stagnated. As human brain tissue research has played a central and often initiating role in identifying most of the targets that have gone to AD clinical trials, it is proposed that the rate of discovery of new targets has been curtailed. Additionally, the continued rejection of cortical biopsy as a diagnostic method for AD has most probably depressed the perceived effect sizes of new medications and contributed to the high Phase II clinical trial failure rates. Despite the relative lack of funding, human brain discovery research has continued to make important contributions to our understanding of neurodegenerative disease, and brain banks have played an essential role. It is likely that the pace of discovery will dramatically accelerate over the coming decades as increasingly powerful tools including genomics, epigenetics, transcriptomics, regulatory RNA, gene expression profiling, proteomics, and metabolomics are applied. To optimize the promise of these new technologies, however, it is critical that brain banks are rejuvenated by enhanced governmental and/or private support. Show more

Keywords: Alzheimer's disease, autopsy, brain, clinical trials, human, neuropathology, postmortem

DOI: 10.3233/JAD-2012-129020

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S219-S233, 2013

Authors: Praticò, Domenico

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia in the elderly. Although the initiating events are still unknown, it is clear that AD results from a combination of genetic and environmental risk factors. Recently proposed diagnostic criteria, in addition to the clinical neuropsychological examination aimed at identifying the typical AD symptoms, include staging criteria based on AD biological measures related to its pathology. Despite the obvious benefits of these new criteria, an accurate diagnosis is not always easily reached because, particularly in its earliest stages, the symptoms of the disease are very variable. Biological measures, or …biomarkers, of the disease should first facilitate an early and accurate diagnosis, have a prognostic and predictive value, and have the capacity to monitor therapeutic efficacy. While amyloid-β and tau represent the two key pathological features of the disease, other aspects of this complex disease are emerging as important mediators in its pathogenesis. Among them, oxidative stress is probably one of the most investigated, and so are biomarkers reflecting it. Intrinsic limitation of biomarkers is the fact that they do not define mechanism of disease, but by nature are associative and/or correlative and unable to prove causality. Longitudinal studies are helping us in this difficult task by providing a clearer picture of the dynamic relationship between biomarkers, AD neuropathology, and cognitive phenotype. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, oxidative stress, tau

DOI: 10.3233/JAD-2012-129023

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S237-S241, 2013

Authors: Sultana, Rukhsana | Butterfield, D. Allan

Article Type: Review Article

Abstract: Aging is the major risk factor associated with neurodegenerative diseases, including Alzheimer's disease (AD). Until now no clear understanding of the mechanisms of initiation and progression of this dementing disorder exists. Based on the studies that have been conducted so far amyloid β-peptide (Aβ), a protein found in senile plaques, one of the key pathological hallmarks of AD, has been reported to be critical in the pathogenesis of AD. Studies from our laboratory and others showed that Aβ can induce oxidative stress, which leads to oxidative modification of biomolecules, thereby diminishing the normal functions of neuronal cells and eventually leading …to loss of neurons and AD. In this review paper, we summarize evidence of oxidative stress in brains of AD and mild cognitive impairment patients, as well as the results from redox proteomics studies. The investigations have provided insights into the downstream effects of oxidative modification of key brain proteins in the pathogenesis of AD. Based on these redox proteomics results, we suggest future areas of research that could be considered to better understand this devastating dementing disorder. Show more

Keywords: Alzheimer's disease, lipid peroxidation, mild cognitive impairment, oxidative stress, protein carbonylation, protein nitration, redox proteomics

DOI: 10.3233/JAD-2012-129018

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S243-S251, 2013

Authors: Zhu, Xiongwei | Perry, George | Smith, Mark A. | Wang, Xinglong

Article Type: Review Article

Abstract: Mitochondrial dysfunction is one of the most early and prominent features in vulnerable neurons in the brain of Alzheimer's disease (AD) patients. Recent studies suggest that mitochondria are highly dynamic organelles characterized by a delicate balance of fission and fusion, a concept that has revolutionized our basic understanding of the regulation of mitochondrial structure and function which has far-reaching significance in studies of health and disease. Tremendous progress has been made in studying changes in mitochondrial dynamics in AD brain and models and the potential underlying mechanisms. This review highlights the recent work demonstrating abnormal mitochondrial dynamics and distribution in …AD models and discusses how these abnormalities may contribute to various aspects of mitochondrial dysfunction and the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, mitochondrial distribution, mitochondrial dynamics, mitochondrial dysfunction, mitochondrial fission, mitochondrial fusion

DOI: 10.3233/JAD-2012-129005

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S253-S262, 2013

Authors: Craft, Suzanne | Cholerton, Brenna | Baker, Laura D.

Article Type: Review Article

Abstract: The recognition of Alzheimer's disease (AD) as a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is essential to move beyond the unidimensional approaches to prevention and therapy that have proven largely ineffective to date. Biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. Our work has focused on identifying the relationship of the insulin network to brain aging, and determining the mechanisms through which insulin dysregulation promotes AD pathological processes. Candidate mechanisms include the effects of insulin on amyloid-β, cerebral glucose metabolism, vascular function, lipid metabolism, and …inflammation/oxidative stress. It is likely that different nodes of the insulin network are perturbed for subgroups of AD patients, or that for some subgroups, pathways independent of insulin are critical pathogenetic factors. New methods from systems network analyses may help to identify these subgroups, which will be critical for devising tailored prevention and treatment strategies. In the following review, we will provide a brief description of the role of insulin in normal brain function, and then focus more closely on recent evidence regarding the mechanisms through which disruption of that role may promote AD pathological processes. Finally, we will discuss the implications of this area for AD therapeutics and prevention. Show more

Keywords: Alzheimer's disease, diabetes, insulin, network analysis

DOI: 10.3233/JAD-2012-129042

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S263-S275, 2013

Authors: Bush, Ashley I.

Article Type: Review Article

Abstract: Brain homeostasis of transition metals is severely perturbed in Alzheimer's disease (AD), with extracellular pooling of zinc and copper in amyloid, and intraneuronal accumulation of iron. Rapidly accumulating evidence indicates that these perturbances themselves may contribute significantly to the cognitive loss and neurodegeneration, even in the absence of AD proteopathy. There is now strong evidence that each of the major protein participants in AD pathology has physiologically important interactions with transition metals: AβPP is the neuronal iron export ferroxidase with a major interaction with ferroportin, presenilins are needed for the import of ≈50% of cellular copper and zinc, and tau …promotes the export of neuronal iron by facilitating the trafficking of AβPP to the surface. Therefore, amyloid and tau pathology arise in a milieu of constitutively high metal flux, and the major components of AD pathology may contribute to the disease by failing in their metal transport roles. Show more

Keywords: Alzheimer's disease, amyloid, copper, iron, presenilin, tau, zinc

DOI: 10.3233/JAD-2012-129011

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S277-S281, 2013

Authors: Watt, Andrew D. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Review Article

Abstract: Over the past 100 years, there has been an exponential increase in our understanding of the underlying pathology of Alzheimer's disease (AD). This growth in knowledge has largely stemmed from the intensification of research into AD which has occurred over the past three decades and the incorporation of the amyloid cascade hypothesis as the generally accepted dogma of AD pathogenesis. While at times contentious, the notion that AD arises from aberrations in amyloid-β (Aβ) production and degradation has led to a number of significant breakthroughs in the way in which AD is currently diagnosed and in the attempts at disease …modifying therapies, from investigations into the underlying factors mediating the aggregation of Aβ to the development of therapeutic strategies and measures of neuroimaging allowing Aβ burden to be monitored within the AD-affected brain. This review focuses on some of the recent work we have conducted toward elucidating the role of Aβ in AD. Show more

Keywords: Biomarker, blood, copper, mass spectrometry, metal chaperone, NMDA, toxicity, zinc

DOI: 10.3233/JAD-2012-129017

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S283-S293, 2013

Authors: Hickman, Suzanne E. | El Khoury, Joseph

Article Type: Review Article

Abstract: It is well established that microglia, the neuroimmune cells of the brain, are associated with amyloid-β (Aβ) deposits in Alzheimer's disease (AD). However, the roles of these cells and other mononuclear phagocytes such as monocytes and macrophages in AD pathogenesis and progression have been elusive. Clues to mononuclear phagocyte involvement came with the demonstration that Aβ directly activates microglia and monocytes to produce neurotoxins, signifying that a receptor mediated interaction of Aβ with these cells may be critical for neurodegeneration seen in AD. Also, in AD brain, mononuclear phagocyte distribution changes from a uniform pattern that covers the brain parenchyma …to distinct clusters intimately associated with areas of Aβ deposition, but the driving force behind this choreography was unclear. Here, we review our recent work identifying mononuclear phagocyte receptors for Aβ and unraveling mechanisms of recruitment of these cells to areas of Aβ deposition. While our findings and those of others have added significantly to our understanding of the role of the neuroimmune system in AD, the glass remains half full (or half empty) and a lot remains to be uncovered. Show more

Keywords: Alzheimer's disease, amyloid-β, chemokines, microglia, mononuclear phagocytes, scavenger receptors

DOI: 10.3233/JAD-2012-129027

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S295-S302, 2013

Authors: Liang, Yuying | Ryan, Natalie S. | Schott, Jonathan M. | Fox, Nick C.

Article Type: Review Article

Abstract: Excess neuronal loss—atrophy—is an inevitable feature of Alzheimer's disease (AD). Following studies in the early 1990 s demonstrating that non-invasive imaging can be used to visualize excess volume loss, i.e., the consequences of atrophy in AD, a major interest has been improving and validating methods to quantify measures of atrophy from serially acquired magnetic resonance imaging. Here we summarize our experience of measuring the extent and pattern of atrophy to understand disease pathogenesis, particularly through studies of individuals with or destined to develop familial AD; to aid diagnosis; and as an outcome measure for treatment trials. As the field moves …toward earlier diagnosis and prevention, we outline the important roles that we believe structural imaging will play alongside other biomarkers both in identifying individuals in the earliest stages of neurodegeneration and assessing the effects of novel therapies. Show more

Keywords: Biomarkers, clinical trials, familial Alzheimer's disease, magnetic resonance imaging, presymptomatic

DOI: 10.3233/JAD-2012-129010

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S305-S312, 2013