Memory loss in Alzheimer's disease.

doi:10.31887/DCNS.2013.15.4/HJAHN

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Memory loss in Alzheimer's disease.

Journal Article•DOI•

Memory loss in Alzheimer's disease.

01 Dec 2013-Dialogues in Clinical Neuroscience (Les Laboratoires Servier)-Vol. 15, Iss: 4, pp 445-454

TL;DR: Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis.

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Abstract: Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. Working memory and long-term declarative memory are affected early during the course of the disease. The individual pattern of impaired memory functions correlates with parameters of structural or functional brain integrity. AD pathology interferes with the formation of memories from the molecular level to the framework of neural networks. The investigation of AD memory loss helps to identify the involved neural structures, such as the default mode network, the influence of epigenetic and genetic factors, such as ApoE4 status, and evolutionary aspects of human cognition. Clinically, the analysis of memory assists the definition of AD subtypes, disease grading, and prognostic predictions. Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis.

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Journal Article•DOI•

Lipopolysaccharide-Induced Neuroinflammation as a Bridge to Understand Neurodegeneration.

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Carla R.A. Batista¹, Giovanni Freitas Gomes¹, Eduardo Candelario-Jalil², Bernd L. Fiebich³, Antônio Carlos Pinheiro de Oliveira¹ - Show less +1 more•Institutions (3)

Universidade Federal de Minas Gerais¹, University of Florida², University of Freiburg³

09 May 2019-International Journal of Molecular Sciences

TL;DR: The use of LPS in various models of neurodegeneration is reviewed as well as the neuroinflammatory mechanisms induced by this toxin that could underpin the pathological events linked to the Neurodegenerative process are discussed.

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Abstract: A large body of experimental evidence suggests that neuroinflammation is a key pathological event triggering and perpetuating the neurodegenerative process associated with many neurological diseases. Therefore, different stimuli, such as lipopolysaccharide (LPS), are used to model neuroinflammation associated with neurodegeneration. By acting at its receptors, LPS activates various intracellular molecules, which alter the expression of a plethora of inflammatory mediators. These factors, in turn, initiate or contribute to the development of neurodegenerative processes. Therefore, LPS is an important tool for the study of neuroinflammation associated with neurodegenerative diseases. However, the serotype, route of administration, and number of injections of this toxin induce varied pathological responses. Thus, here, we review the use of LPS in various models of neurodegeneration as well as discuss the neuroinflammatory mechanisms induced by this toxin that could underpin the pathological events linked to the neurodegenerative process.

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236 citations

Cites background from "Memory loss in Alzheimer's disease...."

...Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, and its main clinical manifestation is progressive dementia [14]....
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Journal Article•DOI•

Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1.

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Bruno Alexandre Quadros Gomes¹, João Paulo Bastos Silva¹, Camila Fernanda Rodrigues Romeiro¹, Sávio Monteiro dos Santos¹, Caroline Azulay Rodrigues¹, Pricila Rodrigues Gonçalves¹, Joni Tetsuo Sakai¹, Paulo Fernando Santos Mendes¹, Everton Luiz Pompeu Varela¹, Marta Chagas Monteiro¹ - Show less +6 more•Institutions (1)

Federal University of Pará¹

30 Oct 2018-Oxidative Medicine and Cellular Longevity

TL;DR: The antioxidant and anti-inflammatory neuroprotective effects of resveratrol are focused on, specifically on its role in SIRT1 and the association with AD pathophysiology.

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Abstract: Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of β-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβ peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aβ peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.

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228 citations

Journal Article•DOI•

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications.

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Jaume Folch, Oriol Busquets¹, Miren Ettcheto, Elena Sánchez-López, Rubén Darío Castro-Torres, Ester Verdaguer, Maria Luisa García¹, Jordi Olloquequi², Gemma Casadesus³, Carlos Beas-Zarate, Carme Pelegrí¹, Jordi Vilaplana¹, Carme Auladell¹, Antoni Camins¹ - Show less +10 more•Institutions (3)

University of Barcelona¹, Autonomous University of Chile², Kent State University³

15 Dec 2017-Journal of Alzheimer's Disease

TL;DR: The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR.

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Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

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136 citations

Cites background from "Memory loss in Alzheimer's disease...."

...The main symptom of AD is memory loss, which is correlated with a decline of neuron population in the hippocampus, a brain area critical for learning and memory [9, 10]....
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Journal Article•DOI•

The role of CREB and BDNF in neurobiology and treatment of Alzheimer's disease

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Meysam Amidfar¹, Jade de Oliveira², Ewa Kucharska, Josiane Budni³, Yong Ku Kim⁴ - Show less +1 more•Institutions (4)

Tehran University of Medical Sciences¹, Universidade Federal do Rio Grande do Sul², Universidade do Extremo Sul Catarinense³, Korea University⁴

15 Sep 2020-Life Sciences

TL;DR: Data demonstrating the role of CREB-BDNF signaling pathway in cognitive status and mediation of Aβ toxicity in AD is summarized and the developing intervention methods for improvement of cognitive decline in AD based on targeting ofCREB- BDNF pathway are focused on.

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134 citations

Journal Article•DOI•

Nec‐1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice

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Seung-Hoon Yang¹, Dongkeun K. Lee¹, Jisu Shin¹, Sejin Lee², Sejin Lee¹, Seungyeop Baek¹, Seungyeop Baek³, Jiyoon Kim², Jiyoon Kim¹, Hoyong Jung⁴, Jung Mi Hah⁴, Young-Soo Kim¹ - Show less +8 more•Institutions (4)

Korea Institute of Science and Technology¹, Korea University of Science and Technology², Yonsei University³, Hanyang University⁴

01 Jan 2017-Embo Molecular Medicine

TL;DR: It is found that an anti‐necroptotic molecule necrostatin‐1 (Nec‐1) directly targets Aβ and tau proteins, alleviates brain cell death and ameliorates cognitive impairment in AD models.

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Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive symptoms of learning and memory deficits. Such cognitive impairments are attributed to brain atrophy resulting from progressive neuronal and synaptic loss; therefore, alleviation of neural cell death is as an important target of treatment as other classical hallmarks of AD, such as aggregation of amyloid-β (Aβ) and hyperphosphorylation of tau. Here, we found that an anti-necroptotic molecule necrostatin-1 (Nec-1) directly targets Aβ and tau proteins, alleviates brain cell death and ameliorates cognitive impairment in AD models. In the cortex and hippocampus of APP/PS1 double-transgenic mice, Nec-1 treatment reduced the levels of Aβ oligomers, plaques and hyperphosphorylated tau without affecting production of Aβ, while it altered the levels of apoptotic marker proteins. Our results showing multiple beneficial modes of action of Nec-1 against AD provide evidence that Nec-1 may serve an important role in the development of preventive approach for AD.

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107 citations

Cites background from "Memory loss in Alzheimer's disease...."

...Formation of such plaques in the cortical and hippocampal regions is directly related to learning and memory deficits in AD (Jahn, 2013)....
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References

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Book•

The magical number seven plus or minus two: some limits on our capacity for processing information

[...]

George A. Miller¹•Institutions (1)

Harvard University¹

01 Jan 1956

TL;DR: The theory provides us with a yardstick for calibrating the authors' stimulus materials and for measuring the performance of their subjects, and the concepts and measures provided by the theory provide a quantitative way of getting at some of these questions.

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Abstract: First, the span of absolute judgment and the span of immediate memory impose severe limitations on the amount of information that we are able to receive, process, and remember. By organizing the stimulus input simultaneously into several dimensions and successively into a sequence or chunks, we manage to break (or at least stretch) this informational bottleneck. Second, the process of recoding is a very important one in human psychology and deserves much more explicit attention than it has received. In particular, the kind of linguistic recoding that people do seems to me to be the very lifeblood of the thought processes. Recoding procedures are a constant concern to clinicians, social psychologists, linguists, and anthropologists and yet, probably because recoding is less accessible to experimental manipulation than nonsense syllables or T mazes, the traditional experimental psychologist has contributed little or nothing to their analysis. Nevertheless, experimental techniques can be used, methods of recoding can be specified, behavioral indicants can be found. And I anticipate that we will find a very orderly set of relations describing what now seems an uncharted wilderness of individual differences. Third, the concepts and measures provided by the theory of information provide a quantitative way of getting at some of these questions. The theory provides us with a yardstick for calibrating our stimulus materials and for measuring the performance of our subjects. In the interests of communication I have suppressed the technical details of information measurement and have tried to express the ideas in more familiar terms; I hope this paraphrase will not lead you to think they are not useful in research. Informational concepts have already proved valuable in the study of discrimination and of language; they promise a great deal in the study of learning and memory; and it has even been proposed that they can be useful in the study of concept formation. A lot of questions that seemed fruitless twenty or thirty years ago may now be worth another look. In fact, I feel that my story here must stop just as it begins to get really interesting. And finally, what about the magical number seven? What about the seven wonders of the world, the seven seas, the seven deadly sins, the seven daughters of Atlas in the Pleiades, the seven ages of man, the seven levels of hell, the seven primary colors, the seven notes of the musical scale, and the seven days of the week? What about the seven-point rating scale, the seven categories for absolute judgment, the seven objects in the span of attention, and the seven digits in the span of immediate memory? For the present I propose to withhold judgment. Perhaps there is something deep and profound behind all these sevens, something just calling out for us to discover it. But I suspect that it is only a pernicious, Pythagorean coincidence.

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16,902 citations

"Memory loss in Alzheimer's disease...." refers background in this paper

...Short-term memory is limited to just a few “chunks” in capacity, and lasts only seconds to minutes.(41) It depends on regions of the frontal lobe and the parietal lobe....
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Journal Article•DOI•

The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

[...]

Guy M. McKhann¹, Guy M. McKhann², David S. Knopman³, Howard Chertkow⁴, Bradley T. Hyman⁵, Clifford R. Jack³, Claudia H. Kawas⁶, William E. Klunk⁷, Walter J. Koroshetz, Jennifer J. Manly⁸, Richard Mayeux⁸, Richard C. Mohs⁹, John C. Morris¹⁰, Martin N. Rossor¹¹, Philip Scheltens¹², Maria C. Carrillo¹³, Bill Thies¹³, Sandra Weintraub¹⁴, Creighton H. Phelps¹⁵ - Show less +15 more•Institutions (15)

Johns Hopkins University¹, Johns Hopkins University School of Medicine², Mayo Clinic³, McGill University⁴, Harvard University⁵, University of California, Irvine⁶, University of Pittsburgh⁷, Columbia University Medical Center⁸, Eli Lilly and Company⁹, Washington University in St. Louis¹⁰, UCL Institute of Neurology¹¹, VU University Medical Center¹², Alzheimer's Association¹³, Northwestern University¹⁴, National Institutes of Health¹⁵

01 May 2011-Alzheimers & Dementia

TL;DR: The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available.

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Abstract: The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

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13,710 citations

Journal Article•DOI•

Neuropathological stageing of Alzheimer-related changes.

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Heiko Braak, Eva Braak

01 Jan 1991-Acta Neuropathologica

TL;DR: The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations, permitting the differentiation of six stages.

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Abstract: Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.

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13,699 citations

Journal Article•DOI•

The Brain's Default Network Anatomy, Function, and Relevance to Disease

[...]

Randy L. Buckner, Jessica R. Andrews-Hanna¹, Daniel L. Schacter¹•Institutions (1)

Harvard University¹

01 Mar 2008-Annals of the New York Academy of Sciences

TL;DR: Past observations are synthesized to provide strong evidence that the default network is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment, and for understanding mental disorders including autism, schizophrenia, and Alzheimer's disease.

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Abstract: Thirty years of brain imaging research has converged to define the brain’s default network—a novel and only recently appreciated brain system that participates in internal modes of cognition Here we synthesize past observations to provide strong evidence that the default network is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment Analysis of connectional anatomy in the monkey supports the presence of an interconnected brain system Providing insight into function, the default network is active when individuals are engaged in internally focused tasks including autobiographical memory retrieval, envisioning the future, and conceiving the perspectives of others Probing the functional anatomy of the network in detail reveals that it is best understood as multiple interacting subsystems The medial temporal lobe subsystem provides information from prior experiences in the form of memories and associations that are the building blocks of mental simulation The medial prefrontal subsystem facilitates the flexible use of this information during the construction of self-relevant mental simulations These two subsystems converge on important nodes of integration including the posterior cingulate cortex The implications of these functional and anatomical observations are discussed in relation to possible adaptive roles of the default network for using past experiences to plan for the future, navigate social interactions, and maximize the utility of moments when we are not otherwise engaged by the external world We conclude by discussing the relevance of the default network for understanding mental disorders including autism, schizophrenia, and Alzheimer’s disease

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8,448 citations

"Memory loss in Alzheimer's disease...." refers background or methods in this paper

...Measurements of glucose metabolism with positron emission tomography (PET), of structural atrophy with MRI, and intrinsic and task-evoked brain activity with fMRI in AD all suggest an increasing disruption in the DMN.(62) When AD patients undergo a FDG-PET the pattern of hypometabolism often mirrors the same regions that belong to the posterior parts of the DMN, namely the posterior cingulate cortex, the retrosplenial cortex, inferior parietal lobule, and the lateral temporal cortex....
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...Probands with a genetic risk for AD of being homozygous for ApoE4 develop this hypometabolism already quite early in the course of the disease.(62,65) Disruption in the DMN at the preclinical stages of the disease by accelerated cortical atrophy affects the medial temporal lobe and the posterior cingulum and the retrosplenial cortex....
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...prefrontal cortex, the dorsomedial prefrontal cortex, the posterior cingulate cortex, the inferior parietal lobe, the lateral temporal cortex, and the hippocampus.(62,76-79) In normal young adults aerobic glycolysis correlated positively and spatially with β-amyloid deposition observed in individuals with Alzheimer’s dementia and cognitively normal participants with already elevated β-amyloid levels, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of AD pathology....
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...Measurements of glucose metabolism with positron emission tomography (PET), of structural atrophy with MRI, and intrinsic and task-evoked brain activity with fMRI in AD all suggest an increasing disruption in the DMN.62 When AD patients undergo a FDG-PET the pattern of hypometabolism often mirrors the same regions that belong to the posterior parts of the DMN, namely the posterior cingulate cortex, the retrosplenial cortex, inferior parietal lobule, and the lateral temporal cortex.63 Such hypometabolism correlates with the mental status while AD progresses.64 Probands with a genetic risk for AD of being homozygous for ApoE4 develop this hypometabolism already quite early in the course of the disease.62,65 Disruption in the DMN at the preclinical stages of the disease by accelerated cortical atrophy affects the medial temporal lobe and the posterior cingulum and the retrosplenial cortex.63,66 Also, analysis of task-induced deactivation and analysis of intrinsic activity correlations show an impaired DMN consistent with metabolic and structural changes.67-69 The DMN is coupled with hippocampus during memory retrieval but not during memory encoding, pointing to the special positioning of the hippocampus between short-term and long-term memory.70 Encoding structures of the DMN are among the first to show accumulation of β-amyloid even before symptoms emerge and images of β-amyloid plaques taken at the earliest stages of AD show a distribution that is remarkably similar to the anatomy of the default network.71 Buckner et al speculate that AD pathology forms preferentially throughout the DMN and may be linked to DMN activity.63 Their basic idea is that the DMN’s continuous activity augments an activity-dependent or metabolism-dependent cascade that starts the β-amyloid cascade in these brain regions....
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...Here only partial network involvement was observed, with apparent decoupling of frontal areas from the DMN.80 An important study by Kang et al used in vivo micro-dialysis in mice and found that the amount of βamyloid in the interstitial brain fluid correlated positively with wakefulness....
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Journal Article•DOI•

Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

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Reisa A. Sperling¹, Paul S. Aisen², Laurel A. Beckett³, David A. Bennett⁴, Suzanne Craft⁵, Anne M. Fagan⁶, Takeshi Iwatsubo⁷, Clifford R. Jack⁸, Jeffrey Kaye⁹, Thomas J. Montine⁵, Denise C. Park¹⁰, Eric M. Reiman, Christopher C. Rowe¹¹, Eric Siemers¹², Yaakov Stern¹³, Kristine Yaffe¹⁴, Maria C. Carrillo¹⁵, Bill Thies¹⁵, Marcelle Morrison-Bogorad¹⁶, Molly V. Wagster¹⁶, Creighton H. Phelps¹⁶ - Show less +17 more•Institutions (16)

Brigham and Women's Hospital¹, University of California, San Diego², University of California, Davis³, Rush University Medical Center⁴, University of Washington⁵, Washington University in St. Louis⁶, University of Tokyo⁷, Mayo Clinic⁸, Oregon Health & Science University⁹, University of Texas at Dallas¹⁰, University of Melbourne¹¹, Eli Lilly and Company¹², Columbia University¹³, University of California, San Francisco¹⁴, Alzheimer's Association¹⁵, National Institutes of Health¹⁶

01 May 2011-Alzheimers & Dementia

TL;DR: A conceptual framework and operational research criteria are proposed, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies and it is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD.

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Abstract: The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

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5,671 citations

"Memory loss in Alzheimer's disease...." refers background in this paper

...The most notable differences are the use of biomarkers such as hippocampal atrophy, and the formalization of earlier disease stages before dementia is apparent, such as mild cognitive impairment due to AD and the newly defined preclinical AD stage.(38,39) While the recommendations of the preclinical AD workgroup are intended purely for research purposes and the aim of diagnosing the disease earlier appears sensible since it is likely that any intervention has to be started early to be successful, it is also clear that we would almost all be defined as having the disease using this definition, given the increasing prevalence of AD in the very old....
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