1.
Perceptual and motor inhibitory abilities in normal aging and Alzheimer disease(AD): A preliminary study.
Source
Department of Psychology: Cognition and Behavior, University of Liège, Belgium; Fund for Scientific Research (F.R.S.-FNRS), Belgium.
Abstract
Deficits in inhibitory abilities are frequently observed in normal aging and AD. However, few studies have explored the generality of these deficits in a single group of participants. A battery of tasks assessing perceptual and motor inhibitory functioning was administered to young and older healthy participants (Study 1), as well as to mild Alzheimer patients (Study 2). Results did not agree with a selective impairment of motor or perceptual inhibition in either AD or normal aging but rather suggest that a decrease in cognitive resources available in working memory could explain inhibitory performance both in normal aging and AD.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
- PMID:
- 22209393
- [PubMed - as supplied by publisher]
Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP).
Source
Deutsches Institut für DemenzPrävention (DIDP), Neurodegeneration and Neurobiology, 66421 Homburg, Germany.
Abstract
Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Aβ) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer's disease (AD). Moreover, our results show that oligomerization and aggregation of Aβ are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease.
Copyright © 2012 Elsevier Inc. All rights reserved.
- PMID:
- 22209004
- [PubMed - as supplied by publisher]
Computational evidence to inhibition of human acetyl cholinesterase by withanolide a for Alzheimer treatment.
Source
Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016, India. sundar@dbeb.iitd.ac.in.
Abstract
Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia. So far only five drugs have been approved by US FDA that temporarily slow worsening of symptoms for about six to twelve months. The limited number of therapeutic options for AD drives the exploration of new drugs. Enhancement of the central cholinergic function by the inhibition of acetylcholinesterase is a prominent clinically effective approach for the treatment of AD. Recently withanolide A, a secondary metabolite from the ayurvedic plant Withania somnifera has shown substantial neuro-protective ability. The present study is an attempt to elucidate the cholinesterase inhibition potential of withanolide A along with the associated binding mechanism. Our docking simulation results predict high binding affinity of the ligand to the receptor. Further, long de novo simulations for 10_ns suggest that ligand interaction with the residues Thr78, Trp81, Ser120 and His442 of human acetylcholinesterase, all of which fall under one or other of the active sites/subsites, could be critical for its inhibitory activity. The study provides evidence for consideration of withanolide A as a valuable small ligand molecule in treatment and prevention of AD associated pathology. The present information could be of high value for computational screening of AD drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of human acetylcholinesterase would further enhance the potential of such analysis in understanding the molecular interaction basis between ligand and receptor.
- PMID:
- 22208270
- [PubMed - in process]
Abstracts of the Alzheimer's Imaging Consortium. July 16-21, 2011. Paris, France.
- PMID:
- 22207911
- [PubMed - indexed for MEDLINE]
Hippocampal Neuronal Atrophy and Cognitive Function in Delayed Poststroke and Aging-Related Dementias.
Source
From the Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, UK.
Abstract
BACKGROUND AND PURPOSE:
We have previously shown delayed poststroke dementia in elderly (≥75 years old) stroke survivors is associated with medial temporal lobe atrophy; however, the basis of the structural and functional changes is unknown.
METHODS:
Using 3-dimensional stereological methods, we quantified hippocampal pyramidal neuronal volumes and densities in a total of 95 postmortem samples from demented and nondemented poststroke survivors within our prospective Cognitive Function after Stroke study and subjects pathologically diagnosed with vascular dementia,Alzheimer disease, and mixed Alzheimer disease and vascular dementia syndrome.
RESULTS:
Hippocampal CA1 but not CA2 subfield neuron density was affected in poststroke, Alzheimer disease, vascular dementia, and mixed dementia groups relative to control subjects (P<0.05). Neuronal volume was reduced in the poststroke dementia relative to poststroke nondemented group in both CA1 and CA2, although there were no apparent differences in neuronal density. Poststroke nondemented neuronal volumes were similar to control subjects but greater than in all dementias (P<0.05). Neuronal volumes positively correlated with global cognitive function and memory function in both CA1 and CA2 in poststroke subjects (P<0.01). Degrees of neuronal atrophy and loss were similar in the poststroke dementia and vascular dementia groups. However, in the entorhinal cortex layer V, neuronal volumes were only impaired in the mixed and Alzheimer disease groups (P<0.05).
CONCLUSIONS:
Our results suggest hippocampal neuronal atrophy is an important substrate for dementia in both cerebrovascular and neurodegenerative disease.
Auditory delta event-related oscillatory responses are decreased inAlzheimer's disease.
Source
Departments of Neurology and Neurosciences; Dokuz Eylül University, Izmir, Turkey Brain Dynamics and Multidisciplinary Research Center, Dokuz Eylül University, Izmir, Turkey Brain Dynamics, Cognition and Complex Systems Research Center, Istanbul Kultur University, Istanbul, Turkey.
Abstract
Background: Visual delta event-related (ERO) and evoked oscillations (EO) of Alzheimer patients (AD) are different than healthy. In the present study, the analysis is extented to include auditory ERO and EO in AD. The rationale is to reveal whether the auditory ERO delta responses are also reduced, and whether this is a general phenomenon in Alzheimerpatients upon applying stimuli with cognitive load. Methods: Thirty-four mild AD subjects [17 de-novo and 17 medicated (cholinergic)] and seventeen healthy controls were included. Auditory oddball paradigm and sensory auditory stimuli were applied to the subjects. Oscillatory responses were analyzed by measuring maximum amplitudes in delta frequency range (0.5-3.5 Hz). Results: Auditory delta ERO (0.5-3.5 Hz) responses of healthy controls were higher than either de-novo AD or medicated AD group, without a difference between two AD subgroups. Furthermore, the auditory EO after presentation of tone bursts yielded no group difference. Conclusion: Our findings imply that delta ERO is highly unstable in AD patients in comparison to age-matched healthy controls only during the cognitive paradigm. Our results favor the hypothesis that neural delta networks are activated during cognitive tasks and that the reduced delta response is a general phenomenon in AD, due to cognitive impairment.
Antioxidants in Down syndrome.
Abstract
Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
Copyright © 2011. Published by Elsevier B.V.
Age- and genotype-related neurophysiologic reactivity to oxidative stress in healthy adults.
Source
Research Center of Neurology RAMS, Moscow, Russia.
Abstract
The epsilon4 allele of the apolipoprotein E gene (ApoE), as well as aging increase the risk of Alzheimer's and vascular diseases. Electroencephalogram (EEG) reactivity to hyperventilation (HV) depends on hypocapnia-induced cerebral vasoconstriction, which may be impaired in subjects with subclinical cerebrovascular disease. Quantitative EEG at rest and under 3-minute HV was examined in 125 healthy subjects divided into younger (age range 28-50) and older (age range 51-82) cohorts and stratified by ApoE genotype. The younger ApoE-epsilon4 carriers had excessive EEG reactivity to HV characterized by the manifestation of high-voltage delta, theta activity and sharp waves, and larger HV-induced changes in EEG relative powers than in the younger ApoE-epsilon4 noncarriers. EEG reactivity to HV decreased with aging, and in the ApoE-epsilon4 carriers the decrease was more pronounced than in the ApoE-epsilon4 noncarriers. The older ApoE-epsilon4 carriers had smaller HV-induced changes in EEG relative powers than the older ApoE-epsilon4 noncarriers. A marked decline of EEG reactivity to HV in the older ApoE-epsilon4 carriers suggests the possible impact of vascular factors on the pathogenesis of ApoE-induced Alzheimer disease.
Copyright © 2010 IBRO. Published by Elsevier Inc. All rights reserved.
New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases.
Source
Servicio de Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Ctra Canyet s/n, 08916, Badalona, Barcelona, Spain, katrinbeyer@hotmail.com.
Abstract
Lewy body diseases (LBDs) include dementia with Lewy bodies (DLB) and Parkinson disease (PD). Alpha-synuclein (AS) aggregation is a key event in the pathogenesis of LBDs and beta-synuclein (BS) inhibits AS aggregation in vitro and in vivo. Recently, BS has been shown to interact directly with AS regulating its functionality and preventing its oligomerization, and a molecular subgroup of pure DLB lacks BS in cortical regions. In this study, we characterized four new BS transcript variants and analyzed their expression in neuronal and non-neuronal tissue, and their differential expression in frozen samples of three areas from brains of patients with pure Lewy body pathology (LBP), common LBP, Alzheimer pathology, and of controls. Relative mRNA expression was determined by real-time PCR with neuron-specific enolase 2 and synaptophysin as housekeeping genes, and expression changes were evaluated by the ΔΔCt method. Two main findings are in concordance with earlier studies. First, all BS isoforms are drastically diminished in the cortex of patients with pure LBP that had presented clinically as DLB but not PD with dementia. Second, an important shift of the isoform expression ratio was observed in the temporal cortex of all LBD cases, and the minor isoforms, normally absent in the midbrain, were detected in the caudate nucleus of all DLB samples. Our results provide further evidence for the role of minor transcript variants in the development of complex diseases and provide new insights into the pathogenesis of LBDs that may be important for the understanding of molecular mechanisms involved in these complex diseases.
Identification of a new plasma biomarker of Alzheimer Disease using metabolomics technology.
Source
Eisai Co Ltd, Japan;
Abstract
In order to precisely quantify variations in desmosterol between normal controls and Alzheimers Disease (AD) patients, we established an analytical method to measure desmosterol and cholesterol concentration using LC/APCI-MS system that allowed separating 5 endogenous main isomers and interfering peaks. The analysis revealed that Desmosterol, a cholesterol precursor, was found to be decreased in AD plasma vs healthy elderly controls plasma. Using this LC-based method, we discovered that desmosterol and desmosterol/ cholesterol ratio are significantly decreased in AD patients, although such changes could not be observed using previous GC methods. Those changes were not observed in samples from Parkinsons disease (PD) and schizophrenia patients samples, suggesting the specific association of desmosterol with AD and or with cognitive decline. Finally the validation of this assay using 109 clinical samples confirmed the decrease of desmosterol in AD patients as well as a change in desmosterol/ cholesterol ratio in AD patients plasma. In addition, the decrease of desmosterol was somewhat more significant in female patients. Although larger sample populations will be needed to confirm this diagnostic marker sensitivity, our studies demonstrate a sensitive and accurate method of detecting plasma desmosterol concentration and suggest that plasma desmosterol could be become a powerful new specific biomarker for the early and easy AD diagnosis.
[A case of encephalopathy that was suspected to be caused by chemotherapy for colon cancer].
Source
Dept. of Surgery, Tokyo Metropolitan Health and Medical Treatment Corporation Toshima Hospital.
Abstract
We report a case of encephalopathy that was suspected to be caused by chemotherapy for liver metastasis from sigmoid colon cancer. A 72-year-old male was suspected that he had drug-induced eukoencephalopathy because he was presented with physical disorders during the FOLFOX/bevacizumab therapy. Although a brain MRI revealedAlzheimer disease, leukoencephalopathy was not excluded from the diagnoses due to a fact that his findings could not be compared before and after the chemotherapy. If leukoencephalopathy was suspected, chemotherapy should have been discontinued as soon as possible. Although a partial response was achieved, chemotherapy had to be discontinued in this case. The cases whose physical and neurological disorders were at risk due to a past history need an examination for nervous system in order to make a comparison with the findings before and after chemotherapy.
The role of mTOR signaling in Alzheimer disease.
Source
Department of Physiology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio. 7703 Floyd Curl Drive, San Antonio, TX 78229.
Abstract
The buildup of Abeta and tau is believed to directly cause or contribute to the progressive cognitive deficits characteristic of Alzheimer disease. However, the molecular pathways linking Abeta and tau accumulation to learning and memory deficits remain elusive. There is growing evidence that soluble forms of Abeta and tau can obstruct learning and memory by interfering with several signaling cascades. In this review, I will present data showing that the mammalian target of rapamycin (mTOR) may play a role in Abeta and tau induced neurodegeneration.
- PMID:
- 22202101
- [PubMed - in process]
Memory after silent stroke: Hippocampus and infarcts both matter.
Source
Correspondence & reprint requests to Dr. Brickman: amb2139@columbia.edu.
Abstract
OBJECTIVE:
Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear.
METHODS:
We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability.
RESULTS:
Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume.
CONCLUSIONS:
Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.
Alzheimer disease: A novel therapeutic approach for Alzheimer disease?
Alzheimer disease: Arterial spin-labeled MRI for diagnosis and monitoring of AD.
Generating recombinant C-terminal prion protein fragments of exact native sequence.
Source
Department of Pathology, The University of Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Victoria, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, Australia; Mental Health Research Institute, Victoria, Australia.
Abstract
Transmissibility and distinctive neuropathology are hallmark features of prion diseases differentiating them from other neurodegenerative disorders, with pathogenesis and transmission appearing closely linked to misfolded conformers (PrP(Sc)) of the ubiquitously expressed cellular form of the prion protein (PrP(C)). Given the apparent pathogenic primacy of misfolded PrP, the utilisation of peptides based on the prion protein has formed an integral approach for providing insights into misfolding pathways and pathogenic mechanisms. In parallel with studies employing prion peptides, similar approaches in other neurodegenerative disorders such as Alzheimer Disease, have demonstrated that differential processing of parent proteins and quite minor variations in the primary sequence of cognate peptides generated from the same constitutive processing (such as Aβ1-40 versus Aβ1-42 produced from γ-secretase activity) can be associated with very different pathogenic consequences. PrP(C) also undergoes constitutive α- or β-cleavage yielding C1 (residues 112-231 human sequence) or C2 (residues 90-231), respectively, with the full cell biological significance of such processing unresolved; however, it is noteworthy that in prion diseases, such as Creutzfeldt-Jakobdisease (CJD) and murine models, the moderately extended C2 fragment predominates in the brain suggesting that the two cleavage events and the consequent C-terminal fragments may differ in their pathogenic significance. Accordingly, studies characterising biologically relevant peptides like C1 and C2, would be most valid if undertaken using peptides completely free of any inherent non-native sequence that arises as a by-product of commonly employed recombinant production techniques. To achieve this aim and thereby facilitate more representative biophysical and neurotoxicity studies, we adapted the combination of high fidelity Taq TA cloning with a SUMO-Hexa-His tag-type approach, incorporating the SUMO protease step. This technique consistently produced sufficient yields (∼10mg/L) of high purity peptides (>95%) equating to C1 and C2 of exact native primary sequence in the α-helical conformation suitable for biological and biophysical investigations.
Copyright © 2011. Published by Elsevier Ltd.
Biochemical label-free tissue imaging with subcellular-resolution synchrotron FTIR with focal plane array detector.
Source
Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
Abstract
The critical questions into the cause of neural degeneration, in Alzheimer disease and other neurodegenerative disorders, are closely related to the question of why certain neurons survive. Answers require detailed understanding of biochemical changes in single cells. Fourier transform infrared microspectroscopy is an excellent tool for biomolecular imaging in situ, but resolution is limited. The mid-infrared beamline IRENI (InfraRed ENvironmental Imaging) at the Synchrotron Radiation Center, University of Wisconsin-Madison, enables label-free subcellular imaging and biochemical analysis of neurons with an increase of two orders of magnitude in pixel spacing over current systems. With IRENI's capabilities, it is now possible to study changes in individual neurons in situ, and to characterize their surroundings, using only the biochemical signatures of naturally-occurring components in unstained, unfixed tissue. We present examples of analyses of brain from two transgenic mouse models of Alzheimer disease (TgCRND8 and 3xTg) that exhibit different features of pathogenesis. Data processing on spectral features for nuclei reveals individual hippocampal neurons, and neurons located in the proximity of amyloid plaque in TgCRND8 mouse. Elevated lipids are detected surrounding and, for the first time, within the dense core of amyloid plaques, offering support for inflammatory and aggregation roles. Analysis of saturated and unsaturated fatty acid ester content in retina allows characterization of neuronal layers. IRENI images also reveal spatially-resolved data with unprecedented clarity and distinct spectral variation, from sub-regions including photoreceptors, neuronal cell bodies and synapses in sections of mouse retina. Biochemical composition of retinal layers can be used to study changes related to disease processes and dietary modification.
Copyright © 2011 Elsevier Inc. All rights reserved.
Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I).
Source
Instituto Cajal, CSIC, Madrid, España.
Abstract
INTRODUCTION:
Many publications consider that the Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the disease in humans, both in the neuropathological changes and cognitive-behavioural symptoms.
DEVELOPMENT:
In this work, the results published (PubMed) on the senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. Even in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein, are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are present in some senile individuals with greater intensity when compared with both normal adult individuals and other senile individuals of the species. The importance of the determination of the longevity of the species in different habitats (natural habitats, new habitats, semi-liberty, captivity) is stressed in these studies.
CONCLUSIONS:
Morphological and histochemical and cognitive-behavioural features similar to those observed in normal aged man are present in senile non-human primates. Moreover, other characteristics of the non-human primates could be indicative of a pathological «Alzheimer type» ageing.
Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
Hypoxia Due to Cardiac Arrest Induces a Time-Dependent Increase in Serum Amyloid β Levels in Humans.
Source
Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Abstract
Amyloid β (Aβ) peptides are proteolytic products from amyloid precursor protein (APP) and are thought to play a role inAlzheimer disease (AD) pathogenesis. While much is known about molecular mechanisms underlying cerebral Aβ accumulation in familial AD, less is known about the cause(s) of brain amyloidosis in sporadic disease. Animal and postmortem studies suggest that Aβ secretion can be up-regulated in response to hypoxia. We employed a new technology (Single Molecule Arrays, SiMoA) capable of ultrasensitive protein measurements and developed a novel assay to look for changes in serum Aβ42 concentration in 25 resuscitated patients with severe hypoxia due to cardiac arrest. After a lag period of 10 or more hours, very clear serum Aβ42 elevations were observed in all patients. Elevations ranged from approximately 80% to over 70-fold, with most elevations in the range of 3-10-fold (average approximately 7-fold). The magnitude of the increase correlated with clinical outcome. These data provide the first direct evidence in living humans that ischemia acutely increases Aβ levels in blood. The results point to the possibility that hypoxia may play a role in the amyloidogenic process of AD.
Bioenergetic Origins of Complexity and Disease.
Source
Michael and Charles Barnett Endowed Chair of Pediatric Mitochondrial, Medicine and Metabolic Disease, Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4302.
Abstract
The organizing power of energy flow is hypothesized to be the origin of biological complexity and its decline the basis of "complex" diseases and aging. Energy flow through organic systems creates nucleic acids, which store information, and the annual accumulation of information generates today's complexity. Energy flow through our bodies is mediated by the mitochondria, symbiotic bacteria whose genomes encompass the mitochondrial DNA (mtDNA) and more than 1000 nuclear genes. Inherited and/or epigenomic variation of the mitochondrial genome determines our initial energetic capacity, but the age-related accumulation of somatic cell mtDNA mutations further erodes energy flow, leading todisease. This bioenergetic perspective on disease provides a unifying pathophysiological and genetic mechanism for neuropsychiatric diseases such as Alzheimer and Parkinson Disease, metabolic diseases such as diabetes and obesity, autoimmune diseases, aging, and cancer.
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