Alzhiemer's Disease Research Articles

International Variations in Dementia and Alzheimer Disease Diagnosis and Certification Habits and Their Associations With Dementia and Alzheimer Disease Mortality: A Cross-Sectional Study of 38 Countries.

To examine international variations in national diagnosis and certification habits prefer recording dementia (D) versus Alzhiemer disease (AD) as the underlying cause of death (UCOD) and their associations with mortality rates of dementia and AD. We calculated proportions of D/D+AD and AD/D+AD deaths as proxies of national diagnosis and certification habits. Pearson correlation coefficients (r) were estimated to assess the associations of proportions with the mortality rates of dementia or AD among adults aged 75 to 84 years across 38 countries. The countries with a high preference for recording dementia as the UCOD were Taiwan and Latvia with proportion of D/D+AD deaths of 92% and 88%, respectively, and those with a high preference for recording AD as the UCOD were Slovenia, Turkey, and Poland with proportion of AD/D+AD deaths of 100%, 99%, and 89%, respectively. The r values for the proportions and mortality rate for dementia and AD were 0.67 (95% CI: 0.44-0.81) and 0.46 (95% CI: 0.16-0.68), respectively. We identified a small number of countries with obvious natonal diagnosis and certification habits preferring dementia or AD and had moderate effects on international variations in the mortality rates of dementia and AD.

Gamma-Glutamylcysteine Production Using Phytochelatin Synthase-Like Enzyme Derived from Nostoc sp. Covalently Immobilized on a Cellulose Carrier.

Gamma-glutamylcysteine (γ-EC) is an intermediate generated in the de novo synthesis of glutathione (GSH). Recent studies have revealed that the administration of γ-EC shows neuroprotective effects against oxidative stress in age-related disorders and chronic diseases like Alzhiemer's disease in model animals, which is not expected function in GSH. A phytochelatin synthase-like enzyme derived from Nostoc sp. (NsPCS) mediates γ-EC synthesis from GSH. To achieve low-cost and stable commercial level supply, the availability of immobilized NsPCS for γ-EC production was investigated in this study. Among the tested immobilization techniques, covalent binding to the cellulose carrier was most effective, and could convert GSH completely to γ-EC without decreasing the yield. The stable conversion of γ-EC from 100 mM GSH was achieved by both batch repeated and continuous reactions using the immobilized NsPCS on cellulose sheet and column shape monolith, respectively. The immobilization of NsPCS on those carriers is promising alternative technique for high-yielding and cost-effective production of γ-EC on its commercial applications.

Phytochemical and Biological Studies on Proteins Isolated From Different Microalgal Species

Microalgae are rich in high protein content that enhances their nutritional and therapeutic benefits in addition to their ability for high mass production. Therefore, the present study was designed to reveal the biological efficiency of the natural proteins isolated form Dunaliella salina, Scenedesmus obliquus and Spirulina platensis. During the current study, it was found that the highest protein content was noticed in S. platensis (48.44%) followed by D. salina (31.75%) then S. obliquus (28.56%). The protein content decreased upon applying some stress conditions on S. platensis and S. obliquus. The electrophoretic detection of the proteins isolated from the microalgal species showed that the vegetative and stressed S. obliquus were physiologically similar to S. platensis by 42.11 and 57.14%, respectively. D. salina was similar to S. platensis by 46.15%. As compared to the vegetative S. obliquus, the stressed S. obliquus and D. salina were similar to 30.77 and 33.33%, respectively. The D. salina was similar to the stressed S. obliquus by 57.14%. The protein pattern was electrophoretically represented by 10 denatured bands in S. platensis, 9 bands in the vegetative S. obliquus, 4 bands in the stressed S. obliquus and 3 bands in D. salina. There was one common band identified in all microalgal species at relative mobility (Rf) 0.95 (Molecular weight (Mwt) 5.27 KDa). There were 5 characteristic (unique) bands identified in the vegetative S. obliquus at Rfs 0.07, 0.17, 0.50, 0.58 and 0.86 (Mwts 214.68, 137.74, 42.37, 30.18 and 12.44 KDa, respectively). The amino acids that were analyzed in the isolated protein hydrolysate showed that 15 amino acids were noticed in S. platensis and S. obliquus. While in D. salina, 17 amino acids were identified. Glutamic acid was the most predominant amino acid and exhibited the highest percentages in D. salina, S. obliquus and S. platensis (4.96%, 3.3% and 7.58%, respectively). Additionally, the in-vitro studies on the isolated proteins showed that the D. salina protein exhibited the highest antioxidant activity at a dose of 100 μg/ml (308.78%) followed by the S. platensis and S. obliquus proteins (140.81% and 124.49%, respectively). Furthermore, D. salina and S. obliquus showed moderate anticholinesterase activity (34% and 36%, respectively). Therefore, microalgal proteins might be used as therapeutic antioxidants and might be used in combination with treatments of Alzhiemer's disease (AD).

Alzheimer hastalığı ve beslenme ile ilişkisi

Alzhiemer disease, which accounts for 70% of dementia caused by damage to the central nervous system, is a disease formed by combining genetic and environmental factors. In the pathogenesis of Alzheimer's disease, amyloid beta accumulation, Tau proteins, neurofibrillary tangles are involved. Inflammation, oxidative damage, insulin resistance, cholesterol, trace elements, metal exposure, carrying the Apolipoprotein E4 (ApoE) gene are risk factors. It is known that Alzheimer's disease does not occur with aging alone, environmental factors are needed. Although there is no definitive nutritional treatment for Alzheimer's disease, the Mediterranean diet is known to be protective and preventive against risk factors of Alzheimer's disease. The Mediterranean diet, which attracts attention with its rich consumption of fruits and vegetables, moderate consumption of white meat, limited in saturated fatty acids and rich in unsaturated fatty acids, is still popular today. Some changes in gout microbiota can affect Alzheimer's disease. Following a nutritional program that reduces inflammation, protects from free radicals and eliminates factors that increase nutritional amyloid beta accumulation can be protective. In addition to this nutrition program, vitamin and mineral supplements and probiotic supplements are recommended as a preventive for Alzheimer's.

Mn(II) based T1 and T2 potential MRI contrast agent appended with tryptamine: Recognition moiety for Aβ-plaques

We report the synthesis and characterization of manganese(II) complexes having pentadentate ligands L1 (2,6-bis(1-(2-phenyl-2-(pyridin-2-yl)hydrazono)ethyl)pyridine), L2 (methyl 2,6-bis((E)-1-(2-phenyl-2-(pyridin-2yl)hydrazono)ethyl)isonicotinate), L3 (N-(2-(1H-indol-3-yl)ethyl)-2,6-bis((E)-1-(2-phenyl-2-(pyridin2yl)hydrazono)ethyl)isonicotiamide) and their application as dual contrast agents for simultaneous T1 and T2 weighted magnetic resonance imaging. Single crystal analysis of all the complexes [MnIIL1, MnIIL2 and MnIIL3] confirm the formation of novel seven-coordinate manganese complexes with an inner sphere water and perchlorate ion. The Magnetic Resonance Imaging (MRI) contrast agent [MnL2] was further modified by incorporating tryptamine as a binding moiety specific to Amyloid Beta-fibrils (Aβ-fibrils) in Alzhiemer's disease (AD) and it's in vitro evaluation for specific binding with Aβ-fibrils indicated as a bio-marker of AD.

Transdermal Rivastigmine Delivery for Alzheimer Disease: Amenability of Exposure Predictions of Rivastigmine and Metabolite, NAP226-90, by Linear Regression Model Using Limited Samples.

Although an optimized delivery of rivastigmine for management of Alzhiemer disease (AD) is provided by the transdermal patch, it is critical to establish a limited sampling strategy for the measurement of exposure of rivastigmine/NAP226-90. The relationship Cmax versus AUC0-24h for rivastigmine/NAP226-90 was established by regression models. The derived regression equations enabled the prediction AUC0-24h for rivastigmine and NAP226-90. Models were evaluated using statistical criteria. Mixed model was used to predict AUC0-24h for rivastigmine/NAP226-90 from time points such as 8 (C8h), 12 (C12h), and 18 (C18h) hours. Excellent correlation was established for between Cmax and AUC0-24h for rivastigmine and NAP226-90. AUC0-24h predictions of either rivastigmine or NAP226-90 were within 0.8- to 1.25-fold difference. The RMSE in the AUC0-24h predictions ranged from 17.6% to 21.9%, and the R for prediction were greater than 0.96 for both rivastigmine and NAP226-90. Use of mixed model for C8h, C12h, and C18h resulted in AUC0-24h within 1.5-fold difference for rivastigmine or NAP226-90. Cmax of rivastigmine and NAP226-90 was highly correlated with the corresponding AUC0-24h values confirming the role of a time point closer to Cmax for an effective AUC measurement of rivastigmine or the metabolite.

Molecular and Cellular Mechanism of Okadaic Acid (OKA)-Induced Neurotoxicity: A Novel Tool for Alzheimer’s Disease Therapeutic Application

Okadaic acid (OKA), a polyether C38 fatty acid toxin extracted from a black sponge Hallichondria okadaii, is a potent and selective inhibitor of protein phosphatase, PP1 and PP2A. OKA has been proved to be a powerful probe for studying the various regulatory mechanisms and neurotoxicity. Because of its property to inhibit phosphatase activity, OKA is associated with protein phosphorylation; it is implicated in hyperphosphorylation of tau and in later stages causes Alzhiemer's disease (AD)-like pathology. AD is a progressive neurodegenerative disorder, pathologically characterized by extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The density of tau tangles in AD pathology is associated with cognitive dysfunction. Recent studies have highlighted the importance of serine/threonine protein phosphatases in many processes including apoptosis and neurotoxicity. Although OKA causes neurotoxicity by various pathways, the exact mechanism is still not clear. The activation of major kinases, such as Ser/Thr, MAPK, ERK, PKA, JNK, PKC, CaMKII, Calpain, and GSK3β, in neurons is associated with AD pathology. These kinases, associated with abnormal hyperphosphorylation of tau, suggest that the cascade of these kinases could exclusively be involved in the pathogenesis of AD. The activity of serine/threonine protein phosphatases needs extensive study as these enzymes are potential targets for novel therapeutics with applications in many diseases including cancer, inflammatory diseases, and neurodegeneration. There is a need to pay ample attention on MAPK kinase pathways in AD, and OKA can be a better tool to study cellular and molecular mechanism for AD pathology. This review elucidates the regulatory mechanism of PP2A and MAPK kinase and their possible mechanisms involved in OKA-induced apoptosis, neurotoxicity, and AD-like pathology.

Amyloid deposition, hypometabolism, and longitudinal cognitive decline

Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements. We examined associations between mean cortical florbetapir uptake, mean (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer's Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG-PET were associated with retrospective decline in longitudinal ADAS-cog measurements. Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir. Although both hypometabolism and β-amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline.

CROSS-SECTIONAL ASSOCIATION BETWEEN POLYFLUOROALKYL CHEMICALS AND TWO MEASURES OF COGNITVE FUNCTION IN THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES)

Background and aims: Epidemiologic and animal research suggests that non-steroidal anti-inflammatory drugs, especially ibuprofen, may be protective against cognitive decline and Alzhiemer disease. The underlying mechanism is unclear but may be related to activation of peroxisome proliferator-activated receptors (PPARs). Polyfluoroalkyl chemicals (PFCs) also appear to activate PPARs; therefore we hypothesized that exposure to PFCs may be inversely related to measures of cognitive function in older adults. Methods: We used data from participants 60 years and older from the 1999-2000 and 2003-2008 National Health and Nutrition Examination Surveys to evaluate the association between serum concentrations of four PFCs, perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), and two measures of cognitive function: performance on the Digit Symbol Substitution Task (DSST) (1999-2000 only) and self-reported functional limitation due to poor memory or periods of confusion (1999-2000 and 2003-2008). Results: In multivariable adjusted models, higher exposure to PFCs was associated with reduced odds of self-reported functional limiation due to poor memory or periods of confusion (OR: 0.84 for a doubling in PFOS, 95% CI: 0.70, 0.99; OR: 0.82 for a doubling in PFOA, 95% CI: 0.66,1.01; OR: 0.84 for a doubling in PFNA, 95% CI: 0.71,0.99; OR: 0.95 for a doubling in PFHxS, 95% CI: 0.75, 1.16). However, there was little evidence to suggest an association between performance on the DSST and PFC exposure in multivariable adjusted models. Conclusions: This cross sectional study suggests that there may be an inverse association between exposure to PFCs and self-reported functional limitation due to poor memory or periods of confusion. However, this study cannot establish temporality and further exploration in prospective analyses is warranted. No association was seen between PFCs and performance on the DSST.

Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease

BackgroundReactive microglia are associated with β-amyloid (Aβ) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear Aβ deposits although they mainly exist in an "activated" state. Oligomeric Aβ (oAβ), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar Aβ (fAβ). However, the role of the different Aβ forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.ResultsWe demonstrated that Aβ(1-42) fibrils, not Aβ(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oAβ(1-42) not only attenuated fAβ(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fAβ(1-42). Compared with the fAβ(1-42) treatment, the oAβ(1-42) treatment resulted in a rapid and transient increase in interleukin 1β (IL-1β) level and produced higher levels of tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fAβ(1-42)-induced microglia was decreased by IL-1β, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-κB (NF-κB) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oAβ-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oAβ(1-42) stimulation reduced the mRNA expression of CD36, integrin β1 (Itgb1), and Ig receptor FcγRIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oAβ(1-42) or the inflammatory and oxidative milieu (IL-1β, LPS or t-BHP) significantly downregulated the fAβ(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells.ConclusionThese results imply that Aβ oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of Aβ fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.

Rivastigmine transdermal system for the treatment of mild to moderate Alzheimer’s disease

Today patients with mild to moderate Alzhiemer's disease (AD) have a treatment approach choice: oral or transdermal delivery. The aim of this review was to provide a concise, comprehensive overview of the clinically relevant safety, tolerability and efficacy information available for the rivastigmine transdermal system. Relevant articles were identified through a MEDLINE search of publications in the past 3 years using the terms 'rivastigmine' and 'transdermal' or 'patch'. Efficacy, safety and tolerability of the rivastigmine patch vs. placebo were established in a large, international, 24-week, double-blind, randomised clinical trial and subsequent 28-week open-label extension study. Drug exposure with the 9.5 mg/24 h rivastigmine patch was not significantly different to that provided by an oral capsule dose of 12 mg/day. Most frequently observed adverse events were gastrointestinal. In the primary study, incidences of nausea, vomiting and diarrhoea were: 5%, 3% and 3% respectively in the placebo group; 7%, 6% and 6% in the 9.5 mg/24 h rivastigmine patch group; and 23%, 17% and 5% in the 12 mg/day capsule group. Most patients experienced no, slight or mild application-site skin reactions. De novo patients or those taking oral rivastigmine or donepezil may tolerate a switch to rivastigmine patch. By providing drug exposure that is not significantly different to the highest recommended rivastigmine capsule dose (12 mg/day), with less fluctuation over 24 h, rivastigmine patch offers similar efficacy with an improved tolerability profile. The rivastigmine patch provides a viable treatment option for patients with mild to moderate AD.

An examination of Bayesian statistical approaches to modeling change in cognitive decline in an Alzheimer's disease population

The mini mental state examination (MMSE) is a common tool for measuring cognitive decline in Alzhiemer's Disease (AD) subjects. Subjects are usually observed for a specified period of time or until death to determine the trajectory of the decline which for the most part appears to be linear. However, it may be noted that the decline may not be modeled by a single linear model over a specified period of time. There may be a point called a change point where the rate or gradient of the decline may change depending on the length of time of observation. A Bayesian approach is used to model the trajectory and determine an appropriate posterior estimate of the change point as well as the predicted model of decline before and after the change point. Estimates of the appropriate parameters as well as their posterior credible regions or regions of interest are established. Coherent prior to posterior analysis using mainly non-informative priors for the parameters of interest is provided. This approach is applied to an existing AD database.

Alzhiemer's disease: Differentiation from other dementias based on quantitative diffusion tensor imaging on 3 Tesla MRI

Alzhiemer's disease: Differentiation from other dementias based on quantitative diffusion tensor imaging on 3 Tesla MRI

La maladie d’Alzheimer et les pharmaciens en contact avec le public

All healthcare professionals are concerned by Alzheimer's disease, which in France will affect, in just a few years, over one million persons, mainly women. Pharmacists have shown particular interest, irrespective of their sector of activity. Here, we wanted to better define the role of colleagues who are constantly in contact with the public, i.e. in France in drug dispensaries and biology laboratories. Within the framework of the French pharmacy committee for health and social education, Cespharm, the Ethics and Communications working group of the 2008-2012 Alzheimer Disease Committee headed by Professor Joël Menard proposed a project worksheet which can be used by French pharmacists in their action to help Alzheimer patients and their caregivers. This project, prepared by Fabienne Blanchet, the Cespharm director and Christine Curty, mission head, was approved by the Menard commission and is inscribed in the National Alzheimer Plan 2008-2012 presented by this commission in November 2007. Here, our objective is to motivate pharmacists to participate in a structured initial and continuing training program proposed by specialists from the School of Pharmacy and other organizations duly approved by the High Committee for Continuing Education in Pharmacy. In keeping with the general operative procedures of Cespharm, information tools should be developed for colleagues and the public. Available interventions, in terms of prevention, diagnosis and treatment should be updated permanently and transmitted to professionals. Information which can be delivered to patients, and most importantly to their caregivers, concerning local assistance programs should be collected and transmitted to the local professionals. The role of the pharmacist can be summarized with four verbs: listen, reassure, orient, support. It is important to identify all available means enabling a confidential relationship with the persons needing help. Of particular interest are the relationship guides which have been developed to help allied professionals adapt their approach to the patient without evoking the diagnosis, which belongs to the medical physician. Finally, we emphasize the importance of the creation of multidisciplinary local networks where healthcare professionals, medicosocial workers, local public authorities, and patient groups and associations can unite their efforts to develop personalized assistance for patients and caregivers. We also mention the evaluation of the actions undertaken, their funding, and the remuneration of colleagues who devote time to these actions. Pharmacists have a special role to play in the assistance for persons suffering from Alzhiemer's disease and other neurodegenerative diseases. More than four million persons visit drug dispensaries or biology laboratories every day in France. These persons often confide in our colleagues, sharing their worries and problems related not only to their medical condition, but also to their psychological and social environment. We should provide our colleagues with the necessary means to fulfill their mission of assistance to patients and families suffering from a poorly understood disease. We encourage pharmacists to participate in the major public health action initiated by the President of the Republic and well defined in the Alzheimer Plan 2008-2012.

Treatment of Alzheimer’s Disease with Anti-Homocysteic acid Antibody

Homocysteic acid (HA) may play an important role in Alzhiemer disease (AD) as we previously reported that HA induced accumulation of intraneuronal A[beta]42. In this study, we first analyzed HA levels in a mouse model of AD. 4-month old pre-pathologic 3xTg-AD mice exhibited higher levels of HA in the hippocampus as compared to age-matched nontransgenic, suggesting that HA accumulation may precede both A[beta] and tau pathologies. To further determine the pathogenic role of HA in AD, we treated young 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to induce the production of HA in the brain. Concominantly, mice received either saline or anti-HA antibody intraventricularly using a guide cannula every 3 days. Mice received anti-HA antibody significantly rescued cognitive impairment induced by vitamin B6 deficiency. Pathologically, 3-week treatment with vitamin B-6 deficient food resulted in strong neurodegeneration in the hippocampal CA1 zone and decreased hippocampal volume. In contrast, anti-HA antibody treatment attenuated these pathological changes. Taken together, we conclude that increased brain HA triggers memory impairment whose condition was deteriorated by amyloid and subsequent neurodegeneration and reduction of neurogenesis. Our results indicate a pathogenic role of HA in AD.

Treatment of Alzheimer's Disease with Anti-Homocysteic acid Antibody

AbstractHomocysteic acid (HA) may play an important role in Alzhiemer disease (AD) as we previously reported that HA induced accumulation of intraneuronal A[beta]42. In this study, we first analyzed HA levels in a mouse model of AD. 4-month old pre-pathologic 3xTg-AD mice exhibited higher levels of HA in the hippocampus as compared to age-matched nontransgenic, suggesting that HA accumulation may precede both A[beta] and tau pathologies. To further determine the pathogenic role of HA in AD, we treated young 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to induce the production of HA in the brain. Concominantly, mice received either saline or anti-HA antibody intraventricularly using a guide cannula every 3 days. Mice received anti-HA antibody significantly rescued cognitive impairment induced by vitamin B6 deficiency. Pathologically, 3-week treatment with vitamin B-6 deficient food resulted in strong neurodegeneration in the hippocampal CA1 zone and decreased hippocampal volume. In contrast, anti-HA antibody treatment attenuated these pathological changes. Taken together, we conclude that increased brain HA triggers memory impairment whose condition was deteriorated by amyloid and subsequent neurodegeneration and reduction of neurogenesis. Our results indicate a pathogenic role of HA in AD.

Treatment of Alzheimer's Disease with Anti-Homocysteic acid Antibody

AbstractHomocysteic acid (HA) may play an important role in Alzhiemer disease (AD) as we previously reported that HA induced accumulation of intraneuronal A[beta]42. In this study, we first analyzed HA levels in a mouse model of AD. 4-month old pre-pathologic 3xTg-AD mice exhibited higher levels of HA in the hippocampus as compared to age-matched nontransgenic, suggesting that HA accumulation may precede both A[beta] and tau pathologies. To further determine the pathogenic role of HA in AD, we treated young 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to induce the production of HA in the brain. Concominantly, mice received either saline or anti-HA antibody intraventricularly using a guide cannula every 3 days. Mice received anti-HA antibody significantly rescued cognitive impairment induced by vitamin B6 deficiency. Pathologically, 3-week treatment with vitamin B-6 deficient food resulted in strong neurodegeneration in the hippocampal CA1 zone and decreased hippocampal volume. In contrast, anti-HA antibody treatment attenuated these pathological changes. Taken together, we conclude that increased brain HA triggers memory impairment whose condition was deteriorated by amyloid and subsequent neurodegeneration and reduction of neurogenesis. Our results indicate a pathogenic role of HA in AD.

P1-301: fMRI activation changes during successful episodic memory encoding and recognition in amnestic mild cognitive impairment relative to cognitively healthy older adults

Episodic memory dysfunction which is thought to be caused by neurodegenerative changes to the medial temporal lobes (MTL) is one of the earliest features of Alzhiemer's disease (AD). Recent evidence from metabolic and amyloid imaging studies also reveal early pathophysiological changes in the posterior cingulate cortex (PCC) and frontal cortex (FC). Previous functional MRI (fMRI) studies of episodic memory function in individuals with amnestic-mild cognitive impairment (AMCI), a prodromal form of AD, have revealed have failed to reveal a consistent pattern of fMRI activation changes (i.e., increases or decreases) in these same brain regions. In the present study, we used fMRI to examine changes in brain activation in individual with AMCI relative to older normal controls (ONC) during successful episodic encoding and recognition using a well-studied, subsequent memory paradigm. We found that the individuals with AMCI displayed reduced activation relative to an older normal control (ONC) group in the left hippocampus and bilaterally in the medial prefrontal and posterior cingulate cortices during episodic recognition. In contrast, individuals with AMCI were found to display greater activation in the right hippocampus relative to the ONC group during the encoding of items that were subsequently recognized accurately. The results of the present study suggest that brain activation differences in individuals with AMCI are modulated by the stage of episodic memory examined (i.e., encoding versus recognition). These findings may help to clarify some of the conflicting findings regarding brain activation changes in AMCI.

Remote technology used to monitor signs of ageing.

Imagine being able to detect subtle changes in an older person's health and behaviour - for example, a change in the height of the steps they take while walking, a shortening of their attention span while undertaking everyday tasks or a fall in blood pressure so slight it has not yet caused a single bout of dizziness. Then imagine this information collected by discreetly placed devices in the person's home, but remotely accessed by using computer technology. Such information would offer an early warning of trouble ahead, and could help provide prevention strategies and treatment to help the older person avoid falls or reduce the effects of Alzhiemer's disease. It would enable them to go on living independently, at home.

P2-063: Effects of Abeta1-42 mutants linked to familial Alzheimer’s disease on recombinant human neuronal nicotinic acetylcholine receptors (nAChRs)

It is thought that Aβ1–42 is the responsible agent for Alzhiemer disease progression, as its accumulation is toxic (Selkoe, 2001). However, the underlying mechanisms remain to be resolved. The inherited form of the disease, familial AD, accounts for only 10% of AD cases but has an earlier onset. In a subset of familial AD cases (Swedish, Dutch and Flemish families), genetic mutations in the amyloid precursor peptide (APP) lead to the over production of Aβ1–42 and result in disease pathology. Neurodegeneration and a loss of nicotinic acetylcholine receptors (nAChRs) are features of both forms of AD. It has been reported that Aβ1–42 binds with high–affinity to α7 and with low–affinity to α4β2 nAChRs and partially blocks the action of ACh on α7 nAChRs (Grassi et al., 2003; Pettit et al., 2001; Wang et al., 2000). The nature of the link between amyloid peptides, nAChRs and AD pathology is yet to be established. Determine the actions of Dutch, Swedish and Flemish variants of Aβ on recombinant nicotinic acetylcholine receptors. We used two–electrode voltage–clamp to study the effects of the Swedish, Dutch and Flemish mutant forms of Aβ1–42 (10 nM) on the ACh–evoked responses of recombinant human α7, α4β2 and α3β4 nAChRs expressed in Xenopus oocytes. We found that the Swedish peptide acted as a non–competitive antagonist of human α7 nAChRs and an allosteric enhancer of ACh–evoked currents mediated by α4β2 nAChRs, but had no effect on α3β4 nAChRs. These actions are identical to the actions of wild type Aβ1–42 on these human neuronal nicotinic receptors (Pym et al., 2005). In contrast to this, both the Flemish and Dutch mutant forms of Aβ1–42 caused an enhancement of ACh–evoked currents in all neuronal nicotinic receptors tested. This is the first demonstration that these mutations in Aβ have specific actions on nAChRs. These results may have implications for the subtle differences in the pathology of familial AD when compared to sporadic AD and highlights the sensitivity of nAChR subtypes to variants of Aβ1–42.