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26 Jun 2019 at 01:30
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Bibliography on: Alzheimer Disease — Treatment


Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 26 Jun 2019 at 01:30 Created: 

Alzheimer Disease — Treatment

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: alzheimer[TIAB] AND treatment[TIAB] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-06-24

Pyenson B, Sawhney TG, Steffens C, et al (2019)

The Real-World Medicare Costs of Alzheimer Disease: Considerations for Policy and Care.

Journal of managed care & specialty pharmacy, 25(7):800-809.

BACKGROUND: Headlines in popular media suggest that Alzheimer disease will bankrupt the Medicare program. Indeed, Alzheimer disease affects more than 5 million older Medicare beneficiaries.

OBJECTIVE: To compare total Medicare-covered (allowed) costs of patients with Alzheimer disease with the risk adjusted costs of beneficiaries without dementia over their last years of life, using claims data.

METHODS: Using the Medicare 5 Percent Limited Data Set claim files from 2006-2015, we conducted a cost impact analysis of costs for up to 8 years before the year of death. Risk adjustment was performed at a beneficiary level using Medicare's 2015 Hierarchical Condition Categories. Beneficiaries were classified into dementia categories based on their diagnoses during the last 3 years of life. Costs were trend adjusted to 2015.

RESULTS: This study found that 40% of deceased beneficiaries have Alzheimer disease or unspecified dementia diagnoses in their claims history. In their last 9 years of life, Alzheimer disease added about 11% to the average $17,000 per year Medicare cost for same-risk beneficiaries without dementia.

CONCLUSIONS: Like many diseases, Alzheimer disease and dementia are associated with aging, but unlike other diseases, families and Medicaid, rather than Medicare, bear most of the substantial cost burden. As research continues into Alzheimer treatments, it is not too early to consider how to better integrate Medicare and Medicaid to fund and improve patient outcomes, which will likely involve better diagnosis, treatment, and care coordination.

DISCLOSURES: Funding for this project was provided by the Alliance for Aging Research, which received funding from Biogen, Eli Lilly, and Janssen Pharmaceuticals. Peschin and Jenkins are employed by the Alliance for Aging Research. Scott was employed by the Alliance for Aging Research at the time of this study and also reports consulting fees from Piramal Imaging, General Electric, and Allergan, outside of this study. Scott is chair of the Board of Directors for the Alliance for Aging Research, which is a volunteer position, and is also president of Applied Policy, a health policy and reimbursement consultancy. Pyenson and Steffens are employed by Milliman, which was contracted to work on this study. Goss Sawhney and Rotter were employed by Milliman at the time this work was performed. Milliman is a consultant to thousands of organizations in the health care industry.

RevDate: 2019-06-22

Lee S, Lee H, Kim KW, et al (2019)

Magnetic resonance imaging texture predicts progression to dementia due to Alzheimer disease earlier than hippocampal volume.

Journal of psychiatry & neuroscience : JPN, 44(5):1-8 [Epub ahead of print].

Background: Early identification of people at risk of imminent progression to dementia due to Alzheimer disease is crucial for timely intervention and treatment. We investigated whether the texture of MRI brain scans could predict the progression of mild cognitive impairment (MCI) to Alzheimer disease earlier than volume.

Methods: We constructed a development data set (121 people who were cognitively normal and 145 who had mild Alzheimer disease) and a validation data set (113 patients with stable MCI who did not progress to Alzheimer disease for 3 years; 40 with early MCI who progressed to Alzheimer disease after 12–36 months; and 41 with late MCI who progressed to Alzheimer disease within 12 months) from the Alzheimer’s Disease Neuroimaging Initiative. We analyzed the texture of the hippocampus, precuneus and posterior cingulate cortex using a grey-level co-occurrence matrix. We constructed texture and volume indices from the development data set using logistic regression. Using area under the curve (AUC) of receiver operator characteristics, we compared the accuracy of hippocampal volume, hippocampal texture and the composite texture of the hippocampus, precuneus and posterior cingulate cortex in predicting conversion from MCI to Alzheimer disease in the validation data set.

Results: Compared with hippocampal volume, hippocampal texture (0.790 v. 0.739, p = 0.047) and composite texture (0.811 v. 0.739, p = 0.007) showed larger AUCs for conversion to Alzheimer disease from both early and late MCI. Hippocampal texture showed a marginally larger AUC than hippocampal volume in early MCI (0.795 v. 0.726, p = 0.060). Composite texture showed a larger AUC for conversion to Alzheimer disease than hippocampal volume in both early (0.817 v. 0.726, p = 0.027) and late MCI (0.805 v. 0.753, p = 0.019).

Limitations: This study was limited by the absence of histological data, and the pathology reflected by the texture measures remains to be validated.

Conclusion: Textures of the hippocampus, precuneus and posterior cingulate cortex predicted conversion from MCI to Alzheimer disease at an earlier time point and with higher accuracy than hippocampal volume.

RevDate: 2019-06-21

Salcher-Konrad M, Naci H, McDaid D, et al (2019)

Effectiveness of interventions for dementia in low- and middle-income countries: protocol for a systematic review, pairwise and network meta-analysis.

BMJ open, 9(6):e027851 pii:bmjopen-2018-027851.

INTRODUCTION: There are more people living with dementia in low- and middle-income countries (LMICs) than in high-income countries. Evidence-based interventions to improve the lives of people living with dementia and their carers are needed, but a systematic mapping of methodologically robust studies in LMICs and synthesis of the effectiveness of dementia interventions in these settings is missing.

METHODS AND ANALYSIS: A systematic review and meta-analysis will be conducted to answer the question: Which dementia interventions were shown to be effective in LMICs and how do they compare to each other? Electronic database searches (MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Global Health, WHO Global Index Medicus, Virtual Health Library, Cochrane CENTRAL, Social Care Online, BASE, MODEM Toolkit, Cochrane Database of Systematic Reviews) will be complemented by hand searching of reference lists and local knowledge of existing studies from an international network of researchers in dementia from LMICs. Studies will be eligible for inclusion if they were published between 2008 and 2018, conducted in LMICs and evaluated the effectiveness of a dementia intervention using a study design that supports causal inference of the treatment effect. We will include both randomised and non-randomised studies due to an anticipated low number of well-conducted randomised trials in LMICs and potentially greater external validity of non-randomised studies conducted in routine care settings. In addition to narrative synthesis of the interventions, feasibility of pairwise and network meta-analyses will be explored to obtain pooled effects of relative treatment effects.

ETHICS AND DISSEMINATION: Secondary analysis of published studies, therefore no ethics approval required. Planned dissemination channels include a peer-reviewed publication as well as a website, DVD and evidence summaries.


RevDate: 2019-06-21

Ahlgrim NS, Garza K, Hoffman C, et al (2019)

Prodromes and Preclinical Detection of Brain Diseases: Surveying the Ethical Landscape of Predicting Brain Health.

eNeuro pii:ENEURO.0439-18.2019 [Epub ahead of print].

The future of medicine lies in disease modification and prevention. The science of preclinical detection is young, but moving rapidly. Preclinical interventions offer the hope to decrease the severity of a disease or delay the development of a disorder substantially. With such promise, the research and practice of detecting brain disorders at a preclinical stage present unique ethical challenges, challenges that must be addressed to ensure the benefit of these technologies. Direct brain interventions have potential to impact not just what a patient has but who they are and who they could become. Further receiving an assessment for a preclinical or prodromal state has potential to impact perceptions about capacity, autonomy and personhood and could become entangled with stigma and discrimination. Discussion of the risks and benefits of the emerging technology will focus on how to ensure beneficence by presenting the limitations of preclinical detection and by contextualizing the risk associated with preclinical status. Exploring ethical issues alongside and integrated into the experimental design and research of these technologies is critical. This review will highlight ethical issues attendant to the current and near future states of preclinical detection across the life span, specifically as it relates to autism spectrum disorder (ASD), schizophrenia, and Alzheimer's disease.Significance Statement Preclinical interventions in developing brain disorders offer the strongest promise of delaying, modifying, or preventing the development of clinical disorders. Although promising, intervening at early stages in disorders inherently linked to identity and personhood presents unique ethical challenges. These challenges must be addressed before the practices are implemented. Both the treatment and the diagnosis itself have the potential to profoundly impact patients. We contextualize the risk of diagnosing preclinical states and present the limitations of preclinical interventions to guide research and policy as the field of preclinical detection rapidly expands.

RevDate: 2019-06-19

Panda SS, N Jhanji (2019)

Natural Products as Potential anti-Alzheimer Agents.

Current medicinal chemistry pii:CMC-EPUB-98945 [Epub ahead of print].

Medicinal plants have curative properties due to the presence of various complex chemical substances of different composition, which are found as secondary metabolites in one or more parts of the plant. The diverse secondary metabolites play an important role in the prevention and cure of various diseases including neurodegenerative diseases like Alzheimer's disease. Naturally occurring compounds such as flavonoids, polyphenols, alkaloids, and glycosides found in various parts of the plant and/or marine sources may potentially protect neurodegeneration as well as improve memory and cognitive function. Many natural compounds show anti-Alzheimer activity through specific pharmacological mechanisms like targeting β-amyloid, Beta-secretase 1 and Acetylcholinesterase. In this review, we have compiled more than 130 natural products with a broad diversity in the class of compounds were isolated from different sources showing anti-Alzheimer properties.

RevDate: 2019-06-19

Ceccariglia S, Cargnoni A, Silini AR, et al (2019)

Autophagy: a potential key contributor to the therapeutic action of mesenchymal stem cells.

Autophagy [Epub ahead of print].

Macroautophagy/autophagy occurs at basal levels in all eukaryotic cells and plays an important role in maintaining bio-energetic homeostasis through the control of molecule degradation and organelle turnover. It can be induced by environmental conditions such as starvation, and is deregulated in many diseases including autoimmune diseases, neurodegenerative disorders, and cancer. Interestingly, the modulation of autophagy in mesenchymal stem cells (MSCs) represents a possible mechanism which, affecting MSC properties, may have an impact on their regenerative, therapeutic potential. Furthermore, the ability of MSCs to modulate autophagy of cells in injured tissues/organs has been recently proposed to be involved in the regeneration of damaged tissues and organs. In particular, MSCs can affect autophagy in immune cells involved in injury-induced inflammation reducing their survival, proliferation, and function and favoring the resolution of inflammation. In addition, MSCs can affect autophagy in endogenous adult or progenitor cells, promoting their survival, proliferation and differentiation supporting the restoration of functional tissue. This review provides, for the first time, an overview of the studies which highlight a possible link between the therapeutic properties of MSCs and their ability to modulate autophagy, and it summarizes examples of disorders where these therapeutic properties have been correlated with such modulation. A better elucidation of the mechanism(s) through which MSCs can modulate the autophagy of target cells and how autophagy can affect MSCs therapeutic properties, can provide a wider perspective for the clinical application of MSCs in the treatment of many diseases. Abbreviations: 3-MA: 3-methyladenine; AD: Alzheimer disease; ATG: autophagy-related; BECN1: beclin 1; BM: bone marrow; CD: cluster of differentiation; EAE: experimental autoimmune encephalomyelitis; IL: interleukin; INF: interferon; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MSCs: mesenchymal stem cells; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson disease; PtdIns3K: class III phosphatidylinositol 3-kinase; ROS: reactive oxygen species; SLE: systemic lupus erythematosus; SQSTM1: sequestosome 1; TBI: traumatic brain injury; TGF: transforming growth factor; TNF: tumor necrosis factor.

RevDate: 2019-06-17

Chen XQ, Qiu K, Liu H, et al (2019)

Application and prospects of butylphthalide for the treatment of neurologic diseases.

Chinese medical journal, 132(12):1467-1477.

OBJECTIVE: The 3-N-butylphthalide (NBP) comprises one of the chemical constituents of celery oil. It has a series of pharmacologic mechanisms including reconstructing microcirculation, protecting mitochondrial function, inhibiting oxidative stress, inhibiting neuronal apoptosis, etc. Based on the complex multi-targets of pharmacologic mechanisms of NBP, the clinical application of NBP is increasing and more clinical researches and animal experiments are also focused on NBP. The aim of this review was to comprehensively and systematically summarize the application of NBP on neurologic diseases and briefly summarize its application to non-neurologic diseases. Moreover, recent progress in experimental models of NBP on animals was summarized.

DATA SOURCES: Literature was collected from PubMed and Wangfang database until November 2018, using the search terms including "3-N-butylphthalide," "microcirculation," "mitochondria," "ischemic stroke," "Alzheimer disease," "vascular dementia," "Parkinson disease," "brain edema," "CO poisoning," "traumatic central nervous system injury," "autoimmune disease," "amyotrophic lateral sclerosis," "seizures," "diabetes," "diabetic cataract," and "atherosclerosis."

STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts and partly derived from Chinese articles. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files.

RESULTS: NBP has become an important adjunct for ischemic stroke. In vascular dementia, the clinical application of NBP to treat severe cognitive dysfunction syndrome caused by the hypoperfusion of brain tissue during cerebrovascular disease is also increasing. Evidence also suggests that NBP has a therapeutic effect for neurodegenerative diseases. Many animal experiments have found that it can also improve symptoms in other neurologic diseases such as epilepsy, cerebral edema, and decreased cognitive function caused by severe acute carbon monoxide poisoning. Moreover, NBP has therapeutic effects for diabetes, diabetes-induced cataracts, and non-neurologic diseases such as atherosclerosis. Mechanistically, NBP mainly improves microcirculation and protects mitochondria. Its broad pharmacologic effects also include inhibiting oxidative stress, nerve cell apoptosis, inflammatory responses, and anti-platelet and anti-thrombotic effects.

CONCLUSIONS: The varied pharmacologic mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacologic effects await further study.

RevDate: 2019-06-17

de Jong DLK, de Heus RAA, Rijpma A, et al (2019)

Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.

Hypertension (Dallas, Tex. : 1979) [Epub ahead of print].

Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.

RevDate: 2019-06-13

Subaraja M, AJ Vanisree (2019)

Counter effects of Asiaticosids-D through putative neurotransmission on rotenone induced cerebral ganglionic injury in Lumbricus terrestris.

IBRO reports, 6:160-175 pii:S2451-8301(18)30096-7.

Asiaticoside-D (AD) was shown to efficacy of ganglionic degenerated Lumbricus terrestris as a pioneering observation in our earlier research. Though, extract molecular mechanisms of AD for degenerative diseases (DDs) remains largely unknown. We investigated the neuroprotective effects of AD against ROT in cerebral ganglions (CGs) of degenerative L. terrestris. Worms were exposed to 0.4 ppm ROT for 7 days were subjected to co- treatment with 15 ppm of AD. After, CGs was removed. The levels oxidant, non-antioxidant, antioxidant status, ganglioside, ceramide and ceramide glycanase (CGase) were estimated. The m-RNA levels of dopamine transporter (DAT), octopamine transporter (OAT), innexins-9 (inx-9), ionotropic glutamate receptor 3 (iGlu3), heat shock proteins (hsp70), XPRLamide neuropeptide precursor, tyramine beta-hydroxylase (tbh-1) and β- adrenergic receptor kinase-2 (β-ARK2-3) by semi-qRT- PCR. The expression pattern of tyramine beta hydroxylase (TBH), glutamate receptor (iGluR), serotonin transporter (SERT), dopamine transporters (DAT), nerve growth factors (NGF), cytochrome C oxidase (COC), NADH dehydogenase subunit-1 (ND-1), neurotrophin receptor p75 (p75NTR), neuronal nitric oxiside synthase (nNOs) interleukin 1- beta (IL1-β) and tumor necrosis factor alpha (TNF-α) by western blotting. Glutaminergic, serotogenic and dopaminergic toxicity variations were also performed. The levels of oxidant, non-antioxidant, antioxidant status, lipids, proteins and m-RNAs were significantly altered (p < 0.001) on ROT-induced (group II) and their levels were significantly changes (p < 0.05) by ROT+AD in CGs. The sensitive study plan concluded the neuroprotective effects of AD against ROT induced degeneration in worms and suggest that the AD deserves future studies for its use as an effective alternative medicine that could minimize the morbidity of ganglionic degenerative diseases patients.

RevDate: 2019-06-10

Adorni MP, Ruscica M, Ferri N, et al (2019)

Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer's Disease.

Frontiers in aging neuroscience, 11:120.

Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment.

RevDate: 2019-06-09

Zakirova EY, Chastukhina IB, Valeeva LR, et al (2019)

Stable Co-Cultivation of the Moss Physcomitrella Patens with Human Cells in vitro as a New Approach to Support Metabolism of Diseased Alzheimer Cells.

Journal of Alzheimer's disease : JAD pii:JAD190333 [Epub ahead of print].

Alzheimer's disease (AD) is a devastating slowly progressive neurodegenerative disorder with no cure. While there are many hypotheses, the exact mechanism causing this pathology is still unknown. Among many other features, AD is characterized by brain hypometabolism and decreased sugar availability, to which neurons eventually succumb. In light of this aspect of the disease, we hypothesized that boosting fuel supply to neurons may help them survive or at least alleviate some of the symptoms. Here we demonstrate that live moss Physcomitrella patens cells can be safely co-cultured with human fibroblasts in vitro and thus have a potential for providing human cells with energy and other vital biomolecules. These data may form the foundation for the development of novel approaches to metabolic bioengineering and treatment of diseased cells based on live plants. In addition, by providing alternative energy sources to human tissues, the biotechnological potential of this interkingdom setup could also serve as a springboard to foster innovative dietary processes addressing current challenges of mankind such as famine or supporting long-haul space flight.

RevDate: 2019-06-06

Yang T, Dang Y, Ostaszewski B, et al (2019)

Target Engagement in an Alzheimer Trial: Crenezumab Lowers Aβ Oligomers in CSF.

Annals of neurology [Epub ahead of print].

OBJECTIVE: Oligomeric forms of amyloid β-protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer's disease, but it is not known whether anti-Aβ antibodies are capable of lowering oAβ levels in humans.

METHODS: We developed an ultrasensitive immunoassay and used it to measure oAβ in CSF from 104 AD subjects participating in the ABBY and BLAZE Phase 2 trials of the anti-Aβ antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every two weeks or else intravenous (IV) crenezumab (15mg/kg) or placebo every four weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oAβ levels, and these were compared to levels at week 69 in placebo (N=28), SC (N=35) and IV (N=35) treated patients.

RESULTS: Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oAβ at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p=0.0035 for SC and p=0.01 for IV crenezumab vs. placebo. The median percentage change was -48% in the SC arm and -43% in the IV arm. No systematic change was observed in the placebo group, with a median change of -13% and equivalent portions with negative and positive change.

INTERPRETATION: Crenezumab lowered CSF oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti-Aβ agents. This article is protected by copyright. All rights reserved.

RevDate: 2019-06-04

Wahidi N, AJ Lerner (2019)

Blood Pressure Control and Protection of the Aging Brain.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics pii:10.1007/s13311-019-00747-y [Epub ahead of print].

Hypertension and dementia are both common disorders whose prevalence increases with age. There are multiple mechanisms by which hypertension affects the brain and alters cognition. These include blood flow dynamics, development of large and small vessel pathology and diverse molecular mechanisms including formation of reactive oxygen species and transcriptional cascades. Blood pressure interacts with Alzheimer disease pathology in numerous and unpredictable ways, affecting both β-amyloid and tau deposition, while also interacting with AD genetic risk factors and other metabolic processes. Treatment of hypertension may prevent cognitive decline and dementia, but methodological issues have limited the ability of randomized clinical trials to show this conclusively. Recent studies have raised hope that hypertension treatment may protect the function and structure of the aging brain from advancing to mild cognitive impairment and dementia.

RevDate: 2019-06-04

von Arnim CAF, Bartsch T, Jacobs AH, et al (2019)

Diagnosis and treatment of cognitive impairment.

Zeitschrift fur Gerontologie und Geriatrie pii:10.1007/s00391-019-01560-0 [Epub ahead of print].

As a result of the aging population dementia is a growing challenge, especially in healthcare. Nevertheless, cognitive disorders are often not systematically evaluated, especially during hospital stays for other reasons; however, cognitive impairment is associated with a number of geriatric syndromes, including falls, delirium, dysphagia and lack of adherence to treatment plans. This article considers the current state of diagnosis and treatment of dementia. Non-pharmacological therapeutic approaches as well as current and future pharmacological treatment options are discussed. The drugs of choice for the symptomatic treatment of cognitive deficits in Alzheimer's disease and Parkinson-associated dementia are cholinesterase inhibitors and memantine; there is no specific pharmacological treatment for other types of dementia. Prevention and treatment of cardiovascular risk factors can potentially retard the progression of possibly all forms of dementia.

RevDate: 2019-06-02

Agüera Sánchez MÁ, Barbancho Ma MÁ, N García-Casares (2019)

[Effect of physical exercise on Alzheimer's disease. A sistematic review].

Atencion primaria pii:S0212-6567(18)30468-2 [Epub ahead of print].

OBJECTIVE: The objective of this review is to analyze through a the scientific evidence about the effects of physical activity in patients with Alzheimer's disease (AD) as a preventive and non-pharmacological treatment.

DESIGN: Systematic review.

DATA SOURCES: We have identified articles from Pubmed, Science Direct, Medline and Scopus databases, with the keywords Alzheimer, Exercise, Neuroimaging, MRI, PET y Physical Activity. Selected articles: We included those studies that evaluated the effects of physical activity on Alzheimer's disease and those which also included magnetic resonance imaging or positron emission tomography with Pittsburg Compound B marker (PiB) analyzing brain atrophy or increase of the beta-amyloid deposit respectively. We excluded studies including other types of dementia, different of AD. We also excluded articles which not included neuroimaging tests, single cases or non-English language articles.

DATA EXTRACTION: The PRISMA quality scale was used for the critical lecture of the studies. The researchers independently assessed the articles and the discrepancies were resolved by consensus.

RESULTS: We identified 75 articles, of which 23 were finally included in the review.

CONCLUSIONS: Most of the studies included do not allow us to know the impact of physical exercise on cognition and the cerebral structural-functional changes in patients at risk of developing AD or in patients who already have the disease. Without being able to rule out a possible beneficial effect, more studies are needed with a better design and methodological rigor that allows a better known about this association.

RevDate: 2019-05-31

El-Hawary SS, Fathy FI, Sleem AA, et al (2019)

Anticholinesterase activity and metabolite profiling of Syagrus romanzoffiana (Cham.) Glassman leaves and fruits via UPLC-QTOF-PDA-MS.

Natural product research [Epub ahead of print].

The purpose of this study is to provide a complete metabolic profile of the hydroalcoholic extracts of the leaves and fruits of Syagrus romanzoffiana (Cham.) Glassman via UPLC-QTOF-PDA-MS and to evaluate their anticholinesterase activities in a model of Alzheimer disease. The current study has identified 39 metabolites belonging to various chemical classes (i.e. flavonols, phenolic acids, fatty acids, stilbenoids and lignans). While the fatty acids predominated in both leaves and fruits, the stilbenoids were more predominant in leaves. Their neuroprotective effect was comparable to Aricept; the standard drug used in treatment of Alzheimer disease. Both extracts significantly decreased the acetylcholinesterase activity and improved the histopathological changes in the cerebral cortex and cerebellum of rat model of aluminium chloride-induced Alzheimer disease. In light of the current study, Syagrus romanzoffiana (Cham.) Glassman is recommended as promising candidate for palliative treatment in Alzheimer disease through inhibition of the acetylcholinesterase activity.

RevDate: 2019-05-30

Bivona G, Gambino CM, Iacolino G, et al (2019)

Vitamin D and the nervous system.

Neurological research [Epub ahead of print].

Objective: to summarise the activities that Vitamin D (VD) carries out in the brain and to clarify the potential role of VD in neurological diseases. Methods: a literature research has been performed in Pubmed using the following keywords: 'Vitamin D', 'nervous system', 'brain'. Results: the studies reviewed show that VD contributes to cerebral activity in both embryonic and adult brain, helping the connectivity of neural circuits responsible for locomotor, emotional and reward-dependent behavior. Low VD serum levels have been found in patients affected by Alzheimer Disease, Parkinson Disease, Multiple Sclerosis, Autism Spectrum Disorders, Sleep Disorders and Schizophrenia. Discussion: findings are controversial and should be interpreted with caution, since most of the studies performed have observational study set and few interventional studies are available, producing conflicting results. Overall, it can be stated that the potential role of Vitamin D in neurological diseases is mostly unclear and further randomised controlled trials are needed to understand better whether Vitamin D supplementation treatment can be useful in brain disorders.

RevDate: 2019-05-29

Alvarez-Mon MA, Llavero-Valero M, Sánchez-Bayona R, et al (2019)

Areas of Interest and Stigmatic Attitudes of the General Public in Five Relevant Medical Conditions: Thematic and Quantitative Analysis Using Twitter.

Journal of medical Internet research, 21(5):e14110 pii:v21i5e14110.

BACKGROUND: Twitter is an indicator of real-world performance, thus, is an appropriate arena to assess the social consideration and attitudes toward psychosis.

OBJECTIVE: The aim of this study was to perform a mixed-methods study of the content and key metrics of tweets referring to psychosis in comparison with tweets referring to control diseases (breast cancer, diabetes, Alzheimer, and human immunodeficiency virus).

METHODS: Each tweet's content was rated as nonmedical (NM: testimonies, health care products, solidarity or awareness and misuse) or medical (M: included a reference to the illness's diagnosis, treatment, prognosis, or prevention). NM tweets were classified as positive or pejorative. We assessed the appropriateness of the medical content. The number of retweets generated and the potential reach and impact of the hashtags analyzed was also investigated.

RESULTS: We analyzed a total of 15,443 tweets: 8055 classified as NM and 7287 as M. Psychosis-related tweets (PRT) had a significantly higher frequency of misuse 33.3% (212/636) vs 1.15% (853/7419; P<.001) and pejorative content 36.2% (231/636) vs 11.33% (840/7419; P<.001). The medical content of the PRT showed the highest scientific appropriateness 100% (391/391) vs 93.66% (6030/6439; P<.001) and had a higher frequency of content about disease prevention. The potential reach and impact of the tweets related to psychosis were low, but they had a high retweet-to-tweet ratio.

CONCLUSIONS: We show a reduced number and a different pattern of contents in tweets about psychosis compared with control diseases. PRT showed a predominance of nonmedical content with increased frequencies of misuse and pejorative tone. However, the medical content of PRT showed high scientific appropriateness aimed toward prevention.

RevDate: 2019-05-29

Müller P, Fendt M, NG Müller (2019)

[Drug treatment of Alzheimer's dementia : Status quo and perspectives].

Der Internist pii:10.1007/s00108-019-0625-4 [Epub ahead of print].

Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system. AD is characterized by progressive impairments of memory as well as other cognitive functions and an increasing loss of autonomy in everyday life. This review article provides an overview of the current state-of-the-art (symptomatic) pharmacological treatment of Alzheimer's disease, specifics in the context of concomitant neuropsychiatric symptoms in multimorbid patients, and drugs currently under development that have a potentially causal (disease modifying) effect are also mentioned.

RevDate: 2019-06-10

Chen XQ, WC Mobley (2019)

Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses.

Frontiers in neuroscience, 13:446.

Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary financial and emotional burdens (Apostolova, 2016). Studies of pathogenesis are essential for defining critical molecular and cellular events and for discovering therapies to prevent or mitigate their effects. Through studies of neuropathology, genetic and cellular, and molecular biology recent decades have provided many important insights. Several hypotheses have been suggested. Documentation in the 1980s of selective loss of cholinergic neurons of the basal forebrain, followed by clinical improvement in those treated with inhibitors of acetylycholinesterase, supported the "cholinergic hypothesis of age-related cognitive dysfunction" (Bartus et al., 1982). A second hypothesis, prompted by the selective loss of cholinergic neurons and the discovery of central nervous system (CNS) neurotrophic factors, including nerve growth factor (NGF), prompted the "deficient neurotrophic hypothesis" (Chen et al., 2018). The most persuasive hypothesis, the amyloid cascade hypothesis first proposed more than 25 years ago (Selkoe and Hardy, 2016), is supported by a wealth of observations. Genetic studies were exceptionally important, pointing to increased dose of the gene for the amyloid precursor protein (APP) in Down syndrome (DS) and a familial AD (FAD) due to duplication of APP and to mutations in APP and in the genes for Presenilin 1 and 2 (PSEN1, 2), which encode the γ-secretase enzyme that processes APP (Dorszewska et al., 2016). The "tau hypothesis" noted the prominence of tau-related pathology and its correlation with dementia (Kametani and Hasegawa, 2018). Recent interest in induction of microglial activation in the AD brain, as well as other manifestations of inflammation, supports the "inflammatory hypothesis" (Mcgeer et al., 2016). We place these findings in the context of the selective, but by no means unique, involvement of BFCNs and their trophic dependence on NGF signaling and speculate as to how pathogenesis in these neurons is initiated, amplified and ultimately results in their dysfunction and death. In so doing we attempt to show how the different hypotheses for AD may interact and reinforce one another. Finally, we address current attempts to prevent and/or treat AD in light of advances in understanding pathogenetic mechanisms and suggest that studies in the DS population may provide unique insights into AD pathogenesis and treatment.

RevDate: 2019-05-27

Wang Z, He C, JS Shi (2019)

Natural Products for the Treatment of Neurodegenerative Diseases.

Current medicinal chemistry pii:CMC-EPUB-98627 [Epub ahead of print].

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. Alzheimer's disease (AD), Parkinson's disease (PD) and spinal cord injury (SCI) are the common neurodegenerative diseases, which typically occur in people over the age of 60. With the rapid development of an aged society, over 60 million people worldwide are suffering from these uncurable diseases. Therefore, the search for new drugs and therapeutic methods has become an increasingly important research topic. Natural products especially those from the traditional Chinese medicines (TCMs), are the most important sources of drugs, and have received extensive interest among pharmacist. In this review, in order to facilitate further chemical modification of those useful natural products by pharmacists, we will bring together recent studies in single natural compound from TCMs with neuroprotective effect.

RevDate: 2019-05-25

Lindauer A, McKenzie G, LaFazia D, et al (2019)

Using Technology to Facilitate Fidelity Assessments: The Tele-STAR Caregiver Intervention.

Journal of medical Internet research, 21(5):e13599 pii:v21i5e13599.

BACKGROUND: Families living with Alzheimer disease and related dementias have more access to support thanks to the development of effective telehealth-based programs. However, as technological science grows, so does the risk that these technology-based interventions will diverge from foundational protocols, diluting their efficacy. Strategies that ensure programs are delivered as intended, with fidelity to guiding protocols, are needed across the intervention spectrum-from development to wide-scale implementation. Few papers address fidelity in their technology-based work. Here, we present our translated telehealth intervention, Tele-STAR, with our fidelity findings.

OBJECTIVE: This study aimed to assess the preliminary efficacy of Tele-STAR on reducing family caregiver burden and depression. Across the implementation phases, we assessed the fidelity of a caregiver education intervention, STAR-C, as it was translated into a telehealth option (Tele-STAR).

METHODS: A total of 13 family caregivers consented to participate in an 8-week, videoconference-based intervention (Tele-STAR). Tele-STAR efficacy in reducing the affective burden of caregiving was assessed using pre- and postintervention paired t tests. Content experts assessed program fidelity by reviewing and rating Tele-STAR materials for adherence to the original STAR-C protocol. These experts assessed treatment fidelity by viewing videos of the intervention and rating adherence on a checklist.

RESULTS: Tele-STAR reduced caregiver burden and retained good program and treatment fidelity to STAR-C.

CONCLUSIONS: We found Tele-STAR reduced caregiver burden and had good fidelity to the original protocol. Assessing fidelity is a complex process that requires incorporation of these procedures early in the research process. The technology used in this study facilitated the accrual of informative data about the fidelity of our translated intervention, Tele-STAR.

RevDate: 2019-05-25

Wang L, Ying J, Fan P, et al (2019)

Effects of Vitamin D Use on Outcomes of Psychotic Symptoms in Alzheimer Disease Patients.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry pii:S1064-7481(19)30321-5 [Epub ahead of print].

OBJECTIVE: To identify medications that may prevent psychosis in patients with Alzheimer disease (AD).

METHODS: The authors compared the frequency of medication usage among patients with AD with or without psychosis symptoms (AD + P versus AD - P). The authors also conducted survival analysis on time to psychosis for patients with AD to identify drugs with beneficial effects. The authors further explored the potential molecular mechanisms of identified drugs by gene-signature analysis. Specifically, the gene expression profiles induced by the identified drug(s) were collected to derive a list of most perturbed genes. These genes were further analyzed by the associations of their genetic variations with AD or psychosis-related phenotypes.

RESULTS: Vitamin D was used more often in AD - P patients than in AD + P patients. Vitamin D was also significantly associated with delayed time to psychosis. AD and/or psychosis-related genes were enriched in the list of genes most perturbed by vitamin D, specifically genes involved in the regulation of calcium signaling downstream of the vitamin D receptor.

CONCLUSION: Vitamin D was associated with delayed onset of psychotic symptoms in patients with AD. Its mechanisms of action provide a novel direction for development of drugs to prevent or treat psychosis in AD. In addition, genetic variations in vitamin D-regulated genes may provide a biomarker signature to identify a subpopulation of patients who can benefit from vitamin D treatment.

RevDate: 2019-06-10

Wang Y, Wang Q, Li J, et al (2019)

Glutamine Improves Oxidative Stress through the Wnt3a/β-Catenin Signaling Pathway in Alzheimer's Disease In Vitro and In Vivo.

BioMed research international, 2019:4690280.

Background/Aims: Alzheimer's disease (AD) is the most common neurodegenerative disease, and all researchers working in this field agree that oxidative stress is intimately associated with Alzheimer disease. In this study, we hypothesized that glutamine (Gln) offers protection against oxidative stress injury in SAMP8 mice as well as the underlying mechanism.

Methods: The SAMP8 mice received glutamine intragastrically for 8 consecutive weeks to evaluate the protective effect of glutamine on oxidative stress in AD mice involving Wnt3a/β-catenin signaling pathway. In addition, rat pheochromocytoma tumor cell line PC12 was pretreated with 32 μM glutamine for 2 h followed by 24 h incubation with 40 μM Aβ25-35 to obtain in vitro data.

Results: In vivo the administration of glutamine was found to ameliorate behavioral deficits and neuron damage, increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-XP) activity, reduce the malondialdehyde (MDA) content, and activate the Wnt3a/β-catenin signaling pathway in SAMP8 mice. In vitro glutamine treatment decreased the toxicity of Aβ25-35 on PC12 cells and prevented apoptosis. Additionally, glutamine treatment increased SOD and GSH-XP activity and decreased MDA content and increased Wnt3a and β-catenin protein levels. Interestingly, the DKK-1 (Wnt3a/β-catenin pathway inhibitor) decreased the antioxidant capacity of glutamine in Aβ25-35-treated PC12 cells.

Conclusion: This study suggests that glutamine could protect against oxidative stress-induced injury in AD mice via the Wnt3a/β-catenin signaling pathway.

RevDate: 2019-05-22

Konstantakopoulos G (2019)

Insight across mental disorders: A multifaceted metacognitive phenomenon.

Psychiatrike = Psychiatriki, 30(1):13-16.

There is now general agreement that lack of insight is not merely a fundamental aspect of delusions and hallucinations, or just a symptom of psychotic disorders but rather a multi-dimensional construct. Several different components of insight have been proposed and empirically examined during the last three decades, such as the ability to recognize that one has a mental illness, the capacity to relabel unusual mental events as pathological, the specific attribution of one's symptoms to having a mental illness, awareness of illness' consequences, and compliance with treatment.1 Insight impairment is an important prognostic factor in schizophrenia, impacting negatively on medication adherence, treatment outcome, and social functioning.2 Although largely investigated in schizophrenia and other psychoses, insight impairments are observed in many, if not all, mental disorders. Varying levels of awareness of mental illness and/or of specific symptoms are expected in patients with bipolar disorders, Alzheimer disease and other neurocognitive disorders, obsessive-compulsive (OCD) and related disorders.1,3 While in DSM-5 an "insight" specifier was incorporated for OCD, body dysmorphic and hoarding disorder, patients' insight has been found ranging from good to absent in other disorders, such as depressive disorders,4 eating disorders,5 and even specific6 and social7 phobias. Moreover, impaired insight is a common reason that many people with clinical depression or anxiety disorders never seek appropriate treatment and most of the people with addictions and personality disorders fail to recognize and address their problems even when the consequences are devastating: personal suffering, broken relationships, and physical health problems. Depending on the disorder and reflecting different conceptual approaches, many different terms are used to describe lack of insight, such as poor self-awareness, denial, anosognosia (mainly in neurological deficits, e.g. hemiplegia), ego-syntonic symptoms, or even self-deception. At any rate, as an aspect of self-knowledge, insight has psychological (defense mechanisms, coping strategies), social and cultural facets. On the other hand, the attitudes and behaviours towards one's illness are products of inference processes and therefore can be influenced by cognitive dysfunctions. Previous research in schizophrenia showed correlations between neurocognitive functions and insight measures but the strength of this association is rather weak.8 Social cognition may be a crucial cognitive determinant of impaired insight in schizophrenia. The correct attitude toward morbid change in oneself relies on the capacity to reflect upon self from the perspective of the other (i.e., "to see ourselves as others see us"). This capacity is clearly linked to the ability to understand mental states (e.g., beliefs, knowledge, and intentions) of others, that is, theory of mind or mentalizing. Recent research has shown that mentalizing deficits may substantially contribute to insight impairment in schizophrenia.9 This effect could be further examined in the broader context of patient's failures in metacognition, i.e. the general ability to think about thinking, and their relationships with insight impairment in schizophrenia. Mentalizing and introspection are closely related developmentally and it is yet unclear which one is the primary ability: we are able to understand others and then apply this understanding to ourselves or we are able to reflect on ourselves and then apply this reflection to others. A recent line of research in schizophrenia is based on the distinction introduced by Beck et al10 between clinical insight (i.e., awareness of illness) and cognitive insight, which describes a metacognitive ability, specifically patients' flexibility towards their beliefs, judgements and experiences. The self-report Beck Cognitive Insight Scale (BCIS) examines two subcomponents: self-certainty, assessing overconfidence about being right (e.g. "I know better than anyone else what mycomponents: self-certainty, assessing overconfidence about being right (e.g. "I know better than anyone else what my problems are"), and self-reflectiveness, assessing willingness to accept external feedback and recognition of dysfunctionalreasoning style (e.g. "Some of the ideas I was certain were true turned out to be false"). Cognitive insight in thisform describes two related but distinct aspects of metacognition in patients with psychosis, differentially associated withclinical insight, symptoms, treatment outcomes, and functioning.11 Another method for assessment of similar metacognitiveskills also used in schizophrenia is a scale (Metacognition Assessment Scale - Abbreviated, MAS-A) that is administeredthrough a specific interview and examines the capacities of self-reflectivity, understanding of the other individuals'mental states, and using metacognitive knowledge to respond to psychosocial challenges. Lysaker and colleaguesfound recently that metacognitive deficits assessed with MAS-A predict impaired insight in schizophrenia independentof symptoms.12 It is questionable whether BCIS and other methods used so far to assess self-reflection in psychoses arevalid and useful for patients with non-psychotic disorders.11 However, the metacognitive conceptualization of insightmight contribute to a new research framework for insight impairments across mental disorders. According to this approach, poor insight is in part a failure of self-reflection, i.e. the process by which we synthesizeand comprehend ideas about ourselves. This may be due to general deficits in metacognitive abilities (self-reflectivity,mentalizing) or may represent limited, domain-specific, or transient dysfunctions in metacognitive processes. Insight hasto be thought of as a relational concept, that is insight into something: insight into illness, current syndrome, specificsymptoms, pathological personality traits, social difficulties etc.1,3 In an integrated model of insight across mental disorders,aspects of metacognition interacting with multiple other (clinical, neurocognitive, emotional, and social) factorsdetermine patient's ability to correctly process information into self-awareness. The identification of these factors andtheir interactions may be a fruitful field in the research of insight.

RevDate: 2019-05-19

Chauhdary Z, Saleem U, Ahmad B, et al (2019)

Neuroprotective evaluation of Tribulus terrestris L. in aluminum chloride induced Alzheimer's disease.

Pakistan journal of pharmaceutical sciences, 32(2 (Supplementary)):805-816.

Tribulus terrestris (T.T) is enriched with steroidal saponins and flavonoids which have neuroprotective effect. The study was aimed to explore the potential of T.T methanol extract (T.T ME) for anti-Alzheirmer activity along with its safety evaluation. Plant was characterized by physicochemical, phytochemical and GCMS analyses whereas acute oral toxicity (OECD 425) was performed for safety evaluation. AlCl3 induced Alzheimer's disease rat model was used for anti-Alzheirmer activity. T.T ME was given orally at 100, 300 and 1000 mg/kg doses for 21 days and behavioral parameters were observed on 22nd study day. Physicochemical parameters were in permissible limits. GCMS analysis showed eight different compounds and benzene dicarboxylic acid showed maximum % peak area (64.19). No mortality was noted in acute toxicity study. Behavioral studies showed highly significant (p<0.001) improvement in T.T ME treated groups. Antioxidant enzymes and acetylcholinesterase levels were significantly (p<0.05) improved on treatment with T.T ME. Histopathological analysis indicated that neurofibrillary tangles were significantly improved in T.T ME treated groups. Biochemical and behavioral results suggested that T.T contained lead compounds which are effective in the treatment of Alzheimer disease.

RevDate: 2019-06-10

Hamaguchi T, Tsutsui-Kimura I, Mimura M, et al (2019)

AppNL-G-F/NL-G-F mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation.

Neurochemistry international, 129:104470 pii:S0197-0186(18)30549-7 [Epub ahead of print].

Apathy is clinically defined as lack of motivation. Apathy is a frequent symptom in patients with Alzheimer's disease (AD). It is unclear whether amyloid β (Aβ) pathology is associated with apathy. To address this question, we employed the AppNL-G-F/NL-G-F mouse, an Aβ deposition-bearing mouse without neurofibrillary tangles and neuronal cell death throughout the lifespan and used a progressive-ratio (PR) task to monitor instrumental motivation between the ages of 16 and 39 weeks. In the PR task, the number of lever presses to receive one reward increases and the number of active lever presses in the final trial a mouse completes represents a break point, which is an index of motivation. During the observation period, AppNL-G-F/NL-G-F mice overall did not show impaired motivation. However, AppNL-G-F/NL-G-F mice showed a dispersion of the break point at 39 weeks of age within the group. Therefore, we examined the association between the degree of the break point and Aβ pathology; the number of cored amyloid plaques in the striatum was inversely correlated with the degree of motivation. Furthermore, we measured the dopamine transporter (DAT) levels in the subcortical tissues including the striatum using western blot analysis and showed that AppNL-G-F/NL-G-F mice have lower DAT levels than do C57BL/6J mice. Although we could not directly determine the effect of core amyloid plaques on the DAT, the results of this study suggest a pathway through which cored amyloid plaques damage the DAT and cause impaired motivation. These results will draw attention to cored amyloid plaques and will aid researchers searching for new strategies that are effective for the prevention and treatment of impaired motivation.

RevDate: 2019-05-17

Guzman-Martinez L, Maccioni RB, Farías GA, et al (2019)

Biomarkers for Alzheimer´s disease.

Current Alzheimer research pii:CAR-EPUB-98536 [Epub ahead of print].

Alzheimer´s disease (AD) and related dementias are impacting the aging population throughout the world, at an alarming rate. World Alzheimer´s Report indicates a prevalence of 46.8 million affected with AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions can be developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Proposed AD biomarkers include detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aβ peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures is not fully solved in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, derives from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with cognitive decline and also with neuroimaging determinations of brain atrophy.

RevDate: 2019-05-28

Singh R, R Bansal (2019)

16,17-N'-(alky/arylsulfonyl)pyrazoline substituted neuroprotective heterosteroids: Synthesis, molecular docking and preclinical efficacy/toxicity studies in rodents.

Steroids, 148:114-124 pii:S0039-128X(19)30093-5 [Epub ahead of print].

The synthesis and neuroprotective efficacy and toxicity studies of a new series of 16,17-N'-(alkyl/arylsulfonyl)pyrazolinyl steroids is presented. Significant suppression of the overexpressed acetylcholinesterase and lipid peroxidation, marked reduction of nitrite, oxidative stress and TNF-α levels and noticeable improvement in cognitive and locomotor functions were observed after treatment with the newly synthesized steroids 2-4a-d in the LPS-treated animal models. Higher neuroprotective effects were produced by some of the pyrazolinyl steroids in comparison to the reference drugs celecoxib and dexamethasone. N'-(4-fluorobenzenesulfonyl) derivative 4c showed the most promising effects on all the analyzed parameters and is the most potent molecule among all compounds of this series. Acute toxicity studies on the most active steroids 2-4c at 50 mg/kg did not reveal any toxic effects on animals, however hepatitis and chronic nephritis were observed in histological examination of liver and kidney of mice after 28 days of treatment. The pyrazolinyl steroids 2-4a-d could be considered as promising candidates for the designing of novel multitarget-directed neuroprotectives for an effective therapy of AD and PD.

RevDate: 2019-05-16

Ansari F, Ghasemi JB, A Niazi (2019)

Three dimensional quantitative structure activity relationship and pharmacophore modeling of tacrine derivatives as acetylcholinesterase inhibitors in Alzheimer's treatment.

Medicinal chemistry (Shariqah (United Arab Emirates)) pii:MC-EPUB-98458 [Epub ahead of print].

BACKGROUND: Three dimensional quantitative structure activity relationship and pharmacophore modeling studied for tacrine derivatives as acetylcholinesterase inhibitors.

METHODS: The three dimensional quantitative structure-activity relationship and pharmacophore methods were used to model the 68 derivatives of tacrine as human acetylcholinesterase inhibitors. The effect of the docked conformer of each molecule in the enzyme cavity was investigated on the predictive ability and statistical quality of the produced models.

RESULTS: The whole data set was divided into two training and test sets using hierarchical clustering method. 3D-QSAR model, based on the comparative molecular field analysis has good statistical parameters as indicated by q2 =0.613, r2 =0.876, and r2pred =0.75. In the case of comparative molecular similarity index analysis, q2, r2 and r2pred values were 0.807, 0.96, and 0.865 respectively. The statistical parameters of the models proved that the inhibition data are well fitted and they have satisfactory predictive abilities.

CONCLUSION: The results from this study illustrate the reliability of using techniques in exploring the likely bonded conformations of the ligands in the active site of the protein target and improve the understanding over the structural and chemical features of AChE.

RevDate: 2019-06-02

Beaver SK, Mesa-Torres N, Pey AL, et al (2019)

NQO1: A target for the treatment of cancer and neurological diseases, and a model to understand loss of function disease mechanisms.

Biochimica et biophysica acta. Proteins and proteomics, 1867(7-8):663-676.

NAD(P)H quinone oxidoreductase 1 (NQO1) is a multi-functional protein that catalyses the reduction of quinones (and other molecules), thus playing roles in xenobiotic detoxification and redox balance, and also has roles in stabilising apoptosis regulators such as p53. The structure and enzymology of NQO1 is well-characterised, showing a substituted enzyme mechanism in which NAD(P)H binds first and reduces an FAD cofactor in the active site, assisted by a charge relay system involving Tyr-155 and His-161. Protein dynamics play important role in physio-pathological aspects of this protein. NQO1 is a good target to treat cancer due to its overexpression in cancer cells. A polymorphic form of NQO1 (p.P187S) is associated with increased cancer risk and certain neurological disorders (such as multiple sclerosis and Alzheimer´s disease), possibly due to its roles in the antioxidant defence. p.P187S has greatly reduced FAD affinity and stability, due to destabilization of the flavin binding site and the C-terminal domain, which leading to reduced activity and enhanced degradation. Suppressor mutations partially restore the activity of p.P187S by local stabilization of these regions, and showing long-range allosteric communication within the protein. Consequently, the correction of NQO1 misfolding by pharmacological chaperones is a viable strategy, which may be useful to treat cancer and some neurological conditions, targeting structural spots linked to specific disease-mechanisms. Thus, NQO1 emerges as a good model to investigate loss of function mechanisms in genetic diseases as well as to improve strategies to discriminate between neutral and pathogenic variants in genome-wide sequencing studies.

RevDate: 2019-05-15

de Heus RAA, Donders R, Santoso AMM, et al (2019)

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

Journal of the American Heart Association, 8(10):e011938.

Background Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the calcium-channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH-related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow-up visits. Mean age of the study population was 72.2±8.2 years and mean Mini-Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by -7.8/-3.9 mm Hg for nilvadipine and by -0.4/-0.8 mm Hg for placebo (P<0.001). Across the 78-week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8-1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH-related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. Conclusions This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild-to-moderate Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02017340.

RevDate: 2019-05-13

McAree M, Dunn A, Furtado J, et al (2019)

Osteopathic Cranial Manipulative Medicine and the Blood-Brain Barrier: A Mechanistic Approach to Alzheimer Prevention.

The Journal of the American Osteopathic Association pii:2733780 [Epub ahead of print].

Recent studies have demonstrated that blood-brain barrier (BBB) dysfunction may be implicated in the pathogenesis of Alzheimer disease, thus establishing a link between disease manifestation and compromised neurovasculature. The authors identify relationships between Alzheimer disease and BBB breakdown, the response of the BBB to increased cerebral blood flow and shear stress, and the impact of osteopathic cranial manipulative medicine on cerebrovascular hemodynamics. They propose and review a rationale for future research to evaluate osteopathic cranial manipulative medicine as a preventive treatment for patients with illnesses of neurovascular origin.

RevDate: 2019-05-21

Huang TH, Lin YW, Huang CP, et al (2019)

Short-term auricular electrical stimulation rapidly elevated cortical blood flow and promoted the expression of nicotinic acetylcholine receptor α4 in the 2 vessel occlusion rats model.

Journal of biomedical science, 26(1):36 pii:10.1186/s12929-019-0526-9.

BACKGROUND: Vascular dementia is the second dementing illness after Alzheimer's disease and caused by reduced blood flow to the brain, and affects cognitive abilities. Our previous study found that auricular electrical stimulation (ES) improved motor and learning impairment, and this phenomenon related with nicotinic acetylcholine receptor (nAChR) expressed cells. However, the underlying mechanism was not clear. In the present study, we investigated the effects of auricular ES on cortical blood flow (CBF) and acetylcholine (ACh) - nAChRs expressed cells.

METHODS: Vascular dementia rat animal model was established by permanent occlusions of common carotid arteries with 6-0 nylon suture filament. At 21 day after surgery, motor impairment was confirmed by rotarod test. 15-Hz auricular ES were applied to the ears for 20 min and CBF was recorded at the mean time. The brains were immediately dissected for immunohistochemical stain and western blot analysis.

RESULTS: Our results showed that 15-Hz auricular ES rapidly elevated CBF in the middle cerebral artery. The numbers of nAChR α4 immuno-positive cells and western blot levels were significally increased by 15-Hz auricular ES in the hippocampal CA2 output cortex. The numbers of choline acetyltransferase (ChAT) - a key enzyme for biosynthesis of ACh - immuno-positive cells and western blot levels had no significant differences.

CONCLUSIONS: The present data suggested that the 15-Hz auricular ES for 20 min rapidly elevated cortical blood flow, promoted the expression of nAChR α4, and would be beneficial for the treatment of Alzheimer type and vascular type dementia.

RevDate: 2019-05-22

Carosi JM, TJ Sargeant (2019)

Rapamycin and Alzheimer disease: a double-edged sword?.

Autophagy [Epub ahead of print].

Numerous studies have reported that inhibition of MTOR (mechanistic target of rapamycin kinase) clearly reduces Alzheimer disease neuropathological hallmarks in mouse models. This has resulted in calls for the use of the MTOR inhibitor rapamycin for the treatment of dementia in humans. Unfortunately, intervention with rapamycin in these mouse studies commenced before or early in the appearance of these pathological hallmarks. Later in Alzheimer disease, when dementia actually manifests, the brain's lysosomal system is severely damaged and treatment with rapamycin is likely to exacerbate this damage. We reassess literature described by a recent perspective article calling for the use of MTOR inhibition in dementia and conclude that rapamycin could be useful, but only in people who are in the earliest stages of Alzheimer disease. We contend that our interpretation of preclinical data concerning use of rapamycin in Alzheimer disease models is necessary if we are to avoid another failed Alzheimer disease drug trial. Abbreviations: AD: Alzheimer disease; APP: amyloid beta precursor protein; MAPT: microtubule associated protein tau; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1.

RevDate: 2019-06-10

Petrov AM, Mast N, Li Y, et al (2019)

The key genes, phosphoproteins, processes, and pathways affected by efavirenz-activated CYP46A1 in the amyloid-decreasing paradigm of efavirenz treatment.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Epub ahead of print].

Efavirenz (EFV) is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is the major brain cholesterol hydroxylase. Previously, we discovered that EFV activates CYP46A1 and improves behavioral performance in 5XFAD mice, an Alzheimer's disease model. Herein, the unbiased omics and other approaches were used to study 5XFAD mice in the amyloid-decreasing paradigm of CYP46A1 activation by EFV. These approaches revealed increases in the brain levels of postsynaptic density protein 95, gephyrin, synaptophysin, synapsin, glial fibrillary acidic protein, and CYP46A1 and documented altered expression and phosphorylation of 66 genes and 77 proteins, respectively. The data obtained pointed to EFV effects at the synaptic level, plasmin-depended amyloid clearance, inflammation and microglia phenotype, oxidative stress and cellular hypoxia, autophagy and ubiquitin-proteasome systems as well as apoptosis. These effects could be realized in part via changes in the Ca2+-, small GTPase, and catenin signaling. A model is proposed, in which CYP46A1-dependent lipid raft rearrangement and subsequent decrease of protein phosphorylation are central in EFV effects and explain behavioral improvements in EFV-treated 5XFAD mice.-Petrov, A. M., Mast, N., Li, Y., Pikuleva, I. A. The key genes, phosphoproteins, processes, and pathways affected by efavirenz-activated CYP46A1 in the amyloid-decreasing paradigm of efavirenz treatment.

RevDate: 2019-06-10

Chernyuk D, Zernov N, Kabirova M, et al (2019)

Antagonist of neuronal store-operated calcium entry exerts beneficial effects in neurons expressing PSEN1ΔE9 mutant linked to familial Alzheimer disease.

Neuroscience, 410:118-127 pii:S0306-4522(19)30292-1 [Epub ahead of print].

Alzheimer's disease (AD) is the neurodegenerative disorder with no cure. Recent studies suggest that dysregulated postsynaptic store-operated calcium entry (nSOCE) may underlie mushroom spine loss that is related to AD pathology. In the present study we observed that PSEN1ΔE9 familial AD (FAD) mutation causes mushroom spine loss in hippocampal neuronal cultures. We also demonstrated that amplitude of TRPC6-mediated nSOCE is increased in PSEN1ΔE9-expressing neurons and we suggested that inhibition of nSOCE may help to rescue synaptic defects in this model. We further established that nSOCE antagonist EVP4593 decreases PSEN1ΔE9-mediated nSOCE upregulation and rescues mushroom spines in PSEN1ΔE9-expressing neurons. Obtained results further highlight the connection between dysregulation of endoplasmic reticulum calcium signaling and synaptic loss in AD and suggest that calcium signaling modulators may have a therapeutic value for treatment of memory loss in AD.

RevDate: 2019-06-10

Tian M, Lin X, Wu L, et al (2019)

Angiotensin II triggers autophagy and apoptosis in PC12 cell line: An in vitro Alzheimer's disease model.

Brain research, 1718:46-52.

OBJECTIVE: The activation of renin angiotensin system is involved in multiple pathological processes. Growing evidence reveal that Angiotensin II (Ang II) contributes to the pathogenesis of Alzheimer disease (AD). However, the underlying mechanisms are still not fully understood.

METHODS: In this study, the effect of Ang II on Aβ1-42 induced neurotoxicity was evaluated in PC12 cells. Apoptosis was examined by flow cytometry analysis and caspase-3 activity assay. Autophagy-related markers were also measured in each group.

RESULTS: The results indicated that Ang II activated autophagy and triggered apoptosis in PC12 cells in a dose-dependent manner, as demonstrated byincreased LC3 II/I ratio and decreased p62 expression. Moreover, inhibition of autophagy by 3-methyladenine markedly attenuated the apoptosis caused by Ang II. In addition, an AT1R antagonist losartan, rather than the AT2R antagonist PD123319, completely reversed the Ang II induced autophagic activation and subsequent cell apoptosis.

CONCLUSIONS: Taken together, our study strengthen the crucial function of Ang II/AT1R axis in the pathogenesis of AD in vitro. These findings have deepened our understanding on the role of Ang II in the pathogenesis of AD and support the use of AT1R antagonists for the treatment of this devastating neurodegenerative disease.

RevDate: 2019-06-10

Chaudhuri A, Hudait N, SS Chakraborty (2019)

Pharmacophore modeling coupled with molecular dynamic simulation approach to identify new leads for meprin-β metalloprotease.

Computational biology and chemistry, 80:292-306 pii:S1476-9271(19)30065-9 [Epub ahead of print].

Human meprin beta metalloprotease, a small subgroup of the astacin family, is a potent drug target for the treatment of several disorders such as fibrosis, neurodegenerative disease in particular Alzheimer and inflammatory bowel diseases. In this study, a ligand-based pharmacophore approach has been used for the selection of potentially active compounds to understand the inhibitory activities of meprin-β by using the sulfonamide scaffold based inhibitors. Using this dataset, a pharmacophore model (Hypo1) was selected on the basis of a highest correlation coefficient (0.959), lowest total cost (105.89) and lowest root mean square deviation (1.31 Å) values. All the pharmacophore hypotheses generated from the candidate inhibitors comprised four features: two hydrogen-bond acceptor, one hydrogen-bond donor and one zinc binder feature. The best validated pharmacophore model (Hypo1) was used for virtual screening of compounds from several databases. The selective hit compounds were filtered by drug likeness property, acceptable ADMET profile, molecular docking and DFT study. Molecular dynamic simulations with the final 10 hit compounds revealed that a large number of non-covalent interactions were formed with the active site and specificity sub-pockets of the meprin beta metalloprotease. This study assists in the development of the new lead molecules as well as gives a better understanding of their interaction with meprin-β.

RevDate: 2019-06-07

Pundir CS, Deswal R, P Kumar (2019)

Quantitative analysis of sarcosine with special emphasis on biosensors: a review.

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, 24(5):415-422.

The quantitative determination of sarcosine is of great importance in clinical chemistry, food and fermentation industries. Elevated sarcosine levels are associated with Alzheimer, dementia, prostate cancer, colorectal cancer, stomach cancer and sarcosinemia. This review summarizes the various methods for quantitative analysis of sarcosine with special emphasis on various strategies of biosensors and their analytical performance. The current bio sensing methods have overcome the drawbacks of conventional methods. Sarcosine biosensors work optimally at pH 7.0 to 8.0 in the linear range of 0.1 to 100 μM within 2 to 17 s and between 25 and 37 °C, within a limit of detection (LOD) between 0.008 and 500 mM. The formulated biosensors can be reused within a stability period of 3-180 days. Future research could be focused to modify existing sarcosine biosensors, leading to simple, reliable, and economical sensors ideally suited for point-of-care treatment. Clinical significance Elevated sarcosine levels are associated with prostate and colorectal cancer, Alzheimer, dementia, stomach cancer and sarcosinemia. Quantitative determination of sarcosine is of great importance in clinical chemistry as well as food and fermentation industries. Attempts made in development of sarcosine biosensors have been reviewed with their advantages and disadvantages, so that scientist and clinicians can improvise the methods of developing more potent sarcosine biosensor applicable in multitudinous fields. This is the first comprehensive review which compares the various immobilization methods, sensing principles, strategies used in biosensors and their analytical performance in detail.

RevDate: 2019-05-05

Díaz-Zúñiga J, Muñoz Y, Melgar-Rodríguez S, et al (2019)

Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?.

Journal of oral microbiology, 11(1):1586423 pii:1586423.

Introduction: Previous reports have proposed that Periodontal disease (PDis) predisposes to Alzheimer's disease (AD), both highly prevalent pathologies among the elderly. The bacteria Aggregatibacter actinomycetemcomitans (Aa), associated with the most aggressive forms of PDis, are classified in different serotypes with distinct virulence according to the antigenicity of their lipopolysaccharide (LPS). Methods: Here, we determined the effects of purified LPS, from serotypes a, b or c of Aa, on primary cultures of microglia or mixed hippocampal cells. Results: We found that both culture types exhibited higher levels of inflammatory cytokines (IL-1β, IL-6 and TNFα) when treated with serotype b-LPS, compared with controls, as quantified by qPCR and/or ELISA. Also, cultures treated with serotype a-LPS displayed increased mRNA levels of the modulatory cytokines IL-4 and IL-10. Mixed hippocampal cultures treated with serotype b-LPS exhibited severe neuronal morphological changes and displayed increased levels of secreted Aβ1-42 peptide. These results indicate that LPS from different Aa serotypes triggers discriminatory immune responses, which differentially affect primary hippocampal cells. Conclusion: Altogether, our results show that treatment with serotype b-LPS triggers the secretion of proinflammatory cytokines by microglia, induces neurite shrinking, and increases the extracellular Aβ1-42 levels, all features strongly associated with the etiology of AD.

RevDate: 2019-04-29

Riedel O, Klotsche J, FE Pisa (2019)

Psychiatric Symptoms in Patients With Dementia: Do Caregivers and Doctors See the Same Thing?.

Alzheimer disease and associated disorders [Epub ahead of print].

PURPOSE: Neuropsychiatric symptoms (NPS) are common in Alzheimer Disease (AD). Treatment could be optimized by supplementing the clinician's impression of a patient with information from the caregiver. Yet the agreement between caregivers and physicians on the presence of NPS in patients with AD is understudied.

METHODS: Data were obtained from a 2-staged survey in neurology outpatient offices. At stage 1, patients (n=403) were documented by their physicians, including an assessment on the presence of NPS. At stage 2, patients' CGs (n=171) were asked about the presence of NPS in the patients, based on questions from the Neuropsychiatric Inventory. Caregivers were screened for depression with the Depression Screening Questionnaire.

PATIENTS: The study sample comprised patients with mild or moderate AD.

RESULTS: NPS frequency varied between 52.6% [95% confidence interval (CI), 44.9%-60.3%] and 67.2% (95% CI, 59.7%-74.2%, reported by CGs) and 34.2% (95% CI, 26.8%-42.1%) and 50.9% (95% CI, 42.9%-58.9%, reported by physicians). Apathy, depression, aggression, and irritability occurred most frequently according to both sources. κ values were lowest for euphoria (κ=0.03; 95% CI, -0.08 to 0.25), and highest for depression (κ=0.26; 95% CI, 0.11-0.43). CG depression was associated with an increased probability (odds ratio=2.9; 95% CI, 1.2-6.7) of disagreement between caregivers and physicians on the patient's mental status.

CONCLUSION: NPS, though very prevalent in dementia patients, are perceived differently by caregivers and physicians. This divergence increases depending on the psychological health of caregivers.

RevDate: 2019-05-02
CmpDate: 2019-05-02

Chen JG, Jiang QC, Wen B, et al (2018)

[Effects of deoxygedunin on Alzheimer-like pathologic dysfunction induced by D-galactose combined with AlCl3].

Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 34(6):496-500.

OBJECTIVE: To investigate the effects of Deoxygedunin on Aβ deposition, learning memory, and oxidative stress induced by D-galactose combined with AlCl3 in model rats with Alzheimer's disease and its possible mechanism.

METHODS: Male SD rats were randomly divided into three groups (n=12):control group, model group (AD) and intervention group (AD+Deo). Morris water maze test was used to detect learning/memory and cognitive function in rats.Glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and malondialdehyde (MDA) contents in homogenate of hippocampus were detected by enzyme-linked immunosorbent assay (ELISA).Tau protein expression in rat cerebral cortex was detected by immunohistochemistry.Western blot was used to detect the expressions of extracellular signal regulated kinase 1(ERK1), protein kinase B (PKB) and tropomyosin-related kinase B (TrkB) on TrkB signaling pathway.

RESULTS: The results of water maze test showed that D-galactose combined with AlCl3 induced a significant increase in the escape latency compared with the control group (P<0.05).Deoxygedunin could reverse the increase of the escape latency of the model group (P<0.05).On the 7th day after removal of the platform, the model group showed an increase in escape latency compared with the control group and the intervention group (P<0.01), and the number of crossing platforms was declined (P<0.05); The results of immunohistochemistry and ELISA showed that the expressions of Aβ and tau protein in the model group were increased significantly compared with those of the control group (P<0.01).The activities of SOD and GSH-Px were decreased significantly and the content of MDA was increased significantly.Compared with the model group, Deoxygedunin could reverse the increase of the expressions of Aβ and tau protein (P<0.01), the decrease of SOD and GSH-Px activities (P<0.05) and the increase of the MDA content (P<0.05).Western blot results showed that Deoxygedunin treatment reversed the decreased phosphorylation levels of TrkB, AKT and ERK1 in hippocampus of the model group.

CONCLUSIONS: Supplement of Deoxygedunin can significantly reverse Aβ deposition, oxidative stress and cognitive deficits by activating the TrkB signal transduction pathway, which suggest that Deoxygedunin may serve as a promising therapeutic candidate for attenuating AD-like pathological dysfunction induced by D-galactose combined with AlCl3.

RevDate: 2019-05-01

Eskandari-Roozbahani N, Shomali T, M Taherianfard (2019)

Neuroprotective Effect of Zataria Multiflora Essential Oil on Rats With Alzheimer Disease: A Mechanistic Study.

Basic and clinical neuroscience, 10(1):85-97.

Introduction: Finding herbs with promising effects to prevent or postpone Alzheimer Disease (AD) is highly demanded. The present study aimed at clarifying plausible effects and related mechanism(s) of Zataria Multiflora Essential Oil (ZMEO) against memory impairment in a rat model of the AD.

Methods: Forty male adult rats were categorized into four groups and treated as follows: 1. The Negative Control (NC): no treatment; 2. Sham control (sham): distilled water by Intracerebroventricular (ICV) injection; 3. The AD control (AD): Aβ 1-42 by ICV injection; and 4. The ZMEO group: Aβ 1-42 by ICV injection and ZMEO at 100 μL/kg/d orally for 20 days.

Results: After Congo red staining of the hippocampus, a relative decrease in amyloid deposits was observed in the ZMEO group. Moreover, rats showed better outcomes in Morris Water Maze (MWM) test, reduced hippocampal acetylcholinesterase (AchE) activity, and higher Brain-Derived Neurotrophic Factor (BDNF) content as compared with the AD group (P<0.05). However, no significant changes in antioxidant status was observed (P>0.05).

Conclusion: ZMEO has a protective effect against memory impairment in rats with AD at least partly via reducing hippocampal AchE activity and enhancement of BDNF levels without a change in antioxidant status. These findings can pave the way for future studies on the usefulness of this herb in AD prevention.

RevDate: 2019-05-24

Zafeer MF, Firdaus F, Anis E, et al (2019)

Prolong treatment with Trans-ferulic acid mitigates bioenergetics loss and restores mitochondrial dynamics in streptozotocin-induced sporadic dementia of Alzheimer's type.

Neurotoxicology, 73:246-257 pii:S0161-813X(18)30357-7 [Epub ahead of print].

Alzheimer disease has been well associated with mitochondrial dysfunctions. Numerous studies have reported changes in the activity of oxidative phosphorylation (OXPHOS) complexes and mitochondrial dynamics. Recently, dynamin-related protein 1 (Drp-1) has been conceived as a potential therapeutic target as well. We have examined the effect of prolonged treatment of Trans-ferulic acid on streptozocin-induced sporadic dementia of Alzheimer's type. We have found the Ferulic Acid (FA,100 mg/kg) can rescue memory and learning problems and also show significant antioxidant effect while preserving morphology of pyramidal cell layer in hippocampi. Furthermore, FA treatment has shown mitigation in intracerebral-ventricular streptozocin (ICV-STZ) induced bioenergetics loss and dynamic changes by regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) protein levels in nucleus and hence, mitigating exacerbation of Drp-1 dependent mitochondrial fission and apoptosis by alleviating loss of mitochondrial membrane potential (ΔΨm), downregulating cytochrome-c release into the cytosol by limiting mitochondrial permeability transition pore (mPTP) opening concomitant increase in caspase3 activation, BAX expression and DNA fragmentation along with downregulating glial fibrillary acidic protein (GFAP) expression. FA also restored protein expression of mitofusin2 (Mfn2) a core component of mitochondrial fusion, necessary for mitophagy. We conclude that FA acid may have the propensity to mitigate mitochondrial dysfunction in Alzheimer's disease on prolonging dietary supplementation.

RevDate: 2019-06-10

Pourshojaei Y, Abiri A, Eskandari R, et al (2019)

Synthesis, biological evaluation, and computational studies of novel fused six-membered O-containing heterocycles as potential acetylcholinesterase inhibitors.

Computational biology and chemistry, 80:249-258 pii:S1476-9271(18)30967-8 [Epub ahead of print].

An efficient, borax-catalyzed protocol for the synthesis of novel 4-aryl-substituted-4H-pyran derivatives fused to α-pyrone ring in a one-pot is described. By this achievement, some novel 4-aryl substituted 4H-pyrans fused to the α-pyrone ring as potential acetylcholinesterase inhibitors (AChEIs) with good to excellent yields are obtained from a one-pot three-component reaction between various aryl aldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one and malononitrile. The method is a facile, inexpensive, practical and highly efficient one to obtain target compounds. The chemical structures of all compounds were characterized by FT-IR, FT-13CNMR and FT-1HNMR, MS spectroscopy and also elemental analyses data. Furthermore, the purity of all novel compounds was checked by HPLC. In addition, both molecular modelling studies and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMETox) prediction nominated all compounds as good acetylcholinesterase inhibitors to the potential treatment of Alzheimer, Parkinson and Autism diseases that among them compound 4f showed the best activity against acetylcholinesterase enzyme.

RevDate: 2019-06-09

Zhao Y, Xin Y, Meng S, et al (2019)

Neurofilament light chain protein in neurodegenerative dementia: A systematic review and network meta-analysis.

Neuroscience and biobehavioral reviews, 102:123-138.

The diagnostic value of neurofilament light chain protein in neurodegenerative dementia diseases is still controversial. A systematic literature search was performed to identify relevant case-control studies conducted through October 2018. Traditional and net meta-analyses were performed based on 42 studies that tested the diagnostic performance of neurofilament light chain protein (NfL) concentration in CSF and serum/plasma from patients with neurodegenerative dementia. CSF and serum/plasma NfL levels were significantly increased in patients with neurodegenerative dementia diseases. Network meta-analysis showed a significant reduction in CSF NfL levels during mild cognitive impairment, whereas an increase was observed in vascular dementia compared to Alzheimer's disease. Surface under the cumulative ranking curve and cluster analysis showed that the NfL concentration in CSF (vascular dementia, frontotemporal dementia, and Alzheimer's disease) and serum/plasma (frontotemporal dementia and Alzheimer's disease) ranked first among neurodegenerative dementia diseases. NfL is an important biomarker that can help clinical neurologists make early diagnoses of neurodegenerative diseases, so patients can receive prompt treatment.

RevDate: 2019-04-26

Vogelgsang J, Heßmann P, Wolff-Menzler C, et al (2019)

Prevalence of affective disorders and dementia in inflammatory polyarthropathies.

European archives of psychiatry and clinical neuroscience pii:10.1007/s00406-019-01015-y [Epub ahead of print].

Comorbid disorders are common in psychiatric diseases and understanding the risk of secondary diseases can aid successful clinical treatment. The objective of this study was to compare the frequency of comorbid dementia, affective disorders, and inflammatory polyarthropathies. Healthcare data obtained via the German Hospital Fees Act from two independent databases with more than 7.4 million cases were analyzed to compare the prevalence of comorbid disorders. Comorbid inflammatory polyarthropathy was observed in 2.27% of patients diagnosed with affective disorders and 1.35% of patients with dementia (p < 0.001). Among patients with a primary diagnosis of inflammatory polyarthropathy, 1.27% of patients were diagnosed with dementia, whereas 4.55% of age-matched patients without inflammatory polyarthropathies had comorbid dementia (p < 0.001). The opposite effect was demonstrated for affective disorders, as 5.77% of patients with a primary diagnosis of inflammatory polyarthropathy also had comorbid affective disorders, while 4.87% of age-matched patients without inflammatory polyarthropathy had an accompanying affective disease (p < 0.001). These findings show an association between the occurrence of inflammatory polyarthropathies, dementia, and affective disorders. This correlation might improve diagnosis and treatment for patients with comorbidities. Moreover, further exploration of the molecular pathophysiology underlying these relationships could be relevant for the development of novel treatment options.

RevDate: 2019-05-16

Anonymous (2019)

Literature Commentary: Take Two!.

Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society, 39(2):279-285.

In this section of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles:1. Brownlee WJ, Miszkiel KA, Tur C, Barkhof F, Miller DH, Ciccarelli O. Inclusion of optic nerve involvement in dissemination in space criteria for multiple sclerosis. Neurology. 2018;91:e1130-e1134.2. Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in the treatment of acute migraine attacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025.3. Rotenstein LS, Torre M, Ramos MA, Rosales RC, Guille C, Sen S, Mata DA. Prevalence of burnout among physicians: a systematic review. JAMA. 2018;320:1131-1150.4. Shosha E, Dubey D, Palace J, Nakashima I, Jacob A, Fujihara K, Takahashi T, Whittam D, Leite MI, Misu T, Yoshiki T, Messina S, Elsone L, Majed M, Flanagan E, Gadoth A, Huebert C, Sagen J, Greenberg BM, Levy M, Banerjee A, Weinshenker B, Pittock SJ. Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD. Neurology. 2018;91:e1642-e1651.5. Raynowska J, Miskin DP, Pramanik B, Asiry S, Anderson T, Boockvar J, Najjar S, Harel A. Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): a rare mimic of tumefactive MS. Neurology. 2018;91:e1423-e1428.6. O'Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP. Association of preclinical Alzheimer disease with optical coherence tomographic angiography findings. JAMA Ophthalmol. 2018;136:1242-1248.

RevDate: 2019-04-19

Lee LY, Li IC, Chen WP, et al (2019)

Thirteen-Week Oral Toxicity Evaluation of Erinacine AEnriched Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), Mycelia in Sprague-Dawley Rats.

International journal of medicinal mushrooms, 21(4):401-411.

Recently, erinacine A-enriched Hericium erinaceus (EAHE) mycelia have demonstrated therapeutic efficacy in animal models of neurodegenerative disease, including Alzheimer and Parkinson disease. Despite promising results from animal models, there have been no reports on its toxicity after long-term consumption. Hence, the present study was designed to evaluate the safety of EAHE mycelia through a 13-week subchronic rodent feeding study. Following 13 weeks of EAHE mycelia feeding at dosages of 0, 875, 1750, and 2625 mg/kg body weight in both male and female Sprague-Dawley rats, findings revealed neither any mortalities nor noticeable toxicological effects in all the rats during the investigation period. Physiological parameters including body weight and feed consumption patterns were unaffected by EAHE mycelia administration. The hematological and biochemical parameters as well as histopathological studies revealed no significant differences between the treatment and control groups. Conclusively, the obtained results suggested that EAHE mycelia could be relatively unharmful when used over an extended period, supporting its safe use in food preparation.

RevDate: 2019-05-11

Quitterer U, S AbdAlla (2019)

Improvements of symptoms of Alzheimer`s disease by inhibition of the angiotensin system.

Pharmacological research pii:S1043-6618(18)31950-9 [Epub ahead of print].

With ageing of the global society, the frequency of ageing-related neurodegenerative diseases such as Alzheimer`s disease (AD) is on the rise worldwide. Currently, there is no cure for AD, and the four drugs approved for AD only have very small effects on AD symptoms. Consequently, there are enormous efforts worldwide to identify new targets for treatment of AD. Approaches that interfere with classical neuropathologic features of AD, such as extracellular senile plaques formed of aggregated amyloid-beta (Abeta), and intracellular neurofibrillary tangles of hyperphosphorylated tau have not been successful so far. In search for a treatment approach of AD, we found that inhibition of the angiotensin-converting enzyme (ACE) by a centrally acting ACE inhibitor retards symptoms of neurodegeneration, Abeta plaque formation and tau hyperphosphorylation in experimental models of AD. Our approach is currently being investigated in a clinical setting. Initial evidence with AD patients shows that a brain-penetrating ACE inhibitor counteracts the process of neurodegeneration and dementia. Moreover, centrally acting ACE inhibitors given in addition to the standard therapy, cholinesterase inhibition, can improve cognitive function of AD patients for several months. This is one of the most promising results for AD treatment since more than a decade.

RevDate: 2019-04-16

Shawky E, El Sohafy SM, de Andrade JP, et al (2019)

Profiling of acetylcholinesterase inhibitory alkaloids from some Crinum, Habranthus and Zephyranthes species by GC-MS combined with multivariate analyses and in silico studies.

Natural product research [Epub ahead of print].

Acetylcholinesterase (AChE) inhibitors remain the class of drugs used for the treatment of Alzheimer disease (AD). For the aim of discovering new sources of potent AChE inhibitors, a combined AChE-inhibitory activity together with alkaloid profiles by GC-MS, combined with multivariate statistical analysis for biomarkers determination and in silico studies were attempted. Strategy was applied on leaves, roots and bulbs of six aquatic and terrestrial Amaryllidaceae species. Thirty alkaloids were identified and the AChE inhibitory activities of the extracts were tested by in-vitro Ellman method. Principal bioactive markers were discovered by correlating AChE inhibitory activity with chemical fingerprints via PLS and OPLS modeling which revealed that galanthamine, lycoramine, caranine, tazettine and N-demethylgalanthamine were the most bio-significant markers. Furthermore, the molecular docking was performed to illustrate binding orientations of the top scoring alkaloids in the active site of human acetylcholinesterase. Suggested strategy revealed that, beside galanthamine, caranine, N-demethylgalanthamine, and lycoramine are promising AChE inhibitors.

RevDate: 2019-04-16

Panossian A, Seo EJ, T Efferth (2019)

Effects of anti-inflammatory and adaptogenic herbal extracts on gene expression of eicosanoids signaling pathways in isolated brain cells.

Phytomedicine : international journal of phytotherapy and phytopharmacology pii:S0944-7113(19)30051-0 [Epub ahead of print].

INTRODUCTION: The adaptogens modulate expression of genes playing key roles in development of aging-related disorders, which are considered as low-grade systemic inflammatory conditions characterized by an imbalance between pro-and anti-inflammatory eicosanoids.

AIM OF THE STUDY: We compared the effects of anti-inflammatory and adaptogenic plant extracts on the expression of genes involved in biosynthesis of eicosanoids with the purpose to find those plants, which selectively upregulated the expression of anti-inflammatory lipoxins signaling pathways and inhibited pro-inflammatory signaling pathways associated with biosynthesis of leukotrienes, prostaglandins and thromboxanes.

MATERIALS AND METHODS: We conducted transcriptome-wide RNA sequencing to profile gene expression alterations in T98G neuroglia cells upon treatment of plant extract and analyzed the relevance of deregulated genes to eicosanoids signaling pathways using in silico models.

RESULTS: For the first time, we demonstrated that Rhodiola rosea, Withania somnifera and Eleutherococcus senticosus downregulate the expression of key genes (ALOX5AP, DPEP2, LTC4S) involved biosynthesis of leukotrienes A, B, C, D and E, resulting in inhibition of leukotriene signaling pathway suggesting their potential benefits in Alzheimer disease. The common feature for all tested anti-inflammatory plants extracts was related to downregulation of ALOX12, which was also associated with neuroprotective action of these medicinal plants as well as their potential benefits in neurodegenerative diseases. None of tested anti-inflammatory and adaptogenic plants selectively activated the ALOX15-mediated signaling pathway, which is associated with generation anti-inflammatory lipoxins. Almost all tested plants upregulated the expression of the prostaglandin E receptor 3 gene (PTGER3) suggesting their potential benefits in the treatment of cancer.

CONCLUSION: Every single plant tested in this study revealed a specific "signature" on eicosanoid signaling-related gene expression, regardless of their common features as anti-inflammatory or adaptogenic activity. Further studies of the combination of Rhodiola with Withania (Adaptra) for the treatment of Alzheimer disease are required.

RevDate: 2019-04-16

Frost PS, Barros-Aragão F, da Silva RT, et al (2019)

Neonatal infection leads to increased susceptibility to Aβ oligomer-induced brain inflammation, synapse loss and cognitive impairment in mice.

Cell death & disease, 10(4):323 pii:10.1038/s41419-019-1529-x.

Harmful environmental stimuli during critical stages of development can profoundly affect behavior and susceptibility to diseases. Alzheimer disease (AD) is the most frequent neurodegenerative disease, and evidence suggest that inflammatory conditions act cumulatively, contributing to disease onset. Here we investigated whether infection early in life can contribute to synapse damage and cognitive impairment induced by amyloid-β oligomers (AβOs), neurotoxins found in AD brains. To this end, wild-type mice were subjected to neonatal (post-natal day 4) infection by Escherichia coli (1 × 104 CFU/g), the main cause of infection in low-birth-weight premature infants in the US. E. coli infection caused a transient inflammatory response in the mouse brain starting shortly after infection. Although infected mice performed normally in behavioral tasks in adulthood, they showed increased susceptibility to synapse damage and memory impairment induced by low doses of AβOs (1 pmol; intracerebroventricular) in the novel object recognition paradigm. Using in vitro and in vivo approaches, we show that microglial cells from E. coli-infected mice undergo exacerbated activation when exposed to low doses of AβOs. In addition, treatment of infected pups with minocycline, an antibiotic that inhibits microglial pro-inflammatory polarization, normalized microglial response to AβOs and restored normal susceptibility of mice to oligomer-induced cognitive impairment. Interestingly, mice infected with by E. coli (1 × 104 CFU/g) during adolescence (post-natal day 21) or adulthood (post-natal day 60) showed normal cognitive performance even in the presence of AβOs (1 pmol), suggesting that only infections at critical stages of development may lead to increased susceptibility to amyloid-β-induced toxicity. Altogether, our findings suggest that neonatal infections can modulate microglial response to AβOs into adulthood, thus contributing to amyloid-β-induced synapse damage and cognitive impairment.

RevDate: 2019-04-14

Chalatsa I, Arvanitis DA, Koulakiotis NS, et al (2019)

The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models.

Frontiers in neuroscience, 13:249.

Crocus sativus L. natural compounds have been extensively used in traditional medicine for thousands of years. Recent research evidence is now emerging in support of its therapeutic potential for different pathologies including neurodegenerative diseases. Herein, the C. sativus L. natural compounds trans-crocin 4 and trans-crocetin were selected for in depth molecular characterization of their potentially protective effects against Alzheimer's Disease (AD), utilizing two AD neuronal cell culture models (SH-SY5Y overexpressing APP and PC12 expressing hyperphosphorylated tau). Biologically relevant concentrations, ranging from 0.1 μM to 1 mM, applied for 24 h or 72 h, were well tolerated by differentiated wild type SH-SY5Y and PC12 cells. When tested on neuronally differentiated SH-SY5Y-APP both trans-crocin 4 and trans-crocetin had significant effects against amyloidogenic pathways. Trans-crocin 4 significantly decreased of β-secretase, a key enzyme of the amyloidogenic pathway, and APP-C99, while it decreased γ-secretases that generate toxic beta-amyloid peptides. Similarly, trans-crocetin treatment led to a reduction in β- and γ-secretases, as well as to accumulation of cellular AβPP. When tested on the neuronally differentiated PC12-htau cells, both compounds proved effective in suppressing the active forms of GSK3β and ERK1/2 kinases, as well as significantly reducing total tau and tau phosphorylation. Collectively, our data demonstrate a potent effect of trans-crocin 4 and trans-crocetin in suppressing key molecular pathways of AD pathogenesis, rendering them a promising tool in the prevention and potentially the treatment of AD.

RevDate: 2019-04-21

Pucci S, Greggi C, Polidoro C, et al (2019)

Clusterin silencing restores myoblasts viability and down modulates the inflammatory process in osteoporotic disease.

Journal of translational medicine, 17(1):118 pii:10.1186/s12967-019-1868-5.

BACKGROUND: Targeting new molecular pathways leading to Osteoporosis (OP) and Osteoarthritis (OA) is a hot topic for drug discovery. Clusterin (CLU) is a glycoprotein involved in inflammation, proliferation, cell death, neoplastic disease, Alzheimer disease and aging. The present study focuses on the expression and the role of CLU in influencing the decrease of muscle mass and fiber senescence in OP-OA condition.

METHODS: Vastus lateralis muscle biopsies were collected from 20 women with OP undergoing surgery for fragility hip fracture and 20 women undergoing arthroplasty for hip osteoarthritis.

RESULTS: We found an overexpression of CLU in degenerated fibers in OP closely correlated with interleukin 6 (IL6) and histone H4 acetylation level. Conversely, in OA muscle tissues we observed a weak expression of CLU but no nuclear histone H4 acetylation. Ex vivo studies on isolated human myoblasts confirmed CLU overexpression in OP as compared to OA (p < 0.001). CLU treatment of isolated OP and OA myoblasts showed: modulation of proliferation, morphological changes, increase of histone H4 acetylation and induction of myogenin (MYOG) activation in OP myoblast only. In OP condition, functional knockdown of CLU by siRNA restores proliferative myoblasts capability and tissue damage repair, carried out by an evident upregulation of Transglutaminase 2 (TGM2). We also observed downmodulation of CX3CR1 expression with consequent impairing of the inflammatory infiltrate recruitment.

CONCLUSIONS: Results obtained suggest a potential role of CLU in OP by influencing myoblasts terminal differentiation, epigenetic regulation of muscle cell differentiation and senescence. Moreover, CLU silencing points out its role in the modulation of tissue damage repair and inflammation, proposing it as a new diagnostic marker for muscle degeneration and a potential target for specific therapeutic intervention in OP related sarcopenia.

RevDate: 2019-06-10

Castillo C, Fernández-Mendívil C, Buendia I, et al (2019)

Neuroprotective effects of EpoL against oxidative stress induced by soluble oligomers of Aβ peptide.

Redox biology, 24:101187 pii:S2213-2317(19)30164-8 [Epub ahead of print].

Erythropoietin is a glycoproteic hormone that regulates hematopoiesis by acting on its specific receptor (EpoR). The expression of EpoR in the central nervous system (CNS) suggests a role for this hormone in the brain. Recently, we developed a new Epo variant without hematopoietic activity called EpoL, which showed marked neuroprotective effects against oxidative stress in brain ischemia related models. In this study, we have evaluated the neuroprotective effects of EpoL against oxidative stress induced by chronic treatment with Aβ. Our results show that EpoL was neuroprotective against Aβ-induced toxicity by a mechanism that implicates EpoR, reduction in reactive oxygen species, and reduction in astrogliosis. Furthermore, EpoL treatment improved calcium handling and SV2 levels. Interestingly, the neuroprotective effect of EpoL against oxidative stress induced by chronic Aβ treatment was achieved at a concentration 10 times lower than that of Epo. In conclusion, EpoL, a new variant of Epo without hematopoietic activity, is of potential interest for the treatment of diseases related to oxidative stress in the CNS such as Alzheimer disease.

RevDate: 2019-04-29

Farr SA, Roesler E, Niehoff ML, et al (2019)

Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer's Disease.

Journal of Alzheimer's disease : JAD, 68(4):1699-1710.

Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia. Recent epidemiological studies suggest that metformin treatment prevents cognitive decline in diabetics. A pilot clinical study found cognitive improvement with metformin in patients with mild cognitive impairment (MCI). Preclinical studies suggest metformin reduces Alzheimer-like pathology in mouse models of Alzheimer's disease (AD). In the current study, we used 11-month-old SAMP8 mice. Mice were given daily injections of metformin at 20 mg/kg/sc or 200 mg/kg/sc for eight weeks. After four weeks, mice were tested in T-maze footshock avoidance, object recognition, and Barnes maze. At the end of the study, brain tissue was collected for analysis of PKC (PKCζ, PKCι, PKCα, PKCγ, PKCɛ), GSK-3β, pGSK-3βser9, pGSK-3βtyr216, pTau404, and APP. Metformin improved both acquisition and retention in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze. Biochemical analysis indicated that metformin increased both atypical and conventional forms of PKC; PKCζ, and PKCα at 20 mg/kg. Metformin significantly increased pGSK-3βser9 at 200 mg/kg, and decreased Aβ at 20 mg/kg and pTau404 and APPc99 at both 20 mg/kg and 200 mg/kg. There were no differences in blood glucose levels between the aged vehicle and metformin treated mice. Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improved memory by decreasing APPc99 and pTau. The current study lends support to the therapeutic potential of metformin for AD.

RevDate: 2019-04-28

Zhu J, Wang LN, Cai R, et al (2019)

Design, synthesis, evaluation and molecular modeling study of 4-N-phenylaminoquinolines for Alzheimer disease treatment.

Bioorganic & medicinal chemistry letters, 29(11):1325-1329.

Dual binding site acetylcholinesterase (AChE) inhibitors and butyrylcholinesterase (BChE) inhibitors have recently emerged as two classes of new anti-Alzheimer agents to positively modify the disease's course. In this work, a new series of 4-N-phenylaminoquinolines was synthesized and evaluated for their abilities to inhibit AChE and BChE. Compound 11b showed significant inhibitory activities on AChE and BChE with IC50 values of 0.86 and 2.65 μM, respectively, a lot better than that of reference drug galanthamine. Furthermore, docking study showed that compound 11b interacted simultaneously not only with active and peripheral sites of AChE, but also with all five regions of BChE active site. These findings suggest that these derivatives could be regarded as promising starting points for further drug discovery developments.

RevDate: 2019-04-30

Meyer PF, Tremblay-Mercier J, Leoutsakos J, et al (2019)

INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.

Neurology, 92(18):e2070-e2080.

OBJECTIVE: To evaluate the safety and efficacy of low-dose naproxen for prevention of progression in presymptomatic Alzheimer disease (AD) among cognitively intact persons at risk.

METHODS: Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease (INTREPAD), a 2-year double-masked pharmaco-prevention trial, enrolled 195 AD family history-positive elderly (mean age 63 years) participants screened carefully to exclude cognitive disorder (NCT-02702817). These were randomized 1:1 to naproxen sodium 220 mg twice daily or placebo. Multimodal imaging, neurosensory, cognitive, and (in ∼50%) CSF biomarker evaluations were performed at baseline, 3, 12, and 24 months. A modified intent-to-treat analysis considered 160 participants who remained on-treatment through their first follow-up examination. The primary outcome was rate of change in a multimodal composite presymptomatic Alzheimer Progression Score (APS).

RESULTS: Naproxen-treated individuals showed a clear excess of adverse events. Among treatment groups combined, the APS increased by 0.102 points/year (SE 0.014; p < 10-12), but rate of change showed little difference by treatment assignment (0.019 points/year). The treatment-related rate ratio of 1.16 (95% confidence interval 0.64-1.96) suggested that naproxen does not reduce the rate of APS progression by more than 36%. Secondary analyses revealed no notable treatment effects on individual CSF, cognitive, or neurosensory biomarker indicators of progressive presymptomatic AD.

CONCLUSIONS: In cognitively intact individuals at risk, sustained treatment with naproxen sodium 220 mg twice daily increases frequency of adverse health effects but does not reduce apparent progression of presymptomatic AD.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for people who are cognitively intact, low-dose naproxen does not significantly reduce progression of a composite indicator of presymptomatic AD.

RevDate: 2019-05-10

Teter B, Morihara T, Lim GP, et al (2019)

Curcumin restores innate immune Alzheimer's disease risk gene expression to ameliorate Alzheimer pathogenesis.

Neurobiology of disease, 127:432-448 pii:S0969-9961(19)30045-2 [Epub ahead of print].

Alzheimer's disease (AD) genetics implies a causal role for innate immune genes, TREM2 and CD33, products that oppose each other in the downstream Syk tyrosine kinase pathway, activating microglial phagocytosis of amyloid (Aβ). We report effects of low (Curc-lo) and high (Curc-hi) doses of curcumin on neuroinflammation in APPsw transgenic mice. Results showed that Curc-lo decreased CD33 and increased TREM2 expression (predicted to decrease AD risk) and also increased TyroBP, which controls a neuroinflammatory gene network implicated in AD as well as phagocytosis markers CD68 and Arg1. Curc-lo coordinately restored tightly correlated relationships between these genes' expression levels, and decreased expression of genes characteristic of toxic pro-inflammatory M1 microglia (CD11b, iNOS, COX-2, IL1β). In contrast, very high dose curcumin did not show these effects, failed to clear amyloid plaques, and dysregulated gene expression relationships. Curc-lo stimulated microglial migration to and phagocytosis of amyloid plaques both in vivo and in ex vivo assays of sections of human AD brain and of mouse brain. Curcumin also reduced levels of miR-155, a micro-RNA reported to drive a neurodegenerative microglial phenotype. In conditions without amyloid (human microglial cells in vitro, aged wild-type mice), Curc-lo similarly decreased CD33 and increased TREM2. Like curcumin, anti-Aβ antibody (also reported to engage the Syk pathway, increase CD68, and decrease amyloid burden in human and mouse brain) increased TREM2 in APPsw mice and decreased amyloid in human AD sections ex vivo. We conclude that curcumin is an immunomodulatory treatment capable of emulating anti-Aβ vaccine in stimulating phagocytic clearance of amyloid by reducing CD33 and increasing TREM2 and TyroBP, while restoring neuroinflammatory networks implicated in neurodegenerative diseases.

RevDate: 2019-04-21

Shinomoto M, Kasai T, Tatebe H, et al (2019)

Plasma neurofilament light chain: A potential prognostic biomarker of dementia in adult Down syndrome patients.

PloS one, 14(4):e0211575 pii:PONE-D-18-27916.

People with Down syndrome (DS) are at high risk of developing Alzheimer disease (AD) with aging. The diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. Plasma neurofilament light chain (NfL) is one of the established biomarkers of AD, suggesting that it may be useful as an indicator of dementia in DS patients. The aims of this study were: 1) to examine whether plasma levels of NfL in DS patients are correlated with decreased adaptive behavior scores one year after sample collection, and 2) to compare plasma levels of NfL in adults with DS and an age-matched healthy control population. In this study, plasma levels of NfL in 24 patients with DS and 24 control participants were measured by the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma NfL levels in the DS compared with the control group. There was a significant correlation between age and levels of plasma NfL in both groups. This age-dependent elevation was steeper in the DS compared with the control group. Moreover, elevated plasma NfL was associated with decreased adaptive behavior scores one year later, after age-adjustment. Previously reported blood-based biomarkers available in Simoa for DS, plasma total tau and phosphorylated tau, were not significantly correlated with the annual decrement of adaptive behavior scores after age-adjustment. These results suggest that plasma NfL has the potential to serve as an objective biomarker to predict dementia in adult DS patients.

RevDate: 2019-04-05

Ishola IO, Jacinta AA, OO Adeyemi (2019)

Cortico-hippocampal memory enhancing activity of hesperetin on scopolamine-induced amnesia in mice: role of antioxidant defense system, cholinergic neurotransmission and expression of BDNF.

Metabolic brain disease pii:10.1007/s11011-019-00409-0 [Epub ahead of print].

Alzheimer disease (AD) is an age related neurodegenerative disease causing severe cognitive and memory decline in elderly people. Flavonoids play neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) or tau peptide into oligomers and fibrils. This study sought to investigate the effect of hesperetin (HPT) on scopolamine-induced memory impairments in mice. Mice were orally pretreated with HPT (1, 5 or 50 mg/kg) or vehicle (normal saline; 10 ml/kg) for 3 consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p.) was administered 5 min before locomotor activity (open field test) and memory function (novel object recognition test (NORT) for 2 consecutive days and Morris water maze task (MWM) for 5 consecutive days). Levels of oxidative stress markers / brain derived neurotrophic factors (BDNF) and acetylcholinesterase activity were determined in the hippocampus and prefrontal cortex after completion of MWM task. Scopolamine caused no significant change in mice exploration of the familiar or novel object in the test session whereas the HPT-treated mice spent more time exploring the novel object more than familiar object in NORT. Scopolamine also increased the escape latency in acquisition phase and decreases time spent in target quadrant in probe phase which were ameliorated by the pretreatment with HPT. Scopolamine-induced alteration of oxidant-antioxidant balance, acetylcholinesterase activity and neurogenesis in the hippocampus and prefrontal cortex were attenuated by HPT treatment. This study showed that HPT ameliorated non-spatial/spatial learning and memory impairment by scopolamine possibly through enhancement of antioxidant defense, cholinergic and BDNF signaling.

RevDate: 2019-04-07

Paley EL (2019)

Diet-Related Metabolic Perturbations of Gut Microbial Shikimate Pathway-Tryptamine-tRNA Aminoacylation-Protein Synthesis in Human Health and Disease.

International journal of tryptophan research : IJTR, 12:1178646919834550 pii:10.1177_1178646919834550.

Human gut bacterial Na(+)-transporting NADH:ubiquinone reductase (NQR) sequence is associated with Alzheimer disease (AD). Here, Alzheimer disease-associated sequence (ADAS) is further characterized in cultured spore-forming Clostridium sp. Tryptophan and NQR substrate ubiquinone have common precursor chorismate in microbial shikimate pathway. Tryptophan-derived tryptamine presents in human diet and gut microbiome. Tryptamine inhibits tryptophanyl-tRNA synthetase (TrpRS) with consequent neurodegeneration in cell and animal models. Tryptophanyl-tRNA synthetase inhibition causes protein biosynthesis impairment similar to that revealed in AD. Tryptamine-induced TrpRS gene-dose reduction is associated with TrpRS protein deficiency and cell death. In animals, tryptamine treatment results in toxicity, weight gain, and prediabetes-related hypoglycemia. Sequence analysis of gut microbiome database reveals 89% to 100% ADAS nucleotide identity in American Indian (Cheyenne and Arapaho [C&A]) Oklahomans, of which ~93% being overweight or obese and 50% self-reporting type 2 diabetes (T2D). Alzheimer disease-associated sequence occurs in 10.8% of C&A vs 1.3% of healthy American population. This observation is of considerable interest because T2D links to AD and obesity. Alzheimer disease-associated sequence prevails in gut microbiome of colorectal cancer, which linked to AD. Metabolomics revealed that tryptamine, chorismate precursor quinate, and chorismate product 4-hydroxybenzoate (ubiquinone precursor) are significantly higher, while tryptophan-containing dipeptides are lower due to tRNA aminoacylation deficiency in C&A compared with non-native Oklahoman who showed no ADAS. Thus, gut microbial tryptamine overproduction correlates with ADAS occurrence. Antibiotic and diet additives induce ADAS and tryptamine. Mitogenic/cytotoxic tryptamine cause microbial and human cell death, gut dysbiosis, and consequent disruption of host-microbe homeostasis. Present analysis of 1246 participants from 17 human gut metagenomics studies revealed ADAS in cell death diseases.

RevDate: 2019-04-29

Luengo E, Buendia I, Fernández-Mendívil C, et al (2019)

Pharmacological doses of melatonin impede cognitive decline in tau-related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux.

Journal of pineal research [Epub ahead of print].

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV-hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau-related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV-hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase-3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.

RevDate: 2019-05-23

Khedr EM, Salama RH, Abdel Hameed M, et al (2019)

Therapeutic Role of Transcranial Direct Current Stimulation in Alzheimer Disease Patients: Double-Blind, Placebo-Controlled Clinical Trial.

Neurorehabilitation and neural repair, 33(5):384-394.

OBJECTIVE: To explore the neuropsychological effects and levels of tau protein (TAU), amyloid β 1-42 (Aβ 1-42), and lipid peroxidase after 10 sessions of anodal transcranial direct current stimulation (tDCS) in patients with mild to moderate Alzheimer disease (AD).

PATIENTS AND METHODS: A total of 46 consecutive patients with probable AD participated in this study. They were classified randomly into 2 equal groups: active versus sham. Each patient received 10 sessions of anodal tDCS over the left and right temporoparietal region for 20 minutes for each side with the cathode on the left arm. Patients were assessed using the Modified Mini Mental State Examination (MMMSE), clock drawing test, Montreal Cognitive Scale (MoCA), and the Cornell Scale for depression. Serum TAU, Aβ 1-42, and lipid peroxidase were measured before and after the 10th session.

RESULTS: There was a significant improvement in the total score of each cognitive rating scale (MMMSE, clock drawing test, and MoCA) in the real group, whereas no such change was observed in the sham group. The Cornell depression score improved significantly in both groups. There was a significant increase in serum Aβ 1-42 (P = .02) in the real but not in the sham group, with a significant Treatment condition × Time interaction (P = .009). There was no significant effect on tau or lipid peroxidase in either group but a significant positive correlation between changes of Aβ1-42 and MMMSE (P = .005) and MoCA (P = .02).

CONCLUSION: The observed cognitive improvements were complemented by parallel changes in serum levels of Aβ 1-42.

RevDate: 2019-05-20

Erbil D, Eren CY, Demirel C, et al (2019)

GLP-1's role in neuroprotection: a systematic review.

Brain injury [Epub ahead of print].

Glucagon-like peptide 1 (GLP-1) is a target for treatment of diabetes; however, its function in the brain is not well studied. In this systematic review, we aimed to analyze the neuroprotective role of GLP-1 and its defined mechanisms.

METHODS: We searched 'Web of Science' and 'Pubmed' to identify relevant studies using GLP-1 as the keyword. Two hundred and eighty-nine clinical and preclinical studies have been included. Data have been presented by grouping neurodegenerative, neurovascular and specific cell culture models.

RESULTS: Recent literature shows that GLP-1 and its agonists, DPP-4 inhibitors and combined GLP-1/GIP molecules are effective in partially or fully reversing the effects of neurotoxic compounds, neurovascular complications of diabetes, neuropathological changes related with Alzheimer's disease, Parkinson's disease or vascular occlusion. Possible mechanisms that provide neuroprotection are enhancing the viability of the neurons and restoring neurite outgrowth by increased neurotrophic factors, increasing subventricular zone progenitor cells, decreasing apoptosis, decreasing the level of pro-inflammatory factors, and strengthening blood-brain barrier.

CONCLUSION: Based on the preclinical studies, GLP-1 modifying agents are promising targets for neuroprotection. On the other hand, the number of clinical studies that investigate GLP-1 as a treatment is low and further clinical trials are needed for a benchside to bedside translation of recent findings.

RevDate: 2019-05-07
CmpDate: 2019-05-07

Hadar A, D Gurwitz (2018)

Peripheral transcriptomic biomarkers for early detection of sporadic Alzheimer disease?.

Dialogues in clinical neuroscience, 20(4):293-300.

Alzheimer disease (AD) is the major epidemic of the 21st century, its prevalence rising along with improved human longevity. Early AD diagnosis is key to successful treatment, as currently available therapeutics only allow small benefits for diagnosed AD patients. By contrast, future therapeutics, including those already in preclinical or clinical trials, are expected to afford neuroprotection prior to widespread brain damage and dementia. Brain imaging technologies are developing as promising tools for early AD diagnostics, yet their high cost limits their utility for screening at-risk populations. Blood or plasma transcriptomics, proteomics, and/or metabolomics may pave the way for cost-effective AD risk screening in middle-aged individuals years ahead of cognitive decline. This notion is exemplified by data mining of blood transcriptomics from a published dataset. Consortia blood sample collection and analysis from large cohorts with mild cognitive impairment followed longitudinally for their cognitive state would allow the development of a reliable and inexpensive early AD screening tool.

RevDate: 2019-05-28

Kaur A, Mann S, Kaur A, et al (2019)

Multi-target-directed triazole derivatives as promising agents for the treatment of Alzheimer's disease.

Bioorganic chemistry, 87:572-584.

A novel series of triazole-based compounds have been designed, synthesised and evaluated as multi-target-directed ligands (MTDLs) against Alzheimer disease (AD). The triazole-based compounds have been designed to target four major AD hallmarks that include Aβ aggregation, metal-induced Aβ aggregation, metal dys-homeostasis and oxidative stress. Among the synthesised compounds, 6n having o-CF3 group on the phenyl ring displayed most potent inhibitory activity (96.89% inhibition, IC50 = 8.065 ± 0.129 μM) against Aβ42 aggregation, compared to the reference compound curcumin (95.14% inhibition, IC50 = 6.385 ± 0.009 μM). Compound 6n disassembled preformed Aβ42 aggregates as effectively as curcumin. Furthermore, 6n displayed metal chelating ability and significantly inhibited Cu2+-induced Aβ42 aggregation and disassembled preformed Cu2+-induced Aβ42 aggregates. 6n successfully controlled the generation of the reactive oxygen species (ROS) by preventing the copper redox cycle. In addition, 6n did not display cytotoxicity and was able to inhibit toxicity induced by Aβ42 aggregates in SH-SY5Y cells. The preferred binding regions and key interactions of 6n with Aβ42 monomer and Aβ42 protofibril structure was evaluated with molecular docking. Compound 6n binds preferably to the C-terminal region of Aβ42 that play a critical role in Aβ42 aggregation. The results of the present study highlight a novel triazole-based compound, 6n, as a promising MTDL against AD.

RevDate: 2019-05-28

Mollazadeh M, Mohammadi-Khanaposhtani M, Zonouzi A, et al (2019)

New benzyl pyridinium derivatives bearing 2,4-dioxochroman moiety as potent agents for treatment of Alzheimer's disease: Design, synthesis, biological evaluation, and docking study.

Bioorganic chemistry, 87:506-515.

A new series of benzyl pyridinium-2,4-dioxochroman derivatives 7a-o was synthesized and evaluated as new anti-Alzheimer agents. Among the synthesized compounds, the compounds 7f and 7i exhibited the most potent anti-AChE and anti-BuChE activities, respectively. The kinetic study of the compound 7f revealed that this compound inhibited AChE in a mixed-type inhibition mode. Furthermore, the docking study of the compounds 7f and 7i showed that these compounds bound to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE, respectively. The compound 7f also exhibited a greater self-induced Aβ peptide aggregation inhibitory activity in compare to donepezil. Furthermore, the neuroprotective activity of this compound at 20 μM was comparable to that of the standard neuroprotective agent (quercetin).

RevDate: 2019-05-22

Iadecola C, RF Gottesman (2019)

Neurovascular and Cognitive Dysfunction in Hypertension.

Circulation research, 124(7):1025-1044.

Hypertension has emerged as a leading cause of age-related cognitive impairment. Long known to be associated with dementia caused by vascular factors, hypertension has more recently been linked also to Alzheimer disease-the major cause of dementia in older people. Thus, although midlife hypertension is a risk factor for late-life dementia, hypertension may also promote the neurodegenerative pathology underlying Alzheimer disease. The mechanistic bases of these harmful effects remain to be established. Hypertension is well known to alter in the structure and function of cerebral blood vessels, but how these cerebrovascular effects lead to cognitive impairment and promote Alzheimer disease pathology is not well understood. Furthermore, critical questions also concern whether treatment of hypertension prevents cognitive impairment, the blood pressure threshold for treatment, and the antihypertensive agents to be used. Recent advances in neurovascular biology, epidemiology, brain imaging, and biomarker development have started to provide new insights into these critical issues. In this review, we will examine the progress made to date, and, after a critical evaluation of the evidence, we will highlight questions still outstanding and seek to provide a path forward for future studies.

RevDate: 2019-04-01

Sung YK, SW Kim (2019)

Recent advances in the development of gene delivery systems.

Biomaterials research, 23:8 pii:156.

Background: Gene delivery systems are essentially necessary for the gene therapy of human genetic diseases. Gene therapy is the unique way that is able to use the adjustable gene to cure any disease. The gene therapy is one of promising therapies for a number of diseases such as inherited disorders, viral infection and cancers. The useful results of gene delivery systems depend open the adjustable targeting gene delivery systems. Some of successful gene delivery systems have recently reported for the practical application of gene therapy.

Main body: The recent developments of viral gene delivery systems and non-viral gene delivery systems for gene therapy have briefly reviewed. The viral gene delivery systems have discussed for the viral vectors based on DNA, RNA and oncolytic viral vectors. The non-viral gene delivery systems have also treated for the physicochemical approaches such as physical methods and chemical methods. Several kinds of successful gene delivery systems have briefly discussed on the bases of the gene delivery systems such as cationic polymers, poly(L-lysine), polysaccharides, and poly(ethylenimine)s.

Conclusion: The goal of the research for gene delivery system is to develop the clinically relevant vectors such as viral and non-viral vectors that use to combat elusive diseases such as AIDS, cancer, Alzheimer, etc. Next step research will focus on advancing DNA and RNA molecular technologies to become the standard treatment options in the clinical area of biomedical application.

RevDate: 2019-03-29

Cox TO, Gunther EC, Brody AH, et al (2019)

Anti-PrPC antibody rescues cognition and synapses in transgenic alzheimer mice.

Annals of clinical and translational neurology, 6(3):554-574 pii:ACN3730.

Objective: Amyloid-beta oligomers (Aßo) trigger the development of Alzheimer's disease (AD) pathophysiology. Cellular prion protein (PrPC) initiates synaptic damage as a high affinity receptor for Aßo. Here, we evaluated the preclinical therapeutic efficacy of a fully human monoclonal antibody against PrPC. This AZ59 antibody selectively targets the Aβo binding site in the amino-terminal unstructured domain of PrPC to avoid any potential risk of direct toxicity.

Methods: Potency of AZ59 was evaluated by binding to PrPC, blockade of Aβo interaction and interruption of Aβo signaling. AZ59 was administered to mice by weekly intraperitoneal dosing and brain antibody measured. APP/PS1 transgenic mice were treated with AZ59 and assessed by memory tests, by brain biochemistry and by histochemistry for Aß, gliosis and synaptic density.

Results: AZ59 binds PrPC with 100 pmol/L affinity and blocks human brain Aßo binding to PrPC, as well as prevents synaptotoxic signaling. Weekly i.p. dosing of 20 mg/kg AZ59 in a murine form achieves trough brain antibody levels greater than 10 nmol/L. Aged symptomatic APP/PS1 transgenic mice treated with AZ59 for 5-7 weeks show a full rescue of behavioral and synaptic loss phenotypes. This recovery occurs without clearance of plaque pathology or elimination of gliosis. AZ59 treatment also normalizes synaptic signaling abnormalities in transgenic brain. These benefits are dose-dependent and persist for at least 1 month after the last dose.

Interpretation: Preclinical data demonstrate that systemic AZ59 therapy rescues central synapses and memory function from transgenic Alzheimer's disease pathology, supporting a disease-modifying therapeutic potential.

RevDate: 2019-03-29

Kang MJ, Park YH, Kim S, et al (2018)

Hydrocephalus in a Patient with Alzheimer's Disease.

Dementia and neurocognitive disorders, 17(1):32-36.

Background: Normal pressure hydrocephalus (NPH) is an etiology of dementia that is reversible following cerebrospinal fluid shunt placement, however, surgical intervention not always clinically effective and the respons to shunt therapy is poorly understood. Furthermore, NPH is a source of comorbidity in diseases with neurodegenerative pathology, such as Alzheimer's disease (AD).

Case Report: A 61-year-old woman presented to the neurology clinic with progressive gait difficulties and cognitive impairment over five years. Nine years after ventriculoperitoneal (VP) shunt treatment, the patient began to experience frequent falls. There was no improvement in clinical symptoms after the alteration of valve pressure on the VP shunt. An 18F-florbetaben amyloid positron emission tomography scan showed increased diffusion uptake over the bilateral cortices, precuneus, and posterior cingulate cortex.

Conclusions: The patient of NPH was unresponsive to shunt therapy due to the development of AD.

RevDate: 2019-03-22

Cao Y, Zhang M, Liu M, et al (2019)

[Research advancement in the determination of neurotransmitters in biological samples and their applications].

Se pu = Chinese journal of chromatography, 37(3):265-273.

Neurotransmitters (NTs) are endogenous chemical messengers that are involved in nerve signal transmission and play important roles in brain function. Changes in NT concentrations in the central nervous system are related to many mental and physiological illnesses. The determination of various NTs has become important in disease diagnosis, monitoring, and treatment interventions. Effective monitoring of NTs in vivo is essential for disease diagnosis and treatment as well as for the research and development of new drugs. This article provides a review of the methods used in NT detection in recent years, including instrumental and electrochemical techniques as well as some new detection methods, and summarizes the applications of the methods for NT detection in some diseases.

RevDate: 2019-04-08

Luo R, Su LY, Li G, et al (2019)

Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model.

Autophagy [Epub ahead of print].

Alzheimer disease (AD) is the most common neurodegenerative disease. An imbalance between the production and clearance of Aβ (amyloid beta) is considered to be actively involved in AD pathogenesis. Macroautophagy/autophagy is a major cellular pathway leading to the removal of aggregated proteins, and upregulation of autophagy represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. PPARA/PPARα (peroxisome proliferator activated receptor alpha) is a transcription factor that regulates genes involved in fatty acid metabolism and activates hepatic autophagy. We hypothesized that PPARA regulates autophagy in the nervous system and PPARA-mediated autophagy affects AD. We found that pharmacological activation of PPARA by the PPARA agonists gemfibrozil and Wy14643 induces autophagy in human microglia (HM) cells and U251 human glioma cells stably expressing the human APP (amyloid beta precursor protein) mutant (APP-p.M671L) and this effect is PPARA-dependent. Administration of PPARA agonists decreases amyloid pathology and reverses memory deficits and anxiety symptoms in APP-PSEN1ΔE9 mice. There is a reduced level of soluble Aβ and insoluble Aβ in hippocampus and cortex tissues from APP-PSEN1ΔE9 mice after treatment with either gemfibrozil or Wy14643, which promoted the recruitment of microglia and astrocytes to the vicinity of Aβ plaques and enhanced autophagosome biogenesis. These results indicated that PPARA is an important factor regulating autophagy in the clearance of Aβ and suggested gemfibrozil be assessed as a possible treatment for AD. Abbreviation: Aβ: amyloid beta; ACTB: actin beta; ADAM10: ADAM metallopeptidase domain 10; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ANOVA: analysis of variance; APOE: apolipoprotein E; APP: amyloid beta precursor protein; APP-PSEN1ΔE9: APPswe/PSEN1dE9; BAFA1: bafilomycin A1; BDNF: brain derived neurotrophic factor; BECN1: beclin 1; CD68: CD68 molecule; CREB1: cAMP responsive element binding protein 1; DAPI: 4',6-diamidino-2-phenylindole; DLG4/PSD-95: discs large MAGUK scaffold protein 4; DMSO: dimethyl sulfoxide; ELISA: enzyme linked immunosorbent assay; FDA: U.S. Food and Drug Administration; FKBP5: FK506 binding protein 5; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; gemfibrozil: 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid; GFAP: glial fibrillary acidic protein; GLI2/THP1: GLI family zinc finger 2; HM: human microglia; IL6: interleukin 6; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NC: negative control; OQ: opposite quadrant; PPARA/PPARα, peroxisome proliferator activated receptor alpha; PSEN1/PS1: presenilin 1; SEM: standard error of the mean; SQSTM1: sequestosome 1; SYP: synaptophysin; TFEB: transcription factor EB; TNF/TNF-α: tumor necrosis factor; TQ: target quadrant; WT: wild type; Wy14643: 2-[4-chloro-6-(2,3-dimethylanilino)pyrimidin-2-yl]sulfanylacetic acid.

RevDate: 2019-03-21

Wei J, Yang F, Gong C, et al (2019)

Protective effect of daidzein against streptozotocin-induced Alzheimer's disease via improving cognitive dysfunction and oxidative stress in rat model.

Journal of biochemical and molecular toxicology [Epub ahead of print].

Oxidative stress is performing an essential role in developing Alzheimer's disease (AD), and age-related disorder and other neurodegenerative diseases. In existing research, we have aimed at investigating the daidzein (4',7-dihydroxyisoflavone) effect (10 and 20 mg/kg of body weight), as a free radical scavenger and antioxidant in streptozotocin (STZ) infused AD in rat model. Daidzein treatment led to significant improvement in intracerebroventricular-streptozotocin (ICV-STZ)-induced memory and learning impairments that was evaluated by Morris water maze test and spontaneous locomotor activity. It significantly restored the alterations in malondialdehyde, catalase, superoxide dismutase, and reduced glutathione levels. In addition, histopathological observations in cerebral cortex and hippocampal areas confirmed the neuroprotective effect of daidzein. These outcomes provide experimental proof showing preventive effect of daidzein on memory, learning dysfunction and oxidative stress in case of ICV-STZ rats. In conclusion, daidzein offers a potential treatment module for various neurodegenerative disorders with regard to mental deficits like AD.

RevDate: 2019-05-10

Camp CJ (2019)

Denial of Human Rights: We Must Change the Paradigm of Dementia Care.

Clinical gerontologist, 42(3):221-223.

In far too many instances treatment of persons with dementia has reflected a fundamental denial of basic human rights. At times, these individuals are treated worse than the treatment of animals when the five basic freedoms of animals, described by Pachana in her editorial, are implemented. A number of such examples of dehumanizing (and "de-animalizing") persons with dementia are presented. A case is made for the position that this is the direct result of the "medicalization" of dementia and "Alzheimer Disease." This has led to the disenfranchisement of persons with dementia and their caregivers regarding the treatment of dementia, while medical "expertise" has led to a paradigm of learned helplessness while waiting for "the cure." While the medicalization of dementia has been a financial success in terms of funding failed researcher to find a cure, it has been a catastrophe for the quality of life of persons with dementia and their caregivers. It is time to take control of the treatment of dementia back, and especially to listen to the voices of persons with dementia. It is time to take action NOW - to become disruptive to the current paradigm. The emperor and his cure have no clothes. We deserve better. We must make this change in paradigm our mission, to demand it, and to accept nothing less. Power to the people.

RevDate: 2019-03-19

Zhao X, Wu Q, Chen Y, et al (2019)

[Pattern recognition analysis of Alzheimer's disease based on brain structure network].

Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi, 36(1):16-23.

Alzheimer' s disease is the most common kind of dementia without effective treatment. Via early diagnosis, early intervention after diagnosis is the most effective way to handle this disease. However, the early diagnosis method remains to be studied. Neuroimaging data can provide a convenient measurement for the brain function and structure. Brain structure network is a good reflection of the fiber structural connectivity patterns between different brain cortical regions, which is the basis of brain's normal psychology function. In the paper, a brain structure network based on pattern recognition analysis was provided to realize an automatic diagnosis research of Alzheimer's disease and gray matter based on structure information. With the feature selection in pattern recognition, this method can provide the abnormal regions of brain structural network. The research in this paper analyzed the patterns of abnormal structural network in Alzheimer's disease from the aspects of connectivity and node, which was expected to provide updated information for the research about the pathological mechanism of Alzheimer's disease.

RevDate: 2019-03-29

Souchet B, Audrain M, Billard JM, et al (2019)

Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice.

Acta neuropathologica communications, 7(1):46 pii:10.1186/s40478-019-0678-6.

Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer's disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1- β, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-β plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD.

RevDate: 2019-04-15

Lin L, Jadoon SS, Liu SZ, et al (2019)

Tanshinone IIA Ameliorates Spatial Learning and Memory Deficits by Inhibiting the Activity of ERK and GSK-3β.

Journal of geriatric psychiatry and neurology, 32(3):152-163.

BACKGROUND: Alzheimer disease (AD) is the most common type of dementia which is becoming a primary problem in the present society, but it lacks effective treatment methods and means of AD. Tanshinone IIA (Tan IIA) has been reported to have neuroprotective effects to restrain the Aβ25-35-mediated apoptosis. However, few studies try to understand how Aβ1-42 affects hyperphosphorylation of tau and how Tan IIA regulates this process at the molecular level.

METHODS: Fifty male Sprague-Dawley rats were randomly divided into 5 groups and infused through the lateral ventricle with Aβ1-42 except the control group. Then the rats were treated with Tan IIA through intragastric administration for 4 weeks. After the ability of learning and memory being measured, histomorphological examination and Western blot were used to detect the possible mechanism in the AD-associated model rats.

RESULTS: We observed that Aβ1-42 infusion could induce spatial learning and memory deficits in rats. Simultaneously, Aβ1-42 also could reduce the neuron in cornu ammonis 1 and dentate gyrus of hippocampus, as well as increase the levels of cleaved caspase 3, hyperphosphorylated tau at the sites Ser396, Ser404, and Thr205 with enhancing staining of black granules in brain. We also found that Aβ1-42 could increase the activity of extracellular signal-regulated protein kinase (ERK) and glycogen synthase kinase-3β (GSK-3β). Meanwhile, these phenomena could be ameliorated when Tan IIA was used.

CONCLUSION: We concluded that Tan IIA might have neuroprotective effect and improving learning and memory ability to be a viable candidate in AD therapy with mechanisms involving the ERK and GSK-3β signal pathway.

RevDate: 2019-04-26

Muhammad T, Ikram M, Ullah R, et al (2019)

Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-κB Signaling.

Nutrients, 11(3): pii:nu11030648.

Glial activation and neuroinflammation play significant roles in apoptosis as well as in the development of cognitive and memory deficits. Neuroinflammation is also a critical feature in the pathogenesis of neurodegenerative disorders such as Alzheimer and Parkinson's diseases. Previously, hesperetin has been shown to be an effective antioxidant and anti-inflammatory agent. In the present study, in vivo and in vitro analyses were performed to evaluate the neuroprotective effects of hesperetin in lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress, neuronal apoptosis and memory impairments. Based on our findings, LPS treatment resulted in microglial activation and astrocytosis and elevated the expression of inflammatory mediators such as phosphorylated-Nuclear factor-κB (p-NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in the cortical and hippocampal regions and in BV2 cells. However, hesperetin cotreatment markedly reduced the expression of inflammatory cytokines by ameliorating Toll-like receptor-4 (TLR4)-mediated ionized calcium-binding adapter molecule 1/glial fibrillary acidic protein (Iba-1/GFAP) expression. Similarly, hesperetin attenuated LPS-induced generation of reactive oxygen species/lipid per oxidation (ROS/LPO) and improved the antioxidant protein level such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Haem-oxygenase (HO-1) in the mouse brain. Additionally, hesperetin ameliorated cytotoxicity and ROS/LPO induced by LPS in HT-22 cells. Moreover, hesperetin rescued LPS-induced neuronal apoptosis by reducing the expression of phosphorylated-c-Jun N-terminal kinases (p-JNK), B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and Caspase-3 protein and promoting the Bcl-2 protein level. Furthermore, hesperetin enhanced synaptic integrity, cognition, and memory processes by enhancing the phosphorylated-cAMP response element binding protein (p-CREB), postsynaptic density protein-95 (PSD-95), and Syntaxin. Overall, our preclinical study suggests that hesperetin conferred neuroprotection by regulating the TLR4/NF-κB signaling pathway against the detrimental effects of LPS.

RevDate: 2019-05-28
CmpDate: 2019-05-28

Dinda B, Dinda M, Kulsi G, et al (2019)

Therapeutic potentials of plant iridoids in Alzheimer's and Parkinson's diseases: A review.

European journal of medicinal chemistry, 169:185-199.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related neurodegenerative disorders, affecting several millions of aged people globally. Among these disorders, AD is more severe, affecting about 7% of individuals aged 65 and above. AD is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while PD is primarily a movement disorder illness having three major kinesia or movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. AD is characterized by deposition of extracellular beta-amyloid (Aβ) proteins and intracellular neurofibrillary tangles (NFT), composed of hyperphosphorylated tau proteins in the neurons located particularly in hippocampus and cerebral cortex regions of brain, resulting the neuronal loss, while PD is characterized by deposition of intraneuronal aggregates of mostly composed of alpha-synuclein gene as Lewy bodies (LB) in the striatal region, known as substantia nigra pars compacta (SNpc) of brain, leading to the death of dopaminergic neurons. These are known as pathological hallmarks of these diseases. However, in some overlapping cases, known as Alzheimer with Parkinson disease or vice versa, alpha-synuclein deposition in AD and tau deposition in PD patients are found. Oxidative stress-induced glial cells activation, neuroinflammation and mitochondrial dysfunction lead to various molecular events in brain neurons causing neuronal cell death in these neurodegenerative disorders. Currently used drugs for treatment of AD and PD only reduce the symptoms of these diseases, but unable to stop the process of neurodegeneration. Therefore, innovation of new synthetic drugs or discovery of natural drugs for the treatment of AD and PD, is a challenging task of basic science and clinical medicine. Plant iridoids such as catalpol and its 10-O-trans-p-coumaroyl derivative, geniposide, harpagoside, and loganin, and seco-iridoids, oleuropein and its aglycone and oleocanthal have been found to exhibit significant neuroprotective effect and the property of slowing down the process of neurogedeneration in AD and PD. These plant metabolites have been shown to ameliorate AD by increasing the expression of insulin degrading enzyme (IDE), neprilysin (NEP), PPAR-γ, and α-secretase, and decreasing the expression of β-secretase (BACE-1) to reduce the levels of Aβ oligomers (AβO) deposition in brain neurons. These plant metabolites reduced the expression of GSK-3β and its receptor gene, PTEN to reduce hyperphosphorylation of tau proteins and neurofibrillary tangles (NFTs) formation. These metabolites improved the expressions of neuroprotective proteins, Bcl-2 via activations of growth-related protein-1 receptor (GLP-1R), PKC, MEK, MAPK/PI3K, and AMPK, and suppressed the expressions of pro-apoptotic proteins, Bax and caspase-3. Furthermore, these plant metabolites improved the lysosomal autophagy process by increasing the expression levels of Beclin-1, LC3II and cathepsin B genes for clearance of Aβ and NFT, and increased the expression of transporter proteins, P-glycoprotein (P-gp) and low density lipoprotein receptor-related protein-1 (LRP-1) for the clearance of Aβ load from brain across the blood-brain barrier (BBB) as well as increased the expression of PPAR-γ and ApoE proteins for clearance of Aβ in ApoE mediated pathway from brain. Moreover, these plant metabolites reduced the cognitive impairment by increasing the expression of synaptic proteins, BDNF, PSD-95, SNAP-25, SYP and GAP-43 for improvement of learning and memory functions in AD. While among these iridoids, catalpol, 10-O-trans-p-coumaroylcatalpol, geniposide and harpagoside, in PD improved the expressions of GDNF and Bcl-2 proteins and TH-positive neurons by increasing the levels of antioxidant enzymes, SOD and GSH-PX and down-regulating insulin/IGF signalling via activation of MEK protein. Moreover, catalpol and its p-coumaroyl derivative in mutant nematode C. elegans model, up-regulated the expression of DAF-16, a FOXO family transcription factor and SKN-1 genes for improvement of lifespan and resistance against oxidative- and other stresses of mutated worms. Furthermore, geniposide increased the expression of autophagy-related LAMP-2A-protein for clearance of LB from dopaminergic neurons in PD brain via improving lysosomal autophagy process. The present review summarizes the neuroprotective activities and molecular mechanisms of these iridoids and secoiridoids, in prevention and/or treatment of both AD and PD. This review will be helpful to find out the research gap on these plant metabolites in this field to use them as potential drugs against these disorders.

RevDate: 2019-03-16

Tzekaki E, Tsolaki M, A Pantazaki (2019)

[Technical characteristics of Alzheimer model based on organ technology (organoid)].

Hellenic journal of nuclear medicine, 22 Suppl:195-208.

Alzheimer's disease (AD) is a serious neurodegenerative disorder that manifests itself as progressive damage to memory and knowledge and is the main cause of dementia in the elderly. AD is characterized by extracellular deposition of amyloid-β plate (Aβ) and by the formation of neurofibrillary tangles, composed of hyperphosphorylated Tau protein. These modifications lead to neuronal cell death, vascular dysfunction and inflammatory disorders. Described as "elderly disease", AD is an escalating threat to developed countries as life expectancy is increasing. Because of its severity, AD has been the subject of extensive studies that address the pathogenesis of the disease. However, its main cause remains unknown. Most research on neurological conditions has been applied to animal models. However, due to their high cost and the uncertain translation of their results to humans along with moral concerns, in recent years, there has been a growing need for in vitro modeling to mimic the brain. The creation of the aforementioned models aims at a better understanding of the factors contributing to the onset of the disease and the faster development of the treatment of diseases affecting the nervous system. Given this need, in this review, new approaches to study neurodegenerative disease were recorded. A three-dimensional (3D) neurosphere-based microfluid chip has been reported and this model imitates the in vivo microenvironment of the brain and provides a steady flow of fluid that is observed in the brain's space. Uniform neurospheres, with cell interactions and contacts in all directions, were formed in a hollow microfuge and a steady interstitial flow rate was maintained using a small pump osmotic system. In this model it was possible to control the toxic effects of amyloid-β. At the end, it was observed that the deposition of amyloid-β through an osmotic micro-pump significantly reduced the viability of the neurospheres and caused destruction of the neuronal networks. Therefore, this model was proposed as an in vitro brain model for neurodegenerative disease and high-throughput drugs.

RevDate: 2019-03-16

Liakakis G (2019)

Biochemical diagnosis of vascular cognitive impairment associated with subcortical small vessels disease.

Hellenic journal of nuclear medicine, 22 Suppl:187-193.

Subcortical small-vessel disease (SSVD) is a disorder that has been fully described in clinical, neuropathological and imaging aspects. It is considered as the most prevalent ischemic CNS disorder and has been associated to arterial hypertension, diabetes mellitus, dyslipidemia and obstructive sleep apnea. The hallmark of SSVD is the ischemic white matter lesions which can be presented as lacunar infracts and global brain hypoperfusion in a common and homogeneous subtype of vascular cognitive impairment (VCI) which is often unrecognized. The special nature and course of SSVD offers the opportunity of collecting knowledge at all stages of its pathogenicity. Arteriosclerosis, hypoxic hypo-perfusion and inflammation act synergistically, causing myelin degeneration and blood brain barrier alteration. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. Brain imaging has advanced substantially the diagnostic tools for SSVD. Diagnostic biomarkers for Alzheimer Disease include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 sometimes with increased total tau levels. However, biomarkers specific for the diagnosis at all stages of SSVD are needed, especially because of the unsatisfactory treatment options at its late stages to date.

RevDate: 2019-04-21

Nday CM, Eleftheriadou D, G Jackson (2019)

Naringin nanoparticles against neurodegenerative processes: A preliminary work.

Hellenic journal of nuclear medicine, 22 Suppl:32-41.

It is well established that during Alzheimer disease (AD), gradual loss of neuronal networks occurs in the brain, consequently, affecting cognition and memory tasks of the patients. Among other causative factors, oxidative stress induces changes that are eventually accompanied by an irreversible disruption of synaptic connectivity and death of neurons. Moreover, aging and oxidative stress cause alterations to the blood brain barrier, leading to increased permeability, which are thought to further aggravate the underlying pathology. Up to date, no effective treatment is available to Alzheimer's disease patients. Lately, scientific efforts are focusing on exploiting the antioxidant properties that natural polyphenol agents such as flavonoids possess and their potential beneficial effect against neurodegenerative diseases. For that reason, the current investigation, aims at developing more effective flavonoid agents by encapsulating naringin into modified PEG 3000 Silica nanoparticles before its use at cellular level. Overall, our findings suggest an enhanced protective capacity of naringin pegylated nanoparticles against Aβ amyloid linked oxidative stress mediated neurodegeneration in primary rat neuronal and glial hippocampal cultures for a certain incubation period. The functional biological reactivities of the novel flavonoid nanoparticles were in line with their physicochemical features and reflect the a) differential nature of the structural assemblies of the new nanoparticles, thereby distinguishing them from other polymeric and liposomal drug carriers, and b) significance and impact of PEG chemistry in the synthetic assembly of the nanocarriers. The ability of the employed nanoparticles to entrap a relatively high dose of otherwise insoluble drugs and their biological activity highlight their potential as brain targeting therapeutics.

RevDate: 2019-06-02

Di Domenico F, Tramutola A, Barone E, et al (2019)

Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome.

Redox biology pii:S2213-2317(18)31010-3 [Epub ahead of print].

Increasing evidences support the notion that the impairment of intracellular degradative machinery is responsible for the accumulation of oxidized/misfolded proteins that ultimately results in the deposition of protein aggregates. These events are key pathological aspects of "protein misfolding diseases", including Alzheimer disease (AD). Interestingly, Down syndrome (DS) neuropathology shares many features with AD, such as the deposition of both amyloid plaques and neurofibrillary tangles. Studies from our group and others demonstrated, in DS brain, the dysfunction of both proteasome and autophagy degradative systems, coupled with increased oxidative damage. Further, we observed the aberrant increase of mTOR signaling and of its down-stream pathways in both DS brain and in Ts65Dn mice. Based on these findings, we support the ability of intranasal rapamycin treatment (InRapa) to restore mTOR pathway but also to restrain oxidative stress resulting in the decreased accumulation of lipoxidized proteins. By proteomics approach, we were able to identify specific proteins that showed decreased levels of HNE-modification after InRapa treatment compared with vehicle group. Among MS-identified proteins, we found that reduced oxidation of arginase-1 (ARG-1) and protein phosphatase 2A (PP2A) might play a key role in reducing brain damage associated with synaptic transmission failure and tau hyperphosphorylation. InRapa treatment, by reducing ARG-1 protein-bound HNE levels, rescues its enzyme activity and conceivably contribute to the recovery of arginase-regulated functions. Further, it was shown that PP2A inhibition induces tau hyperphosphorylation and spatial memory deficits. Our data suggest that InRapa was able to rescue PP2A activity as suggested by reduced p-tau levels. In summary, considering that mTOR pathway is a central hub of multiple intracellular signaling, we propose that InRapa treatment is able to lower the lipoxidation-mediated damage to proteins, thus representing a valuable therapeutic strategy to reduce the early development of AD pathology in DS population.

RevDate: 2019-04-16

Cheng J, Yang H, J Zhang (2019)

Donepezil's Effects on Brain Functions of Patients With Alzheimer Disease: A Regional Homogeneity Study Based on Resting-State Functional Magnetic Resonance Imaging.

Clinical neuropharmacology, 42(2):42-48.

PURPOSE: Donepezil is known to increase cholinergic synaptic transmission in Alzheimer disease (AD), although how it affects cortical brain activity and how it consequently affects brain functions need further clarification. To investigate the therapeutic mechanism of donepezil underlying its effect on brain function, regional homogeneity (ReHo) technology was used in this study.

PATIENTS AND METHODS: This study included 11 mild-to-moderate AD patients who completed 24 weeks of donepezil treatment and 11 matched healthy controls. All participants finished neuropsychological assessment and resting-state functional magnetic resonance imaging scanning to compare whole-brain ReHo before and after donepezil treatment.

RESULTS: Significantly decreased Alzheimer's Disease Assessment Scale-Cognitive Subscale scores (P = 0.010) and increased Mini-Mental State Examination scores (P = 0.043) were observed in the AD patients. In addition, in the right gyrus rectus (P = 0.021), right precentral gyrus (P = 0.026), and left superior temporal gyrus (P = 0.043) of the AD patients, decreased ReHo was exhibited.

CONCLUSION: Donepezil-mediated improvement of cognitive function in AD patients is linked to spontaneous brain activities of the right gyrus rectus, right precentral gyrus, and left superior temporal gyrus, which could be used as potential biomarkers for monitoring the therapeutic effect of donepezil.

RevDate: 2019-05-09

Jarosz-Griffiths HH, Corbett NJ, Rowland HA, et al (2019)

Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-β oligomers.

The Journal of biological chemistry, 294(17):7085-7097.

The cellular prion protein (PrPC) is a key neuronal receptor for β-amyloid oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor. Conversely, siRNA-mediated ADAM10 knockdown reduced PrPC shedding and increased AβO binding, which was blocked by the PrPC-specific antibody 6D11. The retinoic acid receptor analog acitretin, which up-regulates ADAM10, also promoted PrPC shedding and decreased AβO binding in the neuroblastoma cells and in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Pretreatment with acitretin abolished activation of Fyn kinase and prevented an increase in reactive oxygen species caused by AβO binding to PrPC Besides blocking AβO binding and toxicity, acitretin also increased the nonamyloidogenic processing of APP. However, in the iPSC-derived neurons, Aβ and other amyloidogenic processing products did not exhibit a reciprocal decrease upon acitretin treatment. These results indicate that by promoting the shedding of PrPC in human neurons, ADAM10 activation prevents the binding and cytotoxicity of AβO, revealing a potential therapeutic benefit of ADAM10 activation in AD.

RevDate: 2019-04-10

Tantimongcolwat T, Prachayasittikul S, V Prachayasittikul (2019)

Unravelling the interaction mechanism between clioquinol and bovine serum albumin by multi-spectroscopic and molecular docking approaches.

Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy, 216:25-34.

Clioquinol has recently been proposed for the treatment of Alzheimer's disease. It is able to diminish β-amyloid protein aggregation and to restore cognition of Alzheimer's mice. However, its therapeutic benefits for Alzheimer's disease in human remain controversy and need further confirmation. Herein, we have explored the interaction mechanism of clioquinol toward bovine serum albumin (BSA) by means of multi-spectroscopic and docking simulation approaches. Clioquinol interacts with BSA by a combined mechanism of static and dynamic processes. Application of the Hill's equation to fluorescence quenching experiment revealed that the binding constant of the BSA-clioquinol complex is extremely high at 108 M-1 level. Competitive displacement and docking analysis consistently suggested that there are the multiple binding modes of clioquinol toward BSA. Competitive binding study showed that clioquinol shares the binding sites with ibuprofen and digitoxin on albumin, referring to be site II and site III binding compounds. Besides, partial binding in site I was also observed. Docking simulation confirmed that clioquinol favors to bind in site I, site II, site III, fatty acid binding site 5, and the protein cleft between subdomain IB and IIIB of the BSA. Due to its small size and electric dipole property, clioquinol may easily fit in multiple pockets of the BSA. Our finding suggests the potential role of BSA as a clioquinol carrier in the vascular system. Nonetheless, clioquinol-induced BSA aggregation has been observed by the three-dimensional fluorescence technique. This phenomenon may not only impair the BSA, but may also affect other endogenous proteins, which eventually causes adverse effects to human. Therefore, the redesigned or modified molecular structure of clioquinol may reduce its toxicity and improve its bioavailability.

RevDate: 2019-03-29

Alachkar A, Khan N, Łażewska D, et al (2019)

Histamine H3 receptor antagonist E177 attenuates amnesia induced by dizocilpine without modulation of anxiety-like behaviors in rats.

Neuropsychiatric disease and treatment, 15:531-542 pii:ndt-15-531.

Background: Alzheimer disease (AD) is the main cause of dementia in elderly people. The potential of histamine H3 receptor (H3R) antagonists as a pharmacological treatment of several neuropsychiatric diseases is well established.

Methods: The novel non-imidazole-based H3R antagonist E177 was screened for its pro-cognitive effects on the inhibitory avoidance paradigm (IAP) and novel object recognition (NOR) task in a dizocilpine (DIZ)-induced model of amnesia in male Wistar rats. Donepezil, an acetylcholine esterase inhibitor, was used as the reference drug.

Results: Acute systemic treatment with E177 (1.25, 2.5, 5, and 10 mg/kg intraperitoneally [i.p.]) significantly attenuated the cognitive impairments induced by DIZ in the IAP (all P-values <0.05, n=7), and the protective effect of the most promising dose of E177 (5 mg/kg) was abrogated when H3R agonist R-(α)-methylhistamine (RAMH; 10 mg/kg i.p.) was co-administered (P=0.281 for DIZ-amnesia group vs DIZ + E177 + RAMH group, n=7). The discrimination index calculated for E177 (5 mg/kg, i.p.) showed a significant memory-enhancing effect on DIZ-induced short-term memory impairment in the NOR task (P<0.05, n=6), with the enhancement nullified when animals were co-administered RAMH (10 mg/kg). Moreover, the results revealed that E177 (5 and 10 mg/kg, i.p.) did not alter the anxiety levels and locomotor activity of animals naïve to the open-field test (all P-values >0.05, n=8) or the elevated plus maze test (all P-values >0.05, n=6-8), which indicated that the E177-induced enhancement of memory performance in the IAP or NOR task was unrelated to changes in emotional response or in spontaneous locomotor activity.

Conclusion: The observed results suggested a possible contribution of H3Rs in the alteration of brain neurotransmitters that accompany neurodegenerative diseases, such as AD.

RevDate: 2019-03-12

Akbari S, Akrami H, Mostafaei A, et al (2019)

Bowman-Birk inhibitor modifies transcription of autophagy and apoptosis genes in an in vitro model of Alzheimer's disorder.

Journal of cellular biochemistry [Epub ahead of print].

Alzheimer, a current neurodegenerative disorder has adverse effects on memory and behavior. β-Amyloid peptide accumulations are the hallmarks of Alzheimer. Dysfunction of autophagy and apoptosis is detected in Alzheimer's disease. The effect of Bowman-Birk inhibitor (BBI), purified from soybean, was investigated in autophagy and apoptosis in Alzheimer treatment. Treated-PC12 cells with 1000 nM HgCl2 induced amyloid β (Aβ) accumulation. Treatment of PC12 cells with 1000 nM HgCl 2 and then 500 μg/mL BBI could decrease the expression ratio of Bax/Bcl2 and increase the expression of beclin1, Bnip3, Atg5, and autophagy-related genes. These results indicated that BBI could inhibit Aβ accumulation by inducing autophagy, and also the neuroprotective effect was detected through decreasing apoptosis in the in vitro model of Alzheimer's disease. These results provided further evidence for the potential effectiveness of BBI in the treatment of Alzheimer's disease.

RevDate: 2019-03-10

Salimpour Y, WS Anderson (2019)

Cross-Frequency Coupling Based Neuromodulation for Treating Neurological Disorders.

Frontiers in neuroscience, 13:125.

Synchronous, rhythmic changes in the membrane polarization of neurons form oscillations in local field potentials. It is hypothesized that high-frequency brain oscillations reflect local cortical information processing, and low-frequency brain oscillations project information flow across larger cortical networks. This provides complex forms of information transmission due to interactions between oscillations at different frequency bands, which can be rendered with cross-frequency coupling (CFC) metrics. Phase-amplitude coupling (PAC) is one of the most common representations of the CFC. PAC reflects the coupling of the phase of oscillations in a specific frequency band to the amplitude of oscillations in another frequency band. In a normal brain, PAC accompanies multi-item working memory in the hippocampus, and changes in PAC have been associated with diseases such as schizophrenia, obsessive-compulsive disorder (OCD), Alzheimer disease (AD), epilepsy, and Parkinson's disease (PD). The purpose of this article is to explore CFC across the central nervous system and demonstrate its correlation to neurological disorders. Results from previously published studies are reviewed to explore the significant role of CFC in large neuronal network communication and its abnormal behavior in neurological disease. Specifically, the association of effective treatment in PD such as dopaminergic medication and deep brain stimulation with PAC changes is described. Lastly, CFC analysis of the electrocorticographic (ECoG) signals recorded from the motor cortex of a Parkinson's disease patient and the parahippocampal gyrus of an epilepsy patient are demonstrated. This information taken together illuminates possible roles of CFC in the nervous system and its potential as a therapeutic target in disease states. This will require new neural interface technologies such as phase-dependent stimulation triggered by PAC changes, for the accurate recording, monitoring, and modulation of the CFC signal.

RevDate: 2019-04-29
CmpDate: 2019-04-29

Dewey CW, Davies ES, Xie H, et al (2019)

Canine Cognitive Dysfunction: Pathophysiology, Diagnosis, and Treatment.

The Veterinary clinics of North America. Small animal practice, 49(3):477-499.

Canine cognitive dysfunction (CCD) is the canine analog of human Alzheimer disease (AD). The pathophysiology of CCD/AD is multifaceted. CCD is common in aged (>8 years) dogs, affecting between 14% and 35% of the pet dog population. Apparent confusion, anxiety, disturbance of the sleep/wake cycle, and decreased interaction with owners are all common clinical signs of CCD. Although there is no cure for CCD, several proven effective therapeutic approaches are available for improving cognitive ability and maintaining a good quality of life; instituting such therapies early in the disease course is likely to have the greatest positive clinical effect.

RevDate: 2019-04-30

Mesulam MM, Lalehzari N, Rahmani F, et al (2019)

Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology.

Neurology, 92(14):e1580-e1588.

OBJECTIVE: To investigate the status of the basal forebrain cholinergic system in primary progressive aphasia (PPA) as justification for cholinergic therapy.

METHODS: A cohort of 36 brains from PPA participants with the neuropathology of Alzheimer disease (PPA-AD, n = 14) or frontotemporal lobar degeneration (PPA-tau, n = 12; PPA-TDP, n = 10) were used for semiquantitative rating of degeneration and gliosis of basal forebrain cholinergic neurons (BFCN). A subpopulation of 5 PPA-AD and 7 control brains underwent detailed analysis of BFCN pathology and cortical cholinergic axonal loss employing immunohistochemical and histochemical methods and stereologic analysis.

RESULTS: Semiquantitatively, 11 (∼80%) PPA-AD participants were rated as having moderate/severe BFCN loss and gliosis, whereas none of the PPA-tau and only 1 (10%) PPA-TDP participant received such a rating. Detailed analysis in the subpopulation of PPA-AD participants revealed substantial tangle formation, loss of BFCN, and degeneration of cortical cholinergic axons. Compared to controls, loss of p75 low affinity neurotrophin receptor-positive BFCN was detected in the PPA-AD participants (p < 0.01). Acetylcholinesterase-positive cholinergic axons in all cortical areas studied displayed loss in PPA-AD (p < 0.005-0.0001). The loss was more severe in the language-dominant left hemisphere and, within the left hemisphere, in language-affiliated cortical areas.

CONCLUSIONS: Our results demonstrate prominent depletion of BFCN and cortical cholinergic axons in PPA-AD when compared with normal control or other neuropathologic variants of PPA. The demonstration of cholinergic denervation with an anatomy that fits the clinical picture suggests that cholinergic treatment is justified in patients with PPA who have positive AD biomarkers.

RevDate: 2019-03-06

Perna L, Wahl HW, Weberpals J, et al (2019)

Incident depression and mortality among people with different types of dementia: results from a longitudinal cohort study.

Social psychiatry and psychiatric epidemiology pii:10.1007/s00127-019-01683-0 [Epub ahead of print].

PURPOSE: The aim of this study was to investigate the independent and combined association of incident depression and dementia with mortality and to explore whether the magnitude of the association varies according to different types of dementia, including Alzheimer's disease and vascular dementia.

METHODS AND DESIGN: The study was based on a population-based longitudinal cohort consisting of 9940 participants at baseline and followed for over 14 years. The sample used for the analyses included 6114 participants with available information on diagnosis of incident dementia and depression. For survival analyses, Cox regression models with incident dementia (n = 293; 5%) and incident depression (n = 746; 12%) as time-dependent variables were used.

RESULTS: Cox models adjusted for relevant confounders indicated that comorbidity of incident vascular dementia and incident depression was associated with a much higher mortality risk (HR 6.99; 95% CI 3.84-12.75) than vascular dementia in the absence of depression (HR 2.80; 95% CI 1.92-4.08). In contrast, estimates for comorbidity of Alzheimer's disease and depression were slightly lower than those for Alzheimer in absence of depression (HR 3.56; 95% CI 1.83-6.92 and HR 4.19; 95% CI 2.97-5.90, respectively). Incident depression in the absence of incident dementia was only weakly associated with mortality.

CONCLUSIONS: These findings indicate that depression and vascular dementia might have synergistic effects on mortality. The results have relevant public health implications for prevention, routine screening for and early treatment of depression among older people, especially those at risk of vascular dementia.

RevDate: 2019-03-07

Nikmahzar E, Jahanshahi M, Elyasi L, et al (2019)

Human chorionic gonadotropin attenuates amyloid-β plaques induced by streptozotocin in the rat brain by affecting cytochrome c-ir neuron density.

Iranian journal of basic medical sciences, 22(2):166-172.

Objectives: Amyloid β plaques, in Alzheimer's disease, are deposits in different areas of the brain such as prefrontal cortex, molecular layer of the cerebellum, and the hippocampal formation. Amyloid β aggregates lead to the release of cytochrome c and finally neuronal cell death in brain tissue. hCG has critical roles in brain development, neuron differentiation, and function. Therefore, we investigated the effect of hCG on the density of the congophilic Aβ plaque and cytochrome c-ir neurons in the hippocampus, prefrontal cortex, and cerebellum of Streptozotocin (STZ)-treated rats.

Materials and Methods: Alzheimer model in rats (except the control group) was induced by streptozotocin (3 mg/kg, Intracerebroventricularly (ICV)). Experimental group rats received streptozotocin and then different doses of hCG (50, 100, and 200 IU, intraperitoneally) for 3 days. 48 hr after last drug injection and after histological processing, the brain sections were stained by congo red for congophilic amyloid β plaques and cytochrome c in the hippocampus, prefrontal cortex, and cerebellum were immunohistochemically stained.

Results: Density of congophilic Aβ plaques and cytochrome c-immunoreactive neurons was significantly higher in ICV STZ treated rats than controls. Treatment with three doses of hCG significantly decreased the density of congophilic Aβ plaques and cytochrome c-immunoreactive neurons in the rat hippocampus, prefrontal cortex, and cerebellum in ICV STZ-treated rats (P<0.05).

Conclusion: hCG can be useful in AD patients to prevent the congophilic Aβ plaque formation and decrease cytochrome c-immunoreactive neuron density in the brain.

RevDate: 2019-03-04

Pandey S, BK Singh (2019)

De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues through CADD Approaches as an Anti-Alzheimer's.

Current computer-aided drug design pii:CAD-EPUB-96982 [Epub ahead of print].

There are over 44 million persons who suffer with Alzheimer's disease (AD) worldwide. Presently only symptomatic treatments are available for AD but there is no existence of cure. The aim of this study is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy and among the all therapies donepezil used to treat mild-moderate-severe AD. It possesses lowest adverse effects than any other AChEIs and only once-daily dosing is required for the treatment of AD. Therefore donepezil is recognized as a significant prototype for design and development of new drug molecule by using its structural features, optimizing its properties, and improving its activity with the help of CADD approaches. This study also provides an idea about drug-receptor interactions by which we can find a more efficacious molecule with more possibilities for becoming a new drug candidate. In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. Finally 26 compounds have been indicates better inhibitory activity on AChE enzyme and all the screening parameters have also been satisfied by all 26 compounds.

RevDate: 2019-03-02

Schwertner E, Secnik J, Garcia-Ptacek S, et al (2019)

Antipsychotic Treatment Associated With Increased Mortality Risk in Patients With Dementia. A Registry-Based Observational Cohort Study.

Journal of the American Medical Directors Association, 20(3):323-329.e2.

OBJECTIVE: To assess all-cause mortality patients with dementia treated with typical and atypical antipsychotic drugs (APDs).

DESIGN: Registry-based cohort study.

SETTING AND PARTICIPANTS: A total of 58,412 patients diagnosed with dementia and registered in the Swedish Dementia Registry were included in the study. Of the study sample, 2526 of the patients were prescribed APDs. Of these, 602 patients were prescribed typical APDs and 1833 patients were prescribed atypical APDs. Ninety-one patients were prescribed both typical and atypical APDs.

MEASUREMENTS: All-cause mortality based on Swedish Cause of Death Register. Adjusted hazard ratios of mortality were calculated according to class of APDs (typical or atypical) prescribed. Final models were adjusted for age at dementia diagnosis, sex, Charlson comorbidity index, living arrangement, and Mini-Mental State Examination.

RESULTS: In the adjusted models, use of APDs at the time of dementia diagnosis was associated with increased mortality risk in the total cohort (hazard ratio = 1.4; 95% confidence interval 1.3-1.5). After stratifying for dementia types, increased mortality risks associated with APDs were found in patients with Alzheimer's disease, mixed dementia, unspecified dementia, and vascular dementia. Higher risk for mortality was found with typical APDs in patients with mixed and vascular dementia and with atypical APDs in patients with Alzheimer's disease, mixed, unspecified, and vascular dementia. Furthermore, in patients with Alzheimer's disease who had typical APDs, use lower risk of death emerged in comparison with patients with atypical APDs.

CONCLUSIONS/IMPLICATIONS: Both the use of atypical and typical APDs increased the risk of death in patients with dementia even after adjusting for differences in basic characteristics between groups. Although we cannot rule out the influence of residual confounding, these results would seem to add to studies suggesting caution in APD prescription for patients with dementia.

RevDate: 2019-04-01

Karimipour M, Rahbarghazi R, Tayefi H, et al (2019)

Quercetin promotes learning and memory performance concomitantly with neural stem/progenitor cell proliferation and neurogenesis in the adult rat dentate gyrus.

International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 74:18-26.

The decline in neurogenesis is a very critical problem in Alzheimer disease. Different biological activities have been reported for medicinal application of quercetin. Herein, we investigated the neurogenesis potential of quercetin in a rat model of Alzheimer's disease induced by amyloid-beta injection. Rats were randomly divided into Control, Alzheimer + Saline and Alzheimer + Quercetin groups. Following the administration of Amyloid-beta, rats in the Alzheimer + Quercetin group received 40 mg/kg/day quercetin orally for one month. Our data demonstrated amyloid-β injection could impair learning and memory processing in rats indicated by passive avoidance test evaluation. We noted that one-month quercetin treatment alleviated the detrimental effects of amyloid-β on spatial learning and memory parameters using Morris water maze analysis. Quercetin was found to increase the number of proliferating neural stem/progenitor cells. Notably, quercetin increased the number of DCX-expressing cells, indicating the active dynamic growth of neural progenitor cells in the dentate gyrus of the hippocampus. We further observed that the quercetin improved the number of BrdU/NeuN positive cells contributed to enhanced adult neurogenesis. Based on our results, quercetin had the potential to promote the expression of BDNF, NGF, CREB, and EGR-1 genes involved in regulating neurogenesis. These data suggest that quercetin can play a valuable role in alleviating Alzheimer's disease symptoms by enhancing adult neurogenesis mechanism.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )