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25 Sep 2020 at 01:34
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Bibliography on: Alzheimer Disease — Treatment


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RJR: Recommended Bibliography 25 Sep 2020 at 01:34 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: 2020-09-24

Sun K, Jing X, Guo J, et al (2020)

Mitophagy in degenerative joint diseases.

Autophagy [Epub ahead of print].

Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the maintenance of mitochondria homeostasis and function is important. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, functions to maintain mitochondrial quality control and homeostasis. IVDD and OA are similar joint diseases involving the degradation of cartilaginous tissues that are mainly caused by oxidative stress, cell apoptosis and extracellular matrix (ECM) degradation. Over the past decade, accumulating evidence indicates the essential role of mitophagy in the pathogenesis of IVDD and OA. Importantly, strategies by the regulation of mitophagy exert beneficial effects in the pre-clinical experiments. Given the importance and novelty of mitophagy, we provide an overview of mitophagy pathways and discuss the roles of mitophagy in IVDD and OA. We also highlight the potential of targeting mitophagy for the treatment of degenerative joint diseases. Abbreviations: AD: Alzheimer disease; AF: annulus fibrosus; ADORA2A/A2AR: adenosine A2a receptor; AMBRA1: autophagy and beclin 1 regulator 1; BMSCs: bone marrow mesenchymal stem cells; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CDH6: cadherin 6; CEP: cartilaginous endplates; circRNA: circular RNA; DNM1L/DRP1: dynamin 1-like; ECM: extracellular matrix; HIF1A: hypoxia inducible factor 1: alpha subunit; IL1B: interleukin 1 beta; IMM: inner mitochondrial membranes; IVDD: intervertebral disc degeneration; MAPK8/JNK: mitogen-activated protein kinase 8; MFN1: mitofusin 1; MFN2: mitofusin 2; MIA: monosodium iodoacetate; RHOT/MIRO: ras homolog family member T; MMP: mitochondrial transmembrane potential; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NFE2L2: nuclear factor: erythroid 2 like 2; NP: nucleus pulposus; OA: osteoarthritis; OPA1: OPA1: mitochondrial dynamin like GTPase; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PD: Parkinson disease; PGAM5: PGAM family member 5; PPARGC1A/PGC-1A: peroxisome proliferator activated receptor: gamma: coactivator 1 alpha; PHF23: PHD finger protein 23; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SfMSCs: synovial fluid MSCs; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SIRT3: sirtuin 3; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; Ub: ubiquitin; UBL: ubiquitin-like; VDAC: voltage-dependent anion channel.

RevDate: 2020-09-22

Ibrahim MA, Haleem M, AbdelWahab SA, et al (2020)

Sildenafil ameliorates Alzheimer disease via the modulation of vascular endothelial growth factor and vascular cell adhesion molecule-1 in rats.

Human & experimental toxicology [Epub ahead of print].

Alzheimer disease (AD) is a chronic neurodegenerative disease with multi-pathways pathogenesis. Sildenafil is a selective phosphodiesterase-5 inhibitor with a potential benefit in the treatment of AD. This study investigated the possible mechanisms underlying the effect of sildenafil in AD with emphasis on vascular endothelial growth factor (VEGF), and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four adult male rats were classified into four groups; control group: received vehicles, sildenafil-control: received sildenafil (15 mg/kg/day, p.o.), AD group received Aluminum (25 mg/kg/day, p.o.), AD-treated group: received sildenafil (15 mg/kg/day, p.o.) for 6 weeks. AD was assessed by memory performance test and confirmed by histopathological examination and immunostaining of, neurogenesis marker nestin and α-synuclein. The levels of VEGF-A, VCAM-1, oxidative stress markers and TNF-α in brain tissue were evaluated. AD rats showed histopathological evidences of AD; along with increased latency time in the memory test. There was a decrease in VEGF-A, and an increase in VCAM-1, TNF-α, and oxidative stress markers. Immunohistochemical study showed a significant increase in α-synuclein and a significant decrease in nestin expressions in brain tissues. Sildenafil administration ameliorated the histopathological changes and decreased latency time. Such effect was associated with a decrease in VCAM-1, TNF-α and oxidative stress as well as an increase in VEGF-A. Sildenafil caused a significant increase in nestin and a decrease in α-synuclein immunostaining. These findings suggested a protective effect of sildenafil via modulation of VEGF-A, and VCAM-1.

RevDate: 2020-09-22

Wu B, Cai H, Tang S, et al (2020)

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics pii:10.1007/s13311-020-00930-6 [Epub ahead of print].

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.

RevDate: 2020-09-22

Mishra J, Kumar B, Pandey M, et al (2020)

Carbon Nano Tubes: Novel drug delivery system in amelioration of Alzheimer's disease.

Combinatorial chemistry & high throughput screening pii:CCHTS-EPUB-110064 [Epub ahead of print].

BACKGROUND: Alzheimer's disease is an irreversible, progressive brain disorder manifested with symptoms like loss of memory (known as dementia), personality changes, loss of cognition, impaired movement, confusion, deteriorated planning and thought process. Neurodegeneration in Alzheimer's disease is the result of deposition of protein beta-amyloid that forms plaques and another protein called tau, forming tangles that prevent proper functioning of nerve cells in the brain.

METHODS: The goal of the review was to comprehensively study the utilization of nanotechnology and the role that carbon nanotubes can play as a drug delivery system for amelioration of Alzheimer's disease.

RESULTS: Nanotechnology is one of the most researched domains of modern science. It contributes significantly to therapeutics by facilitating drug therapy to reach the target sites, which are otherwise difficult to reach with conventional drug delivery systems. Carbon nanotubes are the allotropes of carbon in which several carbon atoms bind with each other to form a cylindrical or a tube-like structure. The carbon nanotubes possess several unique qualities, which confers them with a high potential of being utilized as an efficient drug delivery system. They offer high drug loading, can readily cross the toughest biological barriers like BBB. Carbon nanotubes also facilitate the passage of drugs to the brain via the olfactory route, which further helps in restoring normal autophagy, thus preventing the elimination of autophagic chemicals. They can carry a vast range of cargos, including drugs, antigens, genetic materials, and biological macromolecules.

CONCLUSION: Carbon nanotubes are highly promising drug delivery system for anti-Alzheimer's drugs. They have potential of overcoming the various biological barriers like BBB. However, more extensive research is required so as to set up a firm base for development of advanced commercial products based on carbon nanotubes for treatment of Alzheimer's disease.

RevDate: 2020-09-22

Kainuma M, Funakoshi K, Ouma S, et al (2020)

The efficacy and safety of hachimijiogan for mild Alzheimer disease in an exploratory, open standard treatment controlled, randomized allocation, multicenter trial: A study protocol.

Medicine, 99(38):e22370.

BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done.

METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021.

DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD.

TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018).

RevDate: 2020-09-18

Lorettu L, Carpita B, Nivoli A, et al (2020)

Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis.

Clinical neuropharmacology, 43(5):158-161.

Although lithium is widely used as a first-line treatment for mood disorders, its mood-stabilizing effects remain not fully understood. A growing body of data are stressing that lithium seems to show broader properties, including neuroprotective effects. Lithium's ability to inhibit glycogen synthase kinase 3β, an enzyme that participates in the phosphorylation of τ, a microtubule-associated protein, stimulated interest in its possible therapeutic role in Alzheimer disease and other neurodegenerative disorders. Preliminary data also support exploration of lithium's potential therapeutic role in multiple sclerosis, an autoimmune disorder that is associated with co-occurring mood disorders. Lithium is associated with teratogenic risks to the developing fetus; however, recently revised downward estimates of its teratogenic risk of causing fetal cardiac malformation suggest that its potential therapeutic benefit to both mothers with bipolar disorder and their offspring should be considered in at least some cases. A 43-year-old woman previously diagnosed with bipolar disorder and MS was treated with lithium and thyroid hormone supplementation as her sole medications during her pregnancy. The patient remained euthymic throughout her pregnancy and over the course of her 5-year follow-up evaluations on this medication regimen. In addition to her stable mood, there has been no symptomatic progression or relapse of her MS, and her daughter continues to develop normally.The case supports consideration of balancing lithium's mood-stabilizing benefit with its known teratogenic risk during pregnancy. The case also supports exploration of possible additional benefit in the context of MS co-occurring with bipolar disorder.

RevDate: 2020-09-18

Peng HB, Noh K, Pan SR, et al (2020)

Human Amyloid-β40 Kinetics after Intravenous and Intracerebroventricular Injections and Calcitriol Treatment in Rats In Vivo.

Drug metabolism and disposition: the biological fate of chemicals, 48(10):944-955.

Amyloid-β peptides of 40 and 42 amino acid lengths, which are synthesized in neurons and degraded in the brain and liver, have the potential to aggregate and form neuritic plaques in Alzheimer disease. The kinetics of human amyloid-β (hAβ) 40 were examined in the rat pursuant to intravenous and intracerebroventricular administration after pretreatment with calcitriol, the active vitamin D receptor ligand (6.4 nmol·kg-1 in 0.3 ml corn oil every other day for four intraperitoneal doses) to induce P-glycoprotein (P-gp) and enhance hAβ40 brain efflux. The interference of hAβ40 by media matrix that suppressed absorbance readings in the ELISA assay was circumvented with use of different calibration curves prepared in Standard Dilution Buffer, undiluted, 10-10,000 or 5-fold diluted plasma, or artificial cerebrospinal fluid. Simultaneous fitting of hAβ40 plasma and cerebrospinal fluid (CSF) data after intravenous and intracerebroventricular administration were described by catenary-mammillary models comprising of a central and two peripheral compartments, the brain, and one to four CSF compartments. The model with only one CSF compartment (model I) best fitted the intravenous data that showed a faster plasma decay t1/2 and slower equilibration between plasma and brain/CSF. Calcitriol induction increased the brain efflux rate constant, k41 (1.8-fold), at the blood-brain barrier when compared with the control group, as confirmed by the 2-fold (P < 0.05) increase in brain P-gp relative protein expression. SIGNIFICANCE STATEMENT: An accurate description of the kinetic behavior of human amyloid-β (hAβ) 40 is needed in defining the toxic peptide as a biomarker of Alzheimer disease. Modeling of hAβ40 data after intravenous and intracerebroventricular administration to the rat revealed an initially faster plasma half-life that reflected faster peripheral distribution but slower equilibration between plasma and brain/cerebrospinal fluid even with calcitriol pretreatment that increased P-glycoprotein protein expression and enhanced efflux clearance from brain.

RevDate: 2020-09-17

Vaz M, S Silvestre (2020)

Alzheimer's disease: Recent treatment strategies.

European journal of pharmacology pii:S0014-2999(20)30646-4 [Epub ahead of print].

Alzheimer Disease (AD) is a neurodegenerative disease characterized by two neuropathological hallmarks: extracellular deposition of amyloid plaques and intracellular neurofibrillary tangles. Current treatment for AD (donepezil, galantamine, rivastigmine and memantine) is only symptomatic and has modest benefits. Thus, the development of drugs with the potential to change the progression of the disease has been a priority. Therapies targeting amyloid β have been the focus for almost 30 years. However, highly promising drugs recently failed to show clinical benefits in phase III trials. Even the positive findings presented by Biogen on Aducanumab are not entirely clear and further data is necessary to confirm its validity. Therefore, researchers are turning their efforts around to tau-targeting therapies, since tau protein appears to be better correlated with the severity of cognitive decline than amyloid β. Currently, most anti-tau agents in clinical trials are immunotherapies and they are in the early stages of clinical research. Four monoclonal antibodies anti-tau (Gosuranemab, Tilavonemab, Semorinemab and Zagotenemab) and one anti-tau vaccine (AADvac1) have reached phase II, so far. In this review, we discuss the potential disease-modifying agents tested in clinical trials and update the information of drugs that are still under clinical evaluation.

RevDate: 2020-09-17

Ballard C, Aarsland D, Cummings J, et al (2020)

Drug repositioning and repurposing for Alzheimer disease.

Nature reviews. Neurology pii:10.1038/s41582-020-0397-4 [Epub ahead of print].

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.

RevDate: 2020-09-16

Semenov VE, Zueva IV, Mukhamedyarov MA, et al (2020)

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease.

Molecules (Basel, Switzerland), 25(18): pii:molecules25184191.

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.

RevDate: 2020-09-15

Elzoghby AO, Abdelmoneem MA, Hassanin IA, et al (2020)

Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand.

Biomaterials, 263:120355 pii:S0142-9612(20)30601-3 [Epub ahead of print].

Recent progress in protein-based nanomedicine, inspired by the success of Abraxane® albumin-paclitaxel nanoparticles, have resulted in novel therapeutics used for treatment of challenging diseases like cancer and viral infections. However, absence of specific drug targeting, poor pharmacokinetics, premature drug release, and off-target toxicity are still formidable challenges in the clinic. Therefore, alternative protein-based nanomedicines were developed to overcome those challenges. In this regard, lactoferrin (Lf), a glycoprotein of transferrin family, offers a promising biodegradable well tolerated material that could be exploited both as an active therapeutic and drug nanocarrier. This review highlights the major pharmacological actions of Lf including anti-cancer, antiviral, and immunomodulatory actions. Delivery technologies of Lf to improve its pries and enhance its efficacy were also reviewed. Moreover, different nano-engineering strategies used for fabrication of drug-loaded Lf nanocarriers were discussed. In addition, the use of Lf for functionalization of drug nanocarriers with emphasis on tumor-targeted drug delivery was illustrated. Besides its wide application in oncology nano-therapeutics, we discussed the recent advances of Lf-based nanocarriers as efficient platforms for delivery of anti-parkinsonian, anti-Alzheimer, anti-viral drugs, immunomodulatory and bone engineering applications.

RevDate: 2020-09-15

Roda AR, Montoliu-Gaya L, Serra-Mir G, et al (2020)

Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice.

International journal of molecular sciences, 21(18): pii:ijms21186630.

Alzheimer's disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice.

RevDate: 2020-09-14

Wang M, Peng H, Peng Z, et al (2020)

Efficacy and safety of ginkgo preparation in patients with vascular dementia: A protocol for systematic review and meta-analysis.

Medicine, 99(37):e22209.

BACKGROUND: Vascular dementia has become the second most common type of dementia after Alzheimer disease. At present, there is no uniform standard for VaD treatment guidelines among countries. The efficacy of ginkgo biloba in the treatment of vascular dementia is still controversial. The purpose of this study is to evaluate the effectiveness and safety of ginkgo biloba in the treatment of vascular dementia through meta-analysis.

METHODS: Six English databases (PubMed, Web of science, Medline, EBASE, Springer Cochrane Library, and WHO International Clinical Trials Registry Platform) and 4 Chinese databases (Wan fang Database, Chinese Scientific Journal Database, China National Knowledge Infrastructure Database(CNKI) and Chinese Biomedical Literature Database) will be searched normatively according to the rule of each database from the inception to August 1, 2020. Two reviewers will independently conduct article selection, data collection, and risk of bias evaluation. Any disagreement will be resolved by discussion with the third reviewer. Either the fixed-effects or random-effects model will be used for data synthesis based on the heterogeneity test. The change in the scores on mini-mental state examination, activity of daily living scale and Montreal cognitive assement will be used as the main outcome measure, Hamilton depression scale, Hastgawa dementia scale, blessed dementia scale, clinical dmentia rating scale as the secondary outcome. Treatment emergent symptom scale, general physical examination (temperature, pulse, respiration, blood pressure), Routine examination of blood, urine and stool, electrocardiogram, liver and kidney function examination as the security indexs. RevMan5.3.5 will be used for meta-analysis.

RESULTS: This study will provide high-quality evidence to assess the effectiveness and safety of ginkgo preparation for vascular dementia.

CONCLUSION: This systematic review will explore whether ginkgo preparation is an effective and safe intervention for vascular dementia.

ETHICS AND DISSEMINATION: Ethical approval are not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and will be shared on social media platforms. This review will be disseminated in a peer-reviewed journal or conference presentation.


RevDate: 2020-09-14

Wang H, Yu H, Song K, et al (2020)

Traditional Chinese medicine for mild cognitive impairment: A protocol for systematic review and network meta-analysis.

Medicine, 99(37):e22187.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer disease, which is the most common form of dementia in the world. In clinical practice, traditional Chinese medicine (TCM) interventions have been administered for MCI, However, there is still uncertain about what strategy of TCM interventions treatment should be preferred in clinical practice. This study aims to evaluate the efficacy and acceptability of different TCM therapies through systematic review and network meta-analysis.

METHODS: According to the strategy, the authors will retrieve a total of 7 electronic databases by August 2020, including PubMed, the Cochrane Library, EMbase, China National Knowledge Infrastructure, China Biological Medicine, Chongqing VIP, and Wan-fang databases. After a series of screening, 2 researchers will use Aggregate Data Drug Information System and Stata software to analyze the data extracted from the randomized controlled trials of TCM therapies for MCI. The primary outcome of this study is the improvement of cognitive function and the secondary outcome is the activities of daily living, clinical efficacy, and adverse events, and the quality of the evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument.

RESULTS: This study will provide a reliable evidence for the selection of TCM therapies in the treatment of MCI.

CONCLUSION: This study will generate evidence for different TCM therapies for MCI and provide a decision-making reference for clinical research.

ETHICS AND DISSEMINATION: This study does not require ethical approval. The results will be disseminated through a peer-reviewed publication.


RevDate: 2020-09-14

Vecchierini MF, Kilic-Huck U, Quera-Salva MA, et al (2020)

Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS).

Revue neurologique pii:S0035-3787(20)30656-1 [Epub ahead of print].

The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.

RevDate: 2020-09-13

Elibol B, Beker M, Terzioglu-Usak S, et al (2020)

Thymoquinone administration ameliorates Alzheimer's disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta1-42 infused rat model.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 79:153324 pii:S0944-7113(20)30156-2 [Epub ahead of print].

BACKGROUND: Thymoquinone (TQ), a biologically active ingredient of Nigella sativa, has anti-inflammatory, anti-oxidative and neuroprotective properties. Therefore, it could be a good candidate in the recovery of Alzheimer`s disease (AD) pathology rather than current symptomatic reliefs.

PURPOSE: In the present study, we examined the molecular healing effects of TQ in amyloid beta 1-42 (Aβ1-42) peptide-infused AD rat hippocampus.

STUDY DESIGN: A micro-osmotic pump containing aggregated Aβ1-42 was cannulated into the hippocampus of adult female rats. After two weeks infusion, the dose of TQ (10 mg/kg or 20 mg/kg) was determined according to the HPLC results of cerebrospinal fluid and TQ was given to rats intragastrically for 15 days.

METHODS: The memory performance of rats was determined by Morris water maze test. Afterwards, the acetylcholinesterase (AChE) level were measured by ELISA. Histopathological examinations of hippocampal tissue were performed for cell survival by Nissl staining, for detection of amyloid plaque deposits by Congo red staining and for determination of degenerating neurons by Fluoro Jade C staining. MicroRNA/mRNA levels and protein expressions of AD-related genes and proteins were analyzed by Real-Time Polymerase Chain Reaction and Western Blotting, respectively.

RESULTS: Administration of TQ enhanced the memory performance of Aβ1-42 infused rats and it also ameliorated the neuronal loss in the cornu ammonis (CA1), but not in the dentate gyrus (DG). In addition, TQ treatment decreased the fibril deposition whose accumulation was significantly higher in the Aβ1-42-infused animals compared to that of the control group. The expression profiles of mir29c and Bax which significantly upregulated in the Aβ1-42-infused animals were attenuated by TQ. Furthermore, administration of TQ decreased the expressions of Aβ, phosphorylated-tau, and BACE-1 proteins. There was no significant therapeutic effect of TQ on the AKT/GSK3β or MAPK signaling pathways which were affected due to Aβ1-42 infusion.

CONCLUSION: TQ has the capacity to recover the neuropathology by removing Aβ plaques and by restoring neuron viability. All might have established the molecular basement of the consolidation in the memory observed by means of TQ treatment.

RevDate: 2020-09-12

Flores J, Noël A, Foveau B, et al (2020)

Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.

Nature communications, 11(1):4571 pii:10.1038/s41467-020-18405-9.

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.

RevDate: 2020-09-11

Guo J, Wang Z, Liu R, et al (2020)

Memantine, Donepezil, or Combination Therapy-What is the best therapy for Alzheimer's Disease? A Network Meta-Analysis.

Brain and behavior [Epub ahead of print].

INTRODUCTION: Alzheimer's disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple treatment comparison meta-analysis assessed the efficacy of these regimens and placebo in the management of AD.

METHODS: We searched PubMed, Embase, the Cochrane Library, and Wanfang Med Online and China National Knowledge Infrastructure for English and Chinese publications from the first records to 17 April 2020. Two investigators scanned articles for placebo-controlled trials of memantine and donepezil alone and in combination. We extracted data on the following outcomes: cognition, global assessment, daily activities, neuropsychiatric symptoms, adverse events, and the acceptability and cost of these treatment regimens.

RESULTS: Of 936 records screened, we included 54 trials in this analysis. The combination therapy was more effective in improving cognition (mean difference (MD)-5.01, 95% credible interval (95% Crl) -10.73 to 0.86 in the Alzheimer's Disease Assessment Scale-Cognitive Subscale; MD 9.61, 95% Crl 2.29 to 16.97 in the Severe Impairment Battery), global assessment (MD -2.88, 95% Crl -6.04 to 0.40), daily activities (MD 13.06, 95% Crl -34.04 to 58.92), and neuropsychiatric symptoms (MD -6.84, 95% Crl -10.62 to -2.82) compared with placebo. Memantine was more acceptable than placebo (MD 0.93, 95% Crl 0.69 to 1.22).

CONCLUSIONS: Memantine plus donepezil showed superior outcomes for cognition, global assessment, daily activities, and neuropsychiatric symptoms, but lower acceptability than monotherapy and placebo. Combination therapy may be more cost-effective, because memantine slows the progression of AD.

RevDate: 2020-09-11

Stazi M, O Wirths (2020)

Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer's Disease.

Molecular neurobiology pii:10.1007/s12035-020-02120-z [Epub ahead of print].

Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer's disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.

RevDate: 2020-09-11

Cirrito JR, Wallace CE, Yan P, et al (2020)

Effect of Escitalopram on Aβ levels and plaque load in an Alzheimer mouse model.

Neurology pii:WNL.0000000000010733 [Epub ahead of print].

RATIONALE: Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into amyloid-β (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter , SERT, would suppress Aβ levels in mice.

OBJECTIVES: We hypothesized that acute treatment with ESC would reduce Aβ generation which would be reflected chronically with a significant reduction in Aβ plaque load.

METHODS: We performed in vivo microdialysis and in vivo two-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/PS1 mouse model of Alzheimer's disease treated with vehicle or ESC. We also chronically treated mice with ESC to determine the effect on plaques histologically.

RESULTS: ESC acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of ESC significantly reduced plaque load by 28% and 34% at 2.5 mg/day and 5 mg/day, respectively. ESC at 5mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.

CONCLUSIONS: ESC significantly reduced Aβ in mice similar to previous findings in humans treated with acute dosing of an SSRI.

RevDate: 2020-09-04

Lee J, Jin C, Cho SY, et al (2020)

Herbal medicine treatment for Alzheimer disease: A protocol for a systematic review and meta-analysis.

Medicine, 99(33):e21745.

BACKGROUND: Alzheimer disease (AD) is a leading progressive neurodegenerative disease worldwide, but treating it is challenging in clinical practice. This review is aimed at evaluating the efficacy and safety of herbal medicine for treating AD.

METHODS AND ANALYSIS: We will search for randomized controlled trials related to the effect and safety of herbal medicine for AD in the following databases: PubMed, Cochrane Central Register of Controlled Trials, Excerpta Medica Database, China National Knowledge Infrastructure database, Oriental Medicine Advanced Searching Integrated system, Korean Traditional Knowledge Portal, and Citation Information by National Institute for Informatics. The risk of bias will be evaluated using the Cochrane risk-of-bias assessment tool. After screening the studies, a meta-analysis will be performed. The primary outcome will be the Mini-Mental State Examination score. Secondary outcomes will consist of other scales for cognitive function and other aspects, such as behavioral and psychological symptoms and plasma levels of amyloid-β.

RESULTS: This study will provide the current status of evidence for herbal medicine to treat AD.

CONCLUSION: The results of this review will determine the efficacy and safety of herbal medicine for AD.

ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on a review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print.

TRIAL REGISTRATION NUMBER: Research Registry reviewregistry933.

RevDate: 2020-09-09

Chai X, Zhang W, Li L, et al (2020)

Profile of MIF in Developing Hippocampus: Association With Cell Proliferation and Neurite Outgrowth.

Frontiers in molecular neuroscience, 13:147.

Proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and has been found involved in many neurological diseases such as Alzheimer disease (AD), epilepsy, and multiple sclerosis. Previous studies have shown that MIF is expressed in neocortex, hippocampus, hypothalamus, cerebellum, and spinal cord in adult mice. It is expressed by astrocytes and activates microglias in neuroinflammation. Further studies have shown that MIF is detected in moss fibers of dentate granule cells and in apical dendrites of pyramidal neurons in adult hippocampus. Only NeuroD-positive immature granule neurons but not NeuN-positive mature neurons express MIF. These findings led us eager to know the exact role of MIF in the development of hippocampus. Therefore, we systematically checked the spatial and temporal expression pattern of MIF and characterized MIF-positive cells in hippocampus from mice aged from postnatal day 0 (P0) to 3 months. Our results showed that the lowest level of MIF protein occurred at P7 and mif mRNA increased from P0, reached a peak at P7, and stably expressed until P30 before declining dramatically at 3 months. MIF was localized in fibers of GFAP- and BLBP-positive radial glial precursor cells in dentate gyrus (DG). DCX-expressing newly generated neurons were MIF-negative. Inhibition of MIF by MIF antagonist S, R-3-(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) reduced BrdU-positive cells. Interestingly, MIF was expressed by NeuN-positive GABAergic interneurons including parvalbumin-and Reelin-expressing cells in the DG. Neither NeuN-positive granule cells nor NeuN-positive pyramidal neurons expressed MIF. In transgenic mice, POMC-EGFP-positive immature dentate granule cells and Thy1-EGFP-positive mature granule cells were MIF-negative. Treatment of neuronal cultures with ISO-1 inhibited neurite outgrowth. Therefore, we conclude that MIF might be important for feature maintenance of neural stem cells and neurite outgrowth during hippocampal development.

RevDate: 2020-09-08

Frederiksen KS, Nielsen TR, Appollonio I, et al (2020)

Biomarker counselling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer´s Disease Consortium survey.

International journal of geriatric psychiatry [Epub ahead of print].

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counselling, management, and follow-up in European expert centers diagnosing patients with MCI.

METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's Disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; Southern Europe: 15 centers) with questions on attitudes towards biomarkers and biomarker counselling in MCI and dementia. This included post-biomarker counselling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI.

RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and post-biomarker counselling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI.

CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counselling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-03

Perera G, Mueller C, R Stewart (2020)

Factors associated with slow progression of cognitive impairment following first dementia diagnosis.

International journal of geriatric psychiatry [Epub ahead of print].

BACKGROUND: The rate of decline in cognitive function varies substantially following a dementia diagnosis, with at least some people experiencing little or no change over several years.

METHODS: A retrospective observational study was conducted using data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register. This study included all patients receiving a first dementia diagnosis between 2006-2017, restricted to those with a baseline Mini-Mental State Examination (MMSE) score within 6 months of initial diagnosis of dementia and at least one MMSE score after 3 years post-diagnosis. Slow progression was defined as a change in MMSE score of -1, 0 or an increase at the follow-up point. This group was compared to the remainder with an MMSE decline of -2 or more.

RESULTS: Overall, 682 patients with slow progression were compared to 1,045 with faster progression. In the confounder-adjusted multivariate logistic regression model slow progression was more likely in younger patients (age 65-74 years; odds ratio (OR): 1.18; 95% confidence intervals: 1.04-1.37), males (1.24; 1.01-1.53), those with moderate or severe dementia according to MMSE, patients with mixed-type dementia (2.06; 1.11-3.82) compared to Alzheimer's disease) and less likely in those receiving acetylcholinesterase inhibitor treatment (0.57; 0.46-0.71).

CONCLUSION: Slow dementia progression after diagnosis was common in patients with mixed Alzheimer's and vascular dementia, younger age, males, and non-receipt of AChEIs, possibly suggesting non-Alzheimer pathologies and clarifying such predictors is important, as there is currently very limited information on which to base prognosis estimates in post-diagnosis counselling. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-05

Zhao L, Li Z, Vong JSL, et al (2020)

Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain.

Nature communications, 11(1):4413 pii:10.1038/s41467-020-18249-3.

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.

RevDate: 2020-09-04

Binda A, Murano C, I Rivolta (2020)

Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer's Disease: A State-of-the-Art (2017-2020).

International journal of nanomedicine, 15:6113-6135 pii:231480.

The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer's disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017-2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.

RevDate: 2020-09-01

Maulik M, Vasan L, Bose A, et al (2020)

Amyloid-β regulates gap junction protein Connexin 43 trafficking in cultured primary astrocytes.

The Journal of biological chemistry pii:RA120.013705 [Epub ahead of print].

Altered expression and function of astroglial gap junction protein Connexin 43 (Cx43) has increasingly been associated to neurotoxicity in Alzheimer disease (AD). While earlier studies have examined the effect of increased amyloid-β (Aβ) on Cx43 expression and function leading to neuronal damage, underlying mechanisms by which Aβ modulates Cx43 in astrocytes remain elusive. Here, using mouse primary astrocyte cultures, we have examined the cellular processes by which Aβ can alter Cx43 gap junctions. We show that Aβ25-35 impairs functional gap junction coupling yet increases hemichannel activity. Interestingly, Aβ25-35 increased the intracellular pool of Cx43 with a parallel decrease in gap junction assembly at the surface. Intracellular Cx43 was found to be partly retained in the endoplasmic reticulum-associated cell compartments. However, forward trafficking of the newly synthesized Cx43 that already reached the Golgi was not affected in Aβ25-35 exposed astrocytes. Supporting this, treatment with 4-phenylbutyrate, a well-known chemical chaperone that improves trafficking of several transmembrane proteins, restored Aβ-induced impaired gap junction coupling between astrocytes. We further show that interruption of Cx43 endocytosis in Aβ25-35 exposed astrocytes resulted in their retention at the cell surface in the form of functional gap junctions indicating that Aβ25-35 causes rapid internalization of Cx43 gap junctions. Additionally, in silico molecular docking suggests that Aβ can bind favorably to Cx43. Our study thus provides novel insights into the cellular mechanisms by which Aβ modulates Cx43 function in astrocytes, the basic understanding of which is vital for the development of alternative therapeutic strategy targeting connexin channels in AD.

RevDate: 2020-08-31

Huang WK, Liu CH, Pang ST, et al (2020)

Type of Androgen Deprivation Therapy and Risk of Dementia Among Patients With Prostate Cancer in Taiwan.

JAMA network open, 3(8):e2015189 pii:2770047.

Importance: It remains unclear whether androgen deprivation therapy (ADT) is associated with subsequent dementia risk in patients with prostate cancer. There are limited data regarding dementia risk across ADT types.

Objective: To examine the association between all-cause dementia, including Alzheimer disease (AD), and different ADT types in patients with prostate cancer.

This cohort study used linked data from the Taiwan National Cancer Registry, the National Health Insurance Research Database, and the Taiwan National Death Registry. A cohort of 23 651 patients with newly diagnosed prostate cancer between January 1, 2008, and December 31, 2015, was identified and followed up from 1 year after diagnosis until December 31, 2017. Data analysis was performed between January 2019 and May 2020.

Exposures: Patients who received and did not receive ADT, including gonadotropin-releasing hormone (GnRH) agonists, orchiectomy, or antiandrogen monotherapy.

Main Outcomes and Measures: The primary outcomes were all-cause dementia or AD. Stabilized inverse probability of treatment weighting was used to balance baseline covariates. The association between dementia and various ADT types was examined using the Cox proportional hazards model. Furthermore, a multivariate Cox proportional model with age as the time scale was conducted for complementary comparison.

Results: In the cohort of 23 651 male patients (median [interquartile range] age, 73 [66-79] years), 6904 (29.2%) did not receive ADT, 11 817 (50.0%) received GnRH agonists, 876 (3.7%) received orchiectomy, and 4054 (17.1%) received antiandrogen monotherapy. Overall, 1525 patients were diagnosed with incident dementia (1.72 per 100 person-years) during a median (interquartile range) follow-up of 3.46 (1.92-5.51) years. Compared with those who did not receive ADT, those using antiandrogen monotherapy showed an increased risk of dementia (weighted hazard ratio [HR], 1.34; 95% CI, 1.16-1.55) and AD (weighted HR, 1.52; 95% CI, 1.13-2.04). The risk of dementia was similar between GnRH agonist use or orchiectomy and no ADT use (GnRH agonist: weighted HR, 1.13; 95% CI, 1.00-1.28; orchiectomy: 1.00; 95% CI, 0.74-1.37). Several sensitivity analyses revealed consistent findings for both outcomes.

Conclusions and Relevance: In this study, the use of antiandrogen monotherapy was associated with increased risk of dementia or AD, while GnRH agonist use and orchiectomy had no significant difference compared with patients who did not receive ADT. Further prospective studies are warranted to confirm these findings.

RevDate: 2020-08-31

Gupta S, Nair A, Jhawat V, et al (2020)

Unwinding Complexities of Diabetic Alzheimer by Potent Novel Molecules.

American journal of Alzheimer's disease and other dementias, 35:1533317520937542.

Diabetes mellitus is one of the aggressive disorders in global society. No pharmacotherapy is available for permanent diabetes cure, although management is possible with drugs and physical activities. One of the recent complications noticed in type 2 diabetes mellitus includes diabetes-induced Alzheimer. It has been proposed that the possible diabetes-induced Alzheimer could be of type 3 diabetes. A variety of cross-sectional studies have proved that type 2 diabetes mellitus is one of the factors responsible for the pathophysiology of Alzheimer. New drug molecules developed by pharmaceutical companies with adequate neuroprotective effect have demonstrated their efficacy in treatment of Alzheimer in various preclinical diabetic studies. Patients of type 2 diabetes mellitus may show the benefit with existing drugs but may not cause complete cure. Extensive studies are being carried out to find new drug molecules that show their potential as antidiabetic drug and could treat type 2 diabetes-induced Alzheimer as well. This review provides an overview about the recent advancement in pharmacotherapy of diabetes-induced Alzheimer. The pathomechanistic links between diabetes and Alzheimer as well as neurochemical changes in diabetes-induced Alzheimer are also briefed.

RevDate: 2020-08-31

Li G, Sun X, Wan X, et al (2020)

Lactoferrin-Loaded PEG/PLA Block Copolymer Targeted With Anti-Transferrin Receptor Antibodies for Alzheimer Disease.

Dose-response : a publication of International Hormesis Society, 18(3):1559325820917836 pii:10.1177_1559325820917836.

Last few years, struggles have been reported to develop the nanovesicles for drug delivery via the brain-blood barrier (BBB). Novel drugs, for instance, iAβ5, are efficient to inhibit the aggregates connected to the treatment of Alzheimer disease and are being evaluated, but most of the reports reflect some drawbacks of the drugs to reach the brain in preferred concentrations owing to the less BBB penetrability of the surface dimensions. In this report, we designed and developed a new approach to enhance the transport of drug via BBB, constructed with lactoferrin (Lf)-coated polyethylene glycol-polylactide nanoparticles (Lf-PPN) with superficial monoclonal antibody-functionalized antitransferrin receptor and anti-Aβ to deliver the iAβ5 hooked on the brain. The porcine brain capillary endothelial cells were utilized as BBB typically to examine the framework efficacy and toxicity. The cellular uptake of the immuno-nanoparticles with measured conveyance of the iAβ5 peptide was significantly enhanced and associated with Lf-PPN without monoclonal antibody functionalizations.

RevDate: 2020-08-28

Lorettu L, Carpita B, Nivoli A, et al (2020)

Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis.

Clinical neuropharmacology [Epub ahead of print].

Although lithium is widely used as a first-line treatment for mood disorders, its mood-stabilizing effects remain not fully understood. A growing body of data are stressing that lithium seems to show broader properties, including neuroprotective effects. Lithium's ability to inhibit glycogen synthase kinase 3β, an enzyme that participates in the phosphorylation of τ, a microtubule-associated protein, stimulated interest in its possible therapeutic role in Alzheimer disease and other neurodegenerative disorders. Preliminary data also support exploration of lithium's potential therapeutic role in multiple sclerosis, an autoimmune disorder that is associated with co-occurring mood disorders. Lithium is associated with teratogenic risks to the developing fetus; however, recently revised downward estimates of its teratogenic risk of causing fetal cardiac malformation suggest that its potential therapeutic benefit to both mothers with bipolar disorder and their offspring should be considered in at least some cases. A 43-year-old woman previously diagnosed with bipolar disorder and MS was treated with lithium and thyroid hormone supplementation as her sole medications during her pregnancy. The patient remained euthymic throughout her pregnancy and over the course of her 5-year follow-up evaluations on this medication regimen. In addition to her stable mood, there has been no symptomatic progression or relapse of her MS, and her daughter continues to develop normally.The case supports consideration of balancing lithium's mood-stabilizing benefit with its known teratogenic risk during pregnancy. The case also supports exploration of possible additional benefit in the context of MS co-occurring with bipolar disorder.

RevDate: 2020-08-28

Wei W, Wang Y, Liu Y, et al (2020)

Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice.

Alzheimer's research & therapy, 12(1):102 pii:10.1186/s13195-020-00666-7.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. The important influence of congenital genetic aberrations on the development of AD provides a novel opportunity to initiate prenatal to early postnatal pharmacological treatment to address the role of this critical period of brain development in the disease.

METHODS: We investigated for the first time the effect of oral treatment during prenatal to early postnatal development with a neurotrophic compound, P021 (Ac-DGGLAG-NH2), on neurobehavior and AD-like pathology in 3xTg-AD, a transgenic mouse model of AD. The transgenic and control wild-type female mice were treated from prenatal day 8 to postnatal day 21 with a custom-made diet containing P021 or a vehicle diet, followed by a standard diet. AD-type cognitive function and pathological features were studied during adulthood and old age.

RESULTS: The P021 treatment rescued cognitive deficits at 4 months, reduced abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology-associated sites, and decreased Aβ plaque load at 22 months in 3xTg-AD mice. Prenatal to early postnatal treatment with P021 also ameliorated certain markers of postsynaptic deficits, including PSD-95 levels and CREB activity, and decreased one measure of neuroinflammation, GFAP level in the brain at 4 and 22 months in 3xTg mice.

CONCLUSIONS: These findings suggest that neurotrophic impairment during early development can be one of the etiopathogenic factors of AD and that the neurotrophic peptide mimetic is a potential early prevention strategy for this disease.

RevDate: 2020-08-27

Suresh J, Khor IW, Kaur P, et al (2020)

Shared signaling pathways in Alzheimer's and metabolic disease may point to new treatment approaches.

The FEBS journal [Epub ahead of print].

"A peculiar severe disease process of the cerebral cortex" - the exact words used by Dr. Alois Alzheimer in 1906 to describe a patient's increasingly severe condition of memory loss, changes in personality, and sleep disturbance. A century later, this 'peculiar' disease has become widely known as Alzheimer's disease (AD), the world's most common neurodegenerative disease, affecting more than 35 million people globally. At the same time, its pathology remains unclear and no successful treatment exists. Several theories for AD aetiology have emerged throughout the past century. In this review we focus on the metabolic mechanisms that are similar between AD and metabolic diseases, based on results from genome wide association studies. We discuss signaling pathways involved in both types of disease and look into new optogenetic methods to study the in vivo mechanisms of AD.

RevDate: 2020-08-27

Dehlin M, Kapetanovic M, Svärd A, et al (2020)

[Consequences of Gout and Hyperuricemia].

Lakartidningen, 117: pii:F3HI.

Hyperuricemia (HU) and gout are strongly associated with CVD, associations that are most likely due to shared etiologies rather than causality. HU is for example causally related to the metabolic syndrome and in particular to obesity. Gout and HU can both be caused by and lead to decreased kidney function. On the other hand, there are observational data suggesting that HU may protect against neurodegenerative diseases such as Alzheimer and Parkinson's disease. Ongoing RCTs with urate and urate lowering therapy (ULT) will help to resolve some of these controversies. Nevertheless, gout is a "curable disease" by ULT, a treatment which in adequate doses may also have positive effect on several associated co-morbidities.

RevDate: 2020-08-27

Izrael M, Slutsky SG, M Revel (2020)

Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease.

Frontiers in neuroscience, 14:824.

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, characterized by a progressive loss of motor neurons that eventually leads to paralysis and death. The current ALS-approved drugs modestly change the clinical course of the disease. The mechanism by which motor neurons progressively degenerate remains unclear but entails a non-cell autonomous process. Astrocytes impaired biological functionality were implicated in multiple neurodegenerative diseases, including ALS, frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer disease (AD). In ALS disease patients, A1 reactive astrocytes were found to play a key role in the pathology of ALS disease and death of motor neurons, via loss or gain of function or acquired toxicity. The contribution of astrocytes to the maintenance of motor neurons by diverse mechanisms makes them a promising therapeutic candidate for the treatment of ALS. Therapeutic approaches targeting at modulating the function of endogenous astrocytes or replacing lost functionality by transplantation of healthy astrocytes, may contribute to the development of therapies which might slow down or even halt the progression ALS diseases. The proposed mechanisms by which astrocytes can potentially ameliorate ALS progression and the status of ALS clinical studies involving astrocytes are discussed.

RevDate: 2020-08-25

Wong W (2020)

Economic burden of Alzheimer disease and managed care considerations.

The American journal of managed care, 26(8 Suppl):S177-S183.

Alzheimer disease is the most common cause of dementia and the fifth leading cause of death in adults older than 65 years. The estimated total healthcare costs for the treatment of Alzheimer disease in 2020 is estimated at $305 billion, with the cost expected to increase to more than $1 trillion as the population ages. Most of the direct costs of care for Alzheimer disease are attributed to skilled nursing care, home healthcare, and hospice care. Indirect costs of care, including quality of life and informal caregiving, are likely underestimated and are associated with significant negative societal and personal burden. Managed care organizations are in a unique position to develop utilization strategies that would positively impact early diagnosis and treatment to lead to better outcomes and lower costs for patients, caregivers, and the healthcare system. Additionally, the recent inclusion of Alzheimer disease diagnoses into risk corridor calculations by the Centers for Medicare & Medicaid Services may encourage Medicare Advantage organizations to invest in programs that aid in its early detection and diagnosis.

RevDate: 2020-08-25

Marasco RA (2020)

Current and evolving treatment strategies for the Alzheimer disease continuum.

The American journal of managed care, 26(8 Suppl):S167-S176.

The burden of Alzheimer disease (AD) on the US healthcare system is substantial and increasing. AD progresses along a continuum from preclinical disease characterized by normal cognition and abnormal brain biomarkers to mild cognitive impairment and then clinically apparent dementia. Diagnosis early in the AD continuum has benefits for patients and caregivers and appears cost-effective, but often, the clinical diagnosis of AD may be delayed. Currently available biomarkers include β-amyloid positron emission tomography and cerebrospinal fluid tests. Collectively, they are expensive, may lead to adverse effects, are not widely available, and are not suited for primary care. Currently available treatment options, cholinesterase inhibitors and memantine, do not alter disease progression, but can help with some symptoms. Benefits of currently available treatments on cognition are difficult to quantify and are offset by a burden of adverse effects that often go unrecognized. More accurate diagnostic biomarkers and disease-modifying drug therapies are critical unmet needs of patients with AD despite decades of clinical research. Because many phase 3 clinical trials that enrolled patients with symptomatic AD have failed, researchers believe that disease-modifying treatment is more likely to demonstrate benefit when utilized early in the disease continuum. Within the past few years, significant achievements that will advance clinical trials in early AD include the Research Framework to define and stage the AD continuum, FDA guidance on study design in early AD, and development of scales to measure cognition that are suitable for early AD. In October 2019, the AD community was re-invigorated by unexpected news that a Biologics License Application will be submitted for aducanumab to treat AD. This article explores the current state of biomarker-driven drug development across the AD continuum and reviews investigational drugs in phase 2/3 clinical development for AD.

RevDate: 2020-08-24

Xuan WT, Wang H, Zhou P, et al (2020)

Berberine ameliorates rats model of combined Alzheimer's disease and type 2 diabetes mellitus via the suppression of endoplasmic reticulum stress.

3 Biotech, 10(8):359.

This study is aimed to investigate the protective effect against type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) of Berberine (BBR), and the underlying mechanism of action is explored. We established a rat model of combined AD and T2DM and used it to investigate the effect of BBR (150 mg/kg) on the course of these pathologies. The Morris water maze, biochemical analysis, hematoxylin-eosin staining, immunohistochemical study, immunofluorescent staining, TUNEL assay, RT-qPCR and western blot were used to reveal the effect of BBR on blood glucose, lipid changes, hippocampal injuries and cognitive impairment. The results showed that BBR could alleviate memory deficits, restore the disordered arrangement of nerve cells, the damage of neurons, improve TUNEL-positive cells and decrease the elevated levels of fasting blood glucose, triglyceride, total cholesterol and glycosylated serum protein levels in Alzheimer diabetic rats. Moreover, BBR treatment reduces the transcription of mRNAs and expression of proteins related to endoplasmic reticulum (ER) stress. These findings conclude that BBR can protect neurons by inhibiting the pathway of ER stress and thereby play an essential role in the preventive and therapeutic of AD and T2DM.

RevDate: 2020-08-24

Wadhwa P, Jain P, HR Jadhav (2020)

Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors.

Current topics in medicinal chemistry, 20(17):1522-1534.

Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer's disease as it is involved in tau phosphorylation. Due to its high specificity concerning substrate recognition, GSK3 has been considered as an important target. In the last decade, several GSK3 inhibitors have been reported and two molecules are in clinical trials. This review collates the information published in the last decade about the role of GSK3 in Alzheimer's disease and progress in the development of its inhibitors. Using this collated information, medicinal chemists can strategize and design novel GSK3 inhibitors that could be useful in the treatment of Alzheimer's disease.

RevDate: 2020-08-21

Pandey M, Choudhury H, Verma RK, et al (2020)

Nanoparticles Based Intranasal Delivery of Drug to Treat Alzheimer's Disease: A Recent Update.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-109274 [Epub ahead of print].

Alzheimer Association Report (2019) stated that the 6th primary cause of death in the USA is Alzheimer's disease (AD) which leads to behaviour and cognitive impairment. Nearly 5.8 million peoples of all ages in the USA have suffered from this disease, including 5.6 million elderly populations. The statistics of the progression of this disease is similar to the global scenario. Still, the treatment of AD is limited to a few conventional oral drugs which often fail to deliver the adequate amount of drug in the brain. The reduction in the therapeutic efficacy of anti-AD drug is due to poor solubility, existence to the blood-brain barrier and low permeability. In this context, nasal drug delivery emerges as a promising route for the delivery of large and small molecular drugs for the treatment of AD. This promising pathway delivers the drug directly into the brain via an olfactory route which leads to the low systemic side effect, enhanced bioavailability, and higher therapeutic efficacy. However, few setbacks such as mucociliary clearance and poor drug mucosal permeation limit its translation from the laboratory to the clinic. Above stated limitation could be overcome by the adaption of nanoparticle as a drug delivery carrier which may lead to prolong delivery of drugs with better permeability and high efficacy. This review highlights the latest work on the development of promising nanoparticles (NPs) via intranasal route for the treatment of AD. Additionally, the current update in this article will drag the attention of the researcher working on these fields and facing challenges in practical applicability.

RevDate: 2020-08-19

Singh M, Singh SP, Yadav D, et al (2020)

Targeted delivery for neurodegenerative disorders using gene therapy vectors: Gen next therapeutic goals.

Current gene therapy pii:CGT-EPUB-109175 [Epub ahead of print].

The technique of gene therapy, ever since its advent nearly fifty years ago, has been utilized by scientists as a po-tential treatment option for various disorders. This review discusses some of the major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), Motor neuron diseases (MND), Spinal muscular atrophy (SMA), Huntington's disease (HD), Multiple sclerosis (MS) etc. and their underlying genetic mechanisms along with therole that gene therapy can play in combating them. The pathogenesis and the molecular mechanisms specifying the altered gene ex-pression of each of these NDDs has also been discussed in elaboration. The use of gene therapy vectors can prove to be an effective tool in the field of curative modern medicine for the generations to come. Therefore, consistent efforts and pro-gressive research towards its implementation can provide us with powerful treatment options for disease conditions that have so far been considered as incurable.

RevDate: 2020-08-12

Övey İS, M Nazıroğlu (2020)

Effects of homocysteine and memantine on oxidative stress related TRP cation channels in in-vitro model of Alzheimer's disease.

Journal of receptor and signal transduction research [Epub ahead of print].

Memantine (MEM) has been used to treat patients with Alzheimer' disease though inhibition of reactive oxygen species (ROS), Ca2+ entry and glutamate receptor. The Ca2+ permeable TRPA1, TRPM2 and TRPV1 channels are activated in the hippocampus by ROS, and antioxidant MEM as a potent TRPA1, TRPM2 and TRPV1 channel antagonist may reduce Aβ-induced oxidative stress and apoptosis in the neurons. In the current study, we investigated the neuroprotective properties of MEM in Aβ-induced hippocampal neuron cultures. Freshly isolated hippocampal neurons of mice were divided into eight groups as control, Aβ, Hcy, MEM, Aβ + Hcy, Aβ + Hcy + MEM, Aβ + MEM and Hcy + MEM. The neurons were exposed to incubated with Aβ (20 µM for 24 h), Hcy (250 µM for 30 min) and MEM (10 µM for 24 h). TRPA1, TRPM2 and TRPV1 of the eight groups were further stimulated by cinnamaldehyde, cumene hydyroperoxide and capsaicin, respectively although they were further inhibited by AP-18, N-(p-Amylcinnamoyl) anthranilic acid (ACA) and capsazepine (CPZ). The [Ca2+] concentration, apoptosis, caspase 3, caspase 9 activations, mitochondrial membrane depolarization and intracellular ROS production values in the neurons were higher in Aβ and Hcy groups than in control although they were lower in the MEM group than in Aβ and Hcy groups. The values were further decreased by MEM + AP-18, MEM + CPZ and MEM + ACA treatments as compared to MEM only. Aβ and Hcy-induced decrease of cell viability level was increased by MEM treatment although Aβ and Hcy-induced increase of caspase 3, caspase 9, PARP1, TRPA1, TRPM2 and TRPV1 expression levels were decreased by MEM treatments. In conclusion, TRPA1, TRPM2 and TRPV1 channels are involved in Aβ and Hcy-induced neuronal death, and modulation of the activity of these channels by MEM treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca2+ entry.

RevDate: 2020-08-10

Haghighijoo Z, Akrami S, Saeedi M, et al (2020)

N-Cyclohexylimidazo[1,2-a]pyridine derivatives as multi-target-directed ligands for treatment of Alzheimer's disease.

Bioorganic chemistry, 103:104146 pii:S0045-2068(20)31443-7 [Epub ahead of print].

Alzheimer's disease (AD) is the most common form of dementia. While drugs that target several pathways underlying AD have been proposed, effective treatments remain to be discovered. BACE1, an enzyme associated with AD progression, is a promising target for developing anti-Alzheimer drugs. To find novel multifunctional anti-Alzheimer agents, we designed and synthesized a series of new substituted benzyl-1H-1,2,3-triazol-4-yl-N-cyclohexylimidazo[1,2-a]pyridin-3-amine. The in vitro screening results revealed that most of the compounds exhibited moderate to potent BACE1 and BuChE inhibitory and antioxidant activities. Compounds 7f and 7g, bearing dichloro (2,3-Cl2 and 3,4-Cl2) moieties on the benzyl pendant were selected as the most active compounds in our BACE1 inhibitory assay with respective IC50 values of about 12 and 8.9 μM. In addition, compounds 7g and 7h (4-bromo derivative) showed the highest BuChE inhibitory activity with IC50 of 3.2 and 2.5 µM, respectively. Compound 7g also possessed antioxidant activity with an IC50 value of 10.2 μM and metal chelation potential. Moreover, docking studies were performed to investigate the possible mechanism of inhibition. Taken together, we demonstrate that N-cyclohexylimidazo[1,2-a]pyridine containing triazole motif derivatives deserve further investigation for anti-Alzheimer drug development.

RevDate: 2020-08-10

Grill JD, Raman R, Ernstrom K, et al (2020)

Short-term Psychological Outcomes of Disclosing Amyloid Imaging Results to Research Participants Who Do Not Have Cognitive Impairment.

JAMA neurology pii:2769022 [Epub ahead of print].

Importance: The goal of preclinical Alzheimer disease (AD) clinical trials is to move diagnosis and treatment to presymptomatic stages, which will require biomarker testing and disclosure.

Objective: To assess the short-term psychological outcomes of disclosing amyloid positron emission tomography results to older adults who did not have cognitive impairment.

This observational study included participants who were screening for a multisite randomized clinical trial that began on February 28, 2014, and is anticipated to be completed in 2022. Participants aged 65 to 85 years who had no known cognitive impairments underwent an amyloid positron emission tomography scan and learned their result from an investigator who used a protocol-specified process that included prescan education and psychological assessments. This report compares participants with elevated amyloid levels with at least 1 available outcome measure with participants who did not have elevated amyloid levels who enrolled in an observational cohort study and received further evaluations. Data were collected from April 2014 to December 2017 and analyzed from March 2019 to October 2019.

Exposures: A personal biomarker result described as either an elevated or not elevated amyloid level.

Main Outcomes and Measures: To assess the immediate and short-term psychological outcome of disclosure, the following validated measures were used: the Geriatric Depression Scale, the state items from the State-Trait Anxiety Inventory, and the Columbia Suicide Severity Rating Scale, as well as the Concerns About AD Scale and the Future Time Perspective Scale to assess changes in participants' perceived risk for AD and perceived remaining life span, respectively.

Results: A total of 1167 participants with elevated amyloid levels and 538 participants with not elevated amyloid levels were included. Participants had a mean (SD) age of 71.5 (4.7) years, 1025 (60.1%) were women, and most were white (1611 [94.5%]) and non-Latino (1638 [96.1%]). Compared with participants who learned that they had a not elevated amyloid result, individuals who learned of an elevated amyloid result were no more likely to experience short-term increases in depression (mean [SD] change in the Geriatric Depression Scale score, 0.02 [1.3] vs 0.04 [1.3]; P = .90), anxiety (mean [SD] change in State-Trait Anxiety Inventory score, -0.02 [3.2] vs -0.15 [3.0]; P = .65), or suicidality (mean [SD] change in the Columbia Suicide Severity Rating Scale score, 0.0 [0.4] vs -0.01 [0.5]; P = .67). Participants with elevated amyloid levels had increased Concern About AD scores (raw change in scores: elevated amyloid group, 0.8 [3.9]; not elevated amyloid group, -0.4 [3.8]; P < .001). Participants with not elevated amyloid levels experienced a slight increase in Future Time Perspective score(mean [SD] score, 1.15 [7.4] points; P < .001); there was no change in time perspective among those receiving an elevated amyloid result (mean [SD] score, 0.33 [7.8] points).

Conclusions and Relevance: In this observational preclinical AD study, participants who learned they had elevated amyloid levels did not experience short-term negative psychological sequelae compared with persons who learned they did not have elevated amyloid levels.

RevDate: 2020-08-09

Cao Q, Anderson DH, Liang WY, et al (2020)

The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin.

The Journal of biological chemistry pii:RA120.013440 [Epub ahead of print].

The protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aβ, a protein associated with Alzheimer's disease. TTR binds Aβ, alters its aggregation, and inhibits its toxicity both in vitro and in vivo In this study, we investigate whether the amyloidogenic ability of TTR and its anti-amyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. Electron microscopy, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aβ oligomer formation and also promotes the formation of non-toxic, non-amyloid amorphous aggregates which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

RevDate: 2020-08-08

Ryder MI (2020)

Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies.

Journal of periodontology [Epub ahead of print].

Epidemiological studies have identified an association between periodontitis and Alzheimer disease (AD); however, the nature of this association has been unclear. Recent work suggests that brain colonization by the periodontal pathogen Porphyromonas gingivalis may link these two inflammatory and degenerative conditions. Evidence of P. gingivalis infiltration has been detected in autopsy specimens from the brains of people with AD and in cerebrospinal fluid of individuals diagnosed with AD. Gingipains, a class of P. gingivalis proteases, are found in association with neurons, tau tangles, and beta-amyloid in specimens from the brains of individuals with AD. The brains of mice orally infected with P. gingivalis show evidence of P. gingivalis infiltration, along with various neuropathological hallmarks of AD. Oral administration of gingipain inhibitors to mice with established brain infections decreases the abundance of P. gingivalis DNA in brain and mitigates the neurotoxic effects of P. gingivalis infection. Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and AD.

RevDate: 2020-08-07

Fu Y, Yang Y, Shi J, et al (2020)

Acori tatarinowii rhizoma extract ameliorates Alzheimer's pathological syndromes by repairing myelin injury and lowering Tau phosphorylation in mice.

Die Pharmazie, 75(8):395-400.

It has been shown that Acori tatarinowii rhizoma (ATR) extract can improve cognitive functions in Alzheimer Diseas (AD) patients or animal models. In this study, we have examined the activity of ATR in 3×Tg-AD model mice with different comprehensive behavioral tests like the Morris water maze and Y-maze test assay for behavior. Moreover, we performed LFB staining for myelin determination in the AD model mouse. By analyzing different pathways, we determined key proteins that are beneficial for ameliorating AD syndrome in the mouse. Periluminally, ATR treatment improved the learning and memory ability that was determined by comprehensive behavioral tests. Moreover, treatment reduces the p-Tau accumulation in the 3×Tg-AD mouse and the level of p-Tau accumulation was at per with the wildtype control mouse and improves the myelin lining in 3×Tg-AD mouse. In conclusion, our results indicate that ATR-treatment can improve the learning ability of AD model mice and the hyperphosphorylation of Tau protein was decreased. ATR can protect myelin lining from damage in AD syndrome.

RevDate: 2020-08-04

Işık M, Ş Beydemir (2020)

The impact of some phenolic compounds on serum acetylcholinesterase: kinetic analysis of an enzyme/inhibitor interaction and molecular docking study.

Journal of biomolecular structure & dynamics [Epub ahead of print].

In the treatment of Alzheimer's disease (AD), it is important to develop alternative cholinesterase inhibitors with antioxidant properties that will reduce acetylcholine deficiency and free radical formation. The aim of this study was to investigate the effect of hydroquinone, 4-hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, caffeic acid, vanillic acid and chlorogenic acid against acetylcholinesterase (AChE), partially purified from serum. Binding of compounds with effective inhibitory potential to the AChE active site as competitive was illuminated by molecular docking. Hydroquinone, chlorogenic acid and 4-hydroxybenzoic acid have been found to have higher inhibitory potential than others against the AChE. IC50 and KI values of the phenolic compounds against AChE were found in the range of 0.26 ± 0.01-36.34 ± 2.72 mM and 0.72 ± 0.00-29.23 ± 2.62 mM, respectively. The effectiveness of the compounds has been associated with its structure. Consequently, the phenolic compounds, which have AChE inhibitory potential and antioxidant properties, can be considered as alternative drugs in the treatment of AD. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-08-04

Kim SH, Sin DS, JY Lim (2019)

Newly Diagnosed Sarcopenia and Alzheimer's Disease in an Older Patient With Chronic Inflammation.

Annals of geriatric medicine and research, 23(1):38-41.

A 78-year-old man presented with the aggravation of weakness in the lower extremities, gait disturbance, and cognitive impairment. He was diagnosed with sarcopenia, distal sensorimotor polyneuropathy, and Alzheimer's disease. Low-grade chronic elevation of inflammatory markers was also revealed. We assumed that chronic low-grade inflammation with aging, also called "inflammaging," contributed to the development of multiple comorbidities. After multidisciplinary treatment and comprehensive rehabilitation, he could ambulate again with minimal to moderate assistance. Various age-related disorders should be suspected when older patients present with chronic low-grade inflammation.

RevDate: 2020-08-03

Naing HL, SP Teo (2020)

Impact of Hypertension on Cognitive Decline and Dementia.

Annals of geriatric medicine and research, 24(1):15-19.

Dementia reduces a person's ability to perform their activities of daily living and is the leading cause of morbidity worldwide. While most preventive measures are ineffective in reducing dementia risk, active treatment of hypertension in middle-aged and older adults without dementia may reduce the incidence of dementia. Hypertension is associated with vascular dementia but may also affect the manifestations of Alzheimer disease. Observational studies support the association between hypertension and white matter lesions, hippocampal atrophy, and cognitive decline. Both increased and decreased blood pressure were related to the development of white matter lesions. Cohort studies showed that hypertension treatment and treatment duration were associated with lower cognitive decline. This review describes findings from randomized controlled studies on the effects of antihypertensives on cognitive decline. Only the Systolic Hypertension in Europe (Syst-Eur) trial using calcium-channel blockers demonstrated a significant reduction in dementia incidence. Further studies are required to evaluate the long-term benefits of antihypertensive treatment in dementia.

RevDate: 2020-08-03

Ahmed Z, Aziz S, Hanif M, et al (2020)

Phytochemical screening and enzymatic and antioxidant activities of Erythrina suberosa (Roxb) bark.

Journal of pharmacy & bioallied sciences, 12(2):192-200.

Background: This study aimed to evaluate the phytochemicals screening of Erythrina suberosa (Roxb) bark and to analyze the enzymatic activities of its various organic fractions.

Materials and Methods: Crude methanolic fraction of E. suberosa (Roxb) bark and its respective fractions were screened for the presence of different phytochemicals with different reagents. On the basis of increasing order of polarity, different organic solvents were used to obtain different fractions. Enzymatic studies were performed on crude methanolic extract of the plant. All the assays were performed under standard in vitro conditions.

Results: The phytochemical analysis shows the presence of alkaloids, phenols, triterpenoids, phytosterols, and flavonoids. Phenolic compounds and flavonoids are the major constituents of the plant. In anticholinesterase assay, the percent inhibition of standard drug (eserine) was 91.27 ± 1.17 and the half maximal inhibitory concentration (IC50) was 0.04 ± 0.0001. For α-glucosidase inhibition, the IC50 value for Dichloromethane fraction was 8.45 ± 0.13, for Methanol fraction it was 64.24 ± 0.15, and for aqueous fraction it was 42.62 ± 0.17 as compared with standard IC50 that is 37.42 (acarbose). Furthermore, results show that all fractions have potential against anti-urease enzyme, but DCM fraction of crude aqueous extract has significant IC50 value (45.26 ± 0.13) than other fractions.

Conclusion: Keeping in view all the results, it is evident that the plant can be used in future for formulating effective drugs against many ailments. Secondary metabolites and their derivatives possess different biological activities, for example, .g. flavonoids in cancer, asthma, and Alzheimer. Furthermore, the extracts of this plant can be used in their crude form, which is an addition to the complementary and alternative treatment strategies.

RevDate: 2020-08-03

Hasegawa T, Kosoku Y, Sano Y, et al (2020)

Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study.

Journal of Alzheimer's disease : JAD pii:JAD200234 [Epub ahead of print].

BACKGROUND: In the treatment of Alzheimer's disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD.

OBJECTIVE: Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD.

METHODS: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients' plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases.

RESULTS: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%.

CONCLUSION: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.

RevDate: 2020-08-01

Abdeljalil AB, de Mauléon A, Baziard M, et al (2020)

Antidepressant Use and Progression of Mild to Moderate Alzheimer's Disease: Results from the European ICTUS Cohort.

Journal of the American Medical Directors Association pii:S1525-8610(20)30539-9 [Epub ahead of print].

OBJECTIVES: Neuropsychiatric symptoms (NPS) are a core and troubling feature among patients with Alzheimer disease (AD). Because of growing safety warnings against antipsychotics, the use of antidepressants (ATD) in AD has increased extensively. We investigated the potential long-term associations between ATD exposure and functional and cognitive progression in patients with mild to moderate AD.

DESIGN: Two-year prospective multicenter cohort ICTUS (Impact of Cholinergic Treatment USe) study with biannual assessments.

SETTING: Twenty-nine memory clinics from 12 European countries.

PARTICIPANTS: Community-dwelling patients with mild to moderate AD.

METHODS: Global cognitive function was measured using the Mini Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Functional impairment was measured using the Activities of Daily Living (ADL). Assessments were performed biannually for 2 years. Antidepressant exposure was defined by an ATD prescription for a minimum period of 6 months. Linear mixed models were used to study the associations between ATD exposure and cognitive and functional progression.

RESULTS: Antidepressant exposure was not associated with cognitive decline [MMSE: β-coefficients of the linear mixed models (Coef) = 0.06, 95% confidence interval (CI) -0.65 to 0.76, P = .87; ADAS-Cog: Coef = -13.9, 95% CI -34.80 to 7.03, P = .19] or with functional decline (ADL: Coef = -0.05, 95% CI -0.21 to 0.09, P = .48) at 2-year follow-up. Antipsychotic exposure at baseline was associated with a greater functional decline in the ADL score (Coef = -0.39, 95% CI - 0.68 to 0.10, P < .01).

CONCLUSIONS AND IMPLICATIONS: Antidepressant exposure was not associated with a faster rate of cognitive or functional decline in patients with mild to moderate AD. Antidepressants might be appropriate alternatives to antipsychotics in the management of NPS in mild to moderate AD.

RevDate: 2020-07-31

Sugin LJS, Murugesan A, Bindu M, et al (2020)

Roflumilast: A potential drug for the treatment of cognitive impairment?.

Neuroscience letters pii:S0304-3940(20)30551-6 [Epub ahead of print].

Phosphodiesterase-4 regulates the intracellular level of cAMP. Roflumilast, a selective PDE-4 inhibitor was the first agent in this class to have reached the market for patients with chronic obstructive pulmonary disease worldwide. Numerous preclinical evidences indicate the role of PDE-4 inhibitors in reversal of ageing-related alterations induced in animal models by various pharmacological agents, overexpression of mutant forms of human amyloid precursor proteins and in aging, as well. Roflumilast was capable of decreasing PDE-4B and 4D subtypes with an increase in the expression of pCREB and BDNF in hippocampus of rats. The beneficial effects of roflumilast on cognition are believed to be mediated through the above-mentioned cellular effects. Recently, our group had shown that roflumilast has improved the short and long-term memory in rodents. Several lines of evidence indicate that targeting PDE-4 inhibition might offer novel approaches in the treatment of age-associated memory impairment and in Alzheimer's disease. Likewise, in a recent report, roflumilast improved the memory functions in humans after administration of 100 µg of the drug, without the typical side effects of PDE-4 inhibitors, which might offer a novel therapeutic option for the treatment of cognitive impairment and Alzheimer disease. In the current article, the author reviews the most recent evidences demonstrating the beneficial effects of roflumilast on learning and memory in animal models and humans.

RevDate: 2020-07-29

Sun Y, Wang Y, Chen ST, et al (2020)

Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21.

Theranostics, 10(18):8430-8445 pii:thnov10p8430.

A viewpoint considering Alzheimer's disease (AD) as "type 3 diabetes" emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid β-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.

RevDate: 2020-07-29

Varano F, Catarzi D, Vigiani E, et al (2020)

Piperazine- and Piperidine-Containing Thiazolo[5,4-d]pyrimidine Derivatives as New Potent and Selective Adenosine A2A Receptor Inverse Agonists.

Pharmaceuticals (Basel, Switzerland), 13(8): pii:ph13080161.

The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A2A AR binding affinity (Ki = 8.62 nM) as well as inverse agonist potency (IC50 = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles.

RevDate: 2020-07-26

Lushchekina SV, P Masson (2020)

Slow-binding inhibitors of acetylcholinesterase of medical interest.

Neuropharmacology pii:S0028-3908(20)30304-X [Epub ahead of print].

Certain ligands slowly bind to acetylcholinesterase. As a result, there is a slow establishment of enzyme-inhibitor equilibrium characterized by a slow onset of inhibition prior reaching steady state. Three mechanisms account for slow-binding inhibition: a) slow binding rate constant kon, b) slow ligand induced-fit following a fast binding step, c) slow conformational selection of an enzyme form. The slow equilibrium may be followed by a chemical step. This later that can be irreversible has been observed with certain alkylating agents and substrate transition state analogs. Slow-binding inhibitors present long residence times on target. This results in prolonged pharmacological or toxicological action. Through several well-known molecules (e.g. huperzine) and new examples (tocopherol, trifluoroacetophenone and a 6-methyluracil alkylammonium derivative), we show that slow-binding inhibitors of acetylcholinesterase are promising drugs for treatment of neurological diseases such as Alzheimer disease and myasthenia gravis. Moreover, they may be of interest for neuroprotection (prophylaxis) against organophosphorus poisoning.

RevDate: 2020-07-27

Tanaka N, Okuda M, Nishigaki T, et al (2020)

Development of a brain-permeable peptide nanofiber that prevents aggregation of Alzheimer pathogenic proteins.

PloS one, 15(7):e0235979 pii:PONE-D-20-06596.

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidβ in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid βby trapping amyloid β onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.

RevDate: 2020-07-24

Mascarenhas AMS, de Almeida RBM, de Araujo Neto MF, et al (2020)

Pharmacophore-based virtual screening and molecular docking to identify promising dual inhibitors of human acetylcholinesterase and butyrylcholinesterase.

Journal of biomolecular structure & dynamics [Epub ahead of print].

The dual inhibition of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) plays an important role in Alzheimer's disease treatment. Thus, this study aims identify promising dual inhibitors against hAChE and hBuChE by in silico approaches (pharmacophore-based virtual screening and molecular docking). Ten 3 D pharmacophore models for dual inhibitors using default genetic parameters were built by GALAHAD™ available on SYBYL-X 2.0. Validation steps were carried out according to Energy (<100.0 kcal/mol), Pareto = 0, Area under the ROC Curve (>0.70), Boltzmann-Enhanced Discrimination of ROC curve (BEDROC >0.50) and structure-activity relationship (SAR) for known inhibitors. The best dual pharmacophore model based on internal/external statistical parameters and SAR data (one hydrogen bond acceptor, two hydrogen bond donors and four hydrophobic centers) was employed in virtual screening at Sigma-Aldrich® subset (n = 214,446) of ZINC database by UNITY module of SYBYL-X 2.0. According to superposition values (QFIT), the best ranked compounds were prioritized for molecular docking and partition coefficient analysis (clog p < 5.0). 37 top-ranked compounds (QFIT > 64.22) from pharmacophore model showed affinity in hAChE (-10.2 < Affinity energy < -6.3 kcal/mol) and hBuChE (-10.9 < Affinity energy < -2.3 kcal/mol) binding sites. Next, liposolubity prediction and commercially available showed that ZINC43198636, ZINC43198637 and ZINC00390718 can be potential dual inhibitors against hAChE and hBuChE. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-07-23

Joseph CR (2020)

Novel MRI Techniques Identifying Vascular Leak and Paravascular Flow Reduction in Early Alzheimer Disease.

Biomedicines, 8(7): pii:biomedicines8070228.

With beta amyloid and tau antibody treatment trial failures, avenues directed to other facets of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood-brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments. Ideally, human medication trials require a minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes. We will review the known physiology and anatomy of the BBB system, and its relationship to the glymphatic system and the microglial surveillance system. Dysfunction of this tripart system occurring in preclinical Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments. High-resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non-invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.

RevDate: 2020-07-17

Ghai R, Nagarajan K, Arora M, et al (2020)

Current Strategies and Novel Drug Approaches for Alzheimer Disease.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-108224 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a chronic devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc are being used to manage the symptoms of Alzheimer's disease.

OBJECTIVE: The paper's objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals.

MATERIALS & METHODS: Enormous literature survey was conducted and published articles of PUBMED, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer's disease.

RESULTS & CONCLUSION: Currently, several strategies are being investigated for the treatment of Alzheimer's disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.

RevDate: 2020-07-17

Sokolova SV, Sozarukova MM, Khannanova AN, et al (2020)

[Antioxidant status in patients with paranoid schizophrenia and Alzheimer disease].

Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 120(6):82-87.

OBJECTIVE: To study the antioxidant profile of blood plasma in patients with paranoid schizophrenia and Alzheimer disease (AD).

MATERIAL AND METHODS: Thirty-three patients with paranoid schizophrenia and 18 patients with AD were included in the study. Patients with schizophrenia were stratified into two subgroups by response to therapy. The indicators of the antioxidant profile were determined using methods based on chemiluminometry and spectrofluorimetry.

RESULTS: Systemic oxidative stress due to insufficiency of low molecular weight plasma antioxidants is not determined neither in AD nor in treatment resistant schizophrenia. At the same time, a «thiol» oxidative stress, which indirectly indicates a deficiency of the glutathione system, is present in both groups. In patients with paranoid schizophrenia responsive to treatment, systemic oxidative stress is more pronounced and «thiol» oxidative stress is less significant. Among the antipsychotics studied, haloperidol, zuclopenthixol, risperidone and ziprasidone do not exhibit antioxidant properties, but periciazine, clozapine and especially chlorpromazine exhibit strong antioxidant properties, but they unlikely affect the antioxidant potential of blood plasma.

CONCLUSIONS: The glutathione part of the antioxidant system is mostly affected, but systemic oxidative stress is not significant in patients with treatment resistant paranoid schizophrenia and AD. Oxidative disorders are more pronounced in treatment responsive paranoid schizophrenia.

RevDate: 2020-07-17

Jin N, Ziyatdinova S, Gureviciene I, et al (2020)

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs.

Scientific reports, 10(1):11851 pii:10.1038/s41598-020-68845-y.

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

RevDate: 2020-07-15

Koch G, Motta C, Bonnì S, et al (2020)

Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial.

JAMA network open, 3(7):e2010372 pii:2768248.

Importance: Impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease (AD).

Objective: To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD.

This phase 2, monocentric, randomized, double-blind, placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September 1, 2019.

Interventions: A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47).

Main Outcomes and Measures: The primary end point was change from baseline on the Alzheimer Disease Assessment Scale-Cognitive Subscale. Secondary end points were changes in Frontal Assessment Battery, Alzheimer Disease Cooperative Study-Activities of Daily Living, and Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography.

Results: Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the primary end point: estimated mean change in Alzheimer Disease Assessment Scale-Cognitive Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study-Activities of Daily Living score (-3.32 [95% CI, -4.02 to -2.62] for rotigotine and -7.24 [95% CI, -7.84 to -6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and -0.66 [95% CI, -0.80 to -0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group.

Conclusions and Relevance: In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living.

Trial Registration: ClinicalTrials.gov Identifier: NCT03250741.

RevDate: 2020-07-15

Wang X, Li W, Marcus J, et al (2020)

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy.

The Journal of pharmacology and experimental therapeutics, 374(2):252-263.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

RevDate: 2020-07-13

Liao Z, Cheng L, Li X, et al (2020)

Meta-analysis of Ginkgo biloba Preparation for the Treatment of Alzheimer's Disease.

Clinical neuropharmacology, 43(4):93-99.

OBJECTIVE: The objective of this study was to investigate the efficacy and safety of Ginkgo biloba preparation for the treatment of Alzheimer disease (AD).

METHODS: Both English (PubMed, Embase, Cochrane Library databases, and the Cochrane Controlled Trials Register) and Chinese (WanFang, Chinese Biomedical, CNKI, and VIP databases) databases were systematically and independently searched by 2 authors from their inception until July 3, 2019. All relevant studies included AD patients who were treated with Ginkgo biloba. The efficacy and safety of the medicine were used as the main measurement index.

RESULTS: Seven studies (N = 939) were identified and analyzed. When compared with placebo, Ginkgo biloba showed exact validity in cognitive function and global clinical assessment (cognitive function section: risk ratio = 1.98, 95% confidence interval = 1.52-2.59, Z = 5.12, P < 0.001; according to Clinical Global Impression Change: odds ratio = 3.119, 95% confidence interval = 2.206-4.410, Z = 6.44, P < 0.001). Adverse events were mild.

CONCLUSIONS: Ginkgo biloba preparation has reliable efficacy of cognitive function and global clinical assessment and safety in the treatment of AD.

RevDate: 2020-07-13

Fantini J, Chahinian H, N Yahi (2020)

Progress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?.

Protein science : a publication of the Protein Society [Epub ahead of print].

After three decades of false hopes and failures, a pipeline of therapeutic drugs that target the actual root cause of Alzheimer's disease (AD) is now available. Challenging the old paradigm that focused on β-amyloid peptide (Aβ) aggregation in amyloid plaques, these compounds are designed to prevent the neurotoxicity of Aβ oligomers that form Ca2+ permeable pores in the membranes of brain cells. By triggering an intracellular Ca2+ overdose, Aβ oligomers induce a cascade of neurotoxic events including oxidative stress, tau hyperphosphorylation, and neuronal loss. Targeting any post-Ca2+ entry steps (e.g., tau) will not address the root cause of the disease. Thus, preventing Aβ oligomers formation and/or blocking their toxicity is by essence the best approach to stop any progression of AD. Three categories of anti-oligomer compounds are already available: antibodies, synthetic peptides, and small drugs. Independent in silico-based designs of a peptide (AmyP53) and a monoclonal antibody (PMN310) converged to identify a histidine motif (H13/H14) that is critical for oligomer neutralization. This "histidine trick" can be viewed as the Achilles' heel of Aβ in the fight against AD. Moreover, lipid rafts and especially gangliosides play a critical role in the formation and toxicity of Aβ oligomers. Recognizing AD as a membrane disorder and gangliosides as the key anti-oligomer targets will provide innovative opportunities to find an efficient cure. A "full efficient" solution would also need to be affordable to anyone, as the number of patients has been following an exponential increase, affecting every part of the globe.

RevDate: 2020-07-11

Rajabi F, Gusbeth C, Frey W, et al (2020)

Nanosecond pulsed electrical fields enhance product recovery in plant cell fermentation.

Protoplasma pii:10.1007/s00709-020-01534-9 [Epub ahead of print].

The potential of pharmacologically active secondary plant metabolites is limited by the low yield from often rare plants, and the lack of economically feasible chemical synthesis of these complex compounds. Plant cell fermentation offers an alternative strategy to overcome these constraints. However, the efficiency of this approach is limited by intracellular sequestration of the products, such that continuous bioprocessing is not possible. As a precondition for such a, more attractive, continuous process, it is of great importance to stimulate the export of the product into the medium without impairing viability and, thus, the productivity of the cells. Using nicotine alkaloids of tobacco as a case study, an alternative strategy is explored, where nanosecond pulsed electric fields (nsPEFs) are applied for the efficient downstream recovery of the products. To maintain cell viability and allow for the further use of biomass, cells were exposed to strong (1-20 kV·cm-1), but very short (10-100 ns) electric pulses, which leads to a temporary permeabilisation of cell membranes. Using two transgenic cell lines, where two key genes involved in the metabolism of the anti-Alzheimer compound nornicotine were overexpressed, we could show that this nsPEF treatment improved the partitioning of some nicotine alkaloids to the culture medium without impairing viability, nor the synthesis of alkaloids. However, this release was only partial and did not work for nornicotine. Thus, nsPEFs produced a fractionation of alkaloids. We explain this electrofractionation by a working model considering the differential intracellular compartmentalization of nicotineic alkaloids.

RevDate: 2020-07-10

Kısa D, Korkmaz N, Taslimi P, et al (2020)

Bioactivity and molecular docking studies of some nickel complexes: New analogues for the treatment of Alzheimer, glaucoma and epileptic diseases.

Bioorganic chemistry, 101:104066 pii:S0045-2068(20)31363-8 [Epub ahead of print].

The interaction of the coordination compounds with biological molecules resulted in the investigation of the drug potential of these molecules. In this study, enzyme inhibition of DSA (1-3) coordination compounds that were previously investigated for their anticancer and antibacterial properties was investigated. Also, DSA (1-3) had Ki values of 635.30 + 152.62, 184.01 + 90.05, and 163.03 ± 60.01 µM against human carbonic anhydrase I, 352.23 ± 143.09, 46.2 ± 15.47, and 54.117 ± 18.80 µM against AChE, 310.64 ± 97.35, 35.54 ± 7.01, and 101.51 ± 15.314 µM against BChE, respectively. The biological activity values of these compounds against enzymes whose name are AChE, BChE, and hCAI were compared. Ellman and Verporte methods were used for the study of these enzymes. Cholinesterase inhibitors, also known as anti-cholinesterase and cholinesterase blocking drugs, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. They may be used as drugs for Alzheimer's and myasthenia gravis. It is a common method for comparing biological activity values of nickel complexes with molecular docking calculations. Nickel complexes were studied against enzymes that are human carbonic anhydrase isozyme I for ID 2CAB (hCA I), butyrylcholinesterase for ID 1P0I (BChE), and acetylcholinesterase for ID 1EEA (AChE), respectively.

RevDate: 2020-07-10

Liu B, Cao Y, Shi F, et al (2020)

The overexpression of RBM3 alleviates TBI-induced behaviour impairment and AD-like tauopathy in mice.

Journal of cellular and molecular medicine [Epub ahead of print].

The therapeutic hypothermia is an effective tool for TBI-associated brain impairment, but its side effects limit in clinical routine use. Hypothermia up-regulates RNA-binding motif protein 3 (RBM3), which is verified to protect synaptic plasticity. Here, we found that cognitive and LTP deficits, loss of spines, AD-like tau pathologies are displayed one month after TBI in mice. In contrast, the deficits of LTP and cognitive, loss of spines and tau abnormal phosphorylation at several sites are obviously reversed in TBI mice combined with hypothermia pre-treatment (HT). But, the neuroprotective role of HT disappears in TBI mouse models under condition of blocking RBM3 expression with RBM3 shRNA. In other hand, overexpressing RBM3 by AAV-RBM3 plasmid can mimic HT-like neuroprotection against TBI-induced chronic brain injuries, such as improving LTP and cognitive, loss of spines and tau hyperphosphorylation in TBI mouse models. Taken together, hypothermia pre-treatment reverses TBI-induced chronic AD-like pathology and behaviour deficits in RBM3 expression dependent manner, RBM3 may be a potential target for neurodegeneration diseases including Alzheimer disease.

RevDate: 2020-07-09

Kumar R, Gulati M, Singh SK, et al (2020)

Road From Nose to Brain for Treatment of Alzheimer: The Bumps and Humps.

CNS & neurological disorders drug targets pii:CNSNDDT-EPUB-107983 [Epub ahead of print].

Vulnerability of the brain milieu to even the subtle changes in its normal physiology is guarded by a highly efficient blood brain barrier. A number of factors i.e. molecular weight of the drug, its route of administration, lipophilic character etc. play a significant role in its sojourn through the blood brain barrier (BBB) and limit the movement of drug into brain tissue through BBB. To overcome these problems, alternative routes of drug administration have been explored to target the drugs to brain tissue. Nasal route has been widely reported for the administration of drugs for treatment of Alzheimer. In this innovative approach, the challenge of BBB is bypassed. Through this route, both the larger as well as polar molecules can be made to reach the brain tissues. Generally, these systems are either pH dependent or temperature dependent. Results: The present review highlights the anatomy of nose, mechanisms of drug delivery from nose to brain, critical factors in the formulation of nasal drug delivery system, nasal formulations of various drugs that have been tried for their nasal delivery for treatment of Alzheimer. Conclusion: It also dives deep to understand the factors that contribute to the success of such formulations to carve out a direction for this niche area to be explored further.

RevDate: 2020-07-09

Azib L, Debbache-Benaida N, Da Costa G, et al (2020)

Neuroprotective effects of Fraxinus angustifolia Vahl. bark extract against Alzheimer's disease.

Journal of chemical neuroanatomy pii:S0891-0618(20)30117-4 [Epub ahead of print].

Alzheimer disease's (AD) is a neurodegenerative disease induced by amyloid-β aggregation and accumulation of neurotoxic metals in the brain. Fraxinus angustifolia Vahl. (Oleaceae) is a Mediterranean plant traditionally used to treat several human problems as nervous system problems. This study aimed to evaluate the neuroprotective effects of F. angustifolia Vahl. bark extract (FAB) in vitro and in vivo against Aβ-aggregation and aluminium induced-neurotoxicity in mice. FAB was characterized by colorimetric methods and its individual compounds were identified and quantified by LC-MS. First, the neuroprotective effect of FAB was evaluated against Aβ25-35-aggregation where it was directly incubated with Aβ25-35 and the kinetic of aggregation was measured by spectrophotometer at 200 nm. Then, the extract was tested against Aβ25-35-induced cytotoxicity on PC12 cells and the cells viability was determined by MTT test. On the other hand, FAB (0.01 - 0.5 mg/mL) was tested against aluminium-activated lipid peroxidation in mice synaptosomal membranes, and in vivo against aluminium-caused neurotoxicity in male N.M.R.I. (Naval Medical Research Institute) mice; this test consisted of daily co-administration of the extract with Al for 60 days. At the end of the treatment, behavioral and memory tests (locomotor activity, black and white and Morris water maze tests) and histological analysis were realized. The identification and quantification of FAB phenolics revealed the presence of different phenolic classes with high concentration of phenylethanoids and hydroxycoumarins. FAB showed a high Aβ25-35 anti-aggregative effect and a dose dependent protective effect on PC12 cells. The extract also demonstrated a significant inhibition of lipid peroxidation and was found to prevent the Al harmful effects where it significantly increased the locomotor activity, decreased the anxiety, improved memory and reduced histological alterations. In conclusion, FAB is rich of bioactive compounds that gave it the ability to inhibit Aβ-aggregation and Al-caused neurotoxicity in mice.

RevDate: 2020-07-09

Ghanbari-Maman A, Ghasemian-Roudsari F, Aliakbari S, et al (2019)

Calcium Channel Blockade Ameliorates Endoplasmic Reticulum Stress in the Hippocampus Induced by Amyloidopathy in the Entorhinal Cortex.

Iranian journal of pharmaceutical research : IJPR, 18(3):1466-1476.

Entorhinal cortex (EC) is one of the first cerebral regions affected in Alzheimer's disease (AD). The pathology propagates to neighboring cerebral regions through a prion-like mechanism. In AD, intracellular calcium dyshomeostasis is associated with endoplasmic reticulum (ER) stress. This study was designed to examine hippocampal ER stress following EC amyloidopathy. Aβ1-42 was bilaterally microinjected into the EC under stereotaxic surgery. Rats were daily treated with 30 μg of isradipine, nimodipine, or placebo over one week. Passive avoidance and novel object recognition (NOR) tasks were performed using shuttle box and NOR test, respectively. GRP78/BiP and CHOP levels were measured in the hippocampal dentate gyrus (DG) by western blot technique. The glutathione (GSH) level and PDI activity were also assessed in the hippocampus by colorimetric spectrophotometer. Aβ treated group developed passive avoidance and novel recognition memory deficit compared to the control group. However, treatment with calcium channel blockers reversed the impairment. BiP and CHOP level increased in the hippocampus following amyloidopathy in the EC. PDI activity and GSH level in the hippocampus decreased in the Aβ treated group, but calcium channel blockers restored them toward the control level. In conclusion, memory impairment due to EC amyloidopathy is associated with ER stress related bio-molecular changes in the hippocampus, and treatment with L-type calcium channel blockers may prevent the changes and ultimately improve cognitive performance.

RevDate: 2020-07-06

Zhang R, Zhang JL, Li BT, et al (2020)

[Study on mechanisms of anti-Alzheimer's disease action of absorbed components of Gardeniae Fructus based on network pharmacology].

Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 45(11):2601-2610.

Gardeniae Fructus has the traditional effects of promoting intelligence and inducing resuscitation, but its mechanism is unclear. In this study, the relationship between Gardeniae Fructus's traditional effect of promoting intelligence and inducing resuscitation and anti-Alzheimer's disease effect was taken as the starting point to investigate the anti-Alzheimer's disease mechanism of the major absorbed components in Gardeniae Fructus by the network pharmacology method. The network pharmacology research model of &quot;absorbed composition-target-pathway-disease&quot; was adopted. In this study, the active components screening and target prediction technology were used to determine the active components and targets of Gardeniae Fructus in treatment of Alzheimer's disease. The enrichment pathway and biological process of Gardeniae Fructus were studied by using the bioinformatics annotation database(DAVID), and the results of molecular docking validation network analysis were used to elaborate the mechanism of Gardeniae Fructus in treatment of Alzheimer's disease. It was found that 35 absorbed components of Gardeniae Fructus not only regulated 48 targets such as cholines-terase(BCHE) and carbonic anhydrase 2(CA2), but also affected 11 biological processes(e.g. transcription factor activity, nuclear receptor activity, steroid hormone receptor activity, amide binding and peptide binding) and 7 metabolic pathways(MAPK signaling pathway, Alzheimer disease and estrogen signaling pathway, etc.). Molecular docking results showed that more than 60% of the active components could be well docked with key targets, and the relevant literature also showed that the active components could inhibit the MAPK1 expression of key targets, indicating a high reliability of results. These results indicated that Gardeniae Fructus may play its anti-Alzheimer's disease action via a &quot;multi-ingredients-multi-targets and multi-pathways&quot; mode, providing a scientific basis for further drug research and development.

RevDate: 2020-07-06

Zhao T, Hu Y, Zang T, et al (2020)

Identifying Protein Biomarkers in Blood for Alzheimer's Disease.

Frontiers in cell and developmental biology, 8:472.

Background: At present, the main diagnostic methods for Alzheimer's disease (AD) are positron emission tomography (PET) scanning of the brain and analysis of cerebrospinal fluid (CSF) sample, but these methods are expensive and harmful to patients. Recently, more researchers focus on diagnosing AD by detecting biomarkers in blood, which is a cheaper and harmless way. Therefore, identifying AD-related proteins in blood can help treatment and diagnosis. Methods: We proposed a hypothesis that similar diseases share similar proteins. Diseases with similar symptoms are caused by abnormalities of similar proteins. Assuming that the similarities between AD and other diseases obey the normal distribution, we developed an iterative method based on disease similarity (IBDS). We combined Elastic Network (EN) with Minimum angle regression (MAR) to find the optimal solution. Finally, we used case studies and Summary data Mendelian Random (SMR) to verify our method. Results: We selected 39 diseases which are highly related to AD. They correspond 1,481 kinds of proteins. One hundred and eighty-four proteins are reported to be related to AD in Uniprot and the number would be 284 with our method. The AUC of our method by cross-validation is 0.9251 which is much higher than previous methods. Conclusion: In this paper, we presented a novel method for prioritizing AD-related proteins. Seven proteins have tissue specificity in blood among these 284 proteins, which could be used to diagnose AD in future. Case studies and SMR have been used to prove the relationship between these 7 proteins and AD. Availability and Implementation: https://github.com/zty2009/Identifying-Protein-Biomarkers-in-Blood-for-Alzheimer-s-Disease.

RevDate: 2020-07-06

Jahangard Y, Monfared H, Moradi A, et al (2020)

Therapeutic Effects of Transplanted Exosomes Containing miR-29b to a Rat Model of Alzheimer's Disease.

Frontiers in neuroscience, 14:564.

Alzheimer disease (AD) is a complex neurodegenerative disorder with no definite treatment. The expression of miR-29 family is significantly reduced in AD, suggesting a part for the family members in pathogenesis of the disease. The recent emergence of microRNA (miRNA)-based therapeutic approaches is emphasized on the efficiency of miRNA transfer to target cells. The endogenously made secretory vesicles could provide a biological vehicle for drug delivery. Characteristics such as small sizes, the ability to cross the blood-brain barrier, the specificity in binding to the right target cells, and most importantly the capacity to be engineered as drug carriers have made exosomes desirable vehicles to deliver genetic materials to the central nervous system. Here, we transfected rat bone marrow mesenchymal stem cells and HEK-293T cells (human embryonic kidney 293 cells) with recombinant expression vectors, carrying either mir-29a or mir-29b precursor sequences. A significant overexpression of miR-29 and downregulation of their targets genes, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and BIM [Bcl-2 interacting mediator of cell death (BCL2-like 11)], were confirmed in the transfected cells. Then, we confirmed the packaging of miR-29 in exosomes secreted from the transfected cells. Finally, we investigated a possible therapeutic effect of the engineered exosomes to reduce the pathological effects of amyloid-β (Aβ) peptide in a rat model of AD. Aβ-treated model rats showed some deficits in spatial learning and memory. However, in animals injected with miR-29-containing exosomes at CA1 (cornu ammonis area), the aforementioned impairments were prevented. In conclusion, our findings provide a new approach for the packaging of miR-29 in exosomes and that the engineered exosomes might have a therapeutic potential in AD.

RevDate: 2020-07-05

Shi Y, Zhang L, Gao X, et al (2020)

Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.

Journal of Alzheimer's disease : JAD pii:JAD200227 [Epub ahead of print].

BACKGROUND/OBJECTIVE: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice.

METHODS: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration.

RESULTS: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice.

CONCLUSIONS: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.

RevDate: 2020-07-04

Bhandari RK, Wang X, Saal FSV, et al (2020)

Transcriptome analysis of testis reveals the effects of developmental exposure to bisphenol a or 17α-ethinylestradiol in medaka (Oryzias latipes).

Aquatic toxicology (Amsterdam, Netherlands), 225:105553 pii:S0166-445X(20)30303-9 [Epub ahead of print].

Endocrine disrupting chemicals (EDCs) can induce abnormalities in organisms via alteration of molecular pathways and subsequent disruption of endocrine functions. Bisphenol A (BPA) and 17α-ethinylestradiol (EE2) are ubiquitous EDCs in the environment. Many aquatic organisms, including fish, are often exposed to varying concentrations of BPA and EE2 throughout their lifespan. Both BPA and EE2 can activate estrogenic signaling pathways and cause adverse effects on reproduction via alteration of pathways associated with steroidogenesis. However, transcriptional pathways that are affected by chronic exposure to these two ubiquitous environmental estrogens during embryonic, larval, and juvenile stages are not clearly understood. In the present study, we examined transcriptional alterations in the testis of medaka fish (Oryzias latipes) chronically exposed to a low concentration of BPA or EE2. Medaka were exposed to BPA (10 μg/L) or EE2 (0.01 μg/L) from 8 h post-fertilization (as embryos) to adulthood 50 days post fertilization (dpf), and transcriptional alterations in the testis were examined by RNA sequencing (RNA-seq). Transcriptomic profiling revealed 651 differentially expressed genes (DEGs) between BPA-exposed and control testes, while 1475 DEGs were found between EE2-exposed and control testes. Gene ontology (GO) analysis showed a significant enrichment of "intracellular receptor signaling pathway", "response to steroid hormone" and "hormone-mediated signaling pathway" in the BPA-induced DEGs, and of "cilium organization", "microtubule-based process" and "organelle assembly" in the EE2-induced DEGs. Pathway analysis showed significant enrichment of "integrin signaling pathway" in both treatment groups, and of "cadherin signaling pathway", "Alzheimer disease-presenilin pathway" in EE2-induced DEGs. Single nucleotide polymorphism (SNP) and insertion-deletion (Indel) analysis found no significant differences in mutation rates with either BPA or EE2 treatments. Taken together, global gene expression differences in testes of medaka during early stages of gametogenesis were responsive to chronic BPA and EE2 exposure.

RevDate: 2020-07-03

Alam J, Jaiswal V, L Sharma (2020)

Screening of Antibiotics against β-amyloid as Anti-amyloidogenic Agents: A Drug Repurposing Approach.

Current computer-aided drug design pii:CAD-EPUB-107878 [Epub ahead of print].

BACKGROUND: β-amyloid (Aβ) production and aggregation is the main culprit of Alzheimer's disease (AD). AD is becoming crisis where no treatment available for halting the disease progression. Antibiotics are used not only to treat infections, but also some of the non-contagious diseases and have found active as anti-amyloidogenic agents.

OBJECTIVE: The work aim's to investigate anti-amyloidogenic activity of antibiotics as re-purposing agents via inhibiting Aβ aggregation and fibril formation employing in-silico and in-vitro approaches. Mehtods: In-silico screening was designed with receptor and ligand preparation, grid formation, docking simulation and its analysis. Thioflavin T-amyloid binding and protease-digestion studies were intended as in-vitro assays. The pharmacological potential of antibiotics as anti-amyloidogenic agents was assessed by these methods.

RESULTS: Paromomycin and Neomycin were identified with higher order of estimated free energy of binding in in-silico sreening. In in-vitro screening, paromomycin significantly (p<0.01) reduced the fluorescence intensity and resistance to tryptic degradation of Aβ(1-42) peptides while neomycin had no or little effect (p<0.01) when compared to control. Results from docking and wet lab studies were found in correlation.

CONCLUSION: Paromomycin exhibited higher anti-Aβ aggregating and defibrillogenic activity than neomycin and leaves an indication for further in-vivo testing and could be a future promising anti-amyloidal candidate for the treatment of several amyloidoses.

RevDate: 2020-07-03

Schwartz L, Peres S, Jolicoeur M, et al (2020)

Cancer and Alzheimer's disease: intracellular pH scales the metabolic disorders.

Biogerontology pii:10.1007/s10522-020-09888-6 [Epub ahead of print].

Alzheimer's disease (AD) and cancer have much in common than previously recognized. These pathologies share common risk factors (inflammation and aging), with similar epidemiological and biochemical features such as impaired mitochondria. Metabolic reprogramming occurs during aging and inflammation. We assume that inflammation is directly responsible of the Warburg effect in cancer cells, with a decreased oxidative phosphorylation and a compensatory highthroughput glycolysis (HTG). Similarly, the Warburg effect in cancer is thought to support an alkaline intracellular pH (pHi), a key component of unrelenting cell growth. In the brain, inflammation results in increased secretion of lactate by astrocytes. The increased uptake of lactic acid by neurons results in the inverse Warburg effect, such as seen in AD. The neuronal activity is dampened by a fall of pHi. Pronounced cytosol acidification results in decreased mitochondrial energy yield as well as apoptotic cell death. The link between AD and cancer is reinforced by the fact that treatment aiming at restoring the mitochondrial activity have been experimentally shown to be effective in both diseases. Low carb diet, lipoic acid, and/or methylene blue could then appear promising in both sets of these clinically diverse diseases.

RevDate: 2020-07-02

Lau YCC, Ding JA, Simental A, et al (2020)

Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients.

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

Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.

RevDate: 2020-07-01

Yu L, Tasaki S, Schneider JA, et al (2020)

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons.

JAMA psychiatry pii:2767297 [Epub ahead of print].

Importance: Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.

Objective: To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.

This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.

Exposures: Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.

Main Outcomes and Measures: The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.

Results: There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience.

Conclusions and Relevance: These protein signals may represent novel targets for the maintenance of cognition in old age.

RevDate: 2020-06-30

Zhang Z, Kang D, H Li (2020)

Testosterone and Cognitive Impairment or Dementia in Middle-Aged or Aging Males: Causation and Intervention, a Systematic Review and Meta-Analysis.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

BACKGROUND AND PURPOSE: To investigate the association between testosterone levels and the risk of dementia and to assess the effectiveness of testosterone supplement treatment in patients with cognitive impairment or dementia.

METHODS: We searched Pubmed, Cochrane Library, and EMBASE on September 30, 2019.

RESULTS: The risk factor portion of the review included 27 studies with 18 599 participants. Studies revealed inconsistent findings on the association between testosterone levels and the risk of all-cause dementia or Alzheimer disease (AD). The result from our meta-analysis showed an increased risk of all-cause dementia with decreasing total testosterone (total-T, 4572 participants, hazard ratio: 1.14, 95% CI: 1.04-1.26). Some studies also found an increased risk of AD with a lower level of total-T, free testosterone, and bioavailable testosterone. Testosterone supplement treatment may improve general cognitive function and motor response in the short term as measured by the Developmental Test of Visual-Motor Integration (mean difference [MD]: 4.4, 95% CI: 1.20-7.59) and the Mini-Mental State Examination (MD: 3.4, 95% CI: 0.83-5.97) and verbal memory as measured by story recall delay at 3 months (MD: 8.4, 95% CI: 0.49-16.3).

CONCLUSION: Lower levels of testosterone may be associated with an increased risk of all-cause dementia or AD. Testosterone supplement treatment may or may not improve general cognitive function in patients with cognitive impairment/AD.

RevDate: 2020-06-30

Park KH, Lim JS, Seo SW, et al (2020)

Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association.

Dementia and neurocognitive disorders, 19(2):39-53.

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Large-scale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.

RevDate: 2020-06-30

Iloun P, Hooshmandi E, Gheibi S, et al (2020)

Roles and Interaction of the MAPK Signaling Cascade in Aβ25-35-Induced Neurotoxicity Using an Isolated Primary Hippocampal Cell Culture System.

Cellular and molecular neurobiology pii:10.1007/s10571-020-00912-4 [Epub ahead of print].

Alzheimer's disease (AD) is characterized with increased formation of amyloid-β (Aβ) in the brain. Aβ peptide toxicity is associated with disturbances of several intracellular signaling pathways such as mitogen activated protein kinases (MAPKs). The aim of this study was to investigate the role of MAPKs and their interactions in Aβ-induced neurotoxicity using isolated hippocampal neurons from the rat. Primary hippocampal cells were cultured in neurobasal medium for 4 days. Cells were treated with Aβ25-35 and/or MAPKs inhibitors for 24 h. Cell viability was determined by an MTT assay and phosphorylated levels of P38, JNK, and ERK were measured by Western blots. Aβ treatment (10-40 µM) significantly decreased hippocampal cell viability in a dose-dependent manner. Inhibition of P38 and ERK did not restore cell viability, while JNK inhibition potentiated the Aβ-induced neurotoxicity. Compared to the controls, Aβ treatment increased levels of phosphorylated JNK, ERK, and c-Jun, while it had no effect on levels of phosphorylated P38. In addition, P38 inhibition led to decreased expression levels of phosphorylated ERK; inhibition of JNK resulted in decreased expression of c-Jun; and inhibition of ERK, decreased phosphorylated levels of JNK. These results strongly suggest that P38, ERK, and JNK are not independently involved in Aβ-induced toxicity in the hippocampal cells. In AD, which is a multifactorial disease, inhibiting a single member of the MAPK signaling pathway, does not seem to be sufficient to mitigate Aβ-induced toxicity and thus their interactions with each other or potentially with different signaling pathways should be taken into account.

RevDate: 2020-06-29

Grammatikopoulou MG, Goulis DG, Gkiouras K, et al (2020)

To Keto or Not to Keto? A Systematic Review of Randomized Controlled Trials Assessing the Effects of Ketogenic Therapy on Alzheimer Disease.

Advances in nutrition (Bethesda, Md.) pii:5864685 [Epub ahead of print].

Alzheimer disease (AD) is a global health concern with the majority of pharmacotherapy choices consisting of symptomatic treatment. Recently, ketogenic therapies have been tested in randomized controlled trials (RCTs), focusing on delaying disease progression and ameliorating cognitive function. The present systematic review aimed to aggregate the results of trials examining the effects of ketogenic therapy on patients with AD/mild cognitive impairment (MCI). A systematic search was conducted on PubMed, CENTRAL, clinicaltrials.gov, and gray literature for RCTs performed on adults, published in English until 1 April, 2019, assessing the effects of ketogenic therapy on MCI and/or AD compared against placebo, usual diet, or meals lacking ketogenic agents. Two researchers independently extracted data and assessed risk of bias with the Cochrane tool. A total of 10 RCTs were identified, fulfilling the inclusion criteria. Interventions were heterogeneous, acute or long term (45-180 d), including adherence to a ketogenic diet, intake of ready-to-consume drinks, medium-chain triglyceride (MCT) powder for drinks preparation, yoghurt enriched with MCTs, MCT capsules, and ketogenic formulas/meals. The use of ketoneurotherapeutics proved effective in improving general cognition using the Alzheimer's Disease Assessment Scale-Cognitive, in interventions of either duration. In addition, long-term ketogenic therapy improved episodic and secondary memory. Psychological health, executive ability, and attention were not improved. Increases in blood ketone concentrations were unanimous and correlated to the neurocognitive battery based on various tests. Cerebral ketone uptake and utilization were improved, as indicated by the global brain cerebral metabolic rate for ketones and [11C] acetoacetate. Ketone concentrations and cognitive performance differed between APOE ε4(+) and APOE ε4(-) participants, indicating a delayed response among the former and an improved response among the latter. Although research on the subject is still in the early stages and highly heterogeneous in terms of study design, interventions, and outcome measures, ketogenic therapy appears promising in improving both acute and long-term cognition among patients with AD/MCI. This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42019128311.

RevDate: 2020-06-29

Ugrumov M (2020)

Development of early diagnosis of Parkinson's disease: Illusion or reality?.

CNS neuroscience & therapeutics [Epub ahead of print].

The fight against neurodegenerative diseases, Alzheimer disease and Parkinson's disease (PD), is a challenge of the 21st century. The low efficacy of treating patients is due to the late diagnosis and start of therapy, after the degeneration of most specific neurons and depletion of neuroplasticity. It is believed that the development of early diagnosis (ED) and preventive treatment will delay the onset of specific symptoms. This review evaluates methodologies for developing ED of PD. Since PD is a systemic disease, and the degeneration of certain neurons precedes that of nigrostriatal dopaminergic neurons that control motor function, the current methodology is based on searching biomarkers, such as premotor symptoms and changes in body fluids (BF) in patients. However, all attempts to develop ED were unsuccessful. Therefore, it is proposed to enhance the current methodology by (i) selecting among biomarkers found in BF in patients at the clinical stage those that are characteristics of animal models of the preclinical stage, (ii) searching biomarkers in BF in subjects at the prodromal stage, selected by detecting premotor symptoms and failure of the nigrostriatal dopaminergic system. Moreover, a new methodology was proposed for the development of ED of PD using a provocative test, which is successfully used in internal medicine.

RevDate: 2020-06-29

Salimi A, Gobadian H, B Sharif Makhmal Zadeh (2020)

Dermal Pharmacokinetics of rivastigmine-loaded liposomes: an Ex vivo- in vivo correlation study.

Journal of liposome research [Epub ahead of print].

The aim of the present study was to develop a topical liposomal formulation as a transdermal delivery of rivastigmine for the treatment of Alzheimer disease as an alternative to the oral dosage form and to achieve smooth continuous drug delivery and maintain plasma levels within the therapeutic window. Rivastigmine-loaded liposomes were prepared by a thin layer hydration technique that was applied in Ex vivo- in vivo correlation study. Permeability parameters through rat skin in Ex vivo study and pharmacokinetic parameters in the in-vivo study were evaluated. The Ex vivo permeation study showed that liposomes provided steady-state flux 0.11 ± 0.01 mg/cm.h that was more than 2-fold the aqueous control. In the in vivo experiments, after topical application of optimized rivastigmine liposomes, the Cmax 208 ng/ml and AUC0-24 3605 (ng.h/ml) were also significantly higher than the control group (both P < 0.01). A point-to-point significant linear correlation was found between ex vivo- in vivo parameters, meaning in vivo pharmacokinetic parameters can be predicted by Ex vivo permeation parameters. These data suggest that a liposomal formulation could be an effective carrier to enhance rivastigmine permeation through the skin and maintain plasma levels within the therapeutic window.

RevDate: 2020-06-28

Volicer L (2020)

Physiological and pathological functions of beta-amyloid in the brain and alzheimer's disease: A review.

The Chinese journal of physiology, 63(3):95-100.

Alzheimer's disease is a major health problem all over the world. The role of beta-amyloid (Aβ) is at the center of investigations trying to discover the disease pathogenesis and to develop drugs for treatment or prevention on Alzheimer's disease. This review summarizes both physiological and pathological functions of Aβ and factors that may participate in the disease development. Known genetic factors are trisomy of chromosome 21, mutations of presenilin 1 and 2, and apolipoprotein E4. Lifetime stresses that increase the risk of development of Alzheimer's disease are described. Another important factor is the level of education, especially of linguistic ability. Lifestyle factors include mental and physical exercise, head injury, social contacts, and diet. All these factors might potentiate the effect of aging on the brain to increase the risk of development of pathological changes. The review summarizes pathological features of Alzheimer brain, Aβ plaques, neurofibrillary tangles composed of hyperphosphorylated tau, and brain atrophy. Consequences of Alzheimer's disease that are reviewed include cognitive deficit, loss of function, and neuropsychiatric symptoms. Because there is no effective treatment, many persons with Alzheimer's disease survive to severe and terminal stages which they may fear. Alzheimer's disease at this stage should be considered a terminal disease for which palliative care is indicated. Importance of advance directives, promoting previous wishes of the person who was developing dementia and who subsequently lost decision-making capacity, and limitations of these directives are discussed. Information in this review is based on author's knowledge and clinical experience that were updated by searches of PubMed.

RevDate: 2020-06-27

Berezutsky MA, Durnova NA, Andronova TA, et al (2020)

[Alzheimer's disease: experimental and clinical researches of Chinese herbal medicine neurobiological effects (a review).].

Advances in gerontology = Uspekhi gerontologii, 33(2):273-281.

The analysis of experiments and clinical data about research of neurobiological effects of chinese herbal medicine, which is used by Alzheimer`s disease treatment, was presented in given overview. The rats with injection of Aβ1-42 or Aβ25-35 peptides, or ibotenic acid, or streptozotocin as well as the natural line of mice SAMP8 with the phenotype of accelerated aging and other were used as the experimental models of Alzheimer`s disease. Various neurobiological effects of various herbal decoctions in the cells of hippocampus were demonstrated - the inhibition of amyloid β peptides aggregation, increasing of neurons quantity with normal morphology and decreasing of apoptotic cells, decreasing of inducible nitric oxide synthase (iNOS) production, decreasing of reactive expression level of RAGE and increasing reactive expression level of LRP-1, decreasing of tau protein phosphorylation at Thr231 and Ser422, inhibition of expression of GSK-3β and CDK-5, decreasing of activation and inflammation of microglia, production of 15 types of N-glycans in the cerebral cortex layers, which are absent in experimental animals. The improvement of memorization and training abilities was established.

RevDate: 2020-06-25

Hung A, Schneider M, Lopez MH, et al (2020)

Preclinical Alzheimer Disease Drug Development: Early Considerations Based on Phase 3 Clinical Trials.

Journal of managed care & specialty pharmacy, 26(7):888-900.

The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.

RevDate: 2020-06-24

Sut S, Maggi F, Bruno S, et al (2020)

Hairy Garlic (Allium subhirsutum) from Sicily (Italy): LC-DAD-MSn Analysis of Secondary Metabolites and In Vitro Biological Properties.

Molecules (Basel, Switzerland), 25(12): pii:molecules25122837.

Allium subhirsutum, known as hairy garlic, is a bulbous plant widespread in the Mediterranean area and locally used as a food and spice. In the present study, the chemical profile of the ethanolic extracts from bulbs (BE) and aerial parts (APE) were analyzed by HPLC-ESI-MSn, and antioxidant properties were evaluated by DPPH, ABTS and TEAC assays. The traditional use in the diet, and the well documented biological activity of Allium species suggest a potential as a new nutraceutical. For this reason, the potential usefulness of this food can be considered in the treatment and prevention of degenerative Alzheimer disease. For this reason, acetylcholinesterase inhibitory property was investigated. Furthermore, due to the observed presence of sulfur-containing and phenolic constituents, the cytotoxicity on tumor cells line was investigated. Results revealed significant AChE inhibitory activity for BE and APE. Both extracts exhibited also moderate antioxidant properties in the in vitro assays. Finally, limited cytotoxic activity was observed towards Human colon carcinoma and adenocarcinoma cell line, with differences between the individual parts tested. HPLC-ESI-MSn analysis showed that hairy garlic is a good source of sulphur compounds, flavonoids and phenylpropanoids derivatives, thus being a valid alternative to the common garlic (A. sativum). This work opens new opportunities for the application of A. subhirsutum as a health-promoting food.

RevDate: 2020-06-24

Stracke S, Lange S, Bornmann S, et al (2020)

Immunoadsorption for Treatment of Patients with Suspected Alzheimer Dementia and Agonistic Autoantibodies against Alpha1a-Adrenoceptor-Rationale and Design of the IMAD Pilot Study.

Journal of clinical medicine, 9(6): pii:jcm9061919.

BACKGROUND: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of α1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer's clinical syndrome within a one-year follow-up period.

METHODS: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19-26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months.

CONCLUSION: IMAD is an important pilot study that will analyze whether the removal of α1AR-agAABs by immunoadsorption in α1AR-agAAB-positive patients with suspected Alzheimer's clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters.

RevDate: 2020-06-26

Sivera R, Capet N, Manera V, et al (2020)

Voxel-based assessments of treatment effects on longitudinal brain changes in the Multidomain Alzheimer Preventive Trial cohort.

Neurobiology of aging, 94:50-59 pii:S0197-4580(20)30131-7 [Epub ahead of print].

The Multidomain Alzheimer Preventive Trial was designed to assess the effect of omega-3 supplementation and multidomain intervention on cognitive decline of subjects with subjective memory complaint. In terms of cognitive testing, no significant effect was found. In this paper, we evaluate the effect of the interventions on the brain morphological changes. Subjects with magnetic resonance imaging acquisitions at baseline and at 36 months were included (N = 376). Morphological changes were characterized by volume measurements and nonlinear deformation. The multidomain intervention was associated with a significant effect on the 3-year brain morphological changes in the deformation-based approach. Differences were mainly located in the left periventricular area next to the temporoparietal junction. These changes were associated with better cognitive performance and mood/behavior stabilization. No effect of the omega-3 supplementation was observed. This result suggests a possible effect on cognition, not yet observable after 3 years. We argue that neuroimaging could help define whether early intervention strategies are effective to delay cognitive decline and dementia.

RevDate: 2020-06-25

Craft S, Raman R, Chow TW, et al (2020)

Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial.

JAMA neurology [Epub ahead of print].

Importance: Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat persons with mild cognitive impairment and Alzheimer's disease dementia remains to be examined in a multi-site trial.

Objective: To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial.

A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer's Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging-Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019.

Interventions: Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices.

Main Outcomes and Measures: The primary outcome (mean score change on the Alzheimer Disease Assessment Scale-cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months.

Results: A total of 289 participants (155 men [54.6%]; mean [SD] age, 70.9 [7.1] years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men [51.3%]; mean [SD] age, 70.8 [7.1] years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, -1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment.

Conclusions and Relevance: In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort.

Trial Registration: ClinicalTrials.gov Identifier: NCT01767909.

RevDate: 2020-06-25

Raghavan NS, Dumitrescu L, Mormino E, et al (2020)

Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease.

JAMA neurology [Epub ahead of print].

Importance: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease.

Objective: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.

In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020.

Main Outcomes and Measures: A genome-wide association study of PET imaging amyloid levels.

Results: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = -0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort.

Conclusions and Relevance: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.

RevDate: 2020-06-20

Gupta SD, CH Pan (2020)

Recent update on discovery and development of Hsp90 inhibitors as senolytic agents.

International journal of biological macromolecules pii:S0141-8130(20)33560-1 [Epub ahead of print].

Hsp90 chaperone is an encouraging target for the development of novel anticancer agents. The failure of Hsp90 inhibitors to get regulatory approval for the treatment of cancer is hindered due to toxicity, cost involved in their development and formulation issues. The inhibitors against this chaperone are also being evaluated in pre-clinical models for the treatment of diseases other than cancer (Alzheimer, malaria, AIDS, etc.). Recently, Hsp90 inhibitors have shown promising senolytic effect that is helpful in increasing the health and life span of mice. The senolytic property of Hsp90 inhibitors will make them less toxic for use in humans. The review focuses on Hsp90 inhibitors discovered till date as senolytic agents along with their future prospects. Further, the various models used for the evaluation of senolytic effect are also discussed.

RevDate: 2020-06-20

Abou Baker DH, Ibrahim BMM, Hassan NS, et al (2020)

Exploiting Citrus aurantium seeds and their secondary metabolites in the management of Alzheimer disease.

Toxicology reports, 7:723-729.

Fruit by-products are considered nature's golden gift for human health and a good starting point to discover new drugs depending on the fact that they contain millions of bio-active compounds that are responsible for therapeutic activities. In this context, the main goal of this study is to recycle Citrus aurantium (C. aurantium) seeds to produce pharmaceutical molecules to be used in the prevention of the progressive neurological damage associated with Alzheimer disease (AD). Donepezil (0.75 mg/kg), hesperidin (125 and 250 mg/kg) and limonoids (50 and 100 mg/kg) were used for treatment of rats for 2 weeks prior to concomitant administration of AlCl3 for three successive weeks. Protection against cognitive deterioration was observed among study group with insignificant difference from normal control group and significant difference from positive control group in the Y-Maze test. On the other hand, treatment with both doses of hesperidin (125 and 250 mg/kg) and high dose of limonoids only (100 mg/kg) produced improvement in psychological state, observed by significant increase in ambulation frequency in comparison to positive control group, however it was not as frequent as normal group, as it was significantly less than normal group in the open field test. Regarding acetylcholine esterase (AChE) and beta-amyloid (β amyloid) levels, the effect of limonoids low dose was the best as it didn't have a significant effect when compared to normal control, also hesperidin in both doses showed insignificant effects on β amyloid levels when compared to normal control group. Our results encourage the use of C. aurantium seeds which are wasted in huge amounts, as Alzheimer prophylactic food additives.

RevDate: 2020-06-19

Loeffler DA (2020)

AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.

Frontiers in neurology, 11:459.

Grifols' recent Alzheimer Management by Albumin Replacement ("AMBAR") study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.

RevDate: 2020-06-19

Rea S, Della-Morte D, Pacifici F, et al (2020)

Insulin and Exendin-4 Reduced Mutated Huntingtin Accumulation in Neuronal Cells.

Frontiers in pharmacology, 11:779.

Patients with diabetes mellitus (DM) are more prone to develop cognitive decline and neurodegenerative diseases. A pathological association between an autosomal dominant neurological disorder caused by brain accumulation in mutated huntingtin (mHTT), known as Huntington disease (HD), and DM, has been reported. By using a diabetic mouse model, we previously suggested a central role of the metabolic pathways of HTT, further suggesting the relevance of this protein in the pathology of DM. Furthermore, it has also been reported that intranasal insulin (Ins) administration improved cognitive function in patients with neurodegenerative disorders such as Alzheimer disease, and that exendin-4 (Ex-4) enhanced lifespan and ameliorated glucose homeostasis in a mouse model of HD. Although antioxidant properties have been proposed, the underlying molecular mechanisms are still missing. Therefore, the aim of the present study was to investigate the intracellular pathways leading to neuroprotective effect of Ins and Ex-4 hypoglycemic drugs by using an in vitro model of HD, developed by differentiated dopaminergic neurons treated with the pro-oxidant neurotoxic compound 6-hydroxydopamine (6-ohda). Our results showed that 6-ohda increased mHTT expression and reduced HTT phosphorylation at Ser421, a post-translational modification, which protects against mHTT accumulation. Pre-treatment with Ins or Ex-4 reverted the harmful effect induced by 6-ohda by activating AKT1 and SGK1 kinases, and by reducing the phosphatase PP2B. AKT1 and SGK1 are crucial nodes on the Ins activation pathway and powerful antioxidants, while PP2B dephosphorylates HTT contributing to mHTT neurotoxic effect. In conclusion, present results highlight that Ins and Ex-4 may counteract the neurotoxic effect induced by mHTT, opening novel pharmacological therapeutic strategies against neurodegenerative disorders, with the main focus on HD, still considered an orphan illness.


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 )