Editors Choice Article | Detecting Non-cognitive Features of Prodromal Neurodegenerative Diseases


Journal Name: Current Aging Science

Author(s): Alon Seifan, Christine A. Ganzer*, Krista Ryon, Michael Lin, Rahman Mahmudur, Henriquez Adolfo, Cindy Shih, Alan R. Jacobs, Molly Greenwald, Richard S. Isaacson.



Background: Prodromal Neurodegenerative Disease (ND) due to tauopathies such as Alzheimer’s Disease (AD) and Synucleinopathies (SN) such as Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB) present subtly. Although ND are considered cognitive disorders, in fact ND present with behavioral and even medical symptomatology years to decades prior to the onset of cognitive changes. Recognizing prodromal ND syndromes is a public health priority because ND is common, disabling and expensive. Diagnosing prodromal ND in real world clinical settings is challenging because ND of the same pathology can present with different symptoms in different people. Individual variability in nature and variability in nurture across the life course influence how ND pathology manifests clinically. The objective of this study was to describe how non-cognitive symptoms from behavioral, medical, neurological and psychiatric domains cluster in prodromal and early stages of ND.

Methods: This was an observational study of patients receiving routine clinical care for memory disorders. All patients receiving a standardized evaluation including complete neurological history and examination and standardized brief neuropsychological testing. A Principal Component Analysis (PCA) considering emotion, motor, sensory and sleep factors was performed on the entire sample of patients in order to identify co-occurring symptom clusters. All patients received a consensus diagnosis adjudicated by at least two dementia experts. Patients were grouped into Cognitively Normal, Detectable Cognitive Impairment, and Mild Cognitive Impairment categories due to AD and/or PD/LBD or NOS pathology. Symptom cluster scores were compared between clinical diagnostic groups. Read out full article at: http://www.eurekaselect.com/169580/article

EDITOR’S CHOICE ARTICLE – The Potential Mechanisms of Exercise-induced Cognitive Protection: A Literature Review

Journal Name: Current Pharmaceutical Design

Author(s): Jennifer E. Norman*, Jennifer Rutkowsky, Sue Bodine, John C. Rutledge.





Dementia has become a major health concern for the aging population of the United States. Studies indicate that participation in moderate exercise, with training, has been shown to have a beneficial impact on cognition. Thus, exercise and its effects on cognitive function has become an important area of research. This review summarizes the current literature on the potential mechanisms of the benefits of exercise for cognitive function.


For more information, please visit: http://www.eurekaselect.com/161070/article

MOST ACCESSED ARTICLE – Estimating Alzheimer’s Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia


Journal Name: Current Alzheimer Research

Author(s): Matthew Davis, Thomas O`Connell,Scott Johnson,Stephanie Cline*, Elizabeth Merikle, Ferenc Martenyi, Kit Simpson.




Background: Alzheimer’s Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum.

Objective: To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes.

Methods: Patient-level longitudinal data from the National Alzheimer’s Coordinating Center for n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional probabilities between normal cognition, MCI due to AD, and AD severity states (defined by Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization for each health state, conditional on age and time from the previous evaluation. These probabilities were used to populate a transition matrix describing the likelihood of progressing to a particular disease state or death for any given current state and age. Finally, a health state model was developed to estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon.

Results: Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10% annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively. This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased life expectancy.

Conclusion: Transition probabilities from normal cognition through AD severity states are important for understanding patient progression across the AD spectrum. These estimates can be used to evaluate the clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health outcomes.


Read more here: http://www.eurekaselect.com/159189


EDITORS CHOICE ARTICLE – Strategies for Continued Successful Treatment in Patients with Alzheimer’s Disease: An Overview of Switching Between Pharmacological Agents


Author(s): Rafael Blesa, Kazuhiro Toriyama*, Kengo Ueda, Sean Knox, George Grossberg.



Introduction: Alzheimer’s disease (AD) is the most common cause of dementia, characterized by a progressive decline in cognition and function. Current treatment options for AD include the cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine, as well as the N-methyl-Daspartate receptor antagonist memantine. Treatment guidelines recommend the use of ChEIs as the standard of care first-line therapy. Several randomized clinical studies have demonstrated the benefits of ChEIs on cognition, global function, behavior and activities of daily living. However, patients may fail to achieve sustained clinical benefits from ChEIs due to lack/loss of efficacy and/or safety, tolerability issues, and poor adherence to the treatment. The purpose of this review is to explore the strategies for continued successful treatment in patients with AD.

Methods: Literature search was performed for articles published in PubMed and MEDLINE, using prespecified search terms. Articles were critically evaluated for inclusion based on their titles, abstracts, and full text of the publication.

Results and Conclusion: The findings of this review indicate that dose up-titration and switching between ChEIs may help to improve response to ChEI treatment and also address issues such as lack/loss of efficacy or safety/tolerability in patients with AD. However, well-designed studies are needed to provide robust evidence.


Read more here: http://www.eurekaselect.com/163056/article

OPEN ACCESS ARTICLE – Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

Journal Name: Current Medicinal Chemistry

Author(s): Yasushi Ikarashi, Kyoji Sekiguchi, Kazushige Mizoguchi*.



Background: Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes.

Objective: The aim of this article is to review the binding characteristics of GM to the 5-HT receptor subtypes in the brains using our own data and previous findings.

Method: Competitive receptor-binding and agonist/antagonist activity assays for several 5-HT receptor subtypes were performed. Moreover, the articles describing pharmacokinetics and brain distribution of GM were searched in PubMed.

Results: GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5- HT4, 5-HT5A, 5-HT6, and 5-HT7. Among these receptors, GM had partial agonistic activity for 5-HT1A receptors and antagonistic activity for 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. Also, GM was metabolized by various CYP isoforms, mainly CYP3A4. Parent/unchanged GM was detected in both the blood and brain of rats after oral administration of YKS. In the brains, GM was presumed to bind to 5- HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors on neuron-like large cells mainly in the frontal cortex.

Conclusion: These results suggest that GM is a pharmacologically important alkaloid that regulates various serotonergic activities or functions by binding to multiple 5-HT receptor subtypes. Thus, this review provides recent 5-HT receptor-related evidence that GM is partly responsible for pharmacological effects of YKS.


READ MORE HERE: http://www.eurekaselect.com/151003 

MOST ACCESSED ARTICLE – Adverse Events of Proton Pump Inhibitors – Current Drug Metabolism

Journal: Current Drug Metabolism

Author(s): Andrea Corsonello*, Fabrizia Lattanzio, Silvia Bustacchini, Sabrina Garasto, Annalisa Cozza,Roberto Schepisi, Federica Lenci, Filippo Luciani, Marcello Giuseppe Maggio, Andrea Ticinesi, Valeria Butto,Sara Tagliaferri, Francesco Corica.

Graphical Abstract:



Objective: We aimed at summarizing current evidence about mechanisms for potentially harmful effects of Proton Pump Inhibitors (PPIs).

Methods: A Pubmed search was performed, and 207 studies concerning the relationship between use of PPIs and cardiovascular diseases, kidney impairment, nutritional disorders, fractures, infections, functional decline, and mortality were selected and reviewed.

Results: PPIs may cause potentially harmful effects by several mechanisms, including endothelial dysfunction, hypomagnesemia, drug interactions, reduced absorption of selected nutrients, increased gastric microbiota and small intestine bacterial overgrowth, reduced immune response, tubular-interstitial inflammation, increased bone turnover, accumulation of amyloid in the brain. Clinical and epidemiologic evidence is not consistent in regard to some negative outcomes during PPI treatment. Data from randomized clinical trials seem to deny most of them, but they are usually designed to investigate efficacy of drugs in ideal conditions and are not powered enough to detect adverse events. Besides being at special risk of experiencing negative outcomes during long-term treatment with PPIs, older and complex patients treated with polypharmacy regimens are persistently excluded from randomized clinical trials. Thus, large observational studies involving real-world patients should be considered as an important informative source about potential risks related to PPIs.

Conclusions: Current evidence suggests that use of PPIs may be associated with negative outcomes by eliciting several different pathophysiologic mechanisms. While short-term PPIs could be considered effective and safe in adult patients with acid-related disorders, their long-term and often inappropriate use in patients carrying vulnerability to adverse events and/or high risk of drug-interactions should be avoided.

Read more here: http://www.eurekaselect.com/158149/article


EDITOR’S CHOICE – Tolfenamic Acid: A Modifier of the Tau Protein and its Role in Cognition and Tauopathy

Journal: Current Alzheimer Research

Author(s): Lingyu Lee*, Yingli Liu


Background: Tangles are deposits of hyperphosphorylated tau, which are found in multiple neurodegenerative disorders that are referred to as tauopathies, of which Alzheimer’s disease (AD) is the most common. Tauopathies are clinically characterized by dementia and share common cortical lesions composed of aggregates of the protein tau.

Objective: In this study, we explored the therapeutic potential of tolfenamic acid (TA), in modifying disease processes in a transgenic animal model that carries the human tau gene (hTau).

Methods: Behavioral tests, Western blotting and Immunohistochemical analysis were used to demonstrate the efficacy of TA.

Results: Treatment of TA improved improving spatial learning deficits and memory impairments in young and aged hTau mice. Western blot analysis of the hTau protein revealed reductions in total tau as well as in sitespecific hyperphosphorylation of tau in response to TA administration. Immunohistochemical analysis for phosphorylated tau protein revealed reduced staining in the frontal cortex, hippocampus, and striatum in animals treated with TA.

Conclusion: TA holds the potential as a disease-modifying agent for the treatment of tauopathies including AD.

Read more here: http://www.eurekaselect.com/159193/article


PRESS RELEASE – Pharmacogenetics of angiotensin-converting enzyme inhibitors for Alzheimer’s disease

This article by Dr. Fabricio Ferreira de Oliveira et al. is published in Current Alzheimer Research, Volume 15, Issue 4, 2018

The angiotensin-converting enzyme is an amyloid-ß-degrading enzyme. While angiotensin-converting enzyme inhibitors could increase amyloid-ß accumulation, they might also slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia. In this study from São Paulo, Brazil, we aimed to investigate whether ACE polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with Alzheimer’s disease dementia, while also taking APOE haplotypes and anti-hypertensive treatment with angiotensin-converting enzyme inhibitors into account for stratification. Overall, 193 consecutive patients with late-onset Alzheimer’s disease dementia were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with angiotensin-converting enzyme inhibitors. Almost 94% of all patients used cholinesterase inhibitors, whereas 155 had arterial hypertension, and 124 used angiotensin-converting enzyme inhibitors. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 — T and rs4291 — A, or for APOE4- carriers of rs1800764 — T or rs4291 — T, angiotensin-converting enzyme inhibitors slowed cognitive decline independently of blood pressure variations, possibly by way of central and peripheral effects. APOE4+ carriers were not responsive to treatment with angiotensin-converting enzyme inhibitors. In conclusion, angiotensin-converting enzyme inhibitors may slow cognitive decline for patients with Alzheimer’s disease dementia, more remarkably for APOE4- carriers of specific ACE genotypes. Future trials should prospectively compare angiotensin-converting enzyme inhibitors according to their brain-penetrating properties since the start of anti-hypertensive therapy, with measurements of cerebrospinal fluid and serum levels and activity of the angiotensin-converting enzyme, as well as genetic profiles and neuroimaging parameters.

For more information on this research, please visit: http://www.eurekaselect.com/156397/article


Press Release for EurekAlert! Neuroinflammation in Alzheimer’s and Parkinson’s diseases

This article by Dr. Jordan A. McKenzie et al. is published in Current Aging Science, Volume 10, Issue 3, 2017

In the journal Current Aging Science, a research team has reviewed modifiable risk factors for Alzheimer’s and Parkinson’s diseases. The reviewers focus on the possible role of neuroinflammation (inflammation of the nervous tissue) in neurodegenerative disease mechanisms. Alzheimer’s disease and Parkinson’s disease are among the most common causes of dementia, and increasingly contribute to morbidity and mortality worldwide. A common hallmark of these two diseases is neuroinflammation, which is initially triggered by the presence of pathological molecular structures associated with these disorders. Chronic neuroinflammation is sustained by persistent activation of the non-neuronal glial cells in the brain, which results in damage or death of neighboring cells, including neurons and glial cells themselves. Persistent neuroinflammation of the brain is hypothesized to contribute to the neurodegeneration observed in Alzheimer’s and Parkinson’s diseases.

The reviewers note four modifiable risk factors for Alzheimer’s and Parkinson’s diseases: physical inactivity, vascular disease-related conditions, obesity and type two diabetes mellitus. These modifiable risk factors contribute to neuroinflammation through specific mechanisms that are directly linked to the pathologies of Alzheimer’s and Parkinson’s diseases. These risk factors are deemed modifiable as their occurrence in the general population can be reduced, or avoided by individuals, through various lifestyle changes, such as improved diet, regular exercise and effective treatment of vascular disease-related conditions such as high blood pressure. This review highlights that the control of the modifiable risk factors is a valid approach for managing the increased incidence of both Alzheimer’s and Parkinson’s diseases. In addition, the neuroinflammatory mechanisms common to Alzheimer’s and Parkinson’s diseases are described, which may link the above four common modifiable risk factors with both of these neurodegenerative diseases. A better understanding of the molecular mechanism of neuroinflammation could help identify new therapeutic targets for combating neurodegenerative diseases.

View the article here: http://www.eurekaselect.com/150884

World Alzheimer’s Day 2017!


World Alzheimer’s Day is observed annually on 21 September each year to raise awareness and challenge the stigma that surrounds dementia. Alzheimer’s disease is the most common form of dementia, a group of disorders that impairs mental functioning.

Bentham Science Publishers is in the forefront in creating awareness about this through the research in the journal:

Current Alzheimer Research

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