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15 Sep 2019 at 01:32
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Bibliography on: Alzheimer Disease — Treatment


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RJR: Recommended Bibliography 15 Sep 2019 at 01:32 Created: 

Alzheimer Disease — Treatment

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

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

Citations The Papers (from PubMed®)

RevDate: 2019-09-14

Guo E, Hu Y, Du T, et al (2019)

Effects of Picrasma quassioides and its active constituents on Alzheimer's disease in vitro and in vivo.

Bioorganic chemistry, 92:103258 pii:S0045-2068(19)30680-7 [Epub ahead of print].

Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Aβ25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-β peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Aβ1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six β-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four β-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE).

RevDate: 2019-09-14

Lavretsky H, Laird KT, Krause-Sorio B, et al (2019)

A Randomized Double-Blind Placebo-Controlled Trial of Combined Escitalopram and Memantine for Older Adults With Major Depression and Subjective Memory Complaints.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry pii:S1064-7481(19)30474-9 [Epub ahead of print].

OBJECTIVE: Geriatric depression is difficult to treat and frequently accompanied by cognitive complaints that increase risk for dementia. New treatment strategies targeting both depression and cognition are urgently needed.

METHODS: We conducted a 6-month double-blind placebo-controlled trial to assess the efficacy and tolerability of escitalopram + memantine (ESC/MEM) compared to escitalopram + placebo (ESC/PBO) for improving mood and cognitive functioning in depressed older adults with subjective memory complaints (NCT01902004). Primary outcome was change in depression as assessed by the HAM-D post-treatment (at 6 months). Remission was defined as HAM-D ≤6; naturalistic follow-up continued until 12 months.

RESULTS: Of the 95 randomized participants, 62 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Mean daily escitalopram dose was 11.1 mg (SD = 3.7; range: 5-20 mg). Mean daily memantine dose was 19.3 mg (SD = 2.6; range 10-20 mg). Remission rate within ESC/MEM was 45.8% and 47.9%, compared to 38.3% and 31.9% in ESC/PBO, at 3 and 6 months, respectively (χ2(1) = 2.0, p = 0.15). Both groups improved significantly on the HAM-D at 3, 6, and 12 months, with no observed between-group differences. ESC/MEM demonstrated greater improvement in delayed recall (F(2,82) = 4.3, p = 0.02) and executive functioning (F(2,82) = 5.1, p = 0.01) at 12 months compared to ESC/PBO.

CONCLUSIONS: The combination of memantine with escitalopram was well tolerated and as effective as escitalopram and placebo in improving depression using HAM-D. Combination memantine and escitalopram was significantly more effective than escitalopram and placebo in improving cognitive outcomes at 12 months. Future reports will address the role of biomarkers of aging in treatment response.

RevDate: 2019-09-13

Mullins RJ, Mustapic M, Chia CW, et al (2019)

A pilot study of exenatide actions in Alzheimer's disease.

Current Alzheimer research pii:CAR-EPUB-100792 [Epub ahead of print].

BACKGROUND: Strong preclinical evidence suggests that exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist used for treating type 2 diabetes, is neuroprotective and disease- modifying in Alzheimer's disease (AD).

OBJECTIVE: We performed an 18-month double-blind randomized placebo-controlled Phase II clinical trial to assess the safety and tolerability of exenatide and explore treatment responses for clinical, cognitive, and bio- marker outcomes in early AD.

METHOD: Eighteen participants with high probability AD based on cerebrospinal fluid (CSF) biomarkers completed the entire study prior to its early termination by the sponsor; partial outcomes were available for twenty-one.

RESULTS: Exenatide was safe and well-tolerated, showing an expectedly higher incidence of nausea and decreased appetite compared to placebo and decreasing glucose and GLP-1 during Oral Glucose Tolerance Tests. Exenatide treatment produced no differences or trends compared to placebo for clinical and cognitive measures, MRI cortical thickness and volume, or biomarkers in CSF, plasma, and plasma neuronal extracellular vesicles (EV) except for a reduction of Aβ42 in EVs.

CONCLUSION: The positive finding of lower EV Aβ42 supports emerging evidence that plasma neuronal EVs provide an effective platform for demonstrating biomarker responses in clinical trials in AD. The study was underpowered due to early termination and therefore we cannot draw any firm conclusions. However, the analysis of secondary outcomes shows no trends in support of the hypothesis that exenatide is disease- modifying in clinical AD, and lowering EV Aβ42 in and of itself may not improve cognitive outcomes in AD.

RevDate: 2019-09-11

Goyal P, Anderson TS, Bernacki GM, et al (2019)

Physician Perspectives on Deprescribing Cardiovascular Medications for Older Adults.

Journal of the American Geriatrics Society [Epub ahead of print].

BACKGROUND/OBJECTIVES: Guideline-based management of cardiovascular disease often involves prescribing multiple medications, which contributes to polypharmacy and risk for adverse drug events in older adults. Deprescribing is a potential strategy to mitigate these risks. We sought to characterize and compare clinician perspectives regarding deprescribing cardiovascular medications across three specialties.

DESIGN: National cross-sectional survey.

SETTING: Ambulatory.

PARTICIPANTS: Random sample of geriatricians, general internists, and cardiologists from the American College of Physicians.

MEASUREMENTS: Electronic survey assessing clinical practice of deprescribing cardiovascular medications, reasons and barriers to deprescribing, and choice of medications to deprescribe in hypothetical clinical cases.

RESULTS: In each specialty, 750 physicians were surveyed, with a response rate of 26% for geriatricians, 26% for general internists, and 12% for cardiologists. Over 80% of respondents within each specialty reported that they had recently considered deprescribing a cardiovascular medication. Adverse drug reactions were the most common reason for deprescribing for all specialties. Geriatricians also commonly reported deprescribing in the setting of limited life expectancy. Barriers to deprescribing were shared across specialties and included concerns about interfering with other physicians' treatment plans and patient reluctance. In hypothetical cases, over 90% of physicians in each specialty chose to deprescribe when patients experienced adverse drug reactions. Geriatricians were most likely and cardiologists were least likely to consider deprescribing cardiovascular medications in cases of limited life expectancy (all P < .001), such as recurrent metastatic cancer (84% of geriatricians, 68% of general internists, and 45% of cardiologists), Alzheimer dementia (92% of geriatricians, 81% of general internists, and 59% of cardiologists), or significant functional impairment (83% of geriatricians, 68% of general internists, and 45% of cardiologists).

CONCLUSIONS: While barriers to deprescribing cardiovascular medications are shared across specialties, reasons for deprescribing, especially in the setting of limited life expectancy, varied. Implementing deprescribing will require improved processes for both physician-physician and physician-patient communication.

RevDate: 2019-09-11

Cenini G, W Voos (2019)

Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update.

Frontiers in pharmacology, 10:902.

Alzheimer disease (AD) is a progressive and deleterious neurodegenerative disorder that affects mostly the elderly population. At the moment, no effective treatments are available in the market, making the whole situation a compelling challenge for societies worldwide. Recently, novel mechanisms have been proposed to explain the etiology of this disease leading to the new concept that AD is a multifactor pathology. Among others, the function of mitochondria has been considered as one of the intracellular processes severely compromised in AD since the early stages and likely represents a common feature of many neurodegenerative diseases. Many mitochondrial parameters decline already during the aging, reaching an extensive functional failure concomitant with the onset of neurodegenerative conditions, although the exact timeline of these events is still unclear. Thereby, it is not surprising that mitochondria have been already considered as therapeutic targets in neurodegenerative diseases including AD. Together with an overview of the role of mitochondrial dysfunction, this review examines the pros and cons of the tested therapeutic approaches targeting mitochondria in the context of AD. Since mitochondrial therapies in AD have shown different degrees of progress, it is imperative to perform a detailed analysis of the significance of mitochondrial deterioration in AD and of a pharmacological treatment at this level. This step would be very important for the field, as an effective drug treatment in AD is still missing and new therapeutic concepts are urgently needed.

RevDate: 2019-09-11

Liu J, L Li (2019)

Targeting Autophagy for the Treatment of Alzheimer's Disease: Challenges and Opportunities.

Frontiers in molecular neuroscience, 12:203.

Alzheimer's disease (AD) is the most common type of dementia which characterized by a progressive loss of memory and cognitive function due to degeneration of synapses and axons. Currently, there is no cure for AD. Deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs) are two hallmark pathologic changes in the brains of Alzheimer's patients. Autophagy is the major mechanism in cells responsible for removing protein aggregates. Accumulation of immature autophagic vacuoles (AVs) in dystrophic neurites of Alzheimer patients' brains suggests that autophagy process is disrupted. Till now, it is far from clear what role autophagy plays in AD, a causative role, a protective role, or just a consequence of the disease process itself. To design more effective therapeutic strategies towards this devastating disorder, it is essential to understand the exact role of autophagy played during different stages of AD.

RevDate: 2019-09-03

Bazzigaluppi P, Beckett TL, Koletar MM, et al (2019)

Combinatorial Treatment Using Umbilical Cord Perivascular Cells and Aβ Clearance Rescues Vascular Function Following Transient Hypertension in a Rat Model of Alzheimer Disease.

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

Transient hypertension is a risk factor for Alzheimer disease (AD), but the effects of this interaction on brain vasculature are understudied. Addressing vascular pathology is a promising avenue to potentiate the efficacy of treatments for AD. We used arterial spin labeling magnetic resonance imaging to longitudinally assess brain vascular function and immunohistopathology to examine cerebrovascular remodeling and amyloid load. Hypertension was induced for 1 month by administration of l-NG-nitroarginine-methyl-ester in TgF344-AD rats at the prodromal stage. Following hypertension, nontransgenic rats showed transient cerebrovascular changes, whereas TgF344-AD animals exhibited sustained alterations in cerebrovascular function. Human umbilical cord perivascular cells in combination with scyllo-inositol, an inhibitor of Aβ oligomerization, resulted in normalization of hippocampal vascular function and remodeling, in contrast to either treatment alone. Prodromal stage hypertension exacerbates latter AD pathology, and the combination of human umbilical cord perivascular cells with amyloid clearance promotes cerebrovascular functional recovery.

RevDate: 2019-09-02

Oh ES, PV Rabins (2019)


Annals of internal medicine, 171(5):ITC33-ITC48.

Alzheimer disease (AD) and other dementia syndromes are becoming more common; an estimated 5.5 million adults aged 65 years or older are living with AD in the United States. It is important for primary care physicians to gain knowledge in this field because most community-dwelling older adults receive their care from them. This article discusses the latest findings in approaches to prevent cognitive decline as well as dementia screening, diagnosis, and treatment. Approaches to address quality of life for persons with dementia and their caregivers are also discussed.

RevDate: 2019-08-31

Shentu YP, Hu WT, Liang JW, et al (2019)

Genistein Decreases APP/tau Phosphorylation and Ameliorates Aβ Over- production Through Inhibiting CIP2A.

Current Alzheimer research pii:CAR-EPUB-100545 [Epub ahead of print].

Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease- related phosphorylation of tau/APP and tau pathology/Aβ overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. In this study, the inhibitory effect of Genistein on tau/APP phosphorylation and Aβ overproduction in AD cell models have been explored. The results showed that Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP and CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aβ production. In the meantime, Genistein ameliorated tau hyperphosphorylation by repressing the inhibitory effect of CIP2A on PP2A. Thus, Genistein has the potential to be used in AD treatment by targeting CIP2A-PP2A signaling in AD therapy.

RevDate: 2019-08-30

Mancioppi G, Fiorini L, Timpano Sportiello M, et al (2019)

Novel Technological Solutions for Assessment, Treatment, and Assistance in Mild Cognitive Impairment.

Frontiers in neuroinformatics, 13:58.

Alzheimer's disease, and dementia, represent a common cause of disability and one of the most relevant challenges in the health world. In addition, these conditions do not have, at moment, a pharmacological treatment that can stop the pathological progress. Mild cognitive impairment (MCI), defined as the borderline between normal aging and early dementia, represents a meaningful field of study because, in the transition to dementia, clinicians have defined a useful therapeutic window. Additionally, due to the lack of effective pharmacological interventions, recent years have seen an increase in research into new technological solutions to assess, stimulate, and assist patients afflicted with Alzheimer's disease. This review aims to outline the use of information and communication technologies in the field studying MCI. Particularly, the goal is to depict the framework and describe the most worthwhile research efforts, in order to display the current technologies available, describe the research objectives, and delineate prospective future researches. Regarding data sources, the research was conducted within three databases, PubMed Central, Web of Science, and Scopus, between January 2009 and December 2017. A total of 646 articles were found in the initial search. Accurate definition of the exclusion criteria and selection strategy allowed identification of the most relevant papers to use for the study. Finally, 56 papers were fully evaluated and included in this review. Three major clinical application areas have been portrayed, namely "Cognitive Assessment," "Treatment," and "Assistance." These have been combined with three main technological solutions, specifically "Sensors," "Personal Devices," and "Robots." Furthermore, the study of the publications time series illustrates a steadily increasing trend, characterized by the enrollment of small groups of subjects, and particularly oriented to the subjects assistance using robots companion. In conclusion, despite the new technological solutions for people with MCI have received much interest, particularly regarding robots for assistance, nowadays it still owns vast room for improvement.

RevDate: 2019-08-29

Magistretti PJ, Geisler FH, Schneider JS, et al (2019)

Gangliosides: Treatment Avenues in Neurodegenerative Disease.

Frontiers in neurology, 10:859.

Gangliosides are cell membrane components, most abundantly in the central nervous system (CNS) where they exert among others neuro-protective and -restorative functions. Clinical development of ganglioside replacement therapy for several neurodegenerative diseases was impeded by the BSE crisis in Europe during the 1990s. Nowadays, gangliosides are produced bovine-free and new pre-clinical and clinical data justify a reevaluation of their therapeutic potential in neurodegenerative diseases. Clinical experience is greatest with monosialo-tetrahexosyl-ganglioside (GM1) in the treatment of stroke. Fourteen randomized controlled trials (RCTs) in overall >2,000 patients revealed no difference in survival, but consistently superior neurological outcomes vs. placebo. GM1 was shown to attenuate ischemic neuronal injuries in diabetes patients by suppression of ERK1/2 phosphorylation and reduction of stress to the endoplasmic reticulum. There is level-I evidence from 5 RCTs of a significantly faster recovery with GM1 vs. placebo in patients with acute and chronic spinal cord injury (SCI), disturbance of consciousness after subarachnoid hemorrhage, or craniocerebral injuries due to closed head trauma. In Parkinson's disease (PD), two RCTs provided evidence of GM1 to be superior to placebo in improving motor symptoms and long-term to result in a slower than expected symptom progression, suggesting disease-modifying potential. In Alzheimer's disease (AD), the role of gangliosides has been controversial, with some studies suggesting a "seeding" role for GM1 in amyloid β polymerization into toxic forms, and others more recently suggesting a rather protective role in vivo. In Huntington's disease (HD), no clinical trials have been conducted yet. However, low GM1 levels observed in HD cells were shown to increase cell susceptibility to apoptosis. Accordingly, treatment with GM1 increased survival of HD cells in vitro and consistently ameliorated pathological phenotypes in several murine HD models, with effects seen at molecular, cellular, and behavioral level. Given that in none of the clinical trials using GM1 any clinically relevant safety issues have occurred to date, current data supports expanding GM1 clinical research, particularly to conditions with high, unmet medical need.

RevDate: 2019-08-23

Kolagar TA, Farzaneh M, Nikkar N, et al (2019)

Human Pluripotent Stem Cells in Neurodegenerative Diseases: Potentials, Advances, and Limitations.

Current stem cell research & therapy pii:CSCR-EPUB-100433 [Epub ahead of print].

Neurodegenerative diseases are progressive and uncontrolled gradual loss of motor neurons function or death of neuron cells in the central nervous system (CNS) and the mechanisms underlying their progressive nature remain elusive. There is urgent need to investigate therapeutic strategies and novel treatments for neural regeneration in disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Currently, the development and identification of pluripotent stem cells enabling the acquisition of a large number of neural cells in order to improve cell recovery after neurodegenerative disorders. Pluripotent stem cells which consist of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are characterized by their ability to indefinitely self-renew and the capacity to differentiate into different types of cells. The first human ESC lines were established from donated human embryos; while, because of a limited supply of donor embryos, human ESCs derivation remains ethically and politically controversial. Hence, hiPSCs-based therapies have been shown as an effective replacement for human ESCs without embryo destruction. Compared to the invasive methods for derivation of human ESCs, human iPSCs has opened possible to reprogram patient-specific cells by defined factors and with minimally invasive procedures. Human pluripotent stem cells are a good source for cell-based research, cell replacement therapies and disease modeling. To date, hundreds of human ESC and human iPSC lines have been generated with the aim of treating various neurodegenerative diseases. In this review, we have highlighted the recent potentials, advances, and limitations of human pluripotent stem cells for the treatment of neurodegenerative disorders.

RevDate: 2019-08-20

Singh AK, Singh SK, Nandi MK, et al (2019)

Berberine: A plant derived alkaloid with therapeutic potential to combat Alzheimer's disease.

Central nervous system agents in medicinal chemistry pii:CNSAMC-EPUB-100362 [Epub ahead of print].

Berberine (A protoberberine isoquinoline alkaloid) has shown promising pharmacological activities, including analgesic, anti-inflammatory, anticancer, antidiabetic, anti-hyperlipidemic, cardioprotective, memory enhancement, antidepressant, antioxidant, anti-nociceptive, antimicrobial, anti-HIV and cholesterol-lowering effects. It is used in the treatment of neurodegenerative disorder. It has strong evidence to serve as potent phytoconstituent in the treatment of various neurodegenerative disorders such as AD. It limits the extracellular amyloid plaques and intracellular neurofibrillary tangles. It also has lipid-glucose lowering ability, hence can be used as a protective agent in atherosclerosis and AD. However, more detailed investigations along with safety assessment of berberine are warranted to clarify its role in limiting various risk factors and AD-related pathologies. This review highlights the pharmacological basis to control oxidative stress, neuroinflammation and protective effect of berberine in AD, which will benefit to the biological scientists in understanding and exploring the new vistas of berberine in combating Alzheimer's disease.

RevDate: 2019-08-18

Xue C, Tran J, Wang H, et al (2019)

Aβ42 fibril formation from predominantly oligomeric samples suggests a link between oligomer heterogeneity and fibril polymorphism.

Royal Society open science, 6(7):190179 pii:rsos190179.

Amyloid-β (Aβ) oligomers play a central role in the pathogenesis of Alzheimer's disease. Oligomers of different sizes, morphology and structures have been reported in both in vivo and in vitro studies, but there is a general lack of understanding about where to place these oligomers in the overall process of Aβ aggregation and fibrillization. Here, we show that Aβ42 spontaneously forms oligomers with a wide range of sizes in the same sample. These Aβ42 samples contain predominantly oligomers, and they quickly form fibrils upon incubation at 37°C. When fractionated using ultrafiltration filters, the samples enriched with smaller oligomers form fibrils at a faster rate than the samples enriched with larger oligomers, with both a shorter lag time and faster fibril growth rate. This observation is independent of Aβ42 batches and hexafluoroisopropanol treatment. Furthermore, the fibrils formed by the samples enriched with larger oligomers are more readily solubilized by epigallocatechin gallate, a main catechin component of green tea. These results suggest that the fibrils formed by larger oligomers may adopt a different structure from fibrils formed by smaller oligomers, pointing to a link between oligomer heterogeneity and fibril polymorphism.

RevDate: 2019-08-16

Koehn SD, Donahue M, Feldman F, et al (2019)

Fostering trust and sharing responsibility to increase access to dementia care for immigrant older adults.

Ethnicity & health [Epub ahead of print].

Objectives: This paper explores the role of immigrant-serving agencies in facilitating access to dementia services and supports provided by dementia service agencies (particularly the health authority and local chapters of the Alzheimer Society) through their propensity to develop trusting relationships between staff and clients. Design: Our research is a qualitative case study of Punjabi and Korean speakers living in the Lower Mainland of BC, Canada. Data are drawn from interviews with 15 dyads of persons with dementia and their family caregivers (10 Punjabi, 5 Korean), six focus groups (one focus group with each of 8-10 older men, older women, and mixed gender working age adults in each community). We also interviewed 20 managerial and frontline staff of dementia service agencies, i.e. the health authority and the local Alzheimer Society (n = 11) and two immigrant-serving agencies (n = 9), each dedicated to either Punjabi or Korean-speaking clients. We adopted the Candidacy framework for understanding access to dementia services and supports and the concept of trust as guiding precepts in this study. Results: Families of persons with dementia are pivotal to identification of a problem requiring professional help, navigation to appropriate services and acceptance of services offered. However, trust in family members should not be taken for granted, since family dynamics are complex. Alternative sources of trusted support are therefore needed. Immigrant-serving agencies are more often instrumental in establishing trusted relationships between their staff and clients, but they often lack detailed knowledge about heath conditions, their treatment and management, and they lack power to implement statutory care. Conclusions: Partnerships between mainstream mental health/dementia services and the community sector have proven successful in increasing the accessibility of specialized resources, while maximizing their combined trustworthiness, accessibility and effectiveness. Such partnerships should become fundamental components of health service strategy and provision for vulnerable and underserved immigrant older adults.

RevDate: 2019-08-22

Lanzillotta C, Di Domenico F, Perluigi M, et al (2019)

Targeting Mitochondria in Alzheimer Disease: Rationale and Perspectives.

CNS drugs pii:10.1007/s40263-019-00658-8 [Epub ahead of print].

A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders, including Alzheimer disease (AD). Mitochondria-the power station of the organism-can affect several different cellular activities, including abnormal cellular energy generation, response to toxic insults, regulation of metabolism, and execution of cell death. In AD subjects, mitochondria are characterized by impaired function such as lowered oxidative phosphorylation, decreased adenosine triphosphate production, significant increased reactive oxygen species generation, and compromised antioxidant defense. The current review discusses the most relevant mitochondrial defects that are considered to play a significant role in AD and that may offer promising therapeutic targets for the treatment/prevention of AD. In addition, we discuss mechanisms of action and translational potential of some promising mitochondrial and bioenergetic therapeutics for AD including compounds able to potentiate energy production, antioxidants to scavenge reactive oxygen species and reduce oxidative damage, glucose metabolism, and candidates that target mitophagy. While mitochondrial therapeutic strategies have shown promise at the preclinical stage, there has been little progress in clinical trials. Thus, there is an urgent need to better understand the mechanisms regulating mitochondrial homeostasis in order to identify powerful drug candidates that target 'in and out' the mitochondria to preserve cognitive functions.

RevDate: 2019-08-29

de Best PB, Raz N, Guy N, et al (2019)

Role of Population Receptive Field Size in Complex Visual Dysfunctions: A Posterior Cortical Atrophy Model.

JAMA neurology pii:2747559 [Epub ahead of print].

Importance: The neuronal mechanism of visual agnosia and foveal crowding that underlies the behavioral symptoms of several classic neurodegenerative diseases, including impaired holistic perception, navigation, and reading, is still unclear. A better understanding of this mechanism is expected to lead to better treatment and rehabilitation.

Objective: To use state-of-the-art neuroimaging protocols to assess a hypothesis that abnormal population receptive fields (pRF) in the visual cortex underlie high-order visual impairments.

Between April 26 and November 21, 2016, patients and controls were recruited from the Hadassah-Hebrew University medical center in a cross-sectional manner. Six patients with posterior cortical atrophy (PCA) were approached and 1 was excluded because of an inability to perform the task. Participants underwent functional magnetic resonance imaging-based cortical visual field mapping and pRF evaluation and performed a masked repetition priming task to evaluate visuospatial perception along the eccentricity axis. The association between pRF sizes and behavioral impairments was assessed to evaluate the role of abnormal pRF sizes in impaired visual perception. Posterior cortical atrophy is a visual variant of Alzheimer disease that is characterized by progressive visual agnosia despite almost 20/20 visual acuity. Patients with PCA are rare but invaluable for studying visual processing abnormalities following neurodegeneration, as atrophy begins in visual cortices but initially spares other brain regions involved in memory and verbal communication.

Exposures: Participants underwent a magnetic resonance imaging scan.

Main Outcomes and Measures: Population receptive field sizes and their association with visual processing along the fovea-to-periphery gradient.

Results: Five patients with PCA (4 men [80%]; mean [SEM] age, 62.9 [3.5] years) were compared with 8 age-matched controls (1 man [25%]; mean [SEM] age, 63.7 [3.7] years) and demonstrated an atypical pRF mapping that varied along the eccentricity axis, which presented as abnormally small peripheral and large foveal pRFs sizes. Abnormality was seen in V1 (peripheral, 4.4° and 5.5°; foveal, 5.5° and 4.5° in patients and controls, respectively; P < .05) as well as in higher visual regions, but not in intermediate ones. Behaviorally, an atypical fovea-to-periphery gradient in visual processing was found that correlated with their pRF properties (r = 0.8; P < .01 for the correlation between pRF and behavioral fovea-to-periphery slopes).

Conclusions and Relevance: High-order visuocognitive functions may depend on abnormalities in basic cortical characteristics. These results may fundamentally change approaches to rehabilitation in such conditions, emphasizing the potential of low-level visual interventions.

RevDate: 2019-08-11

Abdul Manap AS, Vijayabalan S, Madhavan P, et al (2019)

Bacopa monnieri, a Neuroprotective Lead in Alzheimer Disease: A Review on Its Properties, Mechanisms of Action, and Preclinical and Clinical Studies.

Drug target insights, 13:1177392819866412 pii:10.1177_1177392819866412.

Alzheimer disease is a neurodegenerative disease that is signified by cognitive decline, memory loss, and erratic behavior. Till date, no cure for Alzheimer exists and the current Alzheimer medications have limited effectiveness. However, herbal medicines may slow down the disease's progression, which may hopefully reduce the number of cases in the years to come. Numerous studies have been done on characterizing the neuroprotective properties from plants belonging to Scrophulariaceae family, particularly Bacopa monnieri and its polyphenolic compounds known as bacosides. This review presents the findings on bacosides in therapeutic plants and their impact on Alzheimer disease pathology. These reports present data on the clinical, cellular activities, phytochemistry, and biological applications that may be used in new drug treatment for Alzheimer disease.

RevDate: 2019-08-06

Zhan S, Che P, Zhao XK, et al (2019)

Molecular mechanism of tumour necrosis factor alpha regulates hypocretin (orexin) expression, sleep and behaviour.

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

Hypocretin 1 and hypocretin 2 (orexin A and B) regulate sleep, wakefulness and emotion. Tumour necrosis factor alpha (TNF-α) is an important neuroinflammation mediator. Here, we examined the effects of TNF-α treatment on hypocretin expression in vivo and behaviour in mice. TNF-α decreased hypocretin 1 and hypocretin 2 expression in a dose-dependent manner in cultured hypothalamic neurons. TNF-α decreased mRNA stability of prepro-hypocretin, the single precursor of hypocretin 1 and hypocretin 2. Mice challenged with TNF-α demonstrated decreased expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in hypothalamus. In response to TNF-α, prepro-hypocretin mRNA decay was increased in hypothalamus. TNF-α neutralizing antibody restored the expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in vivo in TNF-α challenged mice, supporting hypocretin system can be impaired by increased TNF-α through decreasing hypocretin expression. Repeated TNF-α challenge induced muscle activity during rapid eye movement sleep and sleep fragmentation, but decreased learning, cognition and memory in mice. TNF-α neutralizing antibody blocked the effects of TNF-α; in contrast, hypocretin receptor antagonist enhanced the effects of TNF-α. The data support that TNF-α is involved in the regulation of hypocretin expression, sleep and cognition. The findings shed some lights on the role of neuroinflammation in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

RevDate: 2019-08-06

Abdizadeh R, Hadizadeh F, T Abdizadeh (2019)

Molecular Modeling Studies of Anti-Alzheimer Agents by QSAR, Molecular Docking and Molecular Dynamic Simulations Techniques.

Medicinal chemistry (Shariqah (United Arab Emirates)) pii:MC-EPUB-100156 [Epub ahead of print].

BACKGROUND: Acetylcholinesterase (AChE), a serine hydrolase, is an important drug target in the treatment of Alzheimer's disease (AD). Thus, novel AChE inhibitors were designed and developed as potential drug candidates, for significant therapy of AD.

OBJECTIVE: In this work, molecular modeling studies, including CoMFA, CoMFA-RF, CoMSIA, HQSAR and molecular docking and molecular dynamic simulations were performed on a series of AChE inhibitors to get more potent anti-Alzheimer drugs.

METHODS: The 2D/3D-QSAR models including CoMFA, CoMFA-Rf, CoMSIA, and H-QSAR methods were carried out on 59 pyrimidinylthiourea derivatives as data set by the Sybylx1.2 program. Molecular docking and molecular dynamic simulation were performed using the MOE software and the Sybyl program, respectively. Partial least squares (PLS) model as descriptors was used for QSAR model generation.

RESULTS: The CoMFA (q2, 0.775;〖 r〗_ncv^2, 0.901; 〖 r〗_pred^2, 0.773), CoMFA-RF (q2, 0.629;〖 r〗_ncv^2, 0.901; 〖 r〗_pred^2, 0.824), CoMSIA (q2, 0.754;〖 r〗_ncv^2, 0.919; 〖 r〗_pred^2, 0.874) and HQSAR models (q2, 0.622;〖 r〗_ncv^2, 0.949; 〖 r〗_pred^2, 0.854) for training and test set yielded significant statistical results.

CONCLUSION: These QSAR models were excellent, robust and had good predictive capability. Contour maps obtained from the QSAR models were validated by molecular dynamic simulation-assisted molecular docking study. The resulted QSAR models could be useful for rational design of novel potent AChE inhibitors in Alzheimer's treatment.

RevDate: 2019-08-06

V DK, R C (2019)

Amyloid beta hypothesis in Alzheimer's disease: Major culprits and recent therapeutic strategies.

Current drug targets pii:CDT-EPUB-100154 [Epub ahead of print].

Alzheimer's disease (AD) is one of the most common forms of dementia and has been a global concern for several years. Due to the multifactorial nature of the disease, AD has become irreversible, fatal and imposes a tremendous socio-economic burden. Even though experimental medicines suggested moderate benefits, AD still lacks an effective treatment strategy for the management of symptoms or cure. Among various hypothesises that describe the development and progression of AD, the amyloid hypothesis has been a long-term adherent to the AD due to the involvement of various forms of amyloid beta (Aβ) peptides in the impairment of neuronal and cognitive functions. Hence, the majority of the drug discovery approaches in the past have focused on preventing the accumulation of Aβ peptides. Currently, there are several agents in the phase III clinical trials that target Aβ or the various macromolecules triggering Aβ deposition. In this review, we present the some of the state of the art knowledge on the functional aspects of the key players involved in the amyloid hypothesis. Furthermore, we also discuss anti-amyloid agents present in the Phase III clinical trials.

RevDate: 2019-08-25

Bekrater-Bodmann R, Löffler A, Silvoni S, et al (2019)

Tablet-based sensorimotor home-training system for amnestic mild cognitive impairments in the elderly: design of a randomised clinical trial.

BMJ open, 9(8):e028632 pii:bmjopen-2018-028632.

INTRODUCTION: Dementia (particularly Alzheimer's disease, AD) is a major cause of impaired cognitive functions in the elderly. Amnestic mild cognitive impairment (aMCI) is a prodromal stage of AD, if substantiated by Alzheimer biomarkers. A neuroscientific model of pathological ageing emphasises the loss of brain plasticity, sensorimotor capacities and subsequent cognitive decline. A mechanistic treatment targeting dysfunctional plastic changes associated with ageing should be efficacious in delaying AD. In this trial, we aim to evaluate the effectiveness of a newly developed sensorimotor training, delivered at home, combined with personalised reinforcement, on the progression of aMCI-related cognitive impairments.

METHODS AND ANALYSIS: In a randomised trial, we will compare two aMCI groups (30 subjects each), randomly allocated to a sensorimotor or a cognitive control training. Both trainings consist of an adaptive algorithm, and will last 3 months each. We hypothesise that both trainings will have positive effects on cognitive function with the sensorimotor training being superior compared with the control training based on its improvement in basic perceptual skills underlying memory encoding and retrieval. The primary outcome is episodic memory function, improved hippocampal function during memory tasks will be a secondary outcome. As further exploratory outcomes, we expect improved segregation in sensory and motor maps, better sensory discrimination only in the sensorimotor training and reduced transition to dementia (examined after completion of this study). We expect the experimental training to be evaluated more positively by the users compared with the cognitive training, resulting in reduced rates of discontinuation.

ETHICS AND DISSEMINATION: The Ethics Committee of the Medical Faculty Mannheim, Heidelberg University, approved the study (2015-543N-MA), which adheres to the Declaration of Helsinki. The results will be published in a peer-reviewed journal. Access to raw data is available on request.


RevDate: 2019-08-29

Mezzaroba L, Alfieri DF, Colado Simão AN, et al (2019)

The role of zinc, copper, manganese and iron in neurodegenerative diseases.

Neurotoxicology, 74:230-241 pii:S0161-813X(19)30075-0 [Epub ahead of print].

Metals are involved in different pathophysiological mechanisms associated with neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The aim of this study was to review the effects of the essential metals zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) on the central nervous system (CNS), as well as the mechanisms involved in their neurotoxicity. Low levels of Zn as well as high levels of Cu, Mn, and Fe participate in the activation of signaling pathways of the inflammatory, oxidative and nitrosative stress (IO&NS) response, including nuclear factor kappa B and activator protein-1. The imbalance of these metals impairs the structural, regulatory, and catalytic functions of different enzymes, proteins, receptors, and transporters. Neurodegeneration occurs via association of metals with proteins and subsequent induction of aggregate formation creating a vicious cycle by disrupting mitochondrial function, which depletes adenosine triphosphate and induces IO&NS, cell death by apoptotic and/or necrotic mechanisms. In AD, at low levels, Zn suppresses β-amyloid-induced neurotoxicity by selectively precipitating aggregation intermediates; however, at high levels, the binding of Zn to β-amyloid may enhance formation of fibrillar β-amyloid aggregation, leading to neurodegeneration. High levels of Cu, Mn and Fe participate in the formation α-synuclein aggregates in intracellular inclusions, called Lewy Body, that result in synaptic dysfunction and interruption of axonal transport. In PD, there is focal accumulation of Fe in the substantia nigra, while in AD a diffuse accumulation of Fe occurs in various regions, such as cortex and hippocampus, with Fe marginally increased in the senile plaques. Zn deficiency induces an imbalance between T helper (Th)1 and Th2 cell functions and a failure of Th17 down-regulation, contributing to the pathogenesis of MS. In MS, elevated levels of Fe occur in certain brain regions, such as thalamus and striatum, which may be due to inflammatory processes disrupting the blood-brain barrier and attracting Fe-rich macrophages. Delineating the specific mechanisms by which metals alter redox homeostasis is essential to understand the pathophysiology of AD, PD, and MS and may provide possible new targets for their prevention and treatment of the patients affected by these NDDs.

RevDate: 2019-08-17

Lin M, Zhu L, Wang J, et al (2019)

miR-424-5p maybe regulate blood-brain barrier permeability in a model in vitro with Abeta incubated endothelial cells.

Biochemical and biophysical research communications, 517(3):525-531.

The blood-brain barrier (BBB) in AD patients and in animal models is changed. However, the mechanisms are still unclear. Here, we found that miR-424-5p was upregulated in Abeta-incubated microvascular endothelial cells. TEER and HRP exudation tests showed that miR-424-5p silencing significantly decreased BBB permeability in vitro BBB model with Abeta-incubated. MiR-424-5p silencing upregulated expression of the tight junction proteins, ZO-1 and occludin in Abeta-incubated microvascular endothelial cells. Furthermore, dual luciferase reporter gene assay results confirmed the presence of a potential binding site for miR-424-5p on the 3'UTR of Endophilin-1. Endophilin-1 was down-regulated in Abeta-incubated endothelial cells in which miR-424-5p was silenced. In conclusion, the present study demonstrates that miR-424-5p could affect the expression of tight junction proteins (ZO-1 and occludin) via Endophilin-1 and thereby maybe regulate BBB permeability in an BBB model in vitro with Abeta incubated endothelial cells. MiR-424-5p may thus serve as a protective target for AD and provide a new strategy for the prevention and treatment of AD.

RevDate: 2019-08-02

Chen M, Zheng J, Liu G, et al (2019)

High Dietary Iron Disrupts Iron Homeostasis and Induces Amyloid-β and Phospho-τ Expression in the Hippocampus of Adult Wild-Type and APP/PS1 Transgenic Mice.

The Journal of nutrition pii:5542980 [Epub ahead of print].

BACKGROUND: Brain iron deposition is a feature of Alzheimer disease and may contribute to its development. However, the relative contribution of dietary iron remains unclear.

OBJECTIVES: We investigated the impact of high dietary iron on brain pathological changes and cognitive function in adult wild-type (WT) mice and amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice.

METHODS: Male WT mice and APP/PS1 mice aged 10 wk were fed either a control diet (66 mg Fe/kg) (WT-Ctrl and APP/PS1-Ctrl) or a high iron diet (14 g Fe/kg) (WT-High Fe and APP/PS1-High Fe) for 20 wk. Iron concentrations in brain regions were measured by atomic absorption spectrophotometry. Brain iron staining and amyloid-β (Aβ) immunostaining were performed. Protein expressions in the hippocampus were determined by immunoblotting. Superoxide dismutase (SOD) activity and malondialdehyde concentration were examined. Cognitive functions were tested with the Morris water maze system.

RESULTS: In the hippocampus, APP/PS1-High Fe mice had significantly higher iron concentration (2.5-fold) and ferritin (2.0-fold) than APP/PS1-Ctrl mice (P < 0.001), and WT-High Fe mice had significantly higher ferritin (2.0-fold) than WT-Ctrl mice (P < 0.001). Interestingly, APP/PS1 mice had significantly higher iron concentration (2-3-fold) and ferritin (2-2.5-fold) than WT mice fed either diet (P < 0.001). Histological analysis indicated that iron accumulated in the hippocampal dentate gyrus region in APP/PS1 mice, consistent with the pattern of Aβ deposition. For both mouse strains, iron treatment induced Aβ and phospho-τ expression (1.5-3-fold) in the hippocampus, but had little impact on oxidative stress and cognitive function. Furthermore, APP/PS1 mice had significantly lower SOD activity and higher malondialdehyde concentration than WT mice in the hippocampus (P < 0.0001), paralleled by apparent cognitive dysfunction.

CONCLUSIONS: Dietary iron overload induces iron disorder and Aβ and phospho-τ expression in the hippocampus of adult WT and APP/PS1 transgenic mice.

RevDate: 2019-08-01

Bibi N, Danish Rizvi SM, Batool A, et al (2019)

Inhibitory mechanism of an anticancer drug, Bexarotene against Amyloid β peptide aggregation: Repurposing via neuroinformatics approach.

Current pharmaceutical design pii:CPD-EPUB-100096 [Epub ahead of print].

Aggregation of Amyloid β (Aβ) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, Aβ peptides are misfolded and aggregated to frame amyloid fibrils, that is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-Aβ aggregation potential. Interestingly, in the last few decades, drug repurposing has turned into a fruitful and savvy approach for the treatment of several diseases. Bexarotene is an anticancer drug that has been under consideration for its ability to suppress Aβ-peptide aggregation. However, the exact mechanistic aspect of suppression of Aβ-peptide accumulation has not yet been completely revealed. In the present study, we have attempted to decipher the mechanistic aspects of anti-aggregation potential of bexarotene by using the computational biology approach. We have observed the effect of 'Aβ-bexarotene' interaction on the aggregation ability of the Aβ-peptide and decoded the involvement of receptor for advanced glycation end products (RAGE) and beta-secretase (BACE-1). Deep structural analysis of Aβ upon binding with bexarotene revealed critical binding sites and structural twists involved in Aβ aggregation. It is evident from the present that bexarotene could significantly restrain the process of primary nucleation of Aβ. In addition, bexarotene showed a strong interaction with RAGE and BACE-1, suggesting them as plausible targets for the neuro-therapeutic action of bexarotene. Hence, we could safely suggest that bexarotene is a potent drug candidate that could reduce Aβ-peptide aggregation via applying different mechanistic pathways. These results might boost the portfolio of pharmaceutical companies looking for the development of new chemical entity against AD.

RevDate: 2019-08-01

Nwanna EE, Ibukun EO, G Oboh (2019)

Eggplant (Solanum spp) supplemented fruits diet modulated the activities of ectonucleoside triphosphate diphosphohydrolase (ENTPdase), monoamine oxidase (MAO), and cholinesterases (AChE/BChE) in the brain of diabetic Wistar male rats.

Journal of food biochemistry, 43(8):e12910.

Type 2 diabetes mellitus is associated with complications such as Alzheimer disease (AD). Tropical eggplant (Solanum gilo, Solanum kumba, and Solanum aethiopicum) fruits have been extensively used for the treatment of different ailments. This study assesses the effect of an eggplant supplemented-diet on purinergic, monoaminergic, and cholinergic enzyme systems in diabetic male rats, besides determining the presence of alkaloids using GC-MS chromatography. Results from this study show that eggplant fruit diet modulates the activities of the enzymes in purinergic, monoaminergic, and cholinergic enzyme systems associated with AD-like symptoms. Solanum kumba-supplemented diet significantly (p < 0.05) reduced enzyme activities better than S. gilo and S. aethiopicum, which could be due to its rich phytochemical constituents. In conclusion, eggplant fruits could serve as a holistic measure in the prevention of diabetes-related complications such as neurodegenerative disease. PRACTICAL APPLICATIONS: The therapeutic management of diabetes fails to holistically address inflammatory response which likely contributes to type 2 diabetes mellitus (T2DM) occurrence by causing insulin resistance; this, in turn, is intensified in the presence of hyperglycemia to promote long-term complications such as neurodegenerative disorders. The health benefit of a tropical eggplant fruit diet inform a nutritional and therapeutic approach for the prevention and treatment of T2DM and its associated complications such as neurodegenerative disorders has been proved. The eggplant fruit-supplemented diet, which is cost-effective with little or no side effect, could substantially increase the antioxidant status and also modulate the activities of neuronal enzymes in a diabetic model with dementia, as well as Alzheimer's-like symptoms. This study, therefore, revealed more of the benefits of tropical eggplant fruits vis-à-vis their management in hyperglycemia-mediated neurodegeneration.

RevDate: 2019-08-19

Schelle J, Wegenast-Braun BM, Fritschi SK, et al (2019)

Early Aβ reduction prevents progression of cerebral amyloid angiopathy.

Annals of neurology [Epub ahead of print].

OBJECTIVE: Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition.

METHODS: APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain.

RESULTS: CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies.

INTERPRETATION: This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019.

RevDate: 2019-08-24

Espinosa-Fernández V, Mañas-Ojeda A, Pacheco-Herrero M, et al (2019)

Early intervention with ABA prevents neuroinflammation and memory impairment in a triple transgenic mice model of Alzheimer´s disease.

Behavioural brain research, 374:112106.

Neuroinflammation and insulin resistance in the brain are intimately linked to neurodegenerative disorders, including Alzheimer's disease. Even though traditionally Alzheimer´s disease has been associated to Aβ deposits and hyperphosphorylated Tau intracellular tangles, several studies show that neuroinflammation may be the initial cause that triggers degeneration. Accordingly, a number of natural supplements that improves brain insulin sensitivity and reduce neuroinflammation have been proposed as good choices in the therapeutic prevention of cognitive decline. Further supporting this evidence, we show that phytohormone Abscisic Acid, can prevent memory impairment and neuroinflammation markers in a triple transgenic mouse model, where no peripheral inflammatory changes have occurred. Moreover, our data strongly suggests that early intervention is critical for good prognosis, and that cognitive improvement requires longer treatment than recovering neuroinflammation markers.

RevDate: 2019-08-05

Ruiz-Muelle A, MM López-Rodríguez (2019)

Dance for People with Alzheimer's Disease: A mini-Review.

Current Alzheimer research pii:CAR-EPUB-99973 [Epub ahead of print].

BACKGROUND: In recent years, several reviews have addressed the effectiveness of dance therapy in dementia, healthy older adults, or the elderly in general. However, reviews regarding the effect of this therapy exclusively on patients diagnosed with Alzheimer's disease have not been found.

OBJECTIVE: The purpose of this study is to review the available literature describing clinical trials which explore the effects of dancing on psychological and physical outcomes, functionality, cognitive function, and quality of life in patients diagnosed with Alzheimer's disease. In addition, this review aims to assess the quality of studies that perform dance therapy interventions in these patients.

METHODS: This study is a systematic review of randomized and non-randomized clinical trials regarding the effect of an intervention including a dancing activity in people diagnosed with Alzheimer's disease.

RESULTS: In total, the evidence for this review rests on 12 studies with a total of 349 participants. The findings of this mini review confirm the positive effect of dance therapy on physical and cognitive function, functionality, psychological outcomes, and quality of life in people with Alzheimer's disease.

CONCLUSION: Most of studies implementing dance as part of the therapeutic treatment has shown to improve or slow the worsening in the quality of life of patients with Alzheimer's disease and their caregivers. Future research focused on these patients should use a more exhaustive methodology and make a more detailed description of this kind of interventions.

RevDate: 2019-07-25

Castillo-Álvarez F, ME Marzo-Sola (2019)

Role of the gut microbiota in the development of various neurological diseases.

Neurologia (Barcelona, Spain) pii:S0213-4853(19)30082-9 [Epub ahead of print].

INTRODUCTION: In recent years, the scientific evidence supporting a relationship between the microbiota and various diseases has increased significantly; this trend has also been observed for neurological diseases. This has given rise to the concept of the gut-brain axis and the idea of a relationship between the gut microbiota and several neurological diseases whose aetiopathogenesis is yet to be clearly defined.

DEVELOPMENT: We review the role of the gut microbiota in the gut-brain axis and analyse those neurological diseases in which alterations in the gut microbiota have been described as a result of human studies: specifically, Parkinson's disease, Alzheimer disease, amyotrophic lateral sclerosis, neuromyelitis optica, and multiple sclerosis.

CONCLUSIONS: The body of evidence linking the gut microbiota to various neurological diseases has grown considerably. Several interesting studies show a relationship between the gut microbiota and Parkinson's disease, Alzheimer disease, neuromyelitis optica, and multiple sclerosis, whereas other controversial studies implicate it in amyotrophic lateral sclerosis. Many of these studies place considerable emphasis on modulation of inflammation, particularly by bacteria capable of producing short-chain fatty acids. Despite these encouraging results, many questions remain, and there is a need to demonstrate causality, determine the role of fungi or viruses, and research possible treatment through diet, probiotics, or faecal microbiota transplantation.

RevDate: 2019-08-01
CmpDate: 2019-08-01

Triviño-Ibáñez EM, Sánchez-Vañó R, Sopena-Novales P, et al (2019)

Impact of amyloid-PET in daily clinical management of patients with cognitive impairment fulfilling appropriate use criteria.

Medicine, 98(29):e16509.

To evaluate the use of amyloid-positron emission tomography (PET) in routine clinical practice, in a selected population with cognitive impairment that meets appropriate use criteria (AUC).A multicenter, observational, prospective case-series study of 211patients from 2 level-3 hospitals who fulfilled clinical AUC for amyloid-PET scan in a naturalistic setting. Certainty degree was evaluated using a 5-point Likert scale: 0 (very low probability); 1 (low probability); 2 (intermediate probability); 3 (high probability); and 4 (practically sure), before and after amyloid PET. The treatment plan was considered as cognition-specific or noncognition-specific.Amyloid-PET was positive in 118 patients (55.9%) and negative in 93 patients (44.1%). Diagnostic prescan confidence according amyloid-PET results showed that in both, negative and positive-PET subgroup, the most frequent category was intermediate probability (45.7% and 55.1%, respectively). After the amyloid-PET, the diagnostic confidence showed a very different distribution, that was, in the negative-PET group the most frequent categories are very unlikely (70.7%) and unlikely (29.3%), while in the positive-PET group were very probable (57.6%) and practically sure (39%). Only in 14/211 patients (6.6%) the result of the amyloid-PET did not influence the diagnostic confidence, while in 194 patients (93.4%), the diagnostic confidence improved significantly after amyloid-PET results. The therapeutic intention was modified in 93 patients (44.1%). Specific treatment for Alzheimer disease was started, before amyloid-PET, in 80 patients (37.9%).This naturalistic study provides evidence that the implementation of amyloid-PET is associated with a significant improvement in diagnostic confidence and has a high impact on the therapeutic management of patients with mild cognitive impairment fulfilled clinical AUC.

RevDate: 2019-07-23

Khalifa M, Safar MM, Abdelsalam RM, et al (2019)

Telmisartan Protects Against Aluminum-Induced Alzheimer-like Pathological Changes in Rats.

Neurotoxicity research pii:10.1007/s12640-019-00085-z [Epub ahead of print].

Currently, there is no effective mean for treatment or prevention of Alzheimer's disease (AD). Commonly used AD drugs have a moderate effect and treat only the associated symptoms, therefore there is a strong need to search for more effective agents. Our goal is to examine telmisartan neuroprotective effect in aluminum-induced cognitive impairment in rats. Aluminum chloride (10 mg/kg, i.p) was administered for 2 months then behavioral tests (Y-maze and Morris water maze) were done. Hippocampal biochemical and histological analysis were then carried out. AD-like histological, biochemical, and behavioral alterations appeared in aluminum-treated rats. Telmisartan improved rats' condition on behavioral and histological levels. It reversed the increase in hippocampal amyloid beta protein, phosphorylated tau protein contents together with augmentation of neprilysin level, it also diminished levels of nuclear factor kappa-B, FAS ligand, tumor necrosis factor-alpha, malondialdehyde, and acetylcholinesterase content.These findings show the protective action of telmisartan against AD-like pathological alterations.

RevDate: 2019-08-09

Abugable AA, Morris JLM, Palminha NM, et al (2019)

DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms.

DNA repair pii:S1568-7864(19)30222-8 [Epub ahead of print].

In both replicating and non-replicating cells, the maintenance of genomic stability is of utmost importance. Dividing cells can repair DNA damage during cell division, tolerate the damage by employing potentially mutagenic DNA polymerases or die via apoptosis. However, the options for accurate DNA repair are more limited in non-replicating neuronal cells. If DNA damage is left unresolved, neuronal cells die causing neurodegenerative disorders. A number of pathogenic variants of DNA repair proteins have been linked to multiple neurological diseases. The current challenge is to harness our knowledge of fundamental properties of DNA repair to improve diagnosis, prognosis and treatment of such debilitating disorders. In this perspective, we will focus on recent efforts in identifying novel DNA repair biomarkers for the diagnosis of neurological disorders and their use in monitoring the patient response to therapy. These efforts are greatly facilitated by the development of model organisms such as zebrafish, which will also be summarised.

RevDate: 2019-08-11

van Dyck CH, Nygaard HB, Chen K, et al (2019)

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial.

JAMA neurology pii:2737805 [Epub ahead of print].

Importance: Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease.

Objective: To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated.

This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018.

Interventions: AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks.

Main Outcomes and Measures: Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers.

Results: Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness.

Conclusions and Relevance: Statistically significant effects of AZD530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures.

Trial Registration: ClinicalTrials.gov identifier: NCT02167256.

RevDate: 2019-07-20

Schweig JE, Yao H, Coppola K, et al (2019)

Spleen tyrosine kinase (SYK) blocks autophagic Tau degradation in vitro and in vivo.

The Journal of biological chemistry pii:RA119.008033 [Epub ahead of print].

Spleen tyrosine kinase (SYK) plays a major role in inflammation and in adaptive immune responses and could therefore contribute to the neuroinflammation observed in various neurodegenerative diseases. Indeed, previously we have reported that SYK also regulates amyloid-β production and hyperphosphorylation of Tau protein involved in these diseases. Moreover, SYK hyperactivation occurs in a subset of activated microglia, in dystrophic neurites surrounding Aβ deposits, and in neurons affected by Tau pathology both in individuals with Alzheimer's disease (AD) and in AD mouse models. SYK activation increases Tau phosphorylation and accumulation, suggesting that SYK could be an attractive target for treating AD. However, the mechanism by which SYK affects Tau pathology is not clear. In this study, using cell biology and biochemical approaches, along with immuno-precipitation and -blotting, RT-qPCR, and ELISA assays, we found that SYK inhibition increases autophagic Tau degradation without impacting Tau production. Using neuron-like SH-SY5Y cells, we demonstrate that SYK acts upstream of the mTOR pathway and that pharmacological inhibition or knockdown of SYK decreases mTOR pathway activation and increases autophagic Tau degradation. Interestingly, chronic SYK inhibition in a tauopathy mouse model profoundly reduced Tau accumulation, neuroinflammation, neuronal and synaptic loss and also reversed defective autophagy. Our results further suggest that the SYK up-regulation observed in the brains of individuals with AD contributes to defective autophagic clearance leading to the accumulation of pathogenic Tau species. These findings further highlight SYK as a therapeutic target for the treatment of tauopathies and other neurodegenerative proteinopathies associated with defective autophagic clearance.

RevDate: 2019-07-19

Wan X, Gan C, You C, et al (2019)

Association of APOE ε4 with progressive hemorrhagic injury in patients with traumatic intracerebral hemorrhage.

Journal of neurosurgery pii:2019.4.JNS183472 [Epub ahead of print].

OBJECTIVE: The intracranial hematoma volume in patients with traumatic brain injury is a key parameter for the determination of the management approach and outcome. Apolipoprotein E (APOE) ε4 is reported to be a risk factor for larger hematoma volume, which might contribute to a poor outcome. However, whether APOE ε4 is related to progressive hemorrhagic injury (PHI), a common occurrence in the clinical setting, remains unclear. In this study, the authors aimed to investigate the association between the APOE genotype and occurrence of PHI.

METHODS: This prospective study included a cohort of 123 patients with traumatic intracerebral hemorrhage who initially underwent conservative treatment. These patients were assigned to the PHI or non-PHI group according to the follow-up CT scan. A polymerase chain reaction and sequencing method were carried out to determine the APOE genotype. Multivariate logistic regression analysis was applied to identify predictors of PHI.

RESULTS: The overall frequency of the alleles was as follows: E2/2, 0%; E2/3, 14.6%; E3/3, 57.8%; E2/4, 2.4%; E3/4, 22.8%; and E4/4, 2.4%. Thirty-four patients carried at least one allele of ε4. In this study 60 patients (48.8%) experienced PHI, and the distribution of the alleles was as follows: E2/2, 0%; E2/3, 5.7%; E3/3, 22.8%; E2/4, 2.4%; E3/4, 16.3%; and E4/4, 1.6%, which was significantly different from that in the non-PHI group (p = 0.008). Additionally, the late operation rate in the PHI group was significantly higher than that in the non-PHI group (24.4% vs 11.4%, p = 0.002). Multivariate logistic regression identified APOE ε4 (OR 5.14, 95% CI 2.40-11.62), an elevated international normalized ratio (OR 3.57, 95% CI 1.61-8.26), and higher glucose level (≥ 10 mmol/L) (OR 3.88, 95% CI 1.54-10.77) as independent risk factors for PHI. Moreover, APOE ε4 was not a risk factor for the coagulopathy and outcome of the patients with traumatic intracerebral hemorrhage.

CONCLUSIONS: The presence of APOE ε4, an elevated international normalized ratio, and a higher glucose level (≥ 10 mmol/L) are predictors of PHI. Additionally, APOE ε4 is not associated with traumatic coagulopathy and patient outcome.

RevDate: 2019-07-17

Zhou H, Shao M, Guo B, et al (2019)

Tetramethylpyrazine Analogue T-006 Promotes the Clearance of Alpha-synuclein by Enhancing Proteasome Activity in Parkinson's Disease Models.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics pii:10.1007/s13311-019-00759-8 [Epub ahead of print].

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized in part by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The main pathological hallmark of PD is the intraneuronal accumulation of misfolded α-synuclein (α-syn) aggregates. Mutations in the SNCA gene (encoding α-syn) and variations in its copy number are associated with some forms of familial PD. In the present study, T-006, a new tetramethylpyrazine (TMP) derivative with recently reported anti-Alzheimer activity, is shown to significantly promote α-syn degradation in a cellular PD model. Moreover, we illustrate that T-006 inhibits the accumulation of both Triton-soluble and -insoluble forms of α-syn and protects against α-syn-induced neurotoxicity in A53T-α-syn transgenic mice. The mechanism of action of T-006 was verified by evaluation of a potential protein degradation pathway. We found that T-006 promotes α-syn degradation in a proteasome-dependent and autophagy-independent manner. We further confirmed that T-006 enhances proteasome activity by upregulating 20S proteasome subunit β5i (LMP7) protein expression. A functional study revealed that T-006 activates the PKA/Akt/mTOR/p70S6K pathway to trigger LMP7 expression and enhance chymotrypsin-like proteasomal activity. These findings indicate that T-006 is a potent proteasome activator and a potential therapeutic agent for the prevention and treatment of PD and related diseases.

RevDate: 2019-07-19

Ali MM, Ghouri RG, Ans AH, et al (2019)

Recommendations for Anti-inflammatory Treatments in Alzheimer's Disease: A Comprehensive Review of the Literature.

Cureus, 11(5):e4620.

Alzheimer's disease (AD) is the most common cause of dementia in elderly patients, affecting individuals older than 60 years. It is a complex degenerative brain disease characterized by progressive cognitive impairment. AD constitutes a major global health concern. A central role for inflammation has been implicated in the pathogenesis of AD. Despite the understanding of multiple molecular pathways in the pathophysiology of AD, novel treatment agents with a possible role in modifying the disease activity are still lacking. Our article provides a comprehensive review of various observational studies and randomized trials encompassing the use of anti-inflammatory agents in the management of AD patients and utilizes the conclusions derived therefrom to give recommendations in this regard.

RevDate: 2019-07-20

Mufson EJ, Counts SE, Ginsberg SD, et al (2019)

Nerve Growth Factor Pathobiology During the Progression of Alzheimer's Disease.

Frontiers in neuroscience, 13:533.

The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer's disease (AD). Both transcript and protein data indicate that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75NTR-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75NTR death receptor for the treatment of AD.

RevDate: 2019-08-21

Patel DV, Patel NR, Kanhed AM, et al (2019)

Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents.

ACS chemical neuroscience, 10(8):3635-3661.

The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 μM for AChE and an IC50 value of 1.17 ± 0.09 μM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.

RevDate: 2019-07-18

Sedighi S, Tehranipour M, Vaezi G, et al (2019)

The effect of hydroalcoholic extract of Ziziphora clinopodioides L. on spatial memory and neuronal density of hippocampal CA1 region in rats with sporadic Alzheimer's disease.

Avicenna journal of phytomedicine, 9(4):362-373.

Objective: Alzheimer's disease is a neurodegenerative disorder associated with gradual loss of cognitive and memory abilities. It was shown that the hippocampus is one of the first structures in the brain that is affected by the disease. Ziziphora clinopodioides (Z. clinopodioides) is a member of Lamiaceae family and contains various substances.

Materials and Methods: In this experimental study, 72 adult male Wistar rats were used for behavioral and histopathologic studies. They were divided into nine groups included: control, negative control (Alzheimer), positive control (Alzheimer's treated with rivastigmine), aCSF (artificial cerebrospinal fluid) + ziziphora extract with doses of 200,400, and 600 mg/kg, and STZ (stereptozotocine)+ziziphora extract in 200,400,600 mg/kg doses. The injury was created with bilaterally intraventricular injection. The spatial memory was studied by passive avoidance test and neuronal density was evaluated by dissector method. To examine the histopathological lesions, Congo red and toluidine blue staining were done. Data were analyzed by ANOVA Minitab software.

Results: The memory index (neuronal density and passive avoidance test results) showed a significant decrease in negative control group compared to control (p≤0.001). Treatment with the hydroalcoholic extract at the doses of 400 and 600 mg/kg showed a significant increase in memory index in rats with Alzheimer's disease (p≤0.001). The effect of 200 mg/kg extract was not significantly different from that of the negative control group. The results of histological analysis indicated beta-amyloid plaques formation in the control group as compared to the negative control group while treatment with the extract at the doses of 400 and 600 mg/kg, significantly reduced beta-amyloid plaques formation.

Conclusion: These findings suggest that the extract of Z. clinopodioides can improve Alzheimer's condition and alleviate memory and histopathologic damages; also, it decreases beta-amyloid plaques and apoptosis in CA1 region of the hippocampus.

RevDate: 2019-07-14

Chen XQ, WC Mobley (2019)

Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species.

Frontiers in neuroscience, 13:659.

Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary human and financial burdens. Studies of pathogenesis are essential for defining targets for discovering disease-modifying treatments. Past studies of AD neuropathology provided valuable, albeit limited, insights. Nevertheless, building on these findings, recent studies have provided an increasingly rich harvest of genetic, molecular and cellular data that are creating unprecedented opportunities to both understand and treat AD. Among the most significant are those documenting the presence within the AD brain of toxic oligomeric species of Aβ and tau. Existing data support the view that such species can propagate and spread within neural circuits. To place these findings in context we first review the genetics and neuropathology of AD, including AD in Down syndrome (AD-DS). We detail studies that support the existence of toxic oligomeric species while noting the significant unanswered questions concerning their precise structures, the means by which they spread and undergo amplification and how they induce neuronal dysfunction and degeneration. We conclude by offering a speculative synthesis for how oligomers of Aβ and tau initiate and drive pathogenesis. While 100 years after Alzheimer's first report there is much still to learn about pathogenesis and the discovery of disease-modifying treatments, the application of new concepts and sophisticated new tools are poised to deliver important advances for combatting AD.

RevDate: 2019-07-23

Insel PS, Weiner M, Mackin RS, et al (2019)

Determining clinically meaningful decline in preclinical Alzheimer disease.

Neurology, 93(4):e322-e333.

OBJECTIVE: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)-related decline.

METHODS: In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect.

RESULTS: Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures.

CONCLUSIONS: A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.

RevDate: 2019-08-30

Loera-Valencia R, Cedazo-Minguez A, Kenigsberg PA, et al (2019)

Current and emerging avenues for Alzheimer's disease drug targets.

Journal of internal medicine [Epub ahead of print].

Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aβ) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aβ and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.

RevDate: 2019-07-30

Schneider LS, Thomas RG, Hendrix S, et al (2019)

Safety and Efficacy of Edonerpic Maleate for Patients With Mild to Moderate Alzheimer Disease: A Phase 2 Randomized Clinical Trial.

JAMA neurology pii:2737046 [Epub ahead of print].

Importance: Edonerpic maleate (T-817MA) protects against Aβ40-induced neurotoxic effects and memory deficits, promotes neurite outgrowth, and preserves hippocampal synapses and spatial memory in tau transgenic mice. These effects may be mediated via sigma-1 receptor activation, delivery of synaptic AMPA receptors, or modulation of microglial function and may benefit patients with Alzheimer disease.

Objective: To assess the efficacy, safety, and tolerability of edonerpic for patients with mild to moderate Alzheimer disease.

Randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial conducted over 52 weeks from June 2, 2014, to December 14, 2016, at 52 US clinical and academic centers. Of 822 outpatients screened, 484 met the following criteria and were randomly assigned to treatment: 55 to 85 years of age, probable Alzheimer disease, Mini-Mental State Examination scores from 12 to 22, and taking stable doses of donepezil or rivastigmine with or without memantine.

Interventions: Random assignment (1:1:1 allocation) to placebo or 224 mg or 448 mg of edonerpic maleate, once per day.

Main Outcomes and Measures: Coprimary outcomes were scores on the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinical Impression of Change (ADCS-CGIC) at week 52. Biomarkers were brain, lateral ventricular, and hippocampal volumes, as determined on magnetic resonance imaging, and cerebrospinal fluid Aβ40, Aβ42, total tau, and phospho-tau181. The primary efficacy analysis was performed on the coprimary end points for the modified intention-to-treat population.

Results: Of 482 participants in the safety population, 140 of 158 participants (88.6%) assigned to placebo, 117 of 166 participants (70.5%) to 224 mg of edonerpic maleate, and 120 of 158 participants (76.0%) to 448 mg of edonerpic maleate completed the trial. The mean ADAS-cog score change at week 52 was 7.91 for the placebo group, 7.45 for the 224-mg group, and 7.08 for the 448-mg group. Mean differences from placebo were -0.47 (95% CI, -2.36 to 1.43; P = .63) for the 224-mg group and -0.84 (95% CI, -2.75 to 1.08; P = .39) for the 448-mg group. Mean ADCS-CGIC scores were 5.22 for the placebo group, 5.24 for the 224-mg group, and 5.25 for the 448-mg group, with mean differences from placebo of 0.03 (95% CI, -0.20 to 0.25; P = .81) for the 224-mg group and 0.04 (95% CI, -0.19 to 0.26; P = .76) for the 448-mg group. In the safety population, a total of 7 of 158 participants (4.4%) in the placebo group, 23 of 166 participants (13.9%) in the 224-mg group, and 23 of 158 participants (14.6%) in the 448-mg group discontinued because of adverse events. The most frequent adverse events were diarrhea and vomiting.

Conclusions and Relevance: Edonerpic maleate appeared to be safe and tolerable, with expected gastrointestinal symptoms occurring early but without evidence for a clinical effect among patients with mild to moderate Alzheimer disease.

Trial Registration: ClinicalTrials.gov identifier: NCT02079909.

RevDate: 2019-08-05

Carmona-Iragui M, Videla L, Lleó A, et al (2019)

Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis.

Developmental neurobiology [Epub ahead of print].

Down syndrome (DS) is the main genetic cause of intellectual disability worldwide. The overexpression of the Amyloid Precursor Protein, present in chromosome 21, leads to β-amyloid deposition that results in Alzheimer disease (AD) and, in most cases, also to cerebral amyloid angiopathy (CAA) neuropathology. People with DS invariably develop the neuropathological hallmarks of AD at the age of 40, and they are at an ultra high risk for suffering AD-related cognitive impairment thereafter. In the general population, cerebrovascular disease is a significant contributor to AD-related cognitive impairment, while in DS remains understudied. This review describes the current knowledge on cerebrovascular disease in DS and reviews the potential biomarkers that could be useful in the future studies, focusing on CAA. We also discuss available evidence on sporadic AD or other genetically determined forms of AD. We highlight the urgent need of large biomarker-characterized cohorts, including neuropathological correlations, to study the exact contribution of CAA and related vascular factors that play a role in cognition and occur with aging, their characterization and interrelationships. DS represents a unique context in which to perform these studies as this population is relatively protected from some conventional vascular risk factors and they develop significant CAA, DS represents a particular atheroma-free model to study AD-related vascular pathologies. Only deepening on these underlying mechanisms, new preventive and therapeutic strategies could be designed to improve the quality of life of this population and their caregivers and lead to new avenues of treatment also in the general AD population.

RevDate: 2019-07-28

Krivinko JM, Koppel J, Savonenko A, et al (2019)

Animal Models of Psychosis in Alzheimer Disease.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry pii:S1064-7481(19)30364-1 [Epub ahead of print].

Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes.

RevDate: 2019-08-02
CmpDate: 2019-07-15

Cui CC, Sun Y, Wang XY, et al (2019)

The effect of anti-dementia drugs on Alzheimer disease-induced cognitive impairment: A network meta-analysis.

Medicine, 98(27):e16091.

BACKGROUND: Cognitive impairment is a principal manifestation of Alzheimer disease (AD). To provide a clinical reference for the treatment of AD, a network meta-analysis (NMA) was performed to evaluate the effects of different anti-dementia drugs on the cognitive impairment exhibited by patients with AD.

METHODS: Relevant randomized controlled trials are found through the Pubmed database, Web of Science, Clinical Trials, Embase, Cohranne library, Chinese National Knowledge Infrastructure database, CBM databases, and Wanfang among others. A total of 33 articles were collected, with the earliest document collected having been published in February 2017. The included reports were screened for quality of papers by using strict inclusion and exclusion criteria. All analyses were based on previously published studies reporting de-identified data; thus, no ethical approval or patient consent were required. The Mini-Mental State Examination scores informed the classification of the 33 articles into a mild subgroup, which featured 11 articles, and 12 drugs (besides a placebo); a moderate subgroup, which featured 17 articles and 15 drugs (besides a placebo); and a severe subgroup, which featured 5 articles and 3 drugs (besides a placebo).

RESULTS: While donepezil, galanthamine, and huperzine demonstrated the highest efficacy in the mild cognitive dysfunction subgroup (mean difference = 5.2, 2.5, and 2.4, respectively). Donepezil, huperzine A, and rivastigmine achieved the most significant effects in the moderate cognitive dysfunction subgroup (MD = 3.8, 2.9, and 3.0 respectively). In the severe subgroup, donepezil was demonstrably superior to memantine. Donepezil was thus found to effectively address cognitive impairment in patients with AD regardless of the degrees of cognitive decline.

CONCLUSIONS: Evaluation of the clinically common anti-dementia drugs using NMA affirmed the utility of cholinesterase inhibitors, especially donepezil, in alleviating cognitive dysfunction of patients with AD. This study may therefore help to inform the clinical selection of pharmacotherapeutic interventions addressing cognitive dysfunction in patients with AD.

RevDate: 2019-07-07

Mondragón JD, Salame L, Kraus A, et al (2019)

Clinical Considerations in Physician-Assisted Death for Probable Alzheimer's Disease: Decision-Making Capacity, Anosognosia, and Suffering.

Dementia and geriatric cognitive disorders extra, 9(2):217-226 pii:dee-0009-0217.

Background: Requests for physician-assisted death (PAD) in patients with cognitive impairment are complex and require careful consideration. Of particular difficulty is determination of whether the request is voluntary and well considered.

Results: Euthanasia and physician-assisted suicide (PAS) are both legal in The Netherlands, Luxemburg, Colombia, and Canada. Euthanasia is legal in Belgium, while PAS is legal in Switzerland and Oregon, Washington, Montana, Vermont, and California (USA). Upon a PAD request, evaluation of the capacity to consent medical treatment is relevant for the decision-making process, while evaluation of testamentary capacity is appropriate before an advance euthanasia directive is written. Anosognosia assessment throughout the Alzheimer's disease continuum provides essential and relevant information regarding the voluntary and well-considered nature of the PAD request; meanwhile, early assessment of hypernosognosia or subjective cognitive decline assists in formulation of a clinical prognosis. Furthermore, the assessment of physical and psychological suffering should incorporate verbal and nonverbal cues as well as consideration of the psychosocial factors that might affect due care criteria.

Conclusion: The clinical approach to a PAD request should consider the legal framework and the decision-making capacity, assess memory deficit awareness and the perception of suffering, and evaluate mental competency when considered pertinent.

RevDate: 2019-07-05

Romano RR, Carter MA, Anderson AR, et al (2019)

An integrative review of system-level factors influencing dementia detection in primary care.

Journal of the American Association of Nurse Practitioners [Epub ahead of print].

BACKGROUND AND PURPOSE: The incidence of Alzheimer disease (AD) is increasing in the United States, yet more than half of the people with AD are diagnosed late in the course of the disease. Most are identified outside primary care. New approaches to prevention and treatment means that early detection of AD may improve the quality of life of those affected by the disease. Nurse practitioners (NPs) have an important role in increasing early diagnosis of AD.The purpose of this systematic literature review is to identify health care system factors that contribute to missed or delayed diagnosis of dementia by primary care providers.

METHODS: Articles were identified through a systematic electronic search of the following databases: MEDLINE, the Cochrane Central Register of Controlled Trials, CINAHL, and PsycINFO.

Results indicate considerable variation in the diagnostic accuracy of dementia by primary care providers. Missed or underdiagnosis of dementia results from organizational, provider, and patient factors.New treatments are under investigation that may slow the progression of AD much better than current therapy, emphasizing the need to improve early detection by clinicians, especially primary care NPs.

RevDate: 2019-07-25

Trainor H (2019)

Effects of Using Music Therapy for Patients Suffering From Dementia.

The health care manager, 38(3):206-210.

The purpose of this study was to discuss the mental and physical effects of using music therapy with patients suffering with dementia. Like any type of therapy, there are guidelines for measuring the effects. Music therapy can be used as a substitute for pharmaceuticals with dementia patients. The earlier the diagnosis and the earlier treatment commences for dementia patients, the more likely the treatment will work. Music therapy can reach the part of the brain where we hold memories, which is why it is used as a treatment option for dementia patients. Alzheimer disease and dementia are among the most expensive diseases to treat. However, if the onset of dementia can be delayed, money can be saved. Medicare does not require that music therapy be offered in assisted living, nursing homes, or hospices. Areas of cost savings were identified as use of medication, length of nursing visits, and number and length of home health-aid visits, which can all be measured in total cost savings. For health care managers, it is imperative that new therapies such as music therapy be applied in health care facilities that treat dementia patients.

RevDate: 2019-07-01

Zdarova Karasova J, Soukup O, Korabecny J, et al (2019)

Tacrine and its 7-methoxy derivate; time-change concentration in plasma and brain tissue and basic toxicological profile in rats.

Drug and chemical toxicology [Epub ahead of print].

The search for tacrine derivatives, as potential Alzheimer´s disease treatment, is still being at the forefront of scientific efforts. 7-MEOTA was found to be a potent, centrally active acetylcholinesterase inhibitor free of the serious side effects observed for tacrine. Unfortunately, a relevant argumentation about pharmacokinetics and potential toxicity is incomplete; information about tacrine derivatives absorption and especially CNS penetration are still rare as well as detailed toxicological profile in vivo. Although the structural changes between these compounds are not so distinctive, differences in plasma profile and CNS targeting were found. The maximum plasma concentration were attained at 18th min (tacrine; 38.20 ± 3.91 ng/ml and 7-MEOTA; 88.22 ± 15.19 ng/ml) after i.m. application in rats. Although the brain profiles seem to be similar; tacrine achieved 19.34 ± 0.71 ng/ml in 27 min and 7-MEOTA 15.80 ± 1.13 ng/ml in 22 min; the tacrine Kp (AUCbrain/AUCplasma) fit 1.20 and was significantly higher than 7-MEOTA Kp 0.10. Administration of tacrine and 7-MEOTA showed only mild elevation of some biochemical markers following single p.o. application in 24 hours and 7 days. Also histopathology revealed only mild-to-moderate changes following repeated p.o. administration for 14 days. It seems that small change in tacrine molecule leads to lower ability to penetrate through the biological barriers. The explanation that lower p.o. acute toxicity of 7-MEOTA depends only on differences in metabolic pathways may be now revised to newly described differences in pharmacokinetic and toxicological profiles.

RevDate: 2019-07-31

Rockwood K, Sanon Aigbogun M, Stanley J, et al (2019)

The Symptoms Targeted for Monitoring in a Web-Based Tracking Tool by Caregivers of People With Dementia and Agitation: Cross-Sectional Study.

Journal of medical Internet research, 21(6):e13360 pii:v21i6e13360.

BACKGROUND: In people with dementia, neuropsychiatric symptoms (NPSs), especially agitation, are associated with worse quality of life and caregiver burden. As NPSs may vary with illness severity, knowledge of how people with dementia and their caregivers describe and rate the importance of agitation symptoms can improve the understanding of the clinical meaningfulness of the manifestations of agitation. The internet provides new opportunities to better understand patient experiences, as patients and caregivers increasingly look to Web-based platforms as a means of managing symptoms.

OBJECTIVE: The aim of this study was to examine Web-based reports from a dementia symptom website to better understand the symptoms of agitation and explore how they are being targeted for monitoring by caregivers of people with dementia.

METHODS: The Dementia Guide website hosts a Web-based database used by caregivers (97%) and people with dementia (3%). From its 61 dementia symptoms, users can select relevant symptoms that they deem important to monitor or track the effects of treatment. We employed a staging algorithm to determine if individuals had mild cognitive impairment (MCI) or mild, moderate, or severe dementia. Agitation was defined using terms consistent with the International Psychogeriatrics Association's provisional consensus definition. We compared the proportion of people with NPSs and agitation across stages of dementia severity and studied how many agitation-defining descriptors were selected, and how often they occurred, by stage.

RESULTS: As of March 2017, 4121 people had used the tracking tool, of whom 2577 provided sufficient data to allow disease severity staging. NPSs were tracked by 2127/2577 (82.54%) and agitation by 1898/2577 (73.65%). The proportion in whom agitation was tracked increased with increasing cognitive impairment: 68.5% (491/717) in people with MCI, and 72.50% (754/1040), 73.3% (378/516), and 90.5% (275/304) in mild, moderate, and severe dementia, respectively (χ23=54.9; P<.001). The number of NPS and agitation descriptors selected also increased with severity (median number of NPSs=1, 2, 2, and 3 for MCI, mild, moderate, and severe dementia, respectively, Kruskal-Wallis H Test H3=250.47; P<.001; median number of agitation descriptors=1, 2, 3, and 4, H3=146.11; P<.001).

CONCLUSIONS: NPSs and agitation are common targets for tracking over the course of dementia and appear more frequently with increasing disease severity. These common and distressing symptoms represent clinically meaningful targets in treating people with dementia.

RevDate: 2019-08-08

Hosaka T, Yamashita T, Tamaoka A, et al (2019)

Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.

International journal of molecular sciences, 20(13): pii:ijms20133148.

Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including β-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell-cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS.

RevDate: 2019-07-15

Biddle KD, d'Oleire Uquillas F, Jacobs HIL, et al (2019)

Social Engagement and Amyloid-β-Related Cognitive Decline in Cognitively Normal Older Adults.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry pii:S1064-7481(19)30360-4 [Epub ahead of print].

OBJECTIVE: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-β, the Alzheimer's disease (AD) pathologic marker.

METHODS: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-β was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-β on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-β on change in social engagement.

RESULTS: Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-β-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (β = 0.05, p = 0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (β = 1.1, p = 0.02). This association was not modified by amyloid-β, and there was no direct association of amyloid-β with change in social engagement.

CONCLUSIONS: Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment.

RevDate: 2019-06-27

Haass C, J Levin (2019)

[Did Alzheimer research fail entirely? : Failure of amyloid-based clinical studies].

Der Nervenarzt pii:10.1007/s00115-019-0751-1 [Epub ahead of print].

Numerous amyloid-based clinical studies have recently failed. Does this mean that the mechanisms of Alzheimer's disease have to be reinvestigated and that amyloid is not the trigger of the disease? Strong genetic evidence from familial Alzheimer's disease contradicts this fatalistic opinion. Mutations in all genes associated with familial Alzheimer's disease affect amyloid metabolism and aggregation. Moreover, a protective mutation reduces amyloid production by 20-30% throughout the lifetime. Clinical studies rather failed because secretase inhibitors block cleavage of numerous other physiologically important substrates of secretases. Moreover, the disease is initiated decades before symptoms occur. Successful treatment attempts with anti-amyloid medication based on other prototype amyloidoses are described. Finally, new therapeutic target molecules expressed in microglia cells are discussed.

RevDate: 2019-08-18

Fu CH, Iascone DM, Petrof I, et al (2019)

Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer's Disease Model.

Cell reports, 27(13):3741-3751.e4.

Adult hippocampal neurogenesis has been reported to be decreased, increased, or not changed in Alzheimer's disease (AD) patients and related transgenic mouse models. These disparate findings may relate to differences in disease stage, or the presence of seizures, which are associated with AD and can stimulate neurogenesis. In this study, we investigate a transgenic mouse model of AD that exhibits seizures similarly to AD patients and find that neurogenesis is increased in early stages of disease, as spontaneous seizures became evident, but is decreased below control levels as seizures recur. Treatment with the antiseizure drug levetiracetam restores neurogenesis and improves performance in a neurogenesis-associated spatial discrimination task. Our results suggest that seizures stimulate, and later accelerate the depletion of, the hippocampal neural stem cell pool. These results have implications for AD as well as any disorder accompanied by recurrent seizures, such as epilepsy.

RevDate: 2019-07-01
CmpDate: 2019-07-01

Yazar T, H Olgun Yazar (2019)

The prevalence of sarcopenia and dynapenia according to stage among Alzheimer-type dementia patients.

Ideggyogyaszati szemle, 72(5-6):171-179.

Background and purpose: In this study, the aim was to identify the prevalence of sarcopenia and dynapenia according to disease stage among Alzheimer-type dementia (AD) patients and collect data to suggest precautions related to reducing the disease load.

Methods: The study was completed with 127 patients separated into stages according to Clinical Dementia Rating Scale (CDR) criteria and 279 healthy volunteers aged 18-39 years and 70-80 years abiding by the exclusion criteria who agreed to participate in the research. Our prospective and cross-sectional study applied the CDR and mini mental test (MMSE) to patients with disorder in more than one cognitive area and possible AD diagnosis according to NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) diagnostic criteria. The patient and control groups had skeletal muscle mass index (SMMI), muscle strength and physical performance assessed with sarcopenia diagnosis according to European Working Group on Sarcopenia in Older People (EWGSOP) diagnostic criteria.

Results: In our study, in parallel with the increase in disease stage of AD patients, the prevalence of sarcopenia (led by severe sarcopenia) and dynapenia was higher compared to a control group of similar age.

Conclusion: In chronic, progressive diseases, like AD, identification of changes in parameters, like muscle mass and strength and reductions in physical performance in the early period, is important for identification and to take precautions in the initial stages considering the limitations of the preventive effects of treatment applied after diagnosis of AD.

RevDate: 2019-07-19

Epelbaum S, Paquet C, Hugon J, et al (2019)

How many patients are eligible for disease-modifying treatment in Alzheimer's disease? A French national observational study over 5 years.

BMJ open, 9(6):e029663 pii:bmjopen-2019-029663.

OBJECTIVE: We aimed to study the epidemiology of the prodromal and mild stages of Alzheimer's disease (AD) patients who are eligible for clinical trials with disease-modifying therapies.

SETTINGS: We analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed.

PARTICIPANTS: Patients, 50-85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders.

PRIMARY OUTCOME MEASURE: Descriptive statistics of the population of interest was the primary measure.

RESULTS: In the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients.

CONCLUSIONS: AD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available.

RevDate: 2019-07-07

Huang CN, Wang CJ, Lin CL, et al (2019)

Abelmoschus esculentus subfractions attenuate beta amyloid-induced neuron apoptosis by regulating DPP-4 with improving insulin resistance signals.

PloS one, 14(6):e0217400 pii:PONE-D-19-07370.

The association of Alzheimer disease (AD) and Diabetes (DM) is less clear. Accumulation of beta amyloid (Aβ) and presence of hyperphosphorylated tau (p-tau) are hallmarks of AD, spreading in the region where insulin receptors are also found. Aβ exerts neuron toxicity, and could disturb insulin signaling of phosphatidylinositol 3-kinase (PI3K), glycogen synthase kinase (GSK)-3β and AMP-activated protein kinase (AMPK), but increase IRS-1-Ser307 phosphorylation which is viewed as insulin resistance marker. Previously we reported dipeptidyl peptidase-4 (DPP-4) mediate insulin resistance signals, and Abelmoschus esculentus (AE) subfractions F1 (rich in quercetin glucosides and triterpene ester) and F2 (containing large amount of polysaccharides) attenuate DPP-4-mediated apoptosis. In the present study, we aim to investigate if Aβ induce neuron death by regulating DPP-4 and insulin resistance signals, and the putative effect of F1 and F2. By MTT, microscopy, and Western blotting, we demonstrate treatment of appropriate doses of AE subfractions prevent Aβ-induced neuron apoptosis. F1 attenuate Aβ-induced caspase 3 expression especially at 25 μg/mL, while F2 attenuate caspase 3 activation even at the low dose of 1 μg/mL. Both AE subfractions decrease Aβ-enhanced DPP-4, but increase Aβ-reduced p-AMPK and p-PI3K. The activity analysis reveals that F2 is more valid than F1 to reduce DPP-4 activity. The inhibition of DPP-4 demonstrates it plays the pivotal role in Aβ-induced neuron apoptosis. Moreover, although both F1 and F2 are effective to inhibit p-IRS-1-Ser307, F2 takes advantage to reduce p-Tau while F1 is superior to enhance p-GSK-3β. This implies AE subfractions act on different targets, and could be developed respectively. In conclusion, we demonstrate AE is potential to prevent Aβ-induced neuron damage by regulating DPP-4 and the insulin resistance cascades. AE could be an adjuvant to protect neuron degenerative disease related to Aβ and insulin resistance.

RevDate: 2019-06-24

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

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

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

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

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

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

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

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

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

RevDate: 2019-06-22

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

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

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

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

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

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

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

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

RevDate: 2019-07-07

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

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

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

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

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

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


RevDate: 2019-08-28

Ortega-Martinez S, Palla N, Zhang X, et al (2019)

Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(34):6766-6780.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that presently affects an estimated 5.7 million Americans. Understanding the basis for this disease is key for the development of a future successful treatment. In this effort, we previously reported that mouse prion protein-promoter-driven, ubiquitous expression of familial AD (FAD)-linked human PSEN1 variants in transgenic mice impairs environmental enrichment (EE)-induced proliferation and neurogenesis of adult hippocampal neural progenitor cells (AHNPCs) and in a non-cell autonomous manner. These findings were confirmed in PS1M146V/+ mice that harbor an FAD-linked mutation in the endogenous PSEN1 gene. We now demonstrate that CSF1R antagonist-mediated microglial depletion in transgenic male mice expressing mutant presenilin 1 (PS1) or PS1M146V/+ "knock-in" mice leads to a complete rescue of deficits in proliferation, differentiation and survival of AHNPCs. Moreover, microglia depletion suppressed the heightened baseline anxiety behavior observed in transgenic mice expressing mutant PS1 and PS1M146V/+ mice to levels observed in mice expressing wild-type human PS1 or nontransgenic mice, respectively. These findings demonstrate that in mice expressing FAD-linked PS1, microglia play a critical role in the regulation of EE-dependent AHNPC proliferation and neurogenesis and the modulation of affective behaviors.SIGNIFICANCE STATEMENT Inheritance of mutations in genes encoding presenilin 1 (PS1) causes familial Alzheimer's disease (FAD). Mutant PS1 expression enhances the levels and assembly of toxic Aβ42 peptides and impairs the self-renewal and neuronal differentiation of adult hippocampal neural progenitor cells (AHNPCs) following environmental enrichment (EE) that is associated with heightened baseline anxiety. We now show that microglial depletion fully restores the EE-mediated impairments in AHNPC phenotypes and suppresses the heightened baseline anxiety observed in mice expressing FAD-linked PS1. Thus, we conclude that the memory deficits and anxiety-related behaviors in patients with PS1 mutations is a reflection not just of an increase in the levels of Aβ42 peptides, but to impairments in the self-renewal and neuronal differentiation of AHNPCs that modulate affective behaviors.

RevDate: 2019-06-19

Panda SS, N Jhanji (2019)

Natural Products as Potential anti-Alzheimer Agents.

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

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

RevDate: 2019-07-23

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

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

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

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

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

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

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

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

RevDate: 2019-07-10

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

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

Hypertension (Dallas, Tex. : 1979), 74(2):413-420.

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

RevDate: 2019-06-16

Subaraja M, AJ Vanisree (2019)

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

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

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

RevDate: 2019-06-19

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

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

Autophagy [Epub ahead of print].

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

RevDate: 2019-06-12

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

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

Frontiers in aging neuroscience, 11:120.

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

RevDate: 2019-07-08

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

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

Journal of Alzheimer's disease : JAD, 70(1):75-89.

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

RevDate: 2019-07-14

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

Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid.

Annals of neurology, 86(2):215-224.

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

METHODS: We developed an ultrasensitive immunoassay and used it to measure oAβ in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-Aβ antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oAβ levels, and these were compared to levels at week 69 in placebo (n = 28), SC (n = 35), and IV (n = 35) treated patients.

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

INTERPRETATION: Crenezumab lowered CSF oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti-Aβ agents. ANN NEUROL 2019;86:215-224.

RevDate: 2019-08-29

Wahidi N, AJ Lerner (2019)

Blood Pressure Control and Protection of the Aging Brain.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 16(3):569-579.

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

RevDate: 2019-07-01

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

Diagnosis and treatment of cognitive impairment.

Zeitschrift fur Gerontologie und Geriatrie, 52(4):309-315.

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

RevDate: 2019-06-02

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

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

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

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

DESIGN: Systematic review.

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

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

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

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

RevDate: 2019-05-31

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

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

Natural product research [Epub ahead of print].

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

RevDate: 2019-08-20

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

Vitamin D and the nervous system.

Neurological research, 41(9):827-835.

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

RevDate: 2019-08-02

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

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

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

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

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

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

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

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

RevDate: 2019-08-09

Müller P, Fendt M, NG Müller (2019)

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

Der Internist, 60(7):761-768.

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

RevDate: 2019-06-10

Chen XQ, WC Mobley (2019)

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

Frontiers in neuroscience, 13:446.

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

RevDate: 2019-05-27

Wang Z, He C, JS Shi (2019)

Natural Products for the Treatment of Neurodegenerative Diseases.

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

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

RevDate: 2019-06-28

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

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

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

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

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

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

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

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

RevDate: 2019-08-15

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

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

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 27(9):908-917.

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

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

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

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

RevDate: 2019-06-10

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

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

BioMed research international, 2019:4690280.

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

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

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

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

RevDate: 2019-05-22

Konstantakopoulos G (2019)

Insight across mental disorders: A multifaceted metacognitive phenomenon.

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

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

RevDate: 2019-05-19

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

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

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

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

RevDate: 2019-08-20

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

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

Neurochemistry international, 129:104470.

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

RevDate: 2019-08-28

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

Biomarkers for Alzheimer's Disease.

Current Alzheimer research, 16(6):518-528.

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

RevDate: 2019-06-18

Singh R, R Bansal (2019)

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

Steroids, 148:114-124.

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

RevDate: 2019-05-16

Ansari F, Ghasemi JB, A Niazi (2019)

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

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

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

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

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

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

RevDate: 2019-06-02

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

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

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

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

RevDate: 2019-06-28

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

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

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

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

RevDate: 2019-05-13

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

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

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

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

RevDate: 2019-07-30
CmpDate: 2019-07-30

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

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

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

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

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

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

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

RevDate: 2019-07-18

Carosi JM, TJ Sargeant (2019)

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

Autophagy, 15(8):1460-1462.

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

RevDate: 2019-08-04

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

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

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33(8):8782-8798.

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

RevDate: 2019-08-12

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

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

Neuroscience, 410:118-127.

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

RevDate: 2019-06-10

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

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

Brain research, 1718:46-52.

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

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

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

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

RevDate: 2019-08-05
CmpDate: 2019-08-05

Chaudhuri A, Hudait N, SS Chakraborty (2019)

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

Computational biology and chemistry, 80:292-306.

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


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 )