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Bibliography on: Alzheimer Disease — Current Literature

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

RJR: Recommended Bibliography 18 Aug 2019 at 01:31 Created: 

Alzheimer Disease — Current Literature

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. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: alzheimer[TIAB] and (2017[PDAT] OR [2018[PDAT] OR 2019[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-08-16

Fishman P, Coe NB, White L, et al (2019)

Cost of dementia in Medicare managed care: a systematic literature review.

The American journal of managed care, 25(8):e247-e253 pii:88109.

OBJECTIVES: We conducted a systematic review of studies reporting the direct healthcare costs of treating older adults with diagnosed Alzheimer disease and related dementias (ADRD) within private Medicare managed care plans.

STUDY DESIGN: A systematic review of all studies published in English reporting original empirical analyses of direct costs for older adults with ADRD in Medicare managed care.

METHODS: All papers indexed in PubMed or Web of Science reporting ADRD costs within Medicare managed care plans from 1983 through 2018 were identified and reviewed.

RESULTS: Despite the growth in Medicare managed care enrollment, only 9 papers report the costs of care for individuals with ADRD within these plans, and only 1 study reports data less than 10 years old. This limited literature reports wide ranges for ADRD-attributable costs, with estimates varying from $3738 to $8726 in annual prevalent costs and $8938 to $38,794 in 1-year immediate postdiagnosis incident costs. Reviewed studies also used varied study populations, case and cost ascertainment methods, and analytic methods, making cross-study comparisons difficult.

CONCLUSIONS: The expected continued growth in Medicare managed care enrollment, coupled with the large and growing impact of ADRD on America's healthcare delivery and finance systems, requires more research on the cost of ADRD within managed care. This research should use more consistent approaches to identify ADRD prevalence and provide more detail regarding which components of care are included in analyses and how the costs of care are captured and measured.

RevDate: 2019-08-16

Wei EX, Oh ES, Harun A, et al (2019)

Increased prevalence of vestibular loss in mild cognitive impairment and Alzheimer's disease.

Current Alzheimer research pii:CAR-EPUB-100275 [Epub ahead of print].

BACKGROUND/AIMS: Recent evidence has shown that Alzheimer's disease (AD) patients have reduced vestibular function relative to healthy controls. In this study, we evaluated whether patients with mild cognitive impairment (MCI) also have reduced vestibular function relative to controls, and compared the level of vestibular impairment between MCI and AD patients.

Methods: Vestibular physiologic function was assessed in 77 patients (26 MCI, 51 AD) and 295 matched controls using 3 clinical vestibular tests. The association between vestibular loss and cognitive impairment was evaluated using conditional logistic regression models.

Results: Individuals with vestibular impairment had a 3 to 4-fold increased odds of being in the MCI vs. control group (p-values < 0.05). MCI patients had a level of vestibular impairment that was intermediate between controls and AD.

Conclusion: These findings suggest a dose-response relationship between vestibular loss and cognitive status, and support the hypothesis that vestibular loss contributes to cognitive decline.

RevDate: 2019-08-16

Sturzu A, Sheikh S, Kalbacher H, et al (2019)

Synthesis of a novel curcumin derivative as potential imaging probe in Alzheimer's disease imaging.

Current Alzheimer research pii:CAR-EPUB-100279 [Epub ahead of print].

Curcumin has been of interest in the field of Alzheimer's disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques. However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement. In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl- curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β- amyloid plaques. In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β-amyloid plaques. In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

RevDate: 2019-08-16

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

Le Stunff H, Véret J, Kassis N, et al (2019)

Deciphering the Link Between Hyperhomocysteinemia and Ceramide Metabolism in Alzheimer-Type Neurodegeneration.

Frontiers in neurology, 10:807.

Aging is one of the strongest risk factor for Alzheimer's disease (AD). However, several data suggest that dyslipidemia can either contribute or serve as co-factors in AD appearance. AD could be examined as a metabolic disorder mediated by peripheral insulin resistance. Insulin resistance is associated with dyslipidemia, which results in increased hepatic ceramide generation. Hepatic steatosis induces pro-inflammatory cytokine activation which is mediated by the increased ceramides production. Ceramides levels increased in cells due to perturbation in sphingolipid metabolism and upregulated expression of enzymes involved in ceramide synthesis. Cytotoxic ceramides and related molecules generated in liver promote insulin resistance, traffic through the circulation due to injury or cell death caused by local liver inflammation, and because of their hydrophobic nature, they can cross the blood-brain barrier and thereby exert neurotoxic responses as reducing insulin signaling and increasing pro-inflammatory cytokines. These abnormalities propagate a cascade of neurodegeneration associated with oxidative stress and ceramide generation, which potentiate brain insulin resistance, apoptosis, myelin degeneration, and neuro-inflammation. Therefore, excess of toxic lipids generated in liver can cause neurodegeneration. Elevated homocysteine level is also a risk factor for AD pathology and is narrowly associated with metabolic diseases and non-alcoholic fatty liver disease. The existence of a homocysteine/ceramides signaling pathway suggests that homocysteine toxicity could be partly mediated by intracellular ceramide accumulation due to stimulation of ceramide synthase. In this article, we briefly examined the role of homocysteine and ceramide metabolism linking metabolic diseases and non-alcoholic fatty liver disease to AD. We therefore analyzed the expression of mainly enzymes implicated in ceramide and sphingolipid metabolism and demonstrated deregulation of de novo ceramide biosynthesis and S1P metabolism in liver and brain of hyperhomocysteinemic mice.

RevDate: 2019-08-16

Spencer PS (2019)

Hypothesis: Etiologic and Molecular Mechanistic Leads for Sporadic Neurodegenerative Diseases Based on Experience With Western Pacific ALS/PDC.

Frontiers in neurology, 10:754.

Seventy years of research on Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia Complex (ALS/PDC) have provided invaluable data on the etiology, molecular pathogenesis and latency of this disappearing, largely environmental neurodegenerative disease. ALS/PDC is linked to genotoxic chemicals (notably methylazoxymethanol, MAM) derived from seed of the cycad plant (Cycas spp.) that were used as a traditional food and/or medicine in all three disease-affected Western Pacific populations. MAM, nitrosamines and hydrazines generate methyl free radicals that damage DNA (in the form of O6-methylguanine lesions) that can induce mutations in cycling cells and degenerative changes in post-mitotic cells, notably neurons. This paper explores exposures to naturally occurring and manmade sources of nitrosamines and hydrazines in association with sporadic forms of ALS (with or without frontotemporal degeneration), progressive supranuclear palsy, and Alzheimer disease. Research approaches are suggested to examine whether these associations might have etiological significance.

Lay Summary: Unknown environmental exposures are thought to be risk factors for non-inherited forms of certain progressive brain diseases, such as sporadic forms of amyotrophic lateral sclerosis (sALS), progressive supranuclear palsy (sPSP), and Alzheimer's disease (sAD). Related progressive and fatal brain disorders coalesce in a single neurodegenerative disease of largely environmental origin (ALS-Parkinsonism-dementia Complex) that has affected three genetically distinct populations residing in islands of the Western Pacific region. Prolonged study of this prototypical neurodegenerative disease has provided invaluable information on the probable environmental cause (specific chemical genotoxins) and molecular mechanisms (unrepaired nerve cell DNA-damage) by which brain degeneration begins, evolves and, years or decades later, clinical signs appear, and progress. This information is used as a foundation to explore whether chemically related genotoxins (nitrosamines, hydrazines) are possible risk factors for sALS, sPSP, and sAD. Methods to test this hypothesis in the field and laboratory are proposed.

RevDate: 2019-08-16

Norwitz NG, Mota AS, Norwitz SG, et al (2019)

Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3β, α-Synuclein, and Type 3 Diabetes Hypotheses.

Frontiers in aging neuroscience, 11:184.

As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic.

RevDate: 2019-08-16

Zamponi E, GF Pigino (2019)

Protein Misfolding, Signaling Abnormalities and Altered Fast Axonal Transport: Implications for Alzheimer and Prion Diseases.

Frontiers in cellular neuroscience, 13:350.

Histopathological studies revealed that progressive neuropathies including Alzheimer, and Prion diseases among others, include accumulations of misfolded proteins intracellularly, extracellularly, or both. Experimental evidence suggests that among the accumulated misfolded proteins, small soluble oligomeric conformers represent the most neurotoxic species. Concomitant phenomena shared by different protein misfolding diseases includes alterations in phosphorylation-based signaling pathways synaptic dysfunction, and axonal pathology, but mechanisms linking these pathogenic features to aggregated neuropathogenic proteins remain unknown. Relevant to this issue, results from recent work revealed inhibition of fast axonal transport (AT) as a novel toxic effect elicited by oligomeric forms of amyloid beta and cellular prion protein PrPC, signature pathological proteins associated with Alzheimer and Prion diseases, respectively. Interestingly, the toxic effect of these oligomers was fully prevented by pharmacological inhibitors of casein kinase 2 (CK2), a remarkable discovery with major implications for the development of pharmacological target-driven therapeutic intervention for Alzheimer and Prion diseases.

RevDate: 2019-08-16

Lana E, Gellerbring A, Jung S, et al (2019)

Homomeric and Heteromeric Aβ Species Exist in Human Brain and CSF Regardless of Alzheimer's Disease Status and Risk Genotype.

Frontiers in molecular neuroscience, 12:176.

Background: A fundamental question in Alzheimer's disease (AD) is whether amyloid-β (Aβ) peptides and their deposition in the brain signify a direct pathological role or they are mere outcome of the disease pathophysiological events affecting neuronal function. It is therefore important to decipher their physiological role in the brain. So far, the overwhelming focus has been on the potential toxicity of Aβ, often studied outside the crucial AD characteristics, i.e.: (i) the slow, decades-long disease progression that precedes clinical symptoms; (ii) the link to apolipoprotein-E ε4 allele as major risk factor; (iii) the selective early degeneration of cholinergic neurons. Previous studies, in vitro and cerebrospinal fluid (CSF) only, indicated one possible native function of Aβ peptides is the allosteric modulation of acetylcholine homeostasis, via molecular interactions between Aβ, apolipoprotein-E, and the acetylcholine-degrading enzymes, cholinesterases, resulting in the formation of acetylcholine-hydrolyzing complexes (BAβACs). Methods: Here, by combining sucrose-density gradient fractionation of post-mortem brains and in-house developed sensitive ELISA assays on the obtained fractions, we investigated the presence, levels and molecular interactions between Aβ, apolipoprotein-E and cholinesterases for the first time in brain tissues. We examined three distinct brain regions of Alzheimer and non-demented subjects, plus a large number of Alzheimer CSF samples. Results: We report that both monomeric and oligomeric (homomeric and heteromeric) forms of Aβ peptides are present in the brain of Alzheimer and non-demented individuals. Heteromeric Aβ was found in stable complexes with apolipoprotein-E and/or cholinesterases, irrespective of APOE genotype or disease status, arguing in favor of a physiological dynamic formation and function for these complexes in the brain. The patterns and molecular sizes of the detected soluble Aβ forms were closely matched between CSF and brain samples. This evinces that the detected Aβ-apolipoprotein-E complexes and BAβACs in CSF most likely originate from the interstitial fluids of the brain. Conclusions: In conclusion, both light homomeric Aβ oligomers and heteromeric Aβ-ApoE and BAβACs are present and readily detectable in the brain, regardless of disease status and APOE4 genotype. Deeper knowledge of the physiological function of Aβ is crucial for better understanding the early pathological events that decades later lead to manifestation of AD.

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: 2019-08-15

Hazen J, Vistnes M, Barca ML, et al (2019)

The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia.

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

OBJECTIVE: Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years.

METHODS: Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1β, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE).

RESULTS: No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups.

CONCLUSION: Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.

RevDate: 2019-08-15

Gomes LA, Hipp SA, Rijal Upadhaya A, et al (2019)

Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein.

Acta neuropathologica pii:10.1007/s00401-019-02053-5 [Epub ahead of print].

Extracellular deposition of amyloid β-protein (Aβ) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical and clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between Aβ and τ pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice overexpressing human APP with the Swedish mutation (670/671 KM → NL) (APP23), human wild-type APP (APP51/16), or a proenkephalin signal peptide linked to human Aβ42 (APP48) with τ-transgenic mice overexpressing human mutant 4-repeat τ-protein with the P301S mutation (TAU58). In 6-month-old APP23xTAU58 and APP51/16xTAU58 mice, soluble Aβ was associated with the aggravation of p-τ pathology propagation into the CA1/subiculum region, whereas 6-month-old TAU58 and APP48xTAU58 mice neither exhibited significant amounts of p-τ pathology in the CA1/subiculum region nor displayed significant levels of soluble Aβ in the forebrain. In APP23xTAU58 and APP51/16xTAU58 mice showing an acceleration of p-τ propagation, Aβ and p-τ were co-immunoprecipitated with cellular prion protein (PrPC). A similar interaction between PrPC, p-τ and Aβ was observed in human AD brains. This association was particularly noticed in 60% of the symptomatic AD cases in our sample, suggesting that PrPC may play a role in the progression of AD pathology. An in vitro pull-down assay confirmed that PrPC is capable of interacting with Aβ and p-τ. Using a proximity ligation assay, we could demonstrate proximity (less than ~ 30-40 nm distance) between PrPC and Aβ and between PrPC and p-τ in APP23xTAU58 mouse brain as well as in human AD brain. Proximity between PrPC and p-τ was also seen in APP51/16xTAU58, APP48xTAU58, and TAU58 mice. Based on these findings, it is tempting to speculate that PrPC is a critical player in the interplay between Aβ and p-τ propagation at least in a large group of AD cases. Preexisting p-τ pathology interacting with PrPC, thereby, appears to be a prerequisite for Aβ to function as a p-τ pathology accelerator via PrPC.

RevDate: 2019-08-15

Serra-Añó P, Pedrero-Sánchez JF, Hurtado-Abellán J, et al (2019)

Mobility assessment in people with Alzheimer disease using smartphone sensors.

Journal of neuroengineering and rehabilitation, 16(1):103 pii:10.1186/s12984-019-0576-y.

BACKGROUND: Understanding the functional status of people with Alzheimer Disease (AD), both in a single (ST) and cognitive dual task (DT) activities is essential for identifying signs of early-stage neurodegeneration. This study aims to compare the performance quality of several tasks using sensors embedded in an Android device, among people at different stages of Alzheimer and people without dementia. The secondary aim is to analyze the effect of cognitive task performance on mobility tasks.

METHODS: This is a cross-sectional study including 22 participants in the control group (CG), 18 in the group with mild AD and 22 in the group with moderate AD. They performed two mobility tests, under ST and DT conditions, which were registered using an Android device. Postural control was measured by medial-lateral and anterior-posterior displacements of the COM (MLDisp and APDisp, respectively) and gait, with the vertical and medial-lateral range of the COM (Vrange and MLrange). Further, the sit-to-stand (PStand) and turning and sit power (PTurnSit), the total time required to complete the test and the reaction time were measured.

RESULTS: There were no differences between the two AD stages either for ST or DT in any of the variables (p > 0.05). Nevertheless, people at both stages showed significantly lower values of PStand and PTurnSit and larger Total time and Reaction time compared to CG (p < 0.05). Further, Vrange is also lower in CDR1G than in CG (p < 0.05). The DT had a significant deleterious effect on MLDisp in all groups (p < 0.05) and on APDisp only in moderate AD for DT.

CONCLUSIONS: Our findings indicate that AD patients present impairments in some key functional abilities, such as gait, turning and sitting, sit to stand, and reaction time, both in mild and moderate AD. Nevertheless, an exclusively cognitive task only influences the postural control in people with AD.

RevDate: 2019-08-14

Dede HÖ, Benbir Senel G, D Karadeniz (2019)

REM sleep without atonia constitutes increased risk for neurodegenerative disorders.

Acta neurologica Scandinavica [Epub ahead of print].

OBJECTIVES: REM sleep without atonia (RSWA) is a polysomnographic finding used in diagnosis of REM sleep behavior disorder (RBD). Clinical significance of idiopathic RSWA (iRSWA) unaccompanied by RBD is not known. We designed a prospective study to investigate whether iRSWA constitutes an increased risk for developing neurodegenerative disorders.

MATERIALS & METHODS: Between January 2010 and December 2014, a total of 4,362 patients underwent a full-night video-polysomnography. Upon detailed clinical and polysomnographical examination, patients with iRSWA and idiopathic RBD (iRBD) were enrolled into this study, and followed-up six monthly for 4 years up to 9 years.

RESULTS: We had a total of 31 patients with iRBD and 67 patients with iRSWA. Mean age was higher in iRBD group than those in iRSWA group (p=0.016). Restless Legs Syndrome/Willis-Ekbom Disease was significantly more common in patients with iRBD than those in patient with iRSWA (p<0.001). Eighteen patients with iRSWA (26.8%) developed iRBD after 2.6+2.2 years. Six patients with iRSWA (8.9%) developed neurodegenerative disorders following 2.4+1.5 years; four were diagnosed as Parkinson's disease (PD) and two developed probable Alzheimer-type dementia. In patients with iRBD, 8 patients (25.8%) developed neurodegenerative disorders -all was Parkinson's disease- following 2.6+2.2 years. Development of neurodegenerative diseases was positively correlated with age (p<0.001) and periodic leg movements in sleep in both groups (p<0.010).

CONCLUSIONS: These results show that iRSWA may also be accepted as a risk factor in the development of PD or neurodegenerative diseases. Advanced age and periodic leg movements in sleep seem to be correlated with higher risk. This article is protected by copyright. All rights reserved.

RevDate: 2019-08-14

Lima S, Garrett C, Machado JC, et al (2019)

Quality of life in patients with mild Alzheimer disease: the mediator role of mindfulness and spirituality.

Aging & mental health [Epub ahead of print].

Objectives: This study examined the mediator role of mindfulness and spirituality in the relationship between psychological morbidity, awareness of the disease, functionality, social support, family satisfaction, and quality of life (QoL) in patients with mild AD. Method: The sample consisted of 128 patients who answered the Cognitive and Affective Mindfulness Scale-Revised (CAMS-R), the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD), the Hospital Anxiety and Depression Scales (HADS), the Satisfaction with Social Support Scale (SSSS), the Family Satisfaction Scale (FSS), the Spiritual and Religious Attitudes in Dealing with Illness (SpREUK), the Index of Barthel, and the Quality of Life-Alzheimer's Disease (QoL-AD). Results: Mindfulness and spirituality mediated the relationship between functionality, awareness of the disease, family satisfaction and QoL. Psychological morbidity had a direct negative impact on QoL and was negatively associated with awareness of the disease, family satisfaction and social support. Mindfulness was negatively associated with spirituality and the latter was negatively associated with QoL. More social support was associated with greater awareness of the disease and family satisfaction. More functionality, awareness of the disease and family satisfaction contributed to more QoL and this relationship was mediated by mindfulness and spirituality. Conclusion: Interventions directed at the promotion of the QoL of patients with mild AD should focus on the promotion of mindfulness skills in AD patients, in addition to the reduction of psychological morbidity and the promotion of functionality, awareness of the disease, family relationships and social support.

RevDate: 2019-08-14

Lauterborn JC, Cox CD, Chan SW, et al (2019)

Synaptic Actin Stabilization Protein Loss in Down Syndrome and Alzheimer Disease.

Brain pathology (Zurich, Switzerland) [Epub ahead of print].

Reduced spine densities and an age-dependent accumulation of amyloid β and tau pathology are shared features of Down syndrome (DS) and Alzheimer's disease (AD). Spine morphology and the synaptic plasticity that supports learning both depend upon the actin cytoskeleton, suggesting that disturbances in actin regulatory signaling might underlie spine defects in both disorders. The present study evaluated synaptic levels of two proteins that promote filamentous actin stabilization, the Rho GTPase effector p21-activated kinase 3 (PAK3) and Arp2, in DS versus AD. Fluorescent deconvolution tomography was used to determine postsynaptic PAK3 and Arp2 levels for large numbers of excitatory synapses in parietal cortex of individuals with DS plus AD pathology or AD alone relative to age-matched controls. Although numbers of excitatory synapses were not different between groups, synaptic PAK3 levels were greatly reduced in DS+AD and AD individuals versus controls. Synaptic Arp2 levels also were reduced in both disorders, but to a greater degree in AD. Western blotting detected reduced Arp2 levels in the AD group, but there was no correlation with phosphorylated tau levels suggesting that Arp2 loss does not contribute to mechanisms that drive tau pathology progression. Overall, the results demonstrate marked synaptic disturbances in two actin regulatory proteins in adult DS and AD brains, with greater effects in individuals with AD alone. As both PAK and the Arp2/3 complex play roles in the actin stabilization that supports synaptic plasticity, reductions in these proteins at synapses may be early events in spine dysfunction that contribute to cognitive impairment in these disorders. This article is protected by copyright. All rights reserved.

RevDate: 2019-08-14

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: 2019-08-14

Kaddour L, N Kishita (2019)

Anxiety in Informal Dementia Carers: A Meta-Analysis of Prevalence.

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

Much of the carer literature has focused on depression and burden as primary outcomes and anxiety appear somewhat neglected. Providing evidence on the prevalence of carer anxiety is critical as it can enhance awareness among professionals, which in turn can lead to improved access to efficacious treatments. This meta-analysis updated the previous review conducted in 2007 to estimate the up-to-date prevalence of anxiety in informal carers for people with dementia. Literature searches were conducted in databases of published and unpublished literature. Events and sample size data were pooled using a random effects model to obtain an overall prevalence percentage. A total of 10 studies were included, resulting in a pooled estimate of anxiety prevalence at 32.1% (95% confidence interval: 20.6%-46.2%, P = .01). Significant heterogeneity was found, which was not reduced following sensitivity analysis. This study suggests anxiety is a prevalent difficulty experienced by dementia carers. Additional research recommendations and clinical implications are discussed.

RevDate: 2019-08-13

Kajiwara K, Kako J, H Noto (2019)

Letter in response to: "Determinants of self- and carer-rated quality of life and caregiver burden in Alzheimer disease".

RevDate: 2019-08-12

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: 2019-08-10

Nübling G, Loosli SV, Wlasich E, et al (2019)

[A German version of the Cambridge examination for mental disorders of older people with Down's syndrome and others with intellectual disabilities : A diagnostic procedure for detecting dementia in people with Down's syndrome].

Zeitschrift fur Gerontologie und Geriatrie pii:10.1007/s00391-019-01591-7 [Epub ahead of print].

BACKGROUND: Although people with Down's syndrome (DS) are at a high risk of developing an Alzheimer type dementia (AD) due to a triplication of the amyloid precursor gene, there are practically no internationally available test procedures to detect cognitive deficits in this at risk population in the German language.

OBJECTIVE: The aim was to provide a German translation and intercultural adaptation of the Cambridge examination for mental disorders of older people with Down's syndrome and others with intellectual disabilities (CAMDEX-DS), which is available in English and Spanish. This instrument for diagnostics and monitoring consists of a psychological test examination (CAMCOG-DS) and a caregiver interview.

METHODS: The translation and adaptation of the CAMDEX-DS were achieved through a multistep translation process, whereby two independent forward and back translations were provided by professional translators and a consensus version was finalized and tested. The final version of the caregiver interview was applied to 11 subjects and the CAMCOG-DS was conducted with 28 patients.

RESULTS: The German version of the CAMDEX-DS proved to be easily administered. The CAMCOG-DS could be fully administered to 21 out of 28 patients (75%). The CAMCOG-DS values were much lower for older patients aged ≥45 years than for younger patients (46/109 vs. 73.5/109; p = 0.033).

DISCUSSION: The German version of the CAMDEX-DS provides an internationally recognized tool for the diagnostics and monitoring of cognitive decline in Down's syndrome. Furthermore, the German version can standardize medical care of these patients. In particular it provides a means of participation in international research trials for this at risk population.

RevDate: 2019-08-10

Sakae N, Josephs KA, Litvan I, et al (2019)

Clinicopathologic subtype of Alzheimer's disease presenting as corticobasal syndrome.

Alzheimer's & dementia : the journal of the Alzheimer's Association pii:S1552-5260(19)30115-3 [Epub ahead of print].

INTRODUCTION: The corticobasal syndrome (CBS) is associated with several neuropathologic disorders, including corticobasal degeneration and Alzheimer's disease (AD).

METHOD: In this report, we studied 43 AD patients with CBS (AD-CBS) and compared them with 42 AD patients with typical amnestic syndrome (AD-AS), as well as 15 cases of corticobasal degeneration and CBS pathology.

RESULTS: Unlike AD-AS, AD-CBS had prominent motor problems, including limb apraxia (90%), myoclonus (81%), and gait disorders (70%). Alien limb phenomenon was reported in 26% and cortical sensory loss in 14%. Language problems were also more frequent in AD-CBS, and memory impairment was less frequent. AD-CBS had more tau pathology in perirolandic cortices but less in superior temporal cortex than AD-AS. In addition, AD-CBS had greater neuronal loss in the substantia nigra.

DISCUSSION: AD-CBS is a clinicopathological subtype of AD with an atypical distribution of Alzheimer-type tau pathology. Greater neuronal loss in the substantia nigra may contribute to Parkinsonism which is not a feature of typical AD.

RevDate: 2019-08-09

Peña-Bautista C, López-Cuevas R, Cuevas A, et al (2019)

Lipid peroxidation biomarkers correlation with medial temporal atrophy in early Alzheimer Disease.

Neurochemistry international pii:S0197-0186(19)30310-9 [Epub ahead of print].

Alzheimer Disease (AD) is a pathology that causes millions of deaths every year and it also generates severe economic consequences for families and public health systems. Oxidative stress is related to neurodegenerative diseases damage. In fact, brain lipid oxidation could produce brain atrophy. The main objective of this study is the evaluation of atrophy and lipid peroxidation damage in AD patients. We studied medial temporal brain atrophy by magnetic resonance imaging (MRI) and a set of lipid peroxidation biomarkers from plasma samples, respectively. The participants were AD patients in early stages (n = 80) and healthy controls (n = 32). Some lipid peroxidation compounds (neuroprostanes, isoprostanes, neurofurans, isofurans, 17-epi-17-F2t-dihomo-IsoP, PGF2α) in plasma showed statistically significant correlation with medial temporal atrophy. So, they were selected to generate an AD diagnosis model, showing an AUC-ROC of 0.900, close to accuracy achieved by the model based on neuroimaging analysis (AUC-ROC 0.929). In addition, the new model showed suitable specificity, so it could be used as screening test. The developed model based on plasma biomarkers could reflect white and grey matter lipid peroxidation, which occurs in medial temporal lobe in early AD patients. Nevertheless, more studies are needed in this field in order to evaluate specificity against other dementias or neurodegenerative diseases.

RevDate: 2019-08-09

Gatchel JR, Rabin JS, Buckley RF, et al (2019)

Longitudinal Association of Depression Symptoms With Cognition and Cortical Amyloid Among Community-Dwelling Older Adults.

JAMA network open, 2(8):e198964 pii:2747700.

Importance: Depressive symptoms are prevalent among older adults and may be early manifestations of Alzheimer disease (AD) before onset of mild cognitive impairment. However, it remains unclear whether worsening depressive symptoms in the presence of AD pathology are associated with cognitive decline in older adults.

Objective: To determine the longitudinal association between depressive symptoms, cognition, and cortical amyloid in community-dwelling older adults.

Participants from the Harvard Aging Brain Study, a cohort study, underwent annual assessments of depression and cognition and baseline cortical amyloid measurement (mean, 4.42 years; range, 2-7 years). Data collection was from September 2010 to August 2017 in a convenience sample of community-dwelling adults (276 participants, all cognitively unimpaired) with at most mild depression at entry.

Main Outcomes and Measures: Depression (Geriatric Depression Scale [GDS]), cognition (Preclinical Alzheimer Cognitive Composite [PACC]), and a continuous measure of cortical amyloid (Pittsburgh Compound-B positron emission tomography imaging). Change in GDS and baseline amyloid were examined as interactive predictors of PACC decline in a linear mixed model with backward elimination, adjusting for age, sex, and education.

Results: Participants were 164 women and 112 men (mean [SD] age, 73.5 [6.0] years). At baseline, the mean (SD) GDS score was 3.0 (2.8) (range, 0-12), the mean (SD) PACC score was -0.004 (0.67) (range, -2.32 to 1.88), and the mean (SD) amyloid positron emission tomography distribution volume ratio was 1.16 (0.20) (range, 0.92-1.94). At last follow-up, the mean (SD) GDS score was 3.9 (2.9) (range, 0-12), and the mean (SD) PACC score was -0.09 (1.27) (range, -5.66 to 1.67). The interaction between cortical amyloid and increasing GDS was associated with declining cognition (β = -0.19; 95% CI, -0.27 to -0.12; P < .001).

Conclusions and Relevance: In this study, cortical amyloid moderated the association between worsening depressive symptoms and declining cognition in older adults. While future work is needed to better understand causal associations, these findings may enhance early detection and prevention of AD clinical symptoms.

RevDate: 2019-08-09

Chan C, PB Rosenberg (2019)

Depression Synergy With Amyloid and Increased Risk of Cognitive Decline in Preclinical Alzheimer Disease.

JAMA network open, 2(8):e198970 pii:2747691.

RevDate: 2019-08-09

Smalheiser NR (2019)

Ketamine: A Neglected Therapy for Alzheimer Disease.

Frontiers in aging neuroscience, 11:186.

RevDate: 2019-08-09

Dos Santos Guilherme M, Stoye NM, Rose-John S, et al (2019)

The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients.

Frontiers in aging neuroscience, 11:182.

These days, the important role of retinoids in adult brain functionality and homeostasis is well accepted and has been proven by genomic as well as non-genomic mechanisms. In the healthy brain, numerous biological processes, e.g., cell proliferation, neurogenesis, dendritic spine formation as well as modulation of the immune system, have been attributed to retinoid signaling. This, together with the finding that retinoid metabolism is impaired in Alzheimer's disease (AD), led to preclinical and early clinical testing of natural and synthetic retinoids as innovative pharmaceuticals with multifactorial properties. Acitretin, an aromatic retinoid, was found to exert an anti-amyloidogenic effect in mouse models for AD as well as in human patients by stimulating the alpha-secretase ADAM10. The lipophilic drug was already demonstrated to easily pass the blood brain barrier after i.p. administration and evoked increased nest building capability in the 5xFAD mouse model. Additionally, we analyzed the immune-modulatory capacity of acitretin via a multiplex array in the 5xFAD mouse model and evaluated some of our findings in human CSF derived from a pilot study using acitretin. Although several serum analytes did not display changes, Interleukin-6 (IL-6) was found to be significantly increased in both-mouse and human neural material. This demonstrates that acitretin exerts an immune stimulatory effect-besides the alpha-secretase induction-which could impact the alleviation of learning and memory disabilities observed in the mouse model.

RevDate: 2019-08-08

Azman Iste F, Tezer Filik FI, S Saygi (2019)

SREDA: A Rare but Confusing Benign EEG Variant.

Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society [Epub ahead of print].

INTRODUCTION: Subclinical rhythmic EEG discharges in adults (SREDA) is a very rare benign EEG pattern. The electrophysiological features and atypical variants of SREDA has wide spectrum and they are poorly known. It resembles ictal discharges, and overinterpretation of SREDA may lead to misdiagnosis of epilepsy. Herein, we aimed to report patients with SREDA to identify the frequency and characterized clinical, demographic, electrophysiological features.

METHODS: We reviewed 22,234 EEG reports that are reported by the same experienced clinical neurophysiologists, between 2012 and 2018. The EEGs with SREDA were reevaluated blindly by three clinical neurophysiologists. The demographic, clinical characteristics, and neuroimaging features of the patients were reviewed.

RESULTS: Subclinical rhythmic EEG discharges in adults was present in 14 EEG records (0.06%), in nine patients. The mean age of patients was 52.1 ± 17.7 (range, 21-71) years. The patients had been diagnosed with several neurologic diseases, including cerebrovascular disease, epilepsy, psychogenic nonepileptic seizures, mental retardation, Alzheimer disease, and transient global amnesia. One patient had unilateral lesion, in whom SREDA had appeared on contralateral side of the lesion, whereas other patients with normal or nonlateralized lesions had SREDA bilaterally and symmetrical. This variant had been misdiagnosed as an ictal discharge in previous EEGs in three patients.

CONCLUSIONS: This study indicates that SREDA is difficult to associate with any specific condition. The pathophysiology of SREDA can not be explained by a single mechanism. Even if it is mostly observed in older adults, it is also observed in young adults in this study. It is important to differentiate SREDA from ictal discharge to prevent misdiagnosis of epilepsy especially in nonepileptic paroxysmal events.

RevDate: 2019-08-08

Tejera D, MT Heneka (2019)

Microglia in Neurodegenerative Disorders.

Methods in molecular biology (Clifton, N.J.), 2034:57-67.

Microglia are the brain's resident immune cells. Under physiological conditions, they participate in a myriad of processes mainly involved in housekeeping functions that promote tissue homeostasis. However, the triggering of an immune response is a common feature in neurodegenerative disorders. This shift in microglia cells toward a chronically activated phenotype contributing to neuronal dysfunction and cell death is of great interest nowadays. In this chapter, we review the implications of microglia activation in different neurodegenerative disorders.

RevDate: 2019-08-08

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: 2019-08-08

Doney ASF, Bonney W, Jefferson E, et al (2019)

Investigating the Relationship Between Type 2 Diabetes and Dementia Using Electronic Medical Records in the GoDARTS Bioresource.

Diabetes care pii:dc19-0380 [Epub ahead of print].

OBJECTIVE: To investigate the impact of type 2 diabetes on incidence of major dementia subtypes, Alzheimer and vascular dementia, using electronic medical records (EMR) in the GoDARTS bioresource.

RESEARCH DESIGN AND METHODS: GoDARTS comprises a large case-control study of type 2 diabetes with longitudinal follow-up in EMR. Dementia case subjects after recruitment were passively identified in the EMR, and using a combination of case note review, an Alzheimer-specific weighted genetic risk score (wGRS), and APOE4 genotype, we validated major dementia subtypes. We undertook a retrospective matched cohort study to determine the risk of type 2 diabetes status for incident dementia accounting for competing risk of death.

RESULTS: Type 2 diabetes status was associated with a significant risk of any dementia (cause-specific hazard ratio [csHR] 1.46, 95% CI 1.31-1.64), which was attenuated, but still significant, when competing risk of death was accounted for (subdistribution [sd]HR 1.26, 95% CI 1.13-1.41). The accuracy of EMR-defined cases of Alzheimer or vascular dementia was high-positive predictive value (PPV) 86.4% and PPV 72.8%, respectively-and wGRS significantly predicted Alzheimer dementia (HR 1.23, 95% CI 1.12-1.34) but not vascular dementia (HR 1.02, 95% CI 0.91-1.15). Conversely, type 2 diabetes was strongly associated with vascular dementia (csHR 2.47, 95% C 1.92-3.18) but not Alzheimer dementia, particularly after competing risk of death was accounted for (sdHR 1.02, 95% CI 0.87-1.18).

CONCLUSIONS: Our study indicates that type 2 diabetes is associated with an increased risk of vascular dementia but not with an increased risk of Alzheimer dementia and highlights the potential value of bioresources linked to EMR to study dementia.

RevDate: 2019-08-08

Arroyo-Anlló EM, Dauphin S, Fargeau MN, et al (2019)

Music and emotion in Alzheimer's disease.

Alzheimer's research & therapy, 11(1):69 pii:10.1186/s13195-019-0523-y.

BACKGROUND: Alzheimer's disease may compromise several musical competences, though no clear data is available in the scientific literature. Furthermore, music is capable of communicating basic emotions, but little is known about the emotional aspect of music in patients with Alzheimer's disease. We present a systematic investigation of music processing in relation to extra-musical skills, in particular emotional skills in patients with Alzheimer's disease.

METHODS: We tested 30 patients with mild or moderate Alzheimer's disease and 30 control subjects. We essentially evaluated (a) musical competences, using the extra-linguistic test, Solfeggio test and the recognition test of musical emotions-elaborated by our research team-and the Seashore test, and (b) emotional capacities using emotional memory and emotional prosody tests-made by our research group.

RESULTS: We significantly observed lower total results of every test assessing cognitive, emotional and music competences in Alzheimer's disease patients than those in control subjects, but the score of musical emotion recognition test did not reach to a significant difference between the subjects groups.

CONCLUSIONS: Our findings found a global impairment of music competences in Alzheimer patients with cognitive and emotional troubles. Nevertheless, the performances in the recognition test of musical emotions showed a trend towards a performance difference. We can suggest that Alzheimer's disease currently presents an aphaso-agnoso-apractic-amusia syndrome.

RevDate: 2019-08-07

Caligiuri MP, L Mohammed (2019)

Signature dynamics in Alzheimer's disease.

Forensic science international, 302:109880 pii:S0379-0738(19)30293-2 [Epub ahead of print].

Forensic document examiners are often called upon to opine on the authenticity of handwritten signatures by individuals with diminished mental capacity. Legal arguments surrounding the decisional capacity of an individual with dementia can be found in many cases involving wills, deeds, trusts, and contracts. The purpose of this study was to provide estimates of feature variability derived from dynamic analyses of signatures written by individuals with dementia of the Alzheimer type (AD) compared with age-comparable healthy individuals. Dynamic features of digitally captured signatures were analyzed to test the hypothesis that AD signature features will show greater variability compared with signatures from age-comparable healthy subjects. The study enrolled 69 AD and 74 age comparable healthy subjects. Results revealed four main findings from AD signatures: (1) that the temporal, spatial and fluency characteristics of signature formation did not differ from signatures of healthy writers; (2) variability in dynamic features over a series of repetitive signatures fell within 10% of the natural variation of healthy subjects; (3) there was a significant association between increased dynamic signature feature variability and increased dementia severity for stylized and mixed signatures only; and (4) despite significant decline in cognitive status over a 1-year period, dynamic signature features remained stable. Overall, these results suggest that signature writing is preserved in AD. The association between dementia severity and dynamic feature variability among AD subjects with stylized or mixed signatures warrants further research.

RevDate: 2019-08-07

Dos Santos JPA, Vizuete AF, CA Gonçalves (2019)

Calcineurin-Mediated Hippocampal Inflammatory Alterations in Streptozotocin-Induced Model of Dementia.

Molecular neurobiology pii:10.1007/s12035-019-01718-2 [Epub ahead of print].

Although the pathogenesis of Alzheimer's disease (AD) remains unclear, some molecular aspects that precede or accompany the deposit of β-amyloid in senile plaques attract attention, such as calcium dysregulation and neuroinflammation. It has been suggested that the Ca2+/calmodulin-dependent protein phosphatase, calcineurin (CaN), plays an important role in AD pathogenesis. We hypothesized that CaN activation is involved in the inflammatory changes observed in the streptozotocin (STZ)-induced model of AD. We investigated hippocampal inflammatory and CaN changes in Wistar rats in two moments after intracerebroventricular STZ administration: in the first week (early) and fourth week (later on). We found an early (at 1 week) and persistent (at fourth week) increment in the subunit A of CaN, as well as an increase in the major 48 kDa fragment of this subunit. Glial and inflammatory activation were confirmed by changes of IBA-1, TLR-4, glial fibrillary acidic protein (GFAP), and S100B in the hippocampus. Augmented CaN activity was accompanied by reduced phosphorylation of the pro-apoptotic protein BAD, at Ser 136. Importantly, we found an increase in the nuclear translocation of NFAT4 (more associated to astroglial reactivity) in the hippocampus at 1 and 4 weeks in this model. NFAT3 (more associated with neuronal activation) exhibited an early increase, but decreased later on. Taken together, these data contribute to the understanding of neurochemical changes in the STZ model of sporadic AD, and may explain the persistent inflammatory response in AD, which might occur via the proteolytic activation of CaN, and signaling of NFAT mediated by isoform 4, in activated astrocytes.

RevDate: 2019-08-07

Schwarz AJ, Sundell KL, Charil A, et al (2019)

Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease.

Alzheimer's & dementia (New York, N. Y.), 5:328-337 pii:S2352-8737(19)30028-9.

Introduction: Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid β and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI).

Methods: In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants.

Results: Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3-6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously.

Discussion: In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

RevDate: 2019-08-07

Leake I (2019)

Crosstalk in Alzheimer disease.

Nature reviews. Neuroscience pii:10.1038/s41583-019-0209-2 [Epub ahead of print].

RevDate: 2019-08-07

Alvariño R, Alonso E, Abbasov ME, et al (2019)

Gracilin A derivatives target early events in Alzheimer's disease: in vitro effects on neuroinflammation and oxidative stress.

ACS chemical neuroscience [Epub ahead of print].

The search for compounds capable of targeting early pathological changes of Alzheimer`s disease (AD), such as oxidative stress and neuroinflammation, is an important challenge. Gracilin A derivatives were recently synthesized, using a pharmacophore-directed retrosynthesis strategy, and found to posses potent neuroprotective effects. In this work, the derivatives 21a, 27a, 27b, 29a, 21b, 22 and 23c (1-7) that had demonstrated mitochondrial-mediated, anti-oxidant effects, were chosen. The ability of compounds to modulate the expression of anti-oxidant genes (CAT, GPx, SOD's and Nrf2) was determined in SH-SY5Y cells, being the simplified derivatives 2 and 3 the most effective compounds. The anti-neuroinflammatory properties of derivatives were assessed in BV2 microglial cells activated with lipopolysaccharide (LPS). Derivatives decreased the release of cytokines (Il-1β, IL-6, GM-CSF and TNF-α) and other damaging molecules (ROS, NO). Compounds also regulated the translocation of Nrf2 and NFκB, and reduced p38 activation. These protective effects were confirmed in a trans-well co-culture with both cell lines, in which derivatives added to BV2 cells increased SH-SY5Y survival. This work provides new results that demonstrate the neuroprotective properties of gracilin A derivatives, making them promising candidate drugs for AD. Particularly, derivatives 2 and 3 showed the greatest potential as lead compounds for further development.

RevDate: 2019-08-06

Toepper M, M Falkenstein (2019)

Driving Fitness in Different Forms of Dementia: An Update.

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

BACKGROUND/OBJECTIVES: Most forms of dementia are associated with progressive cognitive and noncognitive impairments that can severely affect fitness to drive. Whether safe driving is still possible in the single case, however, is often difficult to decide and may be dependent on both severity and type of the respective dementia syndrome. Particularly in early disease stages, Alzheimer disease dementia (ADD) and different types of non-Alzheimer dementias, such as vascular dementia (VaD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and Parkinson disease dementia (PDD), might differentially affect fitness to drive.

DESIGN: To examine the effects of severity and type of dementia on driving fitness, we conducted a systematic review with qualitative narrative synthesis, involving different driving outcomes in different forms and stages of dementia.

SETTING: Literature research included MEDLINE and PsycINFO databases with a focus on the most relevant and recent publications on the topic.

PARTICIPANTS: The population of interest included older drivers in different stages of ADD and different forms of non-Alzheimer dementias (VaD, FTD, DLB, and PDD).

MEASUREMENTS: Narrative description of driving outcomes in the population of interest.

RESULTS: Overall, previous studies suggest that driving fitness is severely impaired in moderate and severe dementia, irrespective of the type of dementia. In milder disease stages, fitness to drive appears to be more severely impaired in non-Alzheimer dementias than in ADD, since the non-Alzheimer syndromes are not only associated with driving-relevant cognitive but noncognitive risk factors, such as behavioral or motor symptoms.

CONCLUSIONS: Based on these findings, practical recommendations are presented, including a risk evaluation for driving safety, depending on severity and type of different dementia syndromes.

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

Wang H, Sun R, Shi Y, et al (2019)

Probable novel PSEN1 Gln222Leu mutation in a Chinese family with early-onset Alzheimer's disease.

Current Alzheimer research pii:CAR-EPUB-100158 [Epub ahead of print].

Background:More and more people are suffering from Alzheimer's disease. However, there is still no significant breakthrough in the study of its etiology and pathogenesis. Objective:Screening for Alzheimer's disease pathogenic genes, which may be conducive to elucidation of the pathogenic mechanisms of Alzheimer's disease. Prediction of Pathogenicity by Various Computer Software. Method:Clinical and neuroimaging examination, Whole Exome Sequencing, and Sanger sequencing were performed in the proband, the mutation sites were verified in 158 subjects. Results:We report a proband carrying a probably novel pathogenic mutation, which clinically manifests as progressive memory loss, visual-spatial disorders, apraxia, psychobehavioral disorders, and temperamental and personality changes. Whole Exome Sequencing detected a novel missense mutation at codon 222 (Q222L), which is a heterozygous A to T point mutation at position 665 (c.665A>T) in exon 5 of the presenilin 1 leading to a glutamine-to- leucine substitution. The mutation was also identified by Sanger sequencing in one family member; nevertheless, it wasn't detected in the other 7 unaffected family members, 50 sporadic Alzheimer's disease patients and 100 control subjects. Conclusion:We reported a probably novel mutation in exon 5 of the presenilin 1 gene (Gln222Leu) in a Chinese family with early-onset Alzheimer's disease , besides,we predicted that the missense mutation was probably a novel pathogenic mutation that was reported for the first time in Chinese family with early-onset Alzheimer's disease.

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: 2019-08-07

Harrison IF, Whitaker R, Bertelli PM, et al (2019)

Correction to: Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia.

Acta neuropathologica communications, 7(1):127 pii:10.1186/s40478-019-0780-9.

In the original publication of this article [1], the funding acknowledgement for grant "Alzheimer Society Research Program (ASRP) from the Alzheimer Society of Canada" was missing.

RevDate: 2019-08-06

Guerdoux-Ninot E, Martin S, Jailliard A, et al (2019)

Validity of the French Prospective and Retrospective Memory Questionnaire (PRMQ) in healthy controls and in patients with no cognitive impairment, mild cognitive impairment and Alzheimer disease.

Journal of clinical and experimental neuropsychology [Epub ahead of print].

Introduction: The Prospective and Retrospective Memory Questionnaire (PRMQ) is one of the most commonly used scales to assess both retrospective memory (RM) and prospective memory (PM) complaints. This study aimed to: 1/replicate the previous results concerning the PRMQ latent structure in a French version and 2/provide its psychometric properties in a normal and clinical population. Method: This observational study included 488 participants divided into five subgroups. A sample of 168 healthy participants (no memory consultation sought), served as controls. Patients were recruited in a memory clinic: 98 "functional" patients (subjective memory complaints but no memory impairment), 83 amnestic-Mild Cognitive Impairment (a-MCI), 82 non-amnestic-MCI (na-MCI) and 57 Alzheimer Disease (AD) patients. Structure, validity, consistency, reliabilitiy and reproducibility of the PRMQ were calculated. Novelty, Area Under the Receiver-Operating Characteristics (AUROC) curve, was used to determine the optimal cut-off, to distinguish "functional" patients from control participants. Results: The optimal fit model of the French PMRQ was not a tri but a bi-partite model, with a RM and a PM subscale. The convergent validity showed significant correlation with cognitive difficulties (r = .82 and .78, respectively), anxiety (r = .44 and .48, respectively) and depression (r = .23) scales. Cronbach's alpha was good (α = .79 and .88), as well as the reproducibility (r = .71 and .80). The interaction [Subgroups of participants x PMRQ Subscales] was significant [F(4, 483) = 11.46; p < .001]. The power discrimination was adequate (AUROC = .71 and .74) for detecting "functional" patients compared with controls, in particular for the PM subscale (sensitivity 66.6%, specificity 77.4%). Conclusions: The PMRQ, with minor changes, was validated in its French form with satisfactory psychometric qualities. This self-rating tool appears useful for identifying significant memory complaints in a normal population and may also be helpful in discriminating between functional/na-MCI and a-MCI/AD patients.

RevDate: 2019-08-07

Tábuas-Pereira M, Durães J, Lopes J, et al (2019)

Increased CSF tau is associated with a higher risk of seizures in patients with Alzheimer's disease.

Epilepsy & behavior : E&B, 98(Pt A):207-209 pii:S1525-5050(19)30295-1 [Epub ahead of print].

INTRODUCTION: Neurofibrillary tangles and tau protein, the neuropathological hallmarks of Alzheimer's disease (AD), have been identified in patients with epilepsy. Tau protein was also associated with the modulation of neuronal excitability in animal models of AD.

MATERIALS AND METHODS: We evaluated in 292 patients with AD the association between the risk of seizure development and AD cerebrospinal fluid (CSF) biomarkers, demographic characteristics, baseline Mini-Mental State Examination (MMSE) score, comorbidities, and apolipoprotein E status.

RESULTS: The development of seizures was associated with younger age at dementia's onset, lower baseline MMSE, and higher CSF total tau protein levels, but only MMSE (hazard ratio [HR] = 0.935; 95% confidence interval [CI] = [0.903, 0.968]; p < 0.001) and CSF tau (HR = 1.001; 95%CI = [1.001, 1.002]; p = 0.001) were independent predictors on multivariate analysis.

DISCUSSION: While CSF tau and lower baseline MMSE association with seizure development could in part be explained by a greater degree of cortical damage, the role of tau in the modulation of neuronal excitability may also play a role and should be further investigated.

RevDate: 2019-08-05

Altinoz MA, Guloksuz S, Schmidt-Kastner R, et al (2019)

Involvement of hemoglobins in the pathophysiology of Alzheimer's disease.

Experimental gerontology pii:S0531-5565(19)30311-0 [Epub ahead of print].

Hemoglobins (Hbs) are heme-containing proteins binding oxygen, carbon monoxide, and nitric oxide. While erythrocytes are the most well-known location of Hbs, Hbs also exist in neurons, glia and oligodendroglia; and they are primarily localized in the inner mitochondrial membrane of neurons with likely roles in cellular respiration and buffering protons. Recently, studies have suggested links between hypoxia and neurodegenerative disorders such as Alzheimer Disease (AD) and furthermore suggested involvement of Hbs in the pathogenesis of AD. While cellular immunohistochemical studies on AD brains have observed reduced levels of Hb in the cytoplasm of pre-tangle and tangle-bearing neurons, other studies on homogenates of AD brain samples observed increased Hb levels. This potential discrepancy may result from differential presence and function of intracellular versus extracellular Hbs. Intracellular Hbs may protect neurons against hypoxia and hyperoxia. On the other hand, extracellular free Hb and its degradation products may trigger inflammatory immune and oxidative reactions against neural macromolecules and/or damage the blood-brain barrier. Therefore, biological processes leading to reduction of Hb transcription (including clinically silent Hb mutations) may influence intra-erythrocytic and neural Hbs, and reduce the transport of oxygen, carbon monoxide and nitric oxide which may involve in the (patho)physiology of neurodegenerative disorders such as AD. Agents such as erythropoietin, which stimulate both erythropoiesis, reduce eryptosis and induce intracellular neural Hbs may exert multiple beneficial effects on the onset and course of AD. Thus, evidence accumulates for a role of Hbs in the central nervous system while Hbs deserve more attention as possible candidate molecules involved in AD.

RevDate: 2019-08-05

Wang L, Liu J, Wang Q, et al (2019)

MicroRNA-200a-3p Mediates Neuroprotection in Alzheimer-Related Deficits and Attenuates Amyloid-Beta Overproduction and Tau Hyperphosphorylation via Coregulating BACE1 and PRKACB.

Frontiers in pharmacology, 10:806.

Alzheimer's disease (AD) is characterized by two landmark pathologies, the overproduction of amyloid-beta peptides (Aβ), predominated by the β-amyloid protein precursor cleaving enzyme 1 (BACE1), and hyperphosphorylation of the microtubule protein, tau, because of an imbalance in a kinase/phosphatase system that involves the activation of the protein kinase A (PKA). Current evidence indicates that brain microRNAs participate in multiple aspects of AD pathology. Here, the role and underlying molecular mechanisms of microRNA-200a-3p (miR-200a-3p) in mediating neuroprotection against AD-related deficits were investigated. The expression of miR-200a-3p was measured in the hippocampus of APP/PS1 and SAMP8 mice and in an AD cell model in vitro, as well as in blood plasma extracted from AD patients. The targets of miR-200a-3p were determined using bioinformatics and dual-luciferase assay analyses. In addition, cell apoptosis was detected using flow cytometry, and related protein levels were measured using Western blot and enzyme-linked immunosorbent assay (ELISA) techniques. miR-200a-3p was confirmed to be depressed in microarray miRNA profile analysis in vitro and in vivo, suggesting that miR-200a-3p is a potential biomarker of AD. Subsequently, miR-200a-3p was demonstrated to inhibit cell apoptosis accompanied by the inactivation of the Bax/caspase-3 axis and downregulation of Aβ1-42 and tau phosphorylation levels in vitro. Further mechanistic studies revealed that miR-200a-3p reduced the production of Aβ1-42 and decreased hyperphosphorylation of tau by regulating the protein translocation of BACE1 and the protein kinase cAMP-activated catalytic subunit beta (PRKACB) associated with the three prime untranslated regions, respectively. Importantly, the function of miR-200a-3p was reversed by overexpression of BACE1 or PRKACB in cultured cells. This resulted in an elevation in cell apoptosis and increases in Aβ1-42 and tau hyperphosphorylation levels, involving the epitopes threonine 205 and serine 202, 214, 396, and 356, the favorable phosphorylated sites of PKA. In conclusion, our study suggests that miR-200a-3p is implicated in the pathology of AD, exerting neuroprotective effects against Aβ-induced toxicity by two possible mechanisms: one involving the inhibition of Aβ overproduction via suppression of the expression of BACE1 and synergistically decreasing the hyperphosphorylation of tau via attenuation of the expression of PKA.

RevDate: 2019-08-05

Wajid S, Khatoon A, Khan MA, et al (2019)

Microwave-Assisted Organic Synthesis, structure-activity relationship, kinetics and molecular docking studies of non-cytotoxic benzamide derivatives as selective butyrylcholinesterase inhibitors.

Bioorganic & medicinal chemistry pii:S0968-0896(19)30927-7 [Epub ahead of print].

A series of benzamide derivatives 1-12 with various functional groups (-H, -Br, -F, -OCH3, -OC2H5, and -NO2) was synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) activity in vitro. Structure-activity relationship showed that the substitution of -Br group influenced the inhibitory activity against BCHE enzyme. Synthesized compounds were found to be selective inhibitors of BCHE. In addition, all compounds 1-12 were found to be non-cytotoxic, as compared to the standard cycloheximide (IC50 = 0.8 ± 0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ± 0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Enzyme kinetic studies indicated that compounds 1, 3-4, and 7-8 showed a mixed mode of inhibition against BCHE, while compounds 2, 5-6 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329, and many others.

RevDate: 2019-08-05

Castro A, Coria-Lucero C, Anzulovich A, et al (2019)

Effects of experimental intracerebral ventricular injection of amyloid beta peptide (1-42) aggregates on daily rhythms of Aβ-degrading enzymes in the hippocampus: Relevance to Alzheimer's disease pathophysiology.

Pathophysiology : the official journal of the International Society for Pathophysiology pii:S0928-4680(19)30008-2 [Epub ahead of print].

One of the main pathological features in the Alzheimer disease (AD) is the presence of senile plaques, primarily composed of Aβ peptide aggregates, in cortex and hippocampus. AD late onset, which constitutes 90% of cases, could be mainly attributable to deficiencies in the clearance of the Aß peptide. Here we show that expression of Aβ-degrading enzymes varies on a daily basis in the hippocampus. Interestingly, an intracerebroventricular injection of Aβ aggregates modified temporal patterns of Aβ-degrading proteases, as well as clock proteins (BMAL1 and RORα) and antioxidant enzymes (CAT and GPx) daily rhythms. Our findings showed that the increase of Aβ leads to the alteration of the enzymes involved in the clearance, and, consequently, to an increase of oxidative stress and alteration of the cellular redox state, affecting the functioning of the endogenous clock and daily rhythms of BMAL1, RORα and their target genes, in this disease.

RevDate: 2019-08-04

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.

TRIAL REGISTRATION NUMBER: DRKS00012748.

RevDate: 2019-08-04

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

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

Neurotoxicology 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: 2019-08-03

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 pii:S0006-291X(19)31429-9 [Epub ahead of print].

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: 2019-08-03

Ruiz F, Keeley A, Léglise P, et al (2019)

Sex Differences in Medicine Acceptability: A New Factor to Be Considered in Medicine Formulation.

Pharmaceutics, 11(8): pii:pharmaceutics11080368.

Palatability is a recognized driver of medicine acceptability in pediatrics but deemed less relevant in older populations due to sensory decline. Preliminary findings from an observational study implicated palatability problems with one Alzheimer's medicine. Among 1517 observer reports combining multiple measures on medicines uses in patients aged over 64, we focused on two original formulations of memantine (Ebixa®, tablets (n = 25) and oral solution (n = 60)). Evaluations were scored with an acceptability reference framework (CAST), the rodent Brief Access Taste Aversion (BATA) model tested aversiveness. Focusing on women treated with Ebixa® (n = 54), the oral formulation sub-group was classified as "negatively accepted", while the coated tablet was associated with the "positively accepted" cluster. In men, both formulations belonged to the "positively accepted" profile. Using BATA, the original oral solution was categorized as highly aversive/untolerated while solutions of excipients only were well tolerated. Furthermore, the number of licks was significantly lower in female than in male rats. These results revealed that medicine palatability remains important for acceptability in older populations. Moreover, converging results from humans and animal models highlighted that palatability profiles can significantly vary between the sexes. These drivers should be closely considered during drug development to enhance acceptability in this population.

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: 2019-08-02

Bendlin BB, H Zetterberg (2019)

Screening with a high precision blood-based assay for Alzheimer disease.

RevDate: 2019-08-02

Schindler SE, Bollinger JG, Ovod V, et al (2019)

High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis.

Neurology pii:WNL.0000000000008081 [Epub ahead of print].

OBJECTIVE: We examined whether plasma β-amyloid (Aβ)42/Aβ40, as measured by a high-precision assay, accurately diagnosed brain amyloidosis using amyloid PET or CSF p-tau181/Aβ42 as reference standards.

METHODS: Using an immunoprecipitation and liquid chromatography-mass spectrometry assay, we measured Aβ42/Aβ40 in plasma and CSF samples from 158 mostly cognitively normal individuals that were collected within 18 months of an amyloid PET scan.

RESULTS: Plasma Aβ42/Aβ40 had a high correspondence with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.88, 95% confidence interval [CI] 0.82-0.93) and CSF p-tau181/Aβ42 (AUC 0.85, 95% CI 0.79-0.92). The combination of plasma Aβ42/Aβ40, age, and APOE ε4 status had a very high correspondence with amyloid PET (AUC 0.94, 95% CI 0.90-0.97). Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 (<0.1218) had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40 (p = 0.01).

CONCLUSIONS: Plasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.

RevDate: 2019-08-02

Bateman JR, Filley CM, Kaplan RI, et al (2019)

Lifetime surgical exposure, episodic memory, and forniceal microstructure in older adults.

Journal of clinical and experimental neuropsychology [Epub ahead of print].

Introduction: Aging is associated with heterogeneous cognitive trajectories. There is considerable interest in identifying risk factors for pathological aging, with recent studies demonstrating a link between surgical procedures and proximal cognitive decline; however, the role of lifetime exposure to surgical procedures and cognitive function has been relatively unexplored. This pilot study aimed to evaluate the association between total lifetime surgical procedures and memory function in older adults. Methods: A cohort of 62 older adults underwent a neuropsychological evaluation and health history assessment. Self-reported lifetime surgical history was categorized as "cardiac" or "non-cardiac." General linear models were fit with demographics as nuisance covariates, and the total number of non-cardiac surgeries as our predictor of interest. Total scores on measures of episodic memory, language, working memory, fluency, and visuospatial function were separate outcome variables. In a secondary analysis, vascular risk factors were included as covariates. Diffusion tensor imaging was obtained for exploratory analyses of selected regions of interest. Results: The mean age of participants was 70, and 0-13 lifetime non-cardiac surgical procedures were reported. Higher numbers of lifetime non-cardiac surgical procedures were associated with worse verbal learning and memory (p = .04). The negative association between lifetime non-cardiac procedures and cognition was specific to memory. Exploratory analyses showed that higher number of lifetime non-cardiac procedures was related to lower FA in the fornix body (p = .02). Conclusions: These results of this pilot study suggest that greater lifetime exposure to surgery may be associated with worse verbal learning and memory in healthy older adults. These findings add to a growing body of literature suggesting that cumulative medical events may be risk factors for negative cognitive outcomes.

RevDate: 2019-08-02

Guo Y, Wei X, Yan H, et al (2019)

TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.

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

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α-synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α-synuclein (α-syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild-type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno-associated viral vectors expressing human α-syn (AAV-SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α-syn-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2-conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV-SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti-inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α-syn and exacerbates α-syn-induced neurodegeneration by modulating microglial activation state.-Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.

RevDate: 2019-08-01

Chhugani KJ, Metri K, Babu N, et al (2018)

Effects of Integrated Yoga Intervention on Psychopathologies and Sleep Quality Among Professional Caregivers of Older Adults With Alzheimer's Disease: A Controlled Pilot Study.

Advances in mind-body medicine, 32(3):18-22.

Context: Providing care to patients suffering from chronic neurological problems is a stressful job. While providing care to the patients, professional caregivers experience various kinds of physical and mental challenges that affect their mental health and sleep. Yoga is a form of mind-body medicine shown to be an effective intervention in improving physical and mental health.

Objective: To examine the effects of an integrated yoga (IY) intervention on anxiety, depression, stress, and sleep quality among professional caregivers of older adults with Alzheimer's disease.

Setting: This study was conducted in an Alzheimer care institution located in Bangalore City in southern India.

Participants: Participants were professional female caregivers of older adults with Alzheimer's disease. Participant age range was between 20 and 50 y (mean, 34 ± 8.4 y). A total of 30 participants were enrolled in the study. Seventeen participants followed IY intervention and 13 were considered in a wait-list group.

Intervention: Participants in the IY group received a structured IY intervention comprising yoga asanas, pranayama, meditation, and relaxation techniques, 1 h/d, 6 d/wk, for 1 mo. Participants in the wait-list control group followed their daily activities.

Outcome Measures: Blood pressure, heart rate, anxiety, depression, stress, and sleep quality were assessed at baseline after 1 mo for both the groups. Data were analyzed with an appropriate statistical test using SPSS Version 16 software (IBM, Armonk, NY, USA).

Results: The IY group showed significant improvement in heart rate, blood pressure, stress, depression, anxiety, and sleep quality after 1 mo compared with baseline. In contrast to the IY group, the wait-listed control group showed significant increase in anxiety, depression, and stress and significant decrease in sleep quality after 1 mo compared with baseline.

Conclusions: The present study showed the potential use of IY intervention in reducing stress, anxiety, and depression. The study also suggests that IY improves sleep quality among professional caregivers. However, further studies using a randomized controlled trial method with a larger sample size and for a longer duration should be conducted to confirm the present findings.

RevDate: 2019-08-07

Miles LA, Hermans SJ, Crespi GAN, et al (2019)

Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis.

iScience, 19:110-118 pii:S2589-0042(19)30248-2 [Epub ahead of print].

Polymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer disease (AD), and reduced expression of the CD33 sialic acid-binding domain confers protection. Thus, CD33 inhibition might be an effective therapy against disease progression. Progress toward discovery of selective CD33 inhibitors has been hampered by the absence of an atomic resolution structure. We report here the crystal structures of CD33 alone and bound to a subtype-selective sialic acid mimetic called P22 and use them to identify key binding residues by site-directed mutagenesis and binding assays to reveal the molecular basis for its selectivity toward sialylated glycoproteins and glycolipids. We show that P22, when presented on microparticles, increases uptake of the toxic AD peptide, amyloid-β (Aβ), into microglial cells. Thus, the sialic acid-binding site on CD33 is a promising pharmacophore for developing therapeutics that promote clearance of the Aβ peptide that is thought to cause AD.

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: 2019-08-01

Nilsson M, Jensen N, Gejl M, et al (2019)

Experimental non-severe hypoglycaemia substantially impairs cognitive function in type 2 diabetes: a randomised crossover trial.

Diabetologia pii:10.1007/s00125-019-4964-4 [Epub ahead of print].

AIMS/HYPOTHESIS: Previous studies have demonstrated a relationship between cognitive impairment and hypoglycaemia (<3 mmol/l). This study hypothesised that non-severe insulin-induced hypoglycaemia reduces cognitive function in individuals with type 2 diabetes.

METHODS: In this randomised crossover study, 25 participants with type 2 diabetes attended two experimental visits with hyperinsulinaemic glucose clamping: one hypoglycaemic clamp (plasma glucose 3.0 ± 0.2 mmol/l) and one euglycaemic clamp (plasma glucose 6.0 ± 0.2 mmol/l). Participants were eligible if their diabetes was treated with diet or glucose-lowering medications (except sulfonylureas or insulin), age was 35-70 years, BMI was 23-35 kg/m2 and HbA1c was below 75 mmol/mol (9%). Cognitive function was assessed with a neurocognitive test battery measuring verbal memory, executive function, sustained attention and psychomotor speed. From the examined cognitive domains, a global cognition score was constructed estimating global cognition. A measurement for psychomotor speed was selected as the primary outcome. Participants and people assessing the outcomes were blinded to group assignment.

RESULTS: Cognitive performance was impaired during hypoglycaemia with a mean score in the primary outcome test, Symbol Digit Modalities Test measuring psychomotor speed, of 48.7 ± 9.8 (hypoglycaemia) vs 56.6 ± 12.0 (euglycaemia); i.e. a change of -7.9 points (95% CI -10.9, -4.9; p < 0.0001). In addition, hypoglycaemia reduced global cognitive score by -0.7 (95% CI -0.9, -0.6; p < 0.0001). A stable glucose plateau was achieved during both experimental visits. For the hypoglycaemic clamp, mean plasma glucose concentration (± SD) during neurocognitive testing was 3.1 (± 0.3) mmol/l. Age, sex, fasting C-peptide, counter-regulatory hormones and the severity of hypoglycaemic symptoms did not influence cognitive function.

CONCLUSIONS/INTERPRETATION: Acute non-severe hypoglycaemia (mean plasma glucose 3.1 mmol/l) has a substantial negative impact on cognitive function in individuals with type 2 diabetes.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03014011.

FUNDING: The study was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp (MSD-MA-NORD-007-01). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. Funding was also received from Skibsreder Per Henriksen, R. og hustrus Foundation, The Danish Alzheimer Foundation and Savværksejer Jeppe Juhl og hustrus Foundation.

RevDate: 2019-08-01

Yamazaki Y, Zhao N, Caulfield TR, et al (2019)

Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.

Nature reviews. Neurology pii:10.1038/s41582-019-0228-7 [Epub ahead of print].

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

RevDate: 2019-08-01

Wolters FJ, Zonneveld HI, Licher S, et al (2019)

Hemoglobin and anemia in relation to dementia risk and accompanying changes on brain MRI.

Neurology pii:WNL.0000000000008003 [Epub ahead of print].

OBJECTIVE: To determine the long-term association of hemoglobin levels and anemia with risk of dementia, and explore underlying substrates on brain MRI in the general population.

METHODS: Serum hemoglobin was measured in 12,305 participants without dementia of the population-based Rotterdam Study (mean age 64.6 years, 57.7% women). We determined risk of dementia and Alzheimer disease (AD) (until 2016) in relation to hemoglobin and anemia. Among 5,267 participants without dementia with brain MRI, we assessed hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion.

RESULTS: During a mean follow-up of 12.1 years, 1,520 individuals developed dementia, 1,194 of whom had AD. We observed a U-shaped association between hemoglobin levels and dementia (p = 0.005), such that both low and high hemoglobin levels were associated with increased dementia risk (hazard ratio [95% confidence interval (CI)], lowest vs middle quintile 1.29 [1.09-1.52]; highest vs middle quintile 1.20 [1.00-1.44]). Overall prevalence of anemia was 6.1%, and anemia was associated with a 34% increased risk of dementia (95% CI 11%-62%) and 41% (15%-74%) for AD. Among individuals without dementia with brain MRI, similar U-shaped associations were seen of hemoglobin with white matter hyperintensity volume (p = 0.03), and structural connectivity (for mean diffusivity, p < 0.0001), but not with presence of cortical and lacunar infarcts. Cerebral microbleeds were more common with anemia. Hemoglobin levels inversely correlated to cerebral perfusion (p < 0.0001).

CONCLUSION: Low and high levels of hemoglobin are associated with an increased risk of dementia, including AD, which may relate to differences in white matter integrity and cerebral perfusion.

RevDate: 2019-08-06

Meusel LC, Greenwood CE, Maione A, et al (2019)

Cardiovascular risk and encoding-related hippocampal connectivity in older adults.

BMC neuroscience, 20(1):37 pii:10.1186/s12868-019-0518-4.

BACKGROUND: Cardiovascular conditions contribute to brain volume loss, reduced cerebrovascular health, and increased dementia risk in aging adults. Altered hippocampal connectivity has also been observed in individuals with cardiovascular conditions, yet the functional consequences of these changes remain unclear. In the present study, we collected functional magnetic resonance imaging data during memory encoding and used a psychophysiological interaction analysis to examine whether cardiovascular burden, indexed using the Framingham risk score, was associated with encoding-related hippocampal connectivity and task performance in cognitively-intact older adults between 65 and 85 years of age. Our goal was to better understand the early functional consequences of vascular and metabolic dysfunction in those at risk for cognitive decline.

RESULTS: High Framingham risk scores were associated with lower total brain volumes. In addition, those with high Framingham risk scores showed an altered relationship between left hippocampal-medial prefrontal coupling and task performance compared to those with low Framingham risk scores. Specifically, we found a significant interaction of Framingham risk and learning on connectivity between the left hippocampus and primarily left midline prefrontal regions comprising the left ventral anterior cingulate cortex and medial prefrontal cortex. Those with lower Framingham risk scores showed a pattern of weaker connectivity between left hippocampal and medial prefrontal regions associated with better task performance. Those with higher Framingham risk scores showed the opposite pattern; stronger connectivity was associated with better performance.

CONCLUSIONS: Findings from the current study show that amongst older adults with cardiovascular conditions, higher Framingham risk is associated with lower brain volume and altered left hippocampal-medial prefrontal coupling during task performance compared to those with lower Framingham risk scores. This may reflect a compensatory mechanism in support of memory function and suggests that older adults with elevated cardiovascular risk are vulnerable to early Alzheimer disease-like dysfunction within the episodic memory system.

RevDate: 2019-07-31

Nho K, Kueider-Paisley A, Ahmad S, et al (2019)

Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers.

JAMA network open, 2(7):e197978 pii:2740062.

Importance: Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD.

Objective: To examine whether liver function markers are associated with cognitive dysfunction and the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD.

In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019.

Exposures: Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables.

Main Outcomes and Measures: Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography.

Results: Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], -0.465 [0.180]; P = .02 for memory composite score; β [SE], -0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], -0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], -0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers).

Conclusions and Relevance: Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.

RevDate: 2019-08-05

Manço da Costa Bolson GC, Bezerra de Barros I, Volkmer-Ribeiro C, et al (2019)

Chemical Composition and Biological Activities of Metania and Drulia (Metaniidae) Freshwater Sponges from Amazonia.

Chemistry & biodiversity [Epub ahead of print].

Sponges from freshwater environments, unlike marine's, are poorly known producers of natural compounds with medicinal purposes. Amazonian sponges produce massive large specimens and are widely spread, taxonomically diverse and their metabolites could represent a new frontier on unusual natural products to treat diseases such as Alzheimer's and Malaria. Species of Metania and Drulia (Metaniidae) genera are major contributors to the fauna of Amazonian freshwater sponges. Methanolic extracts from several species from these genera had their inhibitory activities evaluated in vitro, for parasite Plasmodium falciparum and acetyl and butyrylcholinesterase enzymes (AChE and BChE). All extracts were able to inhibit AChE, although no activity was observed towards BChE. Drulia uruguayensis extract was the most potent, inhibiting AChE with IC50 =1.04 mg/mL. For antiplasmodial activity, all species showed inhibition to P. falciparum, but Metania reticulata being the most efficient with IC50 =2.7 μg/mL. Mass spectrometry analyses evidenced the presence of fatty acids and sterols in active extracts.

RevDate: 2019-07-31

Gurel B, Cansev M, Koc C, et al (2019)

Proteomics Analysis of CA1 Region of the Hippocampus in PRE-, Progression and Pathological Stages in a Mouse Model of the Alzheimer's Disease.

Current Alzheimer research pii:CAR-EPUB-100048 [Epub ahead of print].

BACKGROUND: CA1 subregion of the hippocampal formation is one of the primarily affected structures in AD, yet not much is known about proteome alterations in the extracellular milieu of this region.

OBJECTIVE: In this study, we aimed to identify the protein expression alterations throughout the pre-pathological, progression and pathological stages of AD mouse model.

METHOD: The CA1 region perfusates were collected by in-vivo intracerebral push-pull perfusion from transgenic 5XFAD mice and their non-transgenic littermates at 3, 6 and 12 months of age. Morris water maze test and immunohistochemistry staining of Aβ were performed to determine the stages of the disease in this mouse model. The protein expression differences were analyzed by label-free shotgun proteomics analysis.

RESULTS: A total of 251, 213 and 238 proteins were identified in samples obtained from CA1 regions of mice at 3, 6 and 12 months of age, respectively. Of these, 68, 41 and 33 proteins showed statistical significance. Pathway analysis based on the unique and common proteins within the groups revealed that several pathways are dysregulated during different stages of AD. The alterations in glucose and lipid metabolisms respectively in pre-pathologic and progression stages of the disease, lead to imbalances in ROS production via diminished SOD level and impairment of neuronal integrity.

CONCLUSION: We conclude that CA1 region-specific proteomic analysis of hippocampal degeneration may be useful in identifying the earliest as well as progressional changes that are associated with Alzheimer's disease.

RevDate: 2019-07-31

Lin L, Lv S, Liang J, et al (2019)

Level of knowledge about Alzheimer's Disease among nursing staff in Suzhou and its influencing factors.

Current Alzheimer research pii:CAR-EPUB-99979 [Epub ahead of print].

BACKGROUND: With the rapid aging process, an increasing number of individuals will be living with dementia worldwide. A good mastery of knowledge about Alzheimer's Disease (AD) by medical staff has been reported to improve the outcome of patients with AD, making it necessary to assess the level of AD knowledge among nursing staff and address their knowledge deficits in order to upgrade the quality of care and improve quality of life for AD patients.

OBJECTIVE: To assess the level of AD knowledge among nursing staff in Suzhou, using the Alzheimer's Disease Knowledge Scale (ADKS), and analyze its influencing factors.

METHOD: Nursing staff working in healthcare institutes such as hospitals, community centers, nursing homes, etc. in all six districts of Suzhou City were selected by convenience sampling. A self-designed questionnaire was used to collect general information of the participants, including gender, age, education, professional title, workplace, AD-related training, contact with AD patients, experience in caring for AD patients, etc., and the ADKS scale was used to assess their level of AD knowledge.

RESULTS: A total of 1102 in-service nursing staff in Suzhou were included in the study. Univariate analysis showed that age, education, professional titles, bias towards AD patients, AD-related training, contact with AD patients, experience in caring for AD patients were the influencing factors of the total ADKS score; multivariate analysis indicated that age, bias towards AD patients, contact with AD patients are independent influencing factors of the level of AD knowledge among nursing staff in Suzhou.

CONCLUSION: Mastery of AD knowledge among the nursing staff in Suzhou is not satisfactory. It is urgent to change the nursing staff's negative attitude towards AD and put into effect AD-related health education and training courses so that nursing staff can upgrade their level of AD knowledge and provide better care in order to improve the quality of life for AD patients.

RevDate: 2019-07-30

Schultz A, Kloet RW, Sohrabi HR, et al (2019)

Amyloid Imaging of Dutch-type Hereditary Cerebral Amyloid Angiopathy Carriers.

Annals of neurology [Epub ahead of print].

OBJECTIVES: To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh Compound B (PiB) can detect vascular ß-amyloid (Aß) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) mutation.

METHODS: PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB-PET in 19 D-CAA mutation carriers (M+; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation non-carriers (M-). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+, 8 M-). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aß concentrations in 17 M+ and 11 M- participants who underwent lumbar puncture and compared the findings to PiB-PET and CSF Aß in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers.

RESULTS: D-CAA M+ showed greater age-dependent FLR PiB retention (p<0.001) than M-, and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p=0.004). Among M+, greater FLR PiB retention associated with reduced CSF concentrations of Aß40 (r=-0.55, p=0.021) but not Aß42 (r=0.01, p=0.991). Despite comparably low CSF Aß40 and Aß42, PiB retention was substantially less in D-CAA than ADAD (p<0.001).

INTERPRETATION: Increased PiB retention in D-CAA and correlation with reduced CSF Aß40 suggest this compound labels vascular amyloid, though to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. This article is protected by copyright. All rights reserved.

RevDate: 2019-07-30

Ylilauri MPT, Voutilainen S, Lönnroos E, et al (2019)

Associations of dietary choline intake with risk of incident dementia and with cognitive performance: the Kuopio Ischaemic Heart Disease Risk Factor Study.

The American journal of clinical nutrition pii:5540729 [Epub ahead of print].

BACKGROUND: Moderate egg intake has been associated with better cognitive performance in observational studies. This association may be due to the rich content of choline, especially phosphatidylcholine, in eggs because choline has been suggested to have a role in the prevention of cognitive decline.

OBJECTIVES: We investigated the associations of dietary choline intake with the risk of incident dementia and with cognitive performance in middle-aged and older men in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study.

METHODS: A population-based sample of 2497 dementia-free men aged 42-60 y was examined in 1984-1989. A subset of 482 men completed 5 different cognitive performance tests 4 y later. Dementia and Alzheimer disease diagnoses were retrieved from Finnish health registers. Dietary intakes were assessed with the use of 4-d food records at baseline. Cox regression and ANCOVA were used for the analyses. All analyses were also stratified by the apolipoprotein E phenotype (APOE-ε4 compared with other phenotypes). These data were available for 1259 men.

RESULTS: The mean ± SD total choline intake was 431 ± 88 mg/d, of which 188 ± 63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%; P-trend = 0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations.

CONCLUSION: Higher phosphatidylcholine intake was associated with lower risk of incident dementia and better cognitive performance in men in eastern Finland. This trial was registered at clinicaltrials.gov as NCT03221127.

RevDate: 2019-08-02

Dumitrescu L, Mayeda ER, Sharman K, et al (2019)

Sex Differences in the Genetic Architecture of Alzheimer's Disease.

Current genetic medicine reports, 7(1):13-21.

Purpose of Review: Summarize sex-specific contributors to the genetic architecture of Alzheimer's disease (AD).

Recent Findings: There are sex differences in the effects of Apolipoprotein E (APOE), genes along the APOE pathway, and genes along the neurotrophic signaling pathway in predicting AD. Reported sex differences are largely driven by stronger associations among females. Evidence also suggests that genetic predictors of amyloidosis are largely shared across sexes, while sex-specific genetic effects emerge downstream of amyloidosis and drive the clinical manifestation of AD.

Summary: There is a lack of comprehensive assessments of sex differences in genome-wide analyses of AD and a need for more systematic reporting a sex-stratified genetic effects. The emerging emphasis on sex as a biological variable provides an opportunity for transdisciplinary collaborations aimed at addressing major analytical challenges that have hampered advancements in the field. Ultimately, sex-specific genetic association studies represent a logical first step towards precision medicine.

RevDate: 2019-07-30

Abduljabbar TN, Sharp BL, Reid HJ, et al (2019)

Determination of Zn, Cu and Fe in human patients' serum using micro-sampling ICP-MS and sample dilution.

Talanta, 204:663-669.

A high-throughput, sensitive and rapid method was developed for the determination of Zn, Cu and Fe in small volumes (30 μL) of human serum using inductively coupled plasma mass spectrometry (ICP-MS). The sample preparation procedure employed simple 100-fold dilution of the serum samples with 1.0% butanol, 0.5% v/v ammonia, 0.02% v/v Triton X-100 and 0.01% v/v HNO3. The reliability of the method was evaluated using serum UTAK certified reference material, and the results matched well with the certified values. The method was applied to determine Zn, Cu and Fe in 81 human serum samples from participants in Alzheimer disease (AD) and age-related macular degeneration (AMD) studies. No significant differences were found in Zn and Cu levels between age matched controls, AD and AMD patients. Whilst iron levels appeared marginally higher in the AMD group, compared with the AD group, iron showed larger overall variability than the other two elements.

RevDate: 2019-08-07

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 pii:S0166-4328(19)30924-6 [Epub ahead of print].

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

Anonymous (2019)

Yan-Jiang Wang, M.D., Ph.D and Xian-Le Bu, M.D., Ph.D., recipients of the 2019 Alzheimer Award.

Journal of Alzheimer's disease : JAD, 70(2):315-316.

RevDate: 2019-07-29

Reuben DB, Tan ZS, Romero T, et al (2019)

Patient and Caregiver Benefit From a Comprehensive Dementia Care Program: 1-Year Results From the UCLA Alzheimer's and Dementia Care Program.

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

BACKGROUND/OBJECTIVES: Persons with Alzheimer disease and related dementias (ADRDs) require comprehensive care that spans health systems and community-based organizations. This study examined the clinical outcomes of a comprehensive dementia care program and identified subgroups who were more likely to benefit.

DESIGN: Observational, baseline and 1 year after intervention.

SETTING: Urban, academic medical center.

PARTICIPANTS: A total of 554 persons with dementia and their caregivers who had 1-year follow-up evaluations and data on clinical outcomes.

INTERVENTION: Health system-based comprehensive dementia care management program using nurse practitioner dementia care managers.

MEASUREMENTS: Patient measures included the Mini-Mental State Examination (MMSE), the Functional Activities Questionnaire, Basic and Instrumental Activities of Daily Living scales, the Cornell Scale for Depression in Dementia, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity. Caregiver measures included the Modified Caregiver Strain Index, the Patient Health Questionnaire-9, NPI-Q Distress, and the Dementia Burden Scale-Caregiver). We used established minimal clinically important differences and lowest tertiles of baseline symptoms to define improving symptoms and maintaining low symptoms as clinical benefit for patients and caregivers.

RESULTS: At year 1, persons with ADRD improved on all scales, except MMSE and functional status measures; caregivers improved on all scales. Using validated instruments, 314/543 (58%) of patients, 282/447 (63%) of caregivers, and 376/501 (75%) of patients or caregivers demonstrated clinical benefit. In adjusted multivariate models, at year 1, more behavioral symptoms and fewer depression symptoms at baseline were associated with patient improvement; and fewer baseline depression symptoms were associated with maintaining low behavioral symptoms. Male caregiver sex, higher baseline caregiver burden, and caring for patients with fewer baseline depression symptoms were associated with caregiver improvement. Male caregiver sex and patients with fewer depression symptoms, fewer behavioral symptoms, and more functional impairment at baseline were associated with caregivers maintaining low burden at 1 year.

CONCLUSIONS: Health system-based comprehensive dementia care management is a promising approach to improving clinical outcomes, with benefits for both patients and caregivers.

RevDate: 2019-08-02

Pan X, Kaminga AC, Wen SW, et al (2019)

Dopamine and Dopamine Receptors in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

Frontiers in aging neuroscience, 11:175.

Background: The dopaminergic system has been associated with the progression of Alzheimer's disease. But previous studies found inconsistent results regarding the relationship between Alzheimer's disease and dopamine when looking at dopamine receptor concentrations. Objective: The aim of this review was to synthesize, using a random-effects model of meta-analysis, the link between the dopaminergic system and Alzheimer's disease. Methods: A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42018110798). Electronic databases of PubMed, Embase, Web of Science, and Psyc-ARTICLES were searched up to December 2018 for studies that examined dopamine and dopamine receptors in relation to Alzheimer's disease. Standardized mean differences (SMD) were calculated to assess group differences in the levels of dopaminergic neurometabolites. Results: Seventeen studies met the eligibility criteria. Collectively, they included 512 patients and 500 healthy controls. There were significantly lower levels of dopamine in patients with Alzheimer's disease compared with controls (SMD = -1.56, 95% CI: -2.64 to -0.49). In addition, dopamine 1 receptor (SMD = -5.05, 95% CI: -6.14 to -3.97) and dopamine 2 receptor (SMD = -1.13, 95% CI: -1.52 to -0.74) levels were decreased in patients with Alzheimer's disease compared with controls. The results of network meta-analysis indicated that the rank of correlation with Alzheimer's disease from highest to lowest was dopamine (0.74), dopamine 2 receptor (0.49), dopamine 3 receptor (0.46), dopamine 4 receptor (0.33), dopamine 5 receptor (0.31), and dopamine 1 receptor (0.64). Conclusions: Overall, decreased levels of dopaminergic neurotransmitters were linked with the pathophysiology of Alzheimer's disease. Nonetheless, there is a clear need for more prospective studies to validate these hypotheses.

RevDate: 2019-07-29

Sandhof CA, Hoppe SO, Druffel-Augustin S, et al (2019)

Reducing INS-IGF1 signaling protects against non-cell autonomous vesicle rupture caused by SNCA spreading.

Autophagy [Epub ahead of print].

Aging is associated with a gradual decline of cellular proteostasis, giving rise to devastating protein misfolding diseases, such as Alzheimer disease (AD) or Parkinson disease (PD). These diseases often exhibit a complex pathology involving non-cell autonomous proteotoxic effects, which are still poorly understood. Using Caenorhabditis elegans we investigated how local protein misfolding is affecting neighboring cells and tissues showing that misfolded PD-associated SNCA/α-synuclein is accumulating in highly dynamic endo-lysosomal vesicles. Irrespective of whether being expressed in muscle cells or dopaminergic neurons, accumulated proteins were transmitted into the hypodermis with increasing age, indicating that epithelial cells might play a role in remote degradation when the local endo-lysosomal degradation capacity is overloaded. Cell biological and genetic approaches revealed that inter-tissue dissemination of SNCA was regulated by endo- and exocytosis (neuron/muscle to hypodermis) and basement membrane remodeling (muscle to hypodermis). Transferred SNCA conformers were, however, inefficiently cleared and induced endo-lysosomal membrane permeabilization. Remarkably, reducing INS (insulin)-IGF1 (insulin-like growth factor 1) signaling provided protection by maintaining endo-lysosomal integrity. This study suggests that the degradation of lysosomal substrates is coordinated across different tissues in metazoan organisms. Because the chronic dissemination of poorly degradable disease proteins into neighboring tissues exerts a non-cell autonomous toxicity, this implies that restoring endo-lysosomal function not only in cells with pathological inclusions, but also in apparently unaffected cell types might help to halt disease progression. Abbreviations: AD: Alzheimer disease; BM: basement membrane; BWM: body wall muscle; CEP: cephalic sensilla; CLEM: correlative light and electron microscopy; CTNS-1: cystinosin (lysosomal protein) homolog; DA: dopaminergic; DAF-2: abnormal dauer formation; ECM: extracellular matrix; FLIM: fluorescence lifetime imaging microscopy; fps: frames per second; GFP: green fluorescent protein; HPF: high pressure freezing; IGF1: insulin-like growth factor 1; INS: insulin; KD: knockdown; LMP: lysosomal membrane permeabilization; MVB: multivesicular body; NOC: nocodazole; PD: Parkinson disease; RFP: red fluorescent protein; RNAi: RNA interference; sfGFP: superfolder GFP; SNCA: synuclein alpha; TEM: transmission electron microscopy; TNTs: tunneling nanotubes; TCSPC: time correlated single photon counting; YFP: yellow fluorescent protein.

RevDate: 2019-08-05

Szabo S, Lakzadeh P, Cline S, et al (2019)

The clinical and economic burden among caregivers of patients with Alzheimer's disease in Canada.

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

OBJECTIVE: To estimate the clinical and direct medical economic burden among Alzheimer disease (AD) caregivers using real-world, longitudinal patient-level data in Canada.

METHODS/DESIGN: This retrospective observational study assessed the clinical and direct medical economic burden among individuals who cohabitate with AD patients ("AD caregiver cohort") compared with older adults who were cohabiting with another adult without dementia ("comparison cohort") using real-world data from the Southwestern Ontario database, a representative Canadian electronic health record (EHR) longitudinal EHR.

RESULTS: The AD caregiver cohort (n = 2749; mild AD: n = 2254, moderate AD: n = 302, and severe AD, n = 193) had a similar or higher level of clinical and economic burden than the comparison cohort (n = 12 152). The overall AD cohort and caregivers of patients with mild AD had a similar clinical burden to the comparison cohort. Those caregiving for more severely affected AD patients had an increased risk of comorbidities and required more medication, physician attention, and hospital encounters compared with caregivers of less severe AD patients and the comparison cohort. Mean annual costs were higher among the AD caregiver cohort than the comparison cohort, and those caregiving for moderate and severe AD patients incurred the highest costs. Overall mortality was higher in the AD caregiver cohort compared with the comparison cohort.

CONCLUSIONS: Caregivers of patients with mild AD had a similar clinical and direct economic burden to older adults who were not dementia caregivers, whereas the burden among caregivers of moderate and severe AD patients was much greater.

RevDate: 2019-07-30

Pérez-Areales FJ, Turcu AL, Barniol-Xicota M, et al (2019)

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors.

European journal of medicinal chemistry, 180:613-626 pii:S0223-5234(19)30672-5 [Epub ahead of print].

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.

RevDate: 2019-08-07

Potvin O, Chouinard I, Dieumegarde L, et al (2019)

The Canadian Dementia Imaging Protocol: Harmonization validity for morphometry measurements.

NeuroImage. Clinical, 24:101943 pii:S2213-1582(19)30293-1 [Epub ahead of print].

The harmonized Canadian Dementia Imaging Protocol (CDIP) has been developed to suit the needs of a number of co-occurring Canadian studies collecting data on brain changes across adulthood and neurodegeneration. In this study, we verify the impact of CDIP parameters compliance on total brain volume variance using 86 scans of the same individual acquired on various scanners. Data included planned data collection acquired within the Consortium pour l'identification précoce de la maladie Alzheimer - Québec (CIMA-Q) and Canadian Consortium on Neurodegeneration in Aging (CCNA) studies, as well as opportunistic data collection from various protocols. For images acquired from Philips scanners, lower variance in brain volumes were observed when the stated CDIP resolution was set. For images acquired from GE scanners, lower variance in brain volumes were noticed when TE/TR values were within 5% of the CDIP protocol, compared to values farther from that criteria. Together, these results suggest that a harmonized protocol like the CDIP may help to reduce neuromorphometric measurement variability in multi-centric studies.

RevDate: 2019-07-27

Pascual B, Funk Q, Zanotti-Fregonara P, et al (2019)

Multimodal 18F-AV-1451 and MRI findings in non-fluent variant primary progressive aphasia: possible insights on nodal propagation of tau protein across the syntactic network.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.118.225508 [Epub ahead of print].

Although abnormally folded tau protein has been found to self-propagate from neuron to connected neuron, similar propagation through human brain networks has not been fully documented. We studied tau propagation in the left-hemispheric syntactic network, which is composed of an anterior frontal node and a posterior temporal node, connected by the white matter of the left arcuate fasciculus. This network is affected in non-fluent variant primary progressive aphasia, a neurodegenerative disorder with tau accumulation. Methods: Eight patients with non-fluent variant primary progressive aphasia (age 67.0 ± 7.4 years, 4 women) and eight healthy controls (age 69.6 ± 7.0 years, 4 women) were scanned with 18F-AV-1451 tau PET, to determine tau deposition in the brain, and with MRI, to determine the fractional anisotropy of the arcuate fasciculus. Normal syntactic network characteristics were confirmed with structural MRI diffusion imaging in our healthy controls and with BOLD functional imaging in 35 healthy participants from the Alzheimer's Disease Neuroimaging Initiative database. Results: Language scores in patients indicated dysfunction of the anterior node. 18F-AV-1451 deposition was greatest in the two nodes of the syntactic network. The left arcuate fasciculus had decreased fractional anisotropy, particularly near the anterior node. Normal MRI structural connectivity from an area similar to the one containing tau in the anterior, frontal, node projected to an area similar to the one containing tau in the patients, in the posterior, temporal, node. Conclusion: Tau accumulation likely started in the more affected anterior node and, at the stage of the disease when we studied these patients, appeared as well in the brain region, in the temporal lobe, spatially separate but most connected with it. The arcuate fasciculus, connecting both of them, was most severely affected anteriorly, as would correspond to the loss of axons from the anterior node. These findings are suggestive of tau propagation from node to connected node in a natural human brain network and lend support to the idea that neurons that wire together, die together.

RevDate: 2019-08-06

Lee J, Cho E, Kwon H, et al (2019)

The fruit of Crataegus pinnatifida ameliorates memory deficits in β-amyloid protein-induced Alzheimer's disease mouse model.

Journal of ethnopharmacology, 243:112107 pii:S0378-8741(19)30552-5 [Epub ahead of print].

The fruit of Crataegus pinnatifida is a traditional medicine widely used as digestive drug in East Asia. Although Chinese herbal medicine used it for mental health, scientific evidence does not exist, yet.

AIMS OF STUDY: The aim of this study is to show that the ethanol extract of the fruit of Crataegus pinnatifida (CPE) has neuroprotective effect on Alzheimer' disease model mice.

MATERIALS AND METHODS: Intracerebroventricular injection of Aβ was used to induce Alzheimer's disease-like pathology. Passive avoidance and Y-maze tasks were used to examine the effect of CPE on memory impairments by Aβ. Immunohistochemistry was used to examine the effect of CPE on glial activation. ThT assay was used to observe the effect of CPE on Aβ aggregation. MTT and LDH release assays were utilized to examine effects of CPE on Aβ-induced cytotoxicity.

RESULTS: CPE prevented memory deficit in Aβ-induced memory impairment model. Moreover, CPE prevented glial activation in the hippocampus of Aβ-injected model. In in vitro test, CPE inhibited Aβ fibril formation in a concentration-dependent manner. CPE also caused disaggregation of Aβ fibrils. Along with this, CPE blocked neuronal cell death induced by Aβ.

CONCLUSIONS: Collectively, these experimental findings demonstrated that CPE could be a candidate for development of AD therapy.

RevDate: 2019-07-26

Fang Y, Du N, Xing L, et al (2019)

Evaluation of hippocampal volume and serum brain-derived neurotrophic factor as potential diagnostic markers of conversion from amnestic mild cognitive impairment to Alzheimer disease: A STROBE-compliant article.

Medicine, 98(30):e16604.

Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal aging and Alzheimer disease (AD), and is associated with an increased risk of AD. Many studies have shown that apolipoprotein E epsilon 4 (APOE ε4) genotype is a major genetic predictor of AD progression, especially in patients with aMCI. However, the application of APOE genotyping in the diagnosis of MCI progressing to AD is limited by its low sensitivity and specificity, which often leads to high false-positive rate. The aim of this study was to evaluate serum brain-derived neurotrophic factor (BDNF) and hippocampal volume as predictors of aMCI to AD transition in APOE ε4 genotype patients.A total of 178 subjects were diagnosed with aMCI. The patients with aMCI that progressed to AD within 2 years were included in the MCI-AD group (n = 86), those maintaining an aMCI diagnosis after 2 years were placed in the MCI-MCI group (n = 92), and neurologically healthy age-matched individuals were set as controls (n = 90). APOE genotypes were determined. Blood samples from all subjects were drawn at baseline, 12 months, and 24 months for serum BNDF assessments. Hippocampal delineations were monitored by magnetic resonance imaging.Compared to control group, aMCI-AD patients (the patients with aMCI that progressed to AD within 2 years) exhibited worse performance on cognitive and neuropsychological batteries. Meanwhile, we found that aMCI-AD patients were associated with abnormally low serum BDNF level and greater hippocampal volume loss than MCI-MCI patients (patients maintaining an aMCI diagnosis after 2 years). Moreover, patients with aMCI who were carriers of APOE ε4 showed a notable decrease in serum BDNF and a significant reduction in hippocampal volume, especially in those who progressed to AD.The present study demonstrates that aMCI that evolves into AD in patients with the APOE ε4 genotype may be predicted by hippocampal volume and serum BDNF.

RevDate: 2019-07-26

Zukotynski K, Gaudet V, Kuo PH, et al (2019)

The Use of Random Forests to Classify Amyloid Brain PET.

Clinical nuclear medicine [Epub ahead of print].

PURPOSE: To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification.

METHODS: The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB.

RESULTS: A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees).

CONCLUSIONS: Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

RevDate: 2019-07-26

Atatreh N, Al Rawashdah S, Al Neyadi SS, et al (2019)

Discovery of new butyrylcholinesterase inhibitors via structure-based virtual screening.

Journal of enzyme inhibition and medicinal chemistry, 34(1):1373-1379.

Butyrylcholinesterase (BChE) plays an important role in the progression of the Alzheimer's disease. In this study, we used a structure-based virtual screening (VS) approach to discover new BChE inhibitors. A ligand database was filtered and docked to the BChE protein using Glide program. The outcome from VS was filtered and the top ranked hits were thoroughly examined for their fitting into the protein active site. Consequently, the best 38 hits were selected for in vitro testing using Ellman's method, and six of which showed inhibition activity for BChE. Interestingly, the most potent hit (Compound 4) exhibited inhibitory activity against the BChE enzyme in the low micromolar level with an IC50 value of 8.3 µM. Hits obtained from this work can act as a starting point for future SAR studies to discover new BChE inhibitors as anti-Alzheimer agents.

RevDate: 2019-07-26

Khan S, Deshmukh R, Bariwal J, et al (2019)

Phosphodietrase Inhibitors As Molecular Marker For Inflammatory Disease: An Overview.

Current molecular pharmacology pii:CMP-EPUB-99967 [Epub ahead of print].

BACKGROUND: Phosphodiesterase (PDE) inhibitors are counted as biochemical agents which increases the level of cyclic nucleotides (cAMP and cGMP) by PDE inhibition. The pharmacological actions of PDE inhibitors to treat various ailments like Alzheimer disease (AD), Parkinson disease (PD), Asthma, Erectile dysfunction and various inflammatory disorders like Rheumatoid Arthritis (RA) are very significant.

OBJECTIVE: The present work summarizes up-to date information on various PDE inhibitors and their role to treat various disease conditions like RA and recent advancement related with this.

METHODS: The article is presented upon study and findings of various books, literature from online sources including Google scholar, web of science, SciFinder etc. Results: The findings suggested that RA is the chronic inflammatory disease condition, in which imbalance in immune system is generally observed. Since last several years, PDE inhibitors are counted as important biochemical to treat various diseases and therefore PDE inhibitors are in great demand.

CONCLUSION: The present paper covers the pathophysiology, diseases progression, etiology of diseases associated with PDE etc.

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: 2019-07-26

Santangelo R, Dell Edera A, Sala A, et al (2019)

The CSF p-tau181/Aβ42 Ratio Offers a Good Accuracy "in Vivo" in the Differential Diagnosis of Alzheimer's Dementia.

Current Alzheimer research pii:CAR-EPUB-99972 [Epub ahead of print].

BACKGROUND: The incoming disease-modifying therapies against Alzheimer's disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed a good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption.

METHODS: We measured CSF AD biomarkers' concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG- PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings.

RESULTS: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy.

CONCLUSIONS: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost- effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid enrolment of misdiagnosed AD patients.

RevDate: 2019-08-07

Calderón-Garcidueñas L, González-Maciel A, Mukherjee PS, et al (2019)

Combustion- and friction-derived magnetic air pollution nanoparticles in human hearts.

Environmental research, 176:108567 pii:S0013-9351(19)30364-0 [Epub ahead of print].

Air pollution is a risk factor for cardiovascular and Alzheimer's disease (AD). Iron-rich, strongly magnetic, combustion- and friction-derived nanoparticles (CFDNPs) are abundant in particulate air pollution. Metropolitan Mexico City (MMC) young residents have abundant brain CFDNPs associated with AD pathology. We aimed to identify if magnetic CFDNPs are present in urbanites' hearts and associated with cell damage. We used magnetic analysis and transmission electron microscopy (TEM) to identify heart CFDNPs and measured oxidative stress (cellular prion protein, PrPC), and endoplasmic reticulum (ER) stress (glucose regulated protein, GRP78) in 72 subjects age 23.8 ± 9.4y: 63 MMC residents, with Alzheimer Continuum vs 9 controls. Magnetite/maghemite nanoparticles displaying the typical rounded crystal morphologies and fused surface textures of CFDNPs were more abundant in MMC residents' hearts. NPs, ∼2-10 × more abundant in exposed vs controls, were present inside mitochondria in ventricular cardiomyocytes, in ER, at mitochondria-ER contact sites (MERCs), intercalated disks, endothelial and mast cells. Erythrocytes were identified transferring 'hitchhiking' NPs to activated endothelium. Magnetic CFDNP concentrations and particle numbers ranged from 0.2 to 1.7 μg/g and ∼2 to 22 × 109/g, respectively. Co-occurring with cardiomyocyte NPs were abnormal mitochondria and MERCs, dilated ER, and lipofuscin. MMC residents had strong left ventricular PrPC and bi-ventricular GRP78 up-regulation. The health impact of up to ∼22 billion magnetic NPs/g of ventricular tissue are likely reflecting the combination of surface charge, ferrimagnetism, and redox activity, and includes their potential for disruption of the heart's electrical impulse pathways, hyperthermia and alignment and/or rotation in response to magnetic fields. Exposure to solid NPs appears to be directly associated with early and significant cardiac damage. Identification of strongly magnetic CFDNPs in the hearts of children and young adults provides an important novel layer of information for understanding CVD pathogenesis emphasizing the urgent need for prioritization of particulate air pollution control.

RevDate: 2019-07-25

Rochoy M, Bordet R, Gautier S, et al (2019)

Factors associated with the onset of Alzheimer's disease: Data mining in the French nationwide discharge summary database between 2008 and 2014.

PloS one, 14(7):e0220174 pii:PONE-D-18-33071.

INTRODUCTION: Identifying modifiable risk factors for Alzheimer's disease (AD) is critical for research. Data mining may be a useful tool for finding new AD associated factors.

METHODS: We included all patients over 49 years of age, hospitalized in France in 2008 (without dementia) and in 2014. Dependent variable was AD or AD dementia diagnosis in 2014. We recoded the diagnoses of hospital stays (in ICD-10) into 137 explanatory variables.To avoid overweighting the "age" variable, we divided the population into 7 sub-populations of 5 years.

RESULTS: We analyzed 1,390,307 patients in the PMSI in 2008 and 2014: 55,997 patients had coding for AD or AD dementia in 2014 (4.04%). We associated Alzheimer disease in 2014 with about 20 variables including male sex, stroke, diabetes mellitus, mental retardation, bipolar disorder, intoxication, Parkinson disease, depression, anxiety disorders, alcohol, undernutrition, fall and 3 less explored variables: intracranial hypertension (odd radio [95% confidence interval]: 1.16 [1.12-1.20] in 70-80 years group), psychotic disorder (OR: 1.09 [1.07-1.11] in 70-75 years group) and epilepsy (OR: 1.06 [1.05-1.07] after 70 years).

DISCUSSION: We analyzed 137 variables in the PMSI identified some well-known risk factors for AD, and highlighted a possible association with intracranial hypertension, which merits further investigation. Better knowledge of associations could lead to better targeting (identifying) at-risk patients, and better prevention of AD, in order to reduce its impact.

RevDate: 2019-07-25

Sepassi A, JH Watanabe (2019)

Emergency Department Visits for Psychotropic-Related Adverse Drug Events in Older Adults With Alzheimer Disease, 2013-2014.

The Annals of pharmacotherapy [Epub ahead of print].

Background: More than 1.3 million emergency department visits have been associated with adverse drug events (ADEs) in older adults. Increasing Alzheimer's disease (AD) prevalence in the geriatric population poses an additive risk of ADEs because of the array of psychotropic medications prescribed for AD patients. Scant research has been conducted at a nationwide level on psychotropic-related ADEs in this population. Objective: This study aimed to determine the incidence and economic burden of psychotropic ADEs in the geriatric AD population compared with the non-AD geriatric population. Methods: A retrospective analysis was conducted of geriatric AD patients who visited the ED in 2013 with a psychotropic-related ADE to determine the incidence and resource utilization of these events. The relationship between presence of AD and an ADE was analyzed using multiple logistic regression. Results: There were 427 969 Alzheimer's ED visits compared with 20 492 554 ED visits without. Of the AD cases, 1.04% were associated with at least 1 adverse event. AD cases more frequently were admitted as inpatients (64.90% vs 34.92%, P < 0.01). Common drug classes associated with AD-related ADEs were benzodiazepines, antipsychotics, and autonomic nervous system-affecting agents (adrenergic agonists, antimuscarinic agents, anticholinergic agents). There was a significantly higher likelihood for Alzheimer's cases to experience any psychotropic-related adverse event (OR = 1.66; 95% CI = 1.20, 1.82). Conclusion and Relevance: Alzheimer's patients more frequently experienced psychotropic-related adverse events and related adverse outcomes than older adults without Alzheimer's. Application of these findings should be implemented in protocol development to reduce future psychotropic-related adverse outcomes for this population.

RevDate: 2019-07-28

McDermott CL, DA Gruenewald (2019)

Pharmacologic Management of Agitation in Patients with Dementia.

Current geriatrics reports, 8(1):1-11.

Purpose of Review: Agitation is common among older adults with dementia; its origin may be multi-factorial, and it is often difficult to treat. In this paper, we summarize current knowledge and offer considerations on pharmacologic management of behavioral and psychological symptoms of dementia (BPSD).

Recent Findings: We reviewed human studies published from 2013 to 2018 evaluating pharmacologic management of BPSD manifestations including depressive symptoms, mania, psychosis, and other BPSD, as well as severe agitation without determination of underlying cause. After non-pharmacological management is exhausted, the choice of pharmacological options depends on patient comorbidities, specific BPSD presentation, and patient tolerance of medications.

Summary: Depending on manifestations of BPSD, low- to moderate-quality evidence supports the use of anti-depressants, anti-psychotics, or anti-epileptics in conjunction with cholinesterase inhibitors. The current evidence base needs to be augmented with future research that focuses on real-world medication use alongside head-to-head evaluation of medication effectiveness rather than comparison to placebo.

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: 2019-07-24

Hooshmand B, Refsum H, Smith AD, et al (2019)

Association of Methionine to Homocysteine Status With Brain Magnetic Resonance Imaging Measures and Risk of Dementia.

JAMA psychiatry pii:2738056 [Epub ahead of print].

Importance: Impairment of methylation status (ie, methionine to homocysteine ratio) may be a modifiable risk factor for structural brain changes and incident dementia.

Objective: To investigate the association of serum markers of methylation status and sulfur amino acids with risk of incident dementia, Alzheimer disease (AD), and the rate of total brain tissue volume loss during 6 years.

This population-based longitudinal study was performed from March 21, 2001, to October 10, 2010, in a sample of 2570 individuals aged 60 to 102 years from the Swedish Study on Aging and Care in Kungsholmen who were dementia free at baseline and underwent comprehensive examinations and structural brain magnetic resonance imaging (MRI) on 2 to 3 occasions during 6 years. Data analysis was performed from March 1, 2018, to October 1, 2018.

Main Outcomes and Measures: Incident dementia, AD, and the rate of total brain volume loss.

Results: This study included 2570 individuals (mean [SD] age, 73.1 [10.4] years; 1331 [56.5%] female). The methionine to homocysteine ratio was higher in individuals who consumed vitamin supplements (median, 1.9; interquartile range [IQR], 1.5-2.6) compared with those who did not (median, 1.8; IQR, 1.3-2.3; P < .001) and increased per each quartile increase of vitamin B12 or folate. In the multiadjusted model, an elevated baseline serum total homocysteine level was associated with an increased risk of dementia and AD during 6 years: for the highest homocysteine quartile compared with the lowest, the hazard ratios (HRs) were 1.60 (95% CI, 1.01-2.55) for dementia and 2.33 (95% CI, 1.26-4.30) for AD. In contrast, elevated concentrations of methionine were associated with a decreased risk of dementia (HR, 0.54; 95% CI, 0.36-0.81) for the highest quartile compared with the lowest. Higher values of the methionine to homocysteine ratio were significantly associated with lower risk of dementia and AD: for the fourth methionine-homocysteine quartile compared with the first quartile, the HR was 0.44 (95% CI, 0.27-0.71) for incident dementia and 0.43 (95% CI, 0.23-0.80) for AD. In the multiadjusted linear mixed models, a higher methionine to homocysteine ratio was associated with a decreased rate of total brain tissue volume loss during the study period (β [SE] per 1-SD increase, 0.038 [0.014]; P = .007).

Conclusions and Relevance: The methionine to homocysteine status was associated with dementia development and structural brain changes during the 6-year study period, suggesting that a higher methionine to homocysteine ratio may be important in reducing the rate of brain atrophy and decreasing the risk of dementia in older adults.

RevDate: 2019-07-26

Gialluisi A, Di Castelnuovo A, Donati MB, et al (2019)

Machine Learning Approaches for the Estimation of Biological Aging: The Road Ahead for Population Studies.

Frontiers in medicine, 6:146.

In recent years, different machine learning algorithms have been developed for the estimation of Biological Age (BA), defined as the hypothetical underlying age of an organism. BA can be computed based on different circulating and non-circulating biomarkers. In this perspective, identifying biomarkers with a prominent influence on BA and developing reliable models for its estimation is of fundamental importance for monitoring healthy aging, and could provide new tools to screen health status and the risk of clinical events in the general population. Here, we briefly review the different machine learning (ML) approaches used for BA estimation, focusing on those methods with potential application to the Moli-sani study, a prospective population-based cohort study of 24,325 subjects (35-99 years). In particular, we discuss the potential of BA estimation based on blood biomarkers, which likely represents the easiest and most immediate way to compute organismal BA. Similarly, we describe ML methods for the estimation of brain age based on structural neuroimaging features. For each method, we discuss the relation with epidemiological variables (e.g., mortality), genetic and environmental factors, and common age-related diseases (e.g., Alzheimer disease), to examine the potential as aging biomarker in the general population. Finally, we hypothesize new approaches for BA estimation, both at the single organ and at the whole organism level. Overall, here we trace the road ahead in the Big Data era for our and other prospective general population cohorts, presenting ways to exploit the notable amount of data available nowadays.

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

Salcedo-Tacuma D, Melgarejo JD, Mahecha MF, et al (2019)

Differential Methylation Levels in CpGs of the BIN1 Gene in Individuals With Alzheimer Disease.

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

INTRODUCTION: Late-onset Alzheimer disease (LOAD) is the most common dementia worldwide. APOE-[Latin Small Letter Open E]4 and BIN1 (Bridging Integrator 1) have been implicated in the pathogenesis of this disease, but, although DNA methylation of dinucleotide CpGs in the BIN1 gene influences alterations, it has not been studied in Hispanics.

OBJECTIVE: The objective of this study was to evaluate the BIN1 3' intergenic region DNA methylation patterns in a Colombian sample of LOAD patients.

METHODS: A case-control study was conducted in 50 individuals with LOAD and 50 age-sex matched controls to determine associations of LOAD with DNA methylation. DNA was isolated from peripheral blood, and methylation levels of 8 CpGs were estimated by bisulfite conversion followed by Sanger sequencing with direct PCR analysis. Logistic regression models adjusted by age, sex, and APOE were used to calculate risk associations between methylation levels and LOAD.

RESULTS: Overall, participants with LOAD had significantly lower methylation levels on CpG26 (0.86±0.11 vs. 0.95±0.05; P>0.001), CpG44 (0.84±0.09 vs. 0.94±0.06; P=0.001), and CpG87 (0.64±0.12 vs. 0.82±0.10; P>0.001). Adjusted regression models showed that decreased methylation levels of these CpGs remained as risk factors for LOAD (P<0.05).

CONCLUSIONS: Hypomethylation of CpGs in BIN1 might play an important role in the expression of BIN1 and may be a biomarker for identifying individuals at high risk of developing LOAD.

RevDate: 2019-07-23

Bardach SH, Benton B, Walker C, et al (2019)

Perspectives of African American Older Adults on Brain Health: "Brains Get Tired Too".

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

BACKGROUND: Statistics suggest that African Americans have a disproportionately high prevalence of Alzheimer disease (AD), yet are less likely to enroll in AD clinical trials than white individuals. Although research has previously identified various barriers to participation, relatively little is known about how to overcome these barriers and engage African American individuals in AD research. The purpose of this study is to better understand how African Americans conceptualize brain health and their ability to influence healthy brain aging.

METHODS: Three African American community advocates each facilitated a small group of African American participants over 8 to 10 sessions of a photovoice process involving discussion and sharing of images focused on brain health. Sessions were audiotaped and transcribed verbatim and photographs were uploaded.

FINDINGS: Participants recognized a diversity of what brain health can mean and indicated an interconnectedness between brain health and its influences. Key factors that were identified by group members as key to brain health included lifestyle factors, activity, and engagement and nature, resiliency, and positivity.

DISCUSSION: These emic insights into perceptions of brain health may represent important foci for targeted messaging strategies to promote brain health and research engagement within the African American population.

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RJR Experience and Expertise

Researcher

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.

Educator

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.

Administrator

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.

Technologist

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.

Publisher

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.

Speaker

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.

Facilitator

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.

Designer

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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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

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