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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 07 Dec 2019 at 01:32 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: 2019-12-06

Panayiotou E, Fella E, Andreou S, et al (2019)

C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aβ amyloid and preserves memory in a mouse model of familial Alzheimer's disease.

PloS one, 14(12):e0225417 pii:PONE-D-19-19628.

According to the amyloid hypothesis of Alzheimer's disease (AD) the deposition of prefibrillar and fibrillar Aβ peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aβ peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aβ peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aβ peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aβ, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease.

RevDate: 2019-12-06

Shamim SA, Warriach ZI, Tariq MA, et al (2019)

Insomnia: Risk Factor for Neurodegenerative Diseases.

Cureus, 11(10):e6004.

Insomnia can be defined as difficulty falling asleep or maintaining sleep, waking up earlier than expected, or having non-restorative sleep. It is one of the most common sleep disorders in the world. Insomnia is a common symptom of many neurodegenerative diseases but only recently has it been found that it is a risk factor for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. We did a traditional review to analyze the relationship between insomnia and neurodegenerative diseases. We analyzed all the relevant articles on Pubmed and included studies done on humans over the last 10 years with full text available. After reviewing the available literature on Pubmed, we conclude that insomnia is an important risk factor for neurodegenerative diseases. In addition, insomnia and neurodegenerative disorders have a complex and bi-directional relationship. We think it requires further study to understand the sole contribution of insomnia to the development of various neurodegenerative diseases when different factors like mood problems, genetic factors, and environmental factors also contribute to the disease. It would also be advisable to use cognitive screening questionnaires in all sleep clinics in insomnia patients over 50 years of age to diagnose dementia early and to gather more sleep study data for prospective and retrospective research. The role of hypnotics in preventing neurodegenerative diseases through treating insomnia should also be assessed.

RevDate: 2019-12-06

Zoufal V, Mairinger S, Brackhan M, et al (2019)

Imaging P-glycoprotein Induction at the Blood-Brain Barrier of a Beta-Amyloidosis Mouse Model with 11C-Metoclopramide PET.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.119.237198 [Epub ahead of print].

P-glycoprotein (ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting the clearance of neurotoxic beta-amyloid (Aß) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease (AD) patients. Treatment with drugs which induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aß deposits in the brain by enhancing the clearance of Aß peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer 11C-metoclopramide can measure ABCB1 induction at the BBB in a beta-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 days underwent 11C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor (PXR) activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 days. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aß levels. In separate groups of mice, radiolabeled metabolites of 11C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aß levels. There was a significant positive correlation between kE,brain values and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain values was found. Metabolite analysis showed that the majority of radioactivity in the brain was composed of unmetabolized 11C-metoclopramide in all animal groups. Conclusion:11C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in AD patients to non-invasively evaluate strategies to enhance the clearance properties of the BBB.

RevDate: 2019-12-06

Kemp EC, Ebner MK, Ramanan S, et al (2019)

Statin Use and Risk of Cognitive Decline in the ADNI Cohort.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry pii:S1064-7481(19)30559-7 [Epub ahead of print].

OBJECTIVE: To investigate associations between statin use and cognitive change, as well as diagnostic conversion, in individuals with cognitively normal (CN) status, mild cognitive impairment (MCI), and dementia due to Alzheimer disease (AD-dementia).

METHODS: A multicenter cohort study with 1629 adults 48 to 91 years old with CN status, early MCI (EMCI), late MCI (LMCI), or AD-dementia at baseline followed prospectively for 24 months. Statin use was assessed at baseline, and cognition was measured over time with a composite memory score, a composite executive function score, and a global cognition score (Alzheimer's Disease Assessment Scale). Conversion to a more impaired diagnostic category was determined by clinician assessment. Repeated measures linear mixed-effects models were used to evaluate associations between statin use and change in cognition over time. Cox proportional hazards models were used to evaluate associations between statin use and time to diagnostic conversion. All models were stratified by baseline diagnostic group.

RESULTS: Statin use was not associated with change in cognitive measures for CN, LMCI, or AD-dementia participants. Among EMCI participants, statin use was associated with a significantly slower rate of decline on the memory composite, but no other cognitive measure. Statin use was not associated with time to conversion for any diagnostic group.

CONCLUSIONS: This study did not support an association between statin use and diagnostic conversion but suggested a possible association between statin use and cognitive change in EMCI. Additional randomized clinical trials of statins may be warranted in the prodromal EMCI stage of AD.

RevDate: 2019-12-06

Hamm S, Sudres JL, Menouer L, et al (2019)

[Alzheimer's disease and singing: an application in mediated therapy].

Soins. Gerontologie, 24(140):15-19.

A study was conducted on the implementation and evaluation of a therapeutic device by singing in a protected unit for elderly people with Alzheimer's dementia. This randomised and controlled research consists of an experimental group participating in the therapeutic mediation device by singing, and a group benefiting from conventional care. The results indicate that the therapeutic mediation device of singing significantly promotes emotional expression, self-awareness, and acts on the psycho-behavioural disorders of older subjects.

RevDate: 2019-12-05

Boccia S, Pastorino R, Ricciardi W, et al (2019)

How to Integrate Personalized Medicine into Prevention? Recommendations from the Personalized Prevention of Chronic Diseases (PRECeDI) Consortium.

Public health genomics pii:000504652 [Epub ahead of print].

Medical practitioners are increasingly adopting a personalized medicine (PM) approach involving individually tailored patient care. The Personalized Prevention of Chronic Diseases (PRECeDI) consortium project, funded within the Marie Skłodowska Curie Action (MSCA) Research and Innovation Staff Exchange (RISE) scheme, had fostered collaboration on PM research and training with special emphasis on the prevention of chronic diseases. From 2014 to 2018, the PRECeDI consortium trained 50 staff members on personalized prevention of chronic diseases through training and research. The acquisition of skills from researchers came from dedicated secondments from academic and nonacademic institutions aimed at training on several research topics related to personalized prevention of cancer and cardiovascular and neurodegenerative diseases. In detail, 5 research domains were addressed: (1) identification and validation of biomarkers for the primary prevention of cardiovascular diseases, secondary prevention of Alzheimer disease, and tertiary prevention of head and neck cancer; (2) economic evaluation of genomic applications; (3) ethical-legal and policy issues surrounding PM; (4) sociotechnical analysis of the pros and cons of informing healthy individuals on their genome; and (5) identification of organizational models for the provision of predictive genetic testing. Based on the results of the research carried out by the PRECeDI consortium, in November 2018, a set of recommendations for policy makers, scientists, and industry has been issued, with the main goal to foster the integration of PM approaches in the field of chronic disease prevention.

RevDate: 2019-12-05

Monier M, El-Mekabaty A, Abdel-Latif D, et al (2019)

Heterocyclic Steroids: Efficient Routes for Annulation of Pentacyclic Steroidal Pyrimidines.

Steroids pii:S0039-128X(19)30238-7 [Epub ahead of print].

Steroids are components of cell membranes, signaling molecules and are a type of secondary metabolites as a result of their high impact of biological significance. The present review described the literature reports of pentacyclic steroidal pyrimidines as a type of heterocyclic steroids. The main sections included the synthesis of the investigated steroids fused at rings-A or B or D of steroid skeleton, synthesis of binary or linked-type pyrimidines, pyrimidine oxides, macromolecules and mono- or di- or tri-peptides linked-steroidal pyrimidines. Besides, the present research highlighted the biological significance of steroidal pyrimidines, in which the compounds revealed potent anticancer, antioxidant, antibacterial, and anti-Alzheimer agents. In addition, some hetero-steroids were screened for binding DNA assay and gene expression analysis. It was settled that the incorporation of pyrimidine scaffold into steroid basic skeleton is crucial for better biological results.

RevDate: 2019-12-05

Catania M, Giaccone G, Salmona M, et al (2019)

Dreaming of a New World Where Alzheimer's Is a Treatable Disorder.

Frontiers in aging neuroscience, 11:317.

Alzheimer's disease (AD) is the most common form of dementia. It's a chronic and untreatable neurodegenerative disease with irreversible progression and has important social and economic implications in terms of direct medical and social care costs. Despite prolonged and expensive efforts employed by the scientific community over the last few decades, no effective treatments are still available for patients, and the development of disease-modifying drugs is now a really urgent need. The recent failure of clinical trials based on the immunotherapeutic approach against amyloid-β(Aβ) protein questioned the validity of the "amyloid cascade hypothesis" as the molecular machinery causing the disease. Indeed, most attempts to design effective treatments for AD have been based until now on molecular targets suggested to be implicated in AD pathogenesis by the amyloid cascade hypothesis. However, mounting evidence from scientific literature supports the view of AD as a multifactorial disease that results from the concomitant action of multiple molecular players. This view, together with the lack of success of the disease-modifying single-target approaches, strongly suggests that AD drug design needs to be shifted towards multi-targeted compounds or drug combinations acting synergistically on the main core features of disease pathogenesis. The discovery of drug candidates targeting multiple factors involved in AD would greatly improve drug development. So, it is reasonable that upcoming strategies for the design of preventive and/or therapeutic agents for AD point to a multi-pronged approach including more than one druggable target to definitely defeat the disease.

RevDate: 2019-12-05

Cavedo E, Lista S, Houot M, et al (2019)

Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease.

Neurology pii:WNL.0000000000008696 [Epub ahead of print].

OBJECTIVE: To investigate whether baseline concentrations of plasma total tau (t-tau) and neurofilament light (NfL) chain proteins are associated with annual percent change (APC) of the basal forebrain cholinergic system (BFCS) in cognitively intact older adults at risk for Alzheimer disease (AD).

METHODS: This was a large-scale study of 276 cognitively intact older adults from the monocentric INSIGHT-preAD (Investigation of Alzheimer's Predictors in Subjective Memory Complainers) cohort. Participants underwent baseline assessment of plasma t-tau and NfL concentrations as well as baseline and 24-month follow-up MRI scans. Linear models with and without influential observations (calculated using the Cook distance) were carried out to investigate the effect of plasma NfL and t-tau concentrations, and their interaction effect with β-amyloid status and APOE genotype, on the APC of the whole BFCS and its anterior (Ch1/2) and posterior (Ch4) subdivisions separately.

RESULTS: Higher plasma t-tau concentrations at baseline were associated with higher BFCS rate of atrophy (model without influencers: n = 251, F value = 4.6815; p value = 0.031). Subregional analyses showed similar results for both the APC of the Ch1/2 (model without influencers: n = 256, F value = 3.9535, p corrected = 0.047) and Ch4 BFCS sectors (model without influencers: n = 253, F value = 4.9090, p corrected = 0.047). Baseline NfL, β-amyloid load, and APOE ε4 carrier status did not affect APC of the BFCS.

CONCLUSION: Increased concentrations of baseline plasma t-tau may predict in vivo structural BFCS atrophy progression in older adults at risk for AD, independently of β-amyloid status and APOE genotype.

RevDate: 2019-12-05

Dhingra AK, B Chopra (2019)

Inflammation as a Therapeutic Target for Various Deadly Disorders: A Review.

Current drug targets pii:CDT-EPUB-102780 [Epub ahead of print].

Inflammation is the multifaceted biological response of vascular tissues against injurious stimuli such as pathogens, irritants or infection. However, when inflammation goes awry, it leads to produce quite serious life-threatening diseases like Alzheimer's, rheumatoid arthritis, heart attacks, colon cancer etc. Therefore, inflammation suddenly has become one of the hottest areas of medical research. The present review article is aimed to provide a detailed outline of the fundamental causes and the surprising relationship of inflammation in the onset of sundry diseases or illnesses. Further, the role of various anti-inflammatory drugs alone and in combination with other therapeutic drugs, in alleviating the life-threatening diseases is also discussed.

RevDate: 2019-12-04

Ervik AO, Hafstad Solvang SE, Nordrehaug JE, et al (2019)

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia.

International journal of tryptophan research : IJTR, 12:1178646919885637 pii:10.1177_1178646919885637.

Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain.

Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis.

Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis.

Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele (P-value of the interactions < .05).

Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.

RevDate: 2019-12-04

Yoo SY, Yoo JY, Kim HB, et al (2019)

Neuregulin-1 Protects Neuronal Cells Against Damage due to CoCl2-Induced Hypoxia by Suppressing Hypoxia-Inducible Factor-1α and P53 in SH-SY5Y Cells.

International neurourology journal, 23(Suppl 2):S111-118.

PURPOSE: Hypoxia-mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer disease. Neuregulin-1 (NRG1) plays an important role in the development and plasticity of the brain. The aim of the present study was to investigate the neuroprotective effect and the regulating hypoxic inducible factor of NRG1 in cobalt chloride (CoCl2) induced hypoxia.

METHODS: Hypoxia was induced in SH-SY5Y cells by CoCl2 treatment. SH-SY5Y cells were pretreated with NRG1 and then treated with CoCl2. Western blotting, immunocytochemistry, and lactate dehydrogenase (LDH) release assays were performed to examine neuroprotective properties of NRG1 in SH-SY5Y cells.

RESULTS: Our data showed that CoCl2 induced cytotoxicity and changes of hypoxia-inducible factor-1α (HIF-1α) and p53 expression in SH-SY5Y cells. However, pretreatment with NRG1 inhibited CoCl2-induced accumulation of HIF-1α and p53 stability. In addition, NRG1 significantly attenuated cell death of SH-SY5Y induced by CoCl2.

CONCLUSION: NRG1 can regulate HIF-1α and p53 to protect neurons against hypoxic damage.

RevDate: 2019-12-04

Seo DY, Heo JW, Ko JR, et al (2019)

Exercise and Neuroinflammation in Health and Disease.

International neurourology journal, 23(Suppl 2):S82-92.

Neuroinflammation is a central pathological feature of several acute and chronic brain diseases, including Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). It induces microglia activation, mitochondrial dysfunction, the production of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), pro-inflammatory cytokines, and reactive oxygen species. Exercise, which plays an important role in maintaining and improving brain health, might be a highly effective intervention for preventing neuroinflammation-related diseases. Thus, since exercise can improve the neuroimmune response, we hypothesized that exercise would attenuate neuroinflammation-related diseases. In this review, we will highlight (1) the biological mechanisms that underlie AD, PD, ALS, and MS, including the neuroinflammation pathways associated with microglia activation, NF-κB, pro-inflammatory cytokines, mitochondrial dysfunction, and reactive oxygen species, and (2) the role of exercise in neuroinflammation-related neurodegenerative diseases.

RevDate: 2019-12-04

Kim B, Choi Y, Kim HS, et al (2019)

Methyl-CpG Binding Protein 2 in Alzheimer Dementia.

International neurourology journal, 23(Suppl 2):S72-81.

Despite decades of research on Alzheimer disease, understanding the complexity of the genetic and molecular interactions involved in its pathogenesis remains far from our grasp. Methyl-CpG Binding Protein 2 (MeCP2) is an important epigenetic regulator enriched in the brain, and recent findings have implicated MeCP2 as a crucial player in Alzheimer disease. Here, we provide comprehensive insights into the pathophysiological roles of MeCP2 in Alzheimer disease. In particular, we focus on how the alteration of MeCP2 expression can impact Alzheimer disease through risk genes, amyloid-β and tau pathology, cell death and neurodegeneration, and cellular senescence. We suggest that Alzheimer disease can be adversely affected by upregulated MeCP2-dependent repression of risk genes (MEF2C, ADAM10, and PM20D1), increased tau accumulation, and neurodegeneration through neuronal cell death (excitotoxicity and apoptosis). In addition, we propose that the progression of Alzheimer disease could be caused by reduced MeCP2-mediated enhancement of astrocytic and microglial senescence and consequent glial SASP (senescence-associated secretory phenotype)-dependent neuroinflammation. We surmise that any imbalance in MeCP2 function would accelerate or cause Alzheimer disease pathogenesis, implying that MeCP2 may be a potential drug target for the treatment and prevention of Alzheimer disease.

RevDate: 2019-12-04

Yang SH (2019)

Cellular and Molecular Mediators of Neuroinflammation in Alzheimer Disease.

International neurourology journal, 23(Suppl 2):S54-62.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the loss of neuronal cells and the progressive decline of cognitive function. The major pathological culprit of AD is aggregation of amyloid-β (Aβ) and hyperphosphorylation of tau, eventually leading to progressive neuronal cell death and brain atrophy. However, the detailed molecular and cellular mechanisms underlying AD development as a result of neuronal cell death are little known. Although several hypotheses have been proposed regarding the development of AD, increasingly many studies suggest that the pathological progress of AD is not restricted to neuronal components such as Aβ and tau, but is also closely related to inflammatory responses in the brain. Abnormalities of Aβ and tau cause activity of pattern recognition receptors on the brain's immune cells, including microglia and astrocytes, and trigger the innate immune system by releasing inflammatory mediators in the pathogenesis of AD. In this review, we present a basic overview of the current knowledge regarding inflammation and molecular mediators in the pathological progress of AD.

RevDate: 2019-12-04

Im HI (2019)

Molecular and Cellular Substrates of Neuroinflammation in Alzheimer Disease and Depression.

International neurourology journal, 23(Suppl 2):S51-52.

RevDate: 2019-12-04

Bussiere R, Oulès B, Mary A, et al (2019)

Upregulation of the Sarco-Endoplasmic Reticulum Calcium ATPase 1 Truncated Isoform Plays a Pathogenic Role in Alzheimer's Disease.

Cells, 8(12): pii:cells8121539.

Dysregulation of the Endoplasmic Reticulum (ER) Ca2+ homeostasis and subsequent ER stress activation occur in Alzheimer Disease (AD). We studied the contribution of the human truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T) to AD. We examined S1T expression in human AD-affected brains and its functional consequences in cellular and transgenic mice AD models. S1T expression is increased in sporadic AD brains and correlates with amyloid β (Aβ) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated β-amyloid precursor protein (βAPP) or treated with Aβ oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and Aβ through specific increases of β-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and βAPP-derived fragments that could contribute to AD setting and/or progression.

RevDate: 2019-12-04

Smailovic U, Koenig T, Laukka EJ, et al (2019)

EEG time signature in Alzheimer´s disease: Functional brain networks falling apart.

NeuroImage. Clinical, 24:102046 pii:S2213-1582(19)30393-6 [Epub ahead of print].

Spontaneous mental activity is characterized by dynamic alterations of discrete and stabile brain states called functional microstates that are thought to represent distinct steps of human information processing. Electroencephalography (EEG) directly reflects functioning of brain synapses with a uniquely high temporal resolution, necessary for investigation of brain network dynamics. Since synaptic dysfunction is an early event and best correlate of cognitive status and decline in patients along Alzheimer's disease (AD) continuum, EEG microstates might serve as valuable early markers of AD. The present study investigated differences in EEG microstate topographies and parameters (duration, occurrence and contribution) between a large cohort of healthy elderly (n = 308) and memory clinic patients: subjective cognitive decline (SCD, n = 210); mild cognitive impairment (MCI, n = 230) and AD (n = 197) and how they correlate to conventional cerebrospinal fluid (CSF) markers of AD. Four most representative microstate maps assigned as classes A, B (asymmetrical), C and D (symmetrical) were computed from the resting state EEGs since it has been shown previously that this is sufficient to explain most of the resting state EEG data. Statistically different topography of microstate maps were found between the controls and the patient groups for microstate classes A, C and D. Changes in the topography of microstate class C were associated with the CSF Aβ42 levels, whereas changes in the topography of class B were linked with the CSF p-tau levels. Gradient-like increase in the contribution of asymmetrical (A and B) and gradient-like decrease in the contribution of symmetrical (C and D) maps were observed with the more severe stage of cognitive impairment. Our study demonstrated extensive relationship of resting state EEG microstates topographies and parameters with the stage of cognitive impairment and AD biomarkers. Resting state EEG microstates might therefore serve as functional markers of early disruption of neurocognitive networks in patients along AD continuum.

RevDate: 2019-12-05

Hanseeuw BJ, Scott MR, Sikkes SAM, et al (2019)

Evolution of anosognosia in alzheimer disease and its relationship to amyloid.

Annals of neurology [Epub ahead of print].

OBJECTIVE: Unawareness, or anosognosia, of memory deficits is a challenging manifestation of Alzheimer disease (AD) that adversely affects a patient's safety and decision-making. However, there is a lack of consensus regarding the presence, as well as the evolution, of altered awareness of memory function across the preclinical and prodromal stages of AD. Here, we aimed to characterize change in awareness of memory abilities and its relationship to beta-amyloid (Aβ) burden in a large cohort (N = 1,070) of individuals across the disease spectrum.

METHODS: Memory awareness was longitudinally assessed (average number of visits = 4.3) and operationalized using the discrepancy between mean participant and partner report on the Everyday Cognition scale (memory domain). Aβ deposition was measured at baseline using [18F]florbetapir positron emission tomographic imaging.

RESULTS: Aβ predicted longitudinal changes in memory awareness, such that awareness decreased faster in participants with increased Aβ burden. Aβ and clinical group interacted to predict change in memory awareness, demonstrating the strongest effect in dementia participants, but could also be found in the cognitively normal (CN) participants. In a subset of CN participants who progressed to mild cognitive impairment (MCI), heightened memory awareness was observed up to 1.6 years before MCI diagnosis, with memory awareness declining until the time of progression to MCI (-0.08 discrepant-points/yr). In a subset of MCI participants who progressed to dementia, awareness was low initially and continued to decline (-0.23 discrepant-points/yr), reaching anosognosia 3.2 years before dementia onset.

INTERPRETATION: Aβ burden is associated with a progressive decrease in self-awareness of memory deficits, reaching anosognosia approximately 3 years before dementia diagnosis. ANN NEUROL 2019.

RevDate: 2019-12-03

Bonham LW, Sirkis DW, Hess CP, et al (2019)

The Radiogenomics of Late-onset Alzheimer Disease.

Topics in magnetic resonance imaging : TMRI, 28(6):325-334.

Radiogenomics, defined as the integrated analysis of radiologic imaging and genetic data, is a well-established tool shown to augment neuroimaging in the clinical diagnosis, prognostication, and scientific study of late-onset Alzheimer disease (LOAD). Early work using candidate single nucleotide polymorphisms (SNPs) identified genetic variation in APOE, BIN1, CLU, and CR1 as key modifiers of brain structure and function using magnetic resonance imaging (MRI). More recently, polygenic risk scores used in conjunction with MRI and positron emission tomography have shown great promise as a risk-stratification tool for clinical trials and care-management decisions. In addition, recent work using multimodal MRI and positron emission tomography as proxies of LOAD progression has identified novel risk variants that are enhancing our understanding of LOAD pathophysiology and progression. Herein, we highlight key studies and trends in the radiogenomics of LOAD over the past two decades and their implications for clinical practice and scientific research.

RevDate: 2019-12-03

Raji CA, Ly M, TLS Benzinger (2019)

Overview of MR Imaging Volumetric Quantification in Neurocognitive Disorders.

Topics in magnetic resonance imaging : TMRI, 28(6):311-315.

This review article provides a general overview on the various methodologies for quantifying brain structure on magnetic resonance images of the human brain. This overview is followed by examples of applications in Alzheimer dementia and mild cognitive impairment. Other examples will include traumatic brain injury and other neurodegenerative dementias. Finally, an overview of general principles for protocol acquisition of magnetic resonance imaging for volumetric quantification will be discussed along with the current choices of FDA cleared algorithms for use in clinical practice.

RevDate: 2019-12-03

Shepherd TM, GK Nayak (2019)

Clinical Use of Integrated Positron Emission Tomography-Magnetic Resonance Imaging for Dementia Patients.

Topics in magnetic resonance imaging : TMRI, 28(6):299-310.

Combining magnetic resonance imaging (MRI) with 2-deoxy-2-F-fluoro-D-glucose positron emission tomography (FDG-PET) data improve the imaging accuracy for detection of Alzheimer disease and related dementias. Integrated FDG-PET-MRI is a recent technical innovation that allows both imaging modalities to be obtained simultaneously from individual patients with cognitive impairment. This report describes the practical benefits and challenges of using integrated FDG-PET-MRI to support the clinical diagnosis of various dementias. Over the past 7 years, we have performed integrated FDG-PET-MRI on >1500 patients with possible cognitive impairment or dementia. The FDG-PET and MRI protocols are the same as current conventions, but are obtained simultaneously over 25 minutes. An additional Dixon MRI sequence with superimposed bone atlas is used to calculate PET attenuation correction. A single radiologist interprets all imaging data and generates 1 report. The most common positive finding is concordant temporoparietal volume loss and FDG hypometabolism that suggests increased risk for underlying Alzheimer disease. Lobar-specific atrophy and FDG hypometabolism patterns that may be subtle, asymmetric, and focal also are more easily recognized using combined FDG-PET and MRI, thereby improving detection of other neurodegeneration conditions such as primary progressive aphasias and frontotemporal degeneration. Integrated PET-MRI has many practical benefits to individual patients, referrers, and interpreting radiologists. The integrated PET-MRI system requires several modifications to standard imaging center workflows, and requires training individual radiologists to interpret both modalities in conjunction. Reading MRI and FDG-PET together increases imaging diagnostic yield for individual patients; however, both modalities have limitations in specificity.

RevDate: 2019-12-03

Stavoe AKH, ELF Holzbaur (2019)

Neuronal autophagy declines substantially with age and is rescued by overexpression of WIPI2.

Autophagy [Epub ahead of print].

Macroautophagy/autophagy is implicated in age-dependent neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson, Huntington and Alzheimer diseases, suggesting that an age-related decline in neuronal autophagy may contribute to the onset of neurodegeneration. We identified a significant decline in the rate of axonal autophagosome formation in neurons cultured from aged mice, accompanied by a striking increase in the accumulation of autophagic structures with aberrant morphologies. Using live-cell microscopy, we identified the specific step in autophagosome formation that becomes impaired with age, focusing on the role of the phosphoinositide binding protein WIPI2. We determined that the dynamic and local phosphorylation of WIPI2 is a critical regulatory step in autophagosome biogenesis in neurons and that this step is specifically affected by aging. Together, these results provide new insights into the regulation of autophagosome biogenesis in neurons and delineate how autophagosome formation is affected by age. These observations also point to a potential new target for therapeutic intervention.

RevDate: 2019-12-03

Koronyo-Hamaoui M, Sheyn J, Hayden EY, et al (2019)

Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease.

Brain : a journal of neurology pii:5651064 [Epub ahead of print].

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-β1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (∼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-β1-42, vascular and parenchymal amyloid-β deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-β plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ∼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-β1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-β1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-β conformers as well as substantially more effective amyloid-β1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and ∼80% increased extracellular degradation of amyloid-β1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-α), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-β1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-β forms.

RevDate: 2019-12-03

Fowler NR, Perkins AJ, Gao S, et al (2019)

Risks and Benefits of Screening for Dementia in Primary Care: The Indiana University Cognitive Health Outcomes Investigation of the Comparative Effectiveness of Dementia Screening (IU CHOICE)Trial.

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

BACKGROUND/OBJECTIVE: The benefits and harms of screening of Alzheimer disease and related dementias (ADRDs) are unknown. This study addressed the question of whether the benefits outweigh the harms of screening for ADRDs among older adults in primary care.

Single-blinded, two-arm, randomized controlled trial (October 2012-September 2016) in urban, suburban, and rural primary care settings in Indiana. A total of 4005 primary care patients (aged ≥65 years) were randomized to ADRD screening (n = 2008) or control (n = 1997).

INTERVENTION: Patients were screened using the Memory Impairment Screen or the Mini-Cog and referred for a voluntary follow-up diagnostic assessment if they screened positive on either or both screening tests.

MEASUREMENTS: Primary measures were health-related quality of life (HRQOL; Health Utilities Index) at 12 months, depressive symptoms (Patient Health Questionnaire-9), and anxiety symptoms (Generalized Anxiety Disorder seven-item scale) at 1 month.

RESULTS: The mean age was 74.2 years (SD = 6.9 years); 2257 (66%) were female and 2301 (67%) were white. At 12 months, we were unable to detect differences in HRQOL between the groups (effect size = 0.009 [95% confidence interval {CI} = -0.063 to 0.080]; P = .81). At 1 month, differences in mean depressive symptoms (mean difference = -0.23 [90% CI = -0.42 to -0.039]) and anxiety symptoms (mean difference = -0.087 [90% CI = -0.246 to 0.072]) were within prespecified equivalency range. Scores for depressive and anxiety symptoms were similar between the groups at all time points. No differences in healthcare utilization, advance care planning, and ADRD recognition by physicians were detected at 12 months.

CONCLUSION: We were unable to detect a difference in HRQOL for screening for ADRD among older adults. We found no harm from screening measured by symptoms of depression or anxiety. Missing data, low rates of dementia detection, and high rate of refusal for follow-up diagnostic assessments after a positive screen may explain these findings.

RevDate: 2019-12-03

Niculescu AB, Le-Niculescu H, Roseberry K, et al (2019)

Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs.

Molecular psychiatry pii:10.1038/s41380-019-0602-2 [Epub ahead of print].

Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).

RevDate: 2019-12-03

Feustel AC, MacPherson A, Fergusson DA, et al (2019)

Risks and benefits of unapproved, disease-modifying treatments for neurodegenerative disease.

Neurology pii:WNL.0000000000008699 [Epub ahead of print].

OBJECTIVE: To determine whether patients randomized to unapproved, disease-modifying interventions in neurodegenerative disease trials have better outcomes than patients randomized to placebo by performing a systematic review and meta-analysis of risk and benefit experienced by patients in randomized placebo-controlled trials testing investigational treatments for Alzheimer disease, Parkinson disease, Huntington disease, or amyotrophic lateral sclerosis (ALS).

METHODS: We searched MEDLINE, Embase, and ClinicalTrials.gov for results of randomized trials testing non-Food and Drug Administration-approved, putatively disease-modifying interventions from January 2005 to May 2018. Trial characteristics were double-extracted. Coprimary endpoints were the treatment advantage over placebo on efficacy (standardized mean difference in outcomes) and safety (risk ratios of serious adverse events and withdrawals due to adverse events), calculated with random effects meta-analyses. The study was registered on PROSPERO (CRD42018103798).

RESULTS: We included 113 trials (n = 39,875 patients). There was no significant efficacy advantage associated with assignment to putatively disease-modifying interventions compared to placebo for Alzheimer disease (standardized mean difference [SMD] -0.03, 95% confidence interval [CI] -0.07 to 0.01), Parkinson disease (SMD -0.09, 95% CI -0.32 to 0.15), ALS (SMD 0.02, 95% CI -0.25 to 0.30), or Huntington disease (0.02, 95% CI -0.27 to 0.31). Patients with Alzheimer disease assigned to active treatment were at higher risk of experiencing serious adverse events (risk ratio [RR] 1.15, 95% CI 1.04-1.27) and withdrawals due to adverse events (RR 1.44, 95% CI 1.21-1.70).

CONCLUSIONS: Assignment to active treatment was not beneficial for any of the indications examined and may have been slightly disadvantageous for patients with Alzheimer disease. Our findings suggest that patients with neurodegenerative diseases are not, on the whole, harmed by assignment to placebo when participating in trials.

RevDate: 2019-12-02

Nedelska Z, Schwarz CG, Lesnick TG, et al (2019)

Association of Longitudinal β-Amyloid Accumulation Determined by Positron Emission Tomography With Clinical and Cognitive Decline in Adults With Probable Lewy Body Dementia.

JAMA network open, 2(12):e1916439 pii:2756108.

Importance: In patients with probable dementia with Lewy bodies (DLB), overlapping Alzheimer disease pathology is frequent and is associated with faster decline and shorter survival. More than half of patients with DLB have elevated β-amyloid levels on carbon-11 labeled Pittsburgh compound B (PiB) positron emission tomography, but the trajectory of longitudinal β-amyloid accumulation and its associations with clinical and cognitive decline in DLB are not known.

Objectives: To determine the trajectory of β-amyloid accumulation in patients with probable DLB and to investigate the associations of β-amyloid accumulation with measures of clinical and cognitive decline over time in DLB.

This cohort study included 35 consecutive patients with probable DLB from the Mayo Clinic Alzheimer Disease Research Center and matched them by age, sex, and apolipoprotein e4 status with 140 cognitively unimpaired participants from the population-based Mayo Clinic Study of Aging. Participants were observed from April 2010 to September 2017. Data analysis was conducted from January 2018 to January 2019.

Exposure: Baseline and follow-up PiB positron emission tomography and comprehensive clinical evaluations.

Main Outcomes and Measures: Rate of change in PiB standardized uptake value ratios (SUVRs) by PiB SUVR and time in years; the associations between baseline PiB SUVR, change in PiB SUVR, and change in several measures of clinical and cognitive decline.

Results: A total of 175 participants were evaluated (35 [20.0%] with probable DLB; mean [SD] age, 69.6 [7.3] years; 16 [45.7%] apolipoprotein e4 carriers; 31 [88.6%] men; and 140 [80.0%] cognitively unimpaired adults; mean [SD] age, 69.7 [7.2] years; 64 [45.7%] apolipoprotein e4 carriers; 124 [88.6%] men). In both groups, the rates of change in PiB SUVR showed an initial acceleration at lower baseline PiB SUVR followed by a deceleration at higher baseline PiB SUVR, thus forming an inverted-U shape. The trajectories of the rates of change in PiB SUVR did not differ between participants with probable DLB and cognitively unimpaired participants in terms of shape (P = .59) or vertical shift (coefficient [SE] 0.007 [0.006]; P = .22). The integral association of cumulative PiB SUVR with time in years showed a sigmoid-shaped functional form in both groups. In participants with probable DLB, higher baseline PiB SUVR and change in PiB SUVR were associated with more rapid clinical decline, as measured by the Clinical Dementia Rating, sum of boxes (baseline PiB SUVR: regression coefficient [SE], 1.90 [0.63]; P = .005; R2 = 0.215; change in PiB SUVR, regression coefficient [SE], 16.17 [7.47]; P = .04; R2 = 0.124) and the Auditory Verbal Learning Test, delayed recall (baseline PiB SUVR, regression coefficient [SE], -2.09 [0.95]; P = .04; R2 = 0.182; change in PiB SUVR, regression coefficient [SE], -25.05 [10.04]; P = .02; R2 = 0.221).

Conclusions and Relevance: In this study, the rate of change in PiB SUVR among participants with probable DLB increased, peaked, and then decreased, which was similar to the trajectory in cognitively unimpaired participants and the Alzheimer disease dementia continuum. Higher baseline PiB SUVR and change in PiB SUVR were associated with more rapid clinical and cognitive decline over time. Measuring the change in PiB SUVR has implications for designing anti-β-amyloid randomized clinical trials for individuals with probable DLB.

RevDate: 2019-12-02

Burke JF, KM Langa (2019)

Biomarker-Informed Treatment Decisions in Cognitively Impaired Patients Do Not Apply to Preclinical Alzheimer Disease-Reply.

JAMA internal medicine, 179(12):1737.

RevDate: 2019-12-02

Rabinovici GD, MC Carrillo (2019)

Biomarker-Informed Treatment Decisions in Cognitively Impaired Patients Do Not Apply to Preclinical Alzheimer Disease.

JAMA internal medicine, 179(12):1736-1737.

RevDate: 2019-12-02

Aslam MS, L Yuan (2019)

Serpina3n: Potential drug and challenges, mini review.

Journal of drug targeting [Epub ahead of print].

Serpina3n is a secretory serine protease inhibitor belonging to clade "a" exhibiting unique structural and physiological characteristics, playing significant roles ranging from complement cascade, apoptosis, wound healing to Alzheimer by inhibiting a wide range of proteases. Recently studies have reported its significant roles during various pathologies. Although its full range of potential applications are yet to reveal, its reported implications particularly in CNS insults are making it potential therapeutical approach. Here we aim to draw together the literature shedding light on the potential therapeutical applications of Serpina3n/SERPINA3 in various diseases and a brief comparison between murine Serpina3n and its human ortholog SERPINA3 (α1-antichymotrypsin) accounting their biological roles and significance.

RevDate: 2019-12-02

Liu CS, Herrmann N, Gallagher D, et al (2019)

A Pilot Study Comparing Effects of Bifrontal Versus Bitemporal Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Mild Alzheimer Disease.

The journal of ECT [Epub ahead of print].

OBJECTIVE: While transcranial direct current stimulation (tDCS) can enhance aspects of memory in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), there has been wide variability in both the placement of tDCS electrodes and treatment response. This study compared the effects of bifrontal (anodal stimulation over the dorsolateral prefrontal cortices), bitemporal (anodal stimulation over the temporal cortices), and sham tDCS on cognitive performance in MCI and AD.

METHODS: Seventeen patients diagnosed with MCI or mild AD received 3 sessions of anodal tDCS (bifrontal, bitemporal, 2 mA for 20 minutes; and sham) in random order. Sessions were separated by 1 week. The Alzheimer's Disease Assessment Scale-Cognitive Word Recognition Task, Alzheimer's Disease Assessment Scale-Cognitive Word Recall Task, 2-back, and Montreal Cognitive Assessment were used to assess cognition.

RESULTS: There was a significant effect of stimulation condition on 2-back accuracy (F2,28 = 5.28 P = 0.01, ηp = 0.27), with greater improvements following bitemporal tDCS compared with both bifrontal and sham stimulations. There were no significant changes on other outcome measures following any stimulation. Adverse effects from stimulation were mild and temporary.

CONCLUSIONS: These findings demonstrate that improvements in specific memory tasks can be safely achieved after a single session of bitemporal tDCS in MCI and mild AD patients.

RevDate: 2019-12-02

Zhang J, Wang L, Deng X, et al (2019)

Five-Minute Cognitive Test as A New Quick Screening of Cognitive Impairment in The Elderly.

Aging and disease, 10(6):1258-1269 pii:ad-10-6-1258.

This study aims to develop a new evaluation method for quickly and conveniently screening cognitive impairment in the elderly. The five-minute cognitive test (FCT) was designed to capture deficits in five domains of cognitive abilities, including episodic memory, language fluency, time orientation, visuospatial function, and executive function. Subsequently, FCT efficiencies in differentiating normally cognitive ability from cognitive impairment were explored and compared with that of the Mini-Mental Status Evaluation (MMSE). Equipercentile equating method was utilized to create a crosswalk between scores of the FCT and MMSE. Further, the association of scores of the FCT and MMSE with hippocampal volumes was investigated. There were 241 subjects aged 60 years or above enrolled in this study, including 107 adults with cognitive abilities in normal range, 107 patients with mild cognitive impairment (MCI), and 27 patients with mild Alzheimer disease (AD). The AUC of FCT for detection of cognitive impairment (MCI and mild AD) was 0.885 (95% CI 0.838 to 0.922). The sensitivity and specificity of FCT for the diagnosis of cognitive impairment were 80.6% and 84.11 %, respectively. FCT's diagnostic performance was superior to that of MMSE in the same cohort. Mean completion time of FCT was 339.9 ± 67.7 seconds (5-6 min). In addition, a conversion table between scores on the FCT and MMSE was created. Further, the FCT scores were positively correlated with hippocampal volumes. The FCT is a novel, reliable, and valid cognitive screening test for the detection of dementia at early stages.

RevDate: 2019-12-02

Deng W, Xing C, David R, et al (2019)

AmpliSeq Transcriptome of Laser Captured Neurons from Alzheimer Brain: Comparison of Single Cell Versus Neuron Pools.

Aging and disease, 10(6):1146-1158 pii:ad-10-6-1146.

Alzheimer's disease (AD) is the most common cause of dementia in older adults. However, the pathogenesis of AD remains to be fully understood and clinically effective treatments are lacking. Recent advances in single cell RNA sequencing offers an opportunity to characterize the heterogeneity of cell response and explore the molecular mechanism of complex diseases at a single cell level. Here, we present the application of the Ion AmpliSeq transcriptome approach to profile gene expression in single laser captured neurons as well as pooled 10 and 100 neurons from hippocampal CA1 of AD brains versus matching normal aged brains. Our results demonstrated the high sensitivity and high genome coverage of the AmpliSeq transcriptome in single cell sequencing. In addition to capturing the known changes related to AD, our data confirmed the diversity of neuronal profiles in AD brain, which allow the potential identification of single cell response that might be hidden in population analyses. Notably, we also revealed the extensive inhibition of olfactory signaling and confirmed the reduction of neurotransmitter receptors in AD hippocampus. We conclude that although single neuron data show more variance than data from 10 or 100 pooled neurons, single neuron data can be informative. These findings support the utility of the Ion AmpliSeq method for obtaining and analyzing gene expression data from single defined laser captured neurons.

RevDate: 2019-12-02

Padovani A, Benussi A, Cotelli MS, et al (2019)

Transcranial magnetic stimulation and amyloid markers in mild cognitive impairment: impact on diagnostic confidence and diagnostic accuracy.

Alzheimer's research & therapy, 11(1):95 pii:10.1186/s13195-019-0555-3.

BACKGROUND: The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown.

OBJECTIVE: To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise.

METHODS: One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step.

RESULTS: The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers.

CONCLUSIONS: TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.

RevDate: 2019-12-02

Naparstek S, Linkovski O, R O'Hara (2019)

The Future of Dementia Biomarkers Needs Better Neuropsychology.

The American journal of psychiatry, 176(12):1050.

RevDate: 2019-12-02

Licher S, Ikram MK, MA Ikram (2019)

Extending Applicability of Risk Prediction Models: Response to Naparstek et al.

The American journal of psychiatry, 176(12):1050-1051.

RevDate: 2019-12-03

Sol K, Zaheed AB, Kraal AZ, et al (2019)

Psychological predictors of memory decline in a racially and ethnically diverse longitudinal sample of older adults in the United States.

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

OBJECTIVES: In the United States, racial and ethnic disparities in memory dysfunction and Alzheimer disease are evident even after accounting for many risk factors. Psychological factors, such as psychological well-being, perceived control, depressive symptoms, and negative affect, may influence memory dysfunction, and associations may differ by race and ethnicity. This study examined whether psychological factors are differentially associated with episodic memory trajectories across racial and ethnic groups in the United States.

METHODS/DESIGN: The National Health and Aging Trends Study (NHATS), is a US-representative, longitudinal study of Medicare-eligible adults 65+ years old. Analyses of 5 years of data, included a total of 9411 participants without dementia at baseline. Adjusting for relevant covariates, a linear mixed model estimated the associations between psychological predictors and a composite of immediate and delayed trials from a word list memory test.

RESULTS: More depressive symptoms (B = -0.02), lower psychological well-being (B = 0.03), and lower perceived control (B = 0.05) were independently associated with lower initial memory. Depressive symptoms were associated with faster rate of memory decline (B = -0.01). Black (B = -0.34) and Hispanic (B = -0.28) participants evidenced lower initial memory level than whites, but only Hispanic (B = -0.04) participants evidenced faster memory decline than whites. There were no significant interactions between the psychological variables and race and ethnicity.

CONCLUSIONS: Results extend previous studies showing racial and ethnic disparities in episodic memory trajectories, and the longitudinal effects of depressive symptoms on episodic memory in US samples. Epidemiological studies of cognitive aging should incorporate more psychological factors clarify cognitive decline and disparities.

RevDate: 2019-12-03

Sacher C, Blume T, Beyer L, et al (2019)

Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 60(12):1787-1793.

Nonphysiologic overexpression of amyloid-β (Aβ) precursor protein in common transgenic Aβ mouse models of Alzheimer disease likely hampers their translational potential. The novel AppNL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of Alzheimer disease for Aβ-targeting treatment trials. We aimed to establish serial small-animal PET of amyloidosis and neuroinflammation in AppNL-G-F mice as a tool for therapy monitoring. Methods:AppNL-G-F mice (20 homozygous and 21 heterogeneous) and 12 age-matched wild-type mice were investigated longitudinally from 2.5 to 10 mo of age with 18F-florbetaben Aβ PET and 18F-GE-180 18-kDa translocator protein (TSPO) PET. Voxelwise analysis of SUV ratio images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final scan. Quantification of fibrillar Aβ and activated microglia by immunohistochemistry and biochemistry served for validation of the PET results. Results: The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous AppNL-G-F mice had a rising SUV ratio in cortex and hippocampus for Aβ (+9.1%, +3.8%) and TSPO (+19.8%, +14.2%) PET from 2.5 to 10 mo of age (all P < 0.05), whereas heterozygous AppNL-G-F mice did not show significant changes with age. Significant voxelwise clusters of Aβ deposition and microglial activation in homozygous mice appeared at 5 mo of age. Immunohistochemical and biochemical findings correlated strongly with the PET data. Water maze escape latency was significantly elevated in homozygous AppNL-G-F mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. Conclusion: Longitudinal PET in AppNL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice but is insensitive to minor changes in heterozygous animals. The combination of PET with behavioral tasks in AppNL-G-F treatment trials is poised to provide important insights in preclinical drug development.

RevDate: 2019-12-03

Tahmi M, Bou-Zeid W, QR Razlighi (2019)

A Fully Automatic Technique for Precise Localization and Quantification of Amyloid-β PET Scans.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 60(12):1771-1779.

Spatial heterogeneity in the accumulation of amyloid-β plaques throughout the brain during asymptomatic as well as clinical stages of Alzheimer disease calls for precise localization and quantification of this protein using PET imaging. To address this need, we have developed and evaluated a technique that quantifies the extent of amyloid-β pathology on a millimeter-by-millimeter scale in the brain with unprecedented precision using data from PET scans. Methods: An intermodal and intrasubject registration with normalized mutual information as the cost function was used to transform all FreeSurfer neuroanatomic labels into PET image space, which were subsequently used to compute regional SUV ratio (SUVR). We have evaluated our technique using postmortem histopathologic staining data from 52 older participants as the standard-of-truth measurement. Results: Our method resulted in consistently and significantly higher SUVRs in comparison to the conventional method in almost all regions of interest. A 2-way ANOVA revealed a significant main effect of method as well as a significant interaction effect of method on the relationship between computed SUVR and histopathologic staining score. Conclusion: These findings suggest that processing the amyloid-β PET data in subjects' native space can improve the accuracy of the computed SUVRs, as they are more closely associated with the histopathologic staining data than are the results of the conventional approach.

RevDate: 2019-12-03

Toyonaga T, Smith LM, Finnema SJ, et al (2019)

In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 60(12):1780-1786.

11C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted 11C-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD) and found a 41% decrease in specific binding in the hippocampus compared with healthy subjects. We hypothesized that 11C-UCB-J may have potential to be a general biomarker for evaluating AD treatment effects via monitoring of synaptic density changes. In this study, we performed longitudinal 11C-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Methods: Nine wild-type (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1ΔE9 [APP/PS1]) mice underwent 3 11C-UCB-J PET measurements: at baseline, after treatment, and during drug washout. After baseline measurements, saracatinib, a Fyn kinase inhibitor currently in clinical development for AD treatment, was administered by oral gavage for 41 ± 11 d. Treatment-phase measurements were performed on the last day of treatment, and washout-phase measurements occurred more than 27 d after the end of treatment. SUVs from 30 to 60 min after injection of 11C-UCB-J were calculated and normalized by the whole-brain (WB) or brain stem (BS) average values as SUV ratio (SUVR(WB) or SUVR-1(BS)). Results: Hippocampal SUVR(WB) at baseline was significantly lower in APP/PS1 than WT mice (APP/PS1: 1.11 ± 0.04, WT: 1.15 ± 0.02, P = 0.033, unpaired t test). Using SUVR-1(BS) in the hippocampus, there was also a significant difference at baseline (APP/PS1: 0.48 ± 0.13, WT: 0.65 ± 0.10, P = 0.017, unpaired t test). After treatment with saracatinib, hippocampal SUVR(WB) in APP/PS1 mice was significantly increased (P = 0.037, paired t test). A trend-level treatment effect was seen with hippocampal SUVR-1(BS). Saracatinib treatment effects may persist, as there were no significant differences between WT and APP/PS1 mice after drug washout. Conclusion: On the basis of the 11C-UCB-J PET results, hippocampal synaptic density was lower in APP/PS1 mice than in WT mice at baseline, and this deficit was normalized by treatment with saracatinib. These results support the use of 11C-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD.

RevDate: 2019-12-03

Schiller F, Frings L, Thurow J, et al (2019)

Limits for Reduction of Acquisition Time and Administered Activity in 18F-FDG PET Studies of Alzheimer Dementia and Frontotemporal Dementia.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 60(12):1764-1770.

We evaluated the effect of a reduced acquisition time for 18F-FDG PET studies of Alzheimer dementia (AD) and frontotemporal dementia (FTD) to derive a limit for reductions of acquisition time (improving patient compliance) and administered activity (lowering the radiation dose) with uncompromised diagnostic outcome. Methods: We included patients with a clinical diagnosis of AD (n = 13) or FTD (n = 12) who were examined with 18F-FDG PET/CT after injection of 210 ± 9 MBq of 18F-FDG. List-mode data were reconstructed over various time intervals simulating reduced acquisition times or administered activities. Volume-of-interest-based and voxelwise statistical analyses including group contrasts were performed for 15 different acquisition times ranging from 10 min to 2 s. In addition, masked visual reads were obtained from 3 readers independently for 7 different acquisition times down to 30 s, providing a diagnosis of either AD or FTD and the individual diagnostic certainty. Results: Regional mean uptake changed by less than 5% at a reduced acquisition time down to 1 min in all regions and patients except for the posterior cingulate cortex of 1 patient. Voxelwise group contrasts suggest a sufficient measurement time of only 2 min, for which the number of significant voxels decreased by merely 5% while maintaining their spatial pattern. In 450 visual reads at reduced times, no change in the original diagnosis was observed. The diagnostic certainty showed only a very slow and mild decline, with small effect sizes (Cohen's d) of 0.3, at acquisition times of 3 and 2 min compared with the original results at 10 min. Conclusion: Statistical results at a region and voxel level, as well as single-subject visual reads, reveal a considerable potential to reduce the typical 10-min acquisition time (by a factor of 4) without compromising diagnostic quality. Conversely, our data suggest that for a given acquisition time of 10 min and a similar effect size, the administered activity may be reduced to 50 MBq, resulting in an effective dose of less than 1 mSv for the PET examination.

RevDate: 2019-12-01

Sheu JJ, Yang LY, Renuka Sanotra M, et al (2019)

Reduction of AHI1 in the serum of Taiwanese with probable Alzheimer's disease.

Clinical biochemistry pii:S0009-9120(19)30814-8 [Epub ahead of print].

OBJECTIVE: The development of blood-based biomarkers for early diagnosis and treatment of Alzheimer's disease (AD) is desirable. In AD model mouse brain and neuronal cells, Abelson helper integration site-1 (AHI1) protein is reduced. AHI1 facilitates intracellular amyloid precursor protein (APP) translocation to inhibit amyloidogenic pathology of AD, and thus may be an AD biomarker.

METHODS: This study was conducted among 32 AD patients and 54 healthy control (HC) subjects. AHI1-related protein levels from initially collected serum samples in each group were screened using Western blotting. The protein concentrations of AHI1 and amyloid-β (Aβ), peptide(s) derived from APP, from all serum samples were analyzed using ELISA.

RESULTS: In AD serum, AHI1 and a large truncated C-terminal APP fragment were significantly reduced. The average concentrations of serum AHI1 and Aβ in AD were significantly lower than those in HC. Notably, AHI1 concentration in HC serum was decreased in an age-dependent manner, while it was consistently low in AD serum and had no correlation with Aβ or mini-mental state examination score. The receiver operating characteristic analysis on all subjects demonstrated an area under curve (AUC) value of 0.7 for AHI1 on AD diagnosis, while the AUC increased to 0.82 on the subjects younger than 77 years old, suggesting a good diagnostic performance of serum AHI1 for AD especially at relatively young age.

CONCLUSION: An early event of AHI1 reduction in the body of AD patients was observed. Serum AHI1 may be valuable for early diagnosis of AD.

RevDate: 2019-11-29

Foyet HS, Keugong Wado E, Ngatanko Abaissou HH, et al (2019)

Anticholinesterase and Antioxidant Potential of Hydromethanolic Extract of Ziziphus mucronata (Rhamnaceae) Leaves on Scopolamine-Induced Memory and Cognitive Dysfunctions in Mice.

Evidence-based complementary and alternative medicine : eCAM, 2019:4568401.

Ziziphus mucronata Willd, also known as "buffalo thorn," belongs to the family Rhamnaceae. Its bark and leaves are used in folk medicine for the treatment of various deficiencies related to nociception, inflammation, mood, and depression. Still, there is a lack of scientific data regarding its potential effect on learning and memory process. The present study was designed to investigate the neuroprotective potential of Ziziphus mucronata (ZM) on learning and memory impairment in a scopolamine-induced model of dementia in mice. The phytochemical analysis revealed five cyclopeptide alkaloids (sanjoinines) in the extract from Ziziphus Mucronata leaves using LC-HRMS, and the structural characterization of these compounds was determined via MS/MS. Alzheimer-type amnesia was induced by an intraperitoneal injection of scopolamine (1 mg/kg) to mice for 7 consecutive days. ZM (150 mg/kg, 300 mg/kg, and 600 mg/kg) and piracetam (150 mg/kg) were orally administrated to mice daily for a period of 14 days. Memory-related behavioural parameters were evaluated using the radial arm maze task for 7 days, Y-maze, and novel object recognition task. At the end of protocol schedule, animals were sacrificed, and the levels of acetylcholinesterase, malondialdehyde, catalase, and superoxide dismutase were determined in brain homogenates. Histological studies of the hippocampus were subsequently performed. The long-term scopolamine-injected group decreased the spontaneous alternation (Y-maze), the discrimination index, and the time taken to explore the new object (novel object recognition task). These effects were significantly reversed by ZM at all the doses tested. In the radial arm maze task, ZM (300 and 600 mg/kg) significantly decreased the working and reference memory errors when compared with the demented group. Scopolamine-mediated changes in AChE activity were also attenuated by ZM in mice. In addition, extract-treated groups showed a significant increase in the level of CAT and SOD activity and decreased levels of MDA in the mice brains, as compared with the control group. The present study suggests that ZM could have an important role in neuroprotection on this scopolamine-induced model of Alzheimer-type dementia.

RevDate: 2019-11-29

Qi Z, An Y, Zhang M, et al (2019)

Altered Cerebro-Cerebellar Limbic Network in AD Spectrum: A Resting-State fMRI Study.

Frontiers in neural circuits, 13:72.

Recent evidence suggests that the cerebellum is related to motor and non-motor cognitive functions, and that several coupled cerebro-cerebellar networks exist, including links with the limbic network. Since several limbic structures are affected by Alzheimer pathology, even in the preclinical stages of Alzheimer's disease (AD), we aimed to investigate the cerebral limbic network activity from the perspective of the cerebellum. Twenty patients with mild cognitive impairment (MCI), 18 patients with AD, and 26 healthy controls (HC) were recruited to acquire Resting-state functional MRI (rs-fMRI). We used seed-based approach to construct the cerebro-cerebellar limbic network. Two-sample t-tests were carried out to explore the differences of the cerebellar limbic network connectivity. The first result, a sub-scale network including the bilateral posterior part of the orbitofrontal cortex (POFC) extending to the anterior insular cortex (AIC) and left inferior parietal lobule (L-IPL), showed greater functional connectivity in MCI than in HC and less functional connectivity in AD than in MCI. The location of this sub-scale network was in accordance with components of the ventral attention network. Second, there was decreased functional connectivity to the right mid-cingulate cortex (MCC) in the AD and MCI patient groups relative to the HC group. As the cerebellum is not compromised by Alzheimer pathology in the prodromal stage of AD, this pattern indicates that the sub-scale ventral attention network may play a pivotal role in functional compensation through the coupled cerebro-cerebellar limbic network in MCI, and the cerebellum may be a key node in the modulation of social cognition.

RevDate: 2019-11-29

Dinet V, Petry KG, J Badaut (2019)

Brain-Immune Interactions and Neuroinflammation After Traumatic Brain Injury.

Frontiers in neuroscience, 13:1178.

Traumatic brain injury (TBI) is the principal cause of death and disability in children and young adults. Clinical and preclinical research efforts have been carried out to understand the acute, life-threatening pathophysiological events happening after TBI. In the past few years, however, it was recognized that TBI causes significant morbidity weeks, months, or years after the initial injury, thereby contributing substantially to the overall burden of TBI and the decrease of life expectancy in these patients. Long-lasting sequels of TBI include cognitive decline/dementia, sensory-motor dysfunction, and psychiatric disorders, and most important for patients is the need for socio-economic rehabilitation affecting their quality of life. Cerebrovascular alterations have been described during the first week after TBI for direct consequence development of neuroinflammatory process in relation to brain edema. Within the brain-immune interactions, the complement system, which is a family of blood and cell surface proteins, participates in the pathophysiology process. In fact, the complement system is part of the primary defense and clearance component of innate and adaptive immune response. In this review, the complement activation after TBI will be described in relation to the activation of the microglia and astrocytes as well as the blood-brain barrier dysfunction during the first week after the injury. Considering the neuroinflammatory activity as a causal element of neurological handicaps, some major parallel lines of complement activity in multiple sclerosis and Alzheimer pathologies with regard to cognitive impairment will be discussed for chronic TBI. A better understanding of the role of complement activation could facilitate the development of new therapeutic approaches for TBI.

RevDate: 2019-11-29

Mullard A (2019)

NIH launches open science Alzheimer initiative.

Nature reviews. Drug discovery, 18(12):895.

RevDate: 2019-11-29

van der Kant R, Goldstein LSB, R Ossenkoppele (2019)

Amyloid-β-independent regulators of tau pathology in Alzheimer disease.

Nature reviews. Neuroscience pii:10.1038/s41583-019-0240-3 [Epub ahead of print].

The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.

RevDate: 2019-11-29

Bello-Medina PC, González-Franco DA, Vargas-Rodríguez I, et al (2019)

Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease.

Neurologia (Barcelona, Spain) pii:S0213-4853(19)30109-4 [Epub ahead of print].

INTRODUCTION: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response.

DEVELOPMENT: We searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address two factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment.

CONCLUSION: This review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment.

RevDate: 2019-11-29

Levin J (2019)

Parkinsonism in genetic and sporadic Alzheimer's disease.

International review of neurobiology, 149:237-247.

Alzheimer disease (AD) is a neurodegenerative disease characterized by deposition of pathologically aggregated amyloid-β in the extracellular space and pathologically aggregated tau protein in the intracellular space. Mainly affected brain areas are the temporal and the parietal lobe, which cause the classical AD phenotype consisting of increasing forgetfulness and difficulties to orientate. However, AD pathology is not restricted to these brain areas and spreads through the brain as the disease progresses, which can lead to a number of additional symptoms and to atypical presentations. Motor symptoms in AD are the topic of this chapter. Even though motor symptoms are usually not severe and seldomly treated, motor symptoms are quite frequent and can be observed in the majority of AD cases. Motor symptoms are especially frequent in cases with early onset and long disease duration, for example in Apolipoprotein E e4 carriers and in familial early onset AD. In severe cases treatment with pharmacological approaches might be considered. However, treatment strategies largely rely on expert opinions. Due to potential positive impact on prognosis non-pharmacological treatment and exercise might be considered in less advanced cases.

RevDate: 2019-11-29

Fuior EV, AV Gafencu (2019)

Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond.

International journal of molecular sciences, 20(23): pii:ijms20235939.

Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, APOC1 gene is in linkage disequilibrium with APOE gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and-not last-to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene APOC1P, stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.

RevDate: 2019-11-27

Dubbioso R, Ruggiero L, Esposito M, et al (2019)

Different cortical excitability profiles in hereditary brain iron and copper accumulation.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology pii:10.1007/s10072-019-04147-0 [Epub ahead of print].

BACKGROUND AND AIM: Neurodegeneration with brain iron accumulation (NBIA) and Wilson's disease (WD) is considered the prototype of neurodegenerative disorders characterised by the overloading of iron and copper in the central nervous system. Growing evidence has unveiled the involvement of these metals in brain cortical neurotransmission. Aim of this study was to assess cortical excitability profile due to copper and iron overload.

METHODS: Three patients affected by NBIA, namely two patients with a recessive hereditary parkinsonism (PARK9) and one patient with aceruloplasminemia and 7 patients with neurological WD underwent transcranial magnetic stimulation (TMS) protocols to assess cortical excitability. Specifically, we evaluated the motor thresholds that reflect membrane excitability related to the voltage-gated sodium channels in the neurons of the motor system and the ease of activation of motor cortex via glutamatergic networks, and ad hoc TMS protocols to probe inhibitory-GABAergic (short interval intracortical inhibition, SICI; short-latency afferent inhibition, SAI; cortical silent period, CSP) and excitatory intracortical circuitry (intracortical facilitation, ICF).

RESULTS: Patients with NBIA exhibited an abnormal prolongation of CSP respect to HC and WD patients. On the contrary, neurological WD displayed higher motor thresholds and reduced CSP and SICI.

CONCLUSION: Hereditary conditions due to overload of copper and iron exhibited peculiar cortical excitability profiles that can help during differential diagnosis between these conditions. Moreover, such results can give us more clues about the role of metals in acquired neurodegenerative disorders, such as Parkinson disease, Alzheimer disease, and multiple sclerosis.

RevDate: 2019-11-27

Xiao Y, Matsuda I, Inoue M, et al (2019)

NMR-based site-resolved profiling of β-amyloid misfolding reveals structural transitions from pathologically relevant spherical oligomer to fibril.

The Journal of biological chemistry pii:RA119.008522 [Epub ahead of print].

Increasing evidence highlights the central role of neurotoxic oligomers of the 42-residue-long β-amyloid (Aβ42) in Alzheimer's disease (AD). However, very limited information is available on the structural transition from oligomer to fibril, particularly for pathologically relevant amyloids. To the best of our knowledge, we present here the first site-specific structural characterization of Aβ42 misfolding, from toxic oligomeric assembly yielding a similar conformation to an AD-associated Aβ42 oligomer, into a fibril. Transmission EM (TEM) analysis revealed that a spherical amyloid assembly (SPA) of Aβ42 with 15.6 ± 2.1 nm diameter forms in a ~30--mM Aβ42 solution after a ~10-h incubation at 4 ºC, followed by a slow conversion into fibril at ~180 h. Immunological analysis suggested that the SPA has a surface structure similar to that of amylospheroid (ASPD), a patient-derived toxic Aβ oligomer, which had a diameter of 10-15 nm in negative-stain TEM. Solid-state NMR (SSNMR) analyses indicated that the SPA structure involves a β-loop-β motif, which significantly differed from the triple-β motif observed for the Aβ42 fibril. The comparison of the 13C chemical shifts of SPA with those of the fibril prepared in the above conditions and inter-strand distance measurements suggested a large conformational change involving rearrangements of intermolecular β-sheet into inregister parallel β-sheet during the misfolding. A comparison of the SPA and ASPD 13C chemical shifts indicated that SPA is structurally similar to the ASPD relevant to AD. These observations provide insights into the architecture and key structural transitions of amyloid oligomers relevant for AD pathology.

RevDate: 2019-11-27

Moazzami K, Shao IY, Chen LY, et al (2019)

Atrial Fibrillation, Brain Volumes, and Subclinical Cerebrovascular Disease (from the Atherosclerosis Risk in Communities Neurocognitive Study [ARIC-NCS]).

The American journal of cardiology pii:S0002-9149(19)31156-7 [Epub ahead of print].

The aim of the present study was to investigate the association between atrial fibrillation (AF) and total and regional brain volumes among participants in the community-based Atherosclerosis Risk in Communities Neurocognitive study (ARIC-NCS). A total of 1,930 participants (130 with AF) with a mean age of 76.3 ± 5.2, who underwent 3T brain MRI scans in 2011 to 2013 were included. Prevalent AF was ascertained from study ECGs and hospital discharge codes. Brain volumes were measured using FreeSurfer image analysis software. Markers of subclinical cerebrovascular disease included lobar microhemorrhages, subcortical microhemorrhages, cortical infarcts, subcortical infarcts, lacunar infarcts, and volume of white matter hyperintensities. Linear regression models were used to assess the associations between AF status and brain volumes. In adjusted analyses, AF was not associated with markers of subclinical cerebrovascular disease. However, AF was associated with smaller regional brain volumes (including temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus [all p <0.05]) after controlling for demographics, cardiovascular risk factors, prevalent cardiovascular disease, and markers of subclinical cerebrovascular disease. Subgroup analysis revealed a significant interaction between AF and total brain volume with respect to age (p = 0.02), with associations between AF and smaller brain volumes being stronger for older individuals. In conclusion, AF was associated with smaller brain volumes, and the association was stronger among older individuals. This finding may be related to the longer exposure period of the older population to AF or the possibility that older people are more susceptible to the effects of AF on brain volume.

RevDate: 2019-11-26

Jiang W, Hu CY, Li FL, et al (2019)

Elevated parathyroid hormone levels and cognitive function: A systematic review.

Archives of gerontology and geriatrics, 87:103985 pii:S0167-4943(19)30228-6 [Epub ahead of print].

OBJECTIVE: To systematically estimate the association between elevated parathyroid hormone (PTH) levels and cognitive function.

METHODS: This review was conducted on ten papers identified through database searches from inception to 31 October 2018. The quality of studies was assessed using the Downs and Black checklist.

RESULTS: There is a low volume of data reporting on the impact of elevated PTH levels on cognitive impairment. The quality of the identified studies ranged from poor (37 %) to good (76 %). Although the results from studies were mixed, one cross-sectional study and one prospective study suggested a link between elevated PTH levels and a decrease in the Mini-Mental State Examination (MMSE) score. Three cross-sectional studies that assessed other cognitive domain in specific domains, such as language, memory and executive function provided mixed results for an association between elevated PTH levels and cognitive function. Two studies showed mixed evidence for a link between elevated PTH levels and poor executive function. One prospective study, one cross-sectional study and three case-control studies provide mixed evidence for an association between higher PTH levels and Alzheimer´s disease (AD). Two studies showed limited evidence for an association between elevated PTH levels and vascular dementia.

CONCLUSION: This review presented that the level of evidence available to support an association between elevated PTH levels and cognitive function was generally weak and inconsistent. Future studies with more better methodological quality are needed.

RevDate: 2019-11-26

Lang F, Ma K, CB Leibrock (2019)

1,25(OH)2D3 in Brain Function and Neuropsychiatric Disease.

Neuro-Signals, 27(1):40-49.

1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol) is a powerful regulator of mineral metabolism. The hormone increases calcium and phosphate plasma concentrations in part by stimulation of intestinal absorption and renal reabsorption of calcium and phosphate. It is primarily, but not exclusively, produced in the kidney. Renal 1,25(OH)2D3 formation is stimulated by calcium and phosphate deficiency and by parathyroid hormone which is up-regulated by hypocalcemia. 1,25(OH)2D3 formation is inhibited by fibroblast growth factor FGF23, which is up-regulated by phosphate excess and requires Klotho to become effective. Klotho- or FGF23-deficiency leads to excessive plasma 1,25(OH)2D3-, Ca2+- and phosphate-concentrations with severe soft tissue calcification and accelerated aging. Tissue calcification and premature aging are prevented by NH4Cl without affecting 1,25(OH)2D3-formation. 1,25(OH)2D3 has powerful effects apparently unrelated to mineral metabolism, including anti-inflammatory actions and modification of multiple brain functions. Excessive 1,25(OH)2D3 formation in klotho-deficient NH4Cl-treated mice leads to an amazing surge of exploratory behavior, lack of anxiety and decreased depression, effects dissipated by low vitamin D diet. Conversely, vitamin D deficient mice display reduced explorative behavior, enhanced anxiety, aberrant grooming, submissive social behavior, social neglect and maternal cannibalism. 1,25(OH)2D3 is generated in human brain, and acts on diverse structures including prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra. In neurons 1,25(OH)2D3 suppresses oxidative stress, inhibits inflammation, provides neuroprotection, down-regulates a variety of inflammatory mediators and up-regulates a wide variety of neurotrophins. Diseases postulated to be favorably modified by 1,25(OH)2D3 include multiple sclerosis, Parkinson´s disease, Alzheimer´s disease, depression, bipolar disorder and schizophrenia. Clearly, substantial additional experimentation is required to fully understand the neuro-psycho-pathophysiological role of 1,25(OH)2D3 and to exploit 1,25(OH)2D3 or related agonists in the treatment of neuro-psychiatric disorders.

RevDate: 2019-11-26

Yu JH, Han K, Park S, et al (2019)

Incidence and Risk Factors for Dementia in Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Korea.

Diabetes & metabolism journal pii:43.e62 [Epub ahead of print].

BACKGROUND: Diabetes mellitus is associated with an increased risk of dementia. We aimed to comprehensively analyze the incidence and risk factors for dementia and young-onset dementia (YOD) in diabetic patients in Korea using the National Health Insurance Service data.

METHODS: Between January 1, 2009 and December 31, 2012, a total of 1,917,702 participants with diabetes were included and followed until the date of dementia diagnosis or until December 31, 2015. We evaluated the incidence and risk factors for all dementia, Alzheimer's disease (AD), and vascular dementia (VaD) by Cox proportional hazards analyses. We also compared the impact of risk factors on the occurrence of YOD and late-onset dementia (LOD).

RESULTS: During an average of 5.1 years of follow-up, the incidence of all types of dementia, AD, or VaD was 9.5, 6.8, and 1.3/1,000 person-years, respectively, in participants with diabetes. YOD comprised 4.8% of all dementia occurrence, and the ratio of AD/VaD was 2.1 for YOD compared with 5.5 for LOD. Current smokers and subjects with lower income, plasma glucose levels, body mass index (BMI), and subjects with hypertension, dyslipidemia, vascular complications, depression, and insulin treatment developed dementia more frequently. Vascular risk factors such as smoking, hypertension, and previous cardiovascular diseases were more strongly associated with the development of VaD than AD. Low BMI and a history of stroke or depression had a stronger influence on the development of YOD than LOD.

CONCLUSION: The optimal management of modifiable risk factors may be important for preventing dementia in subjects with diabetes mellitus.

RevDate: 2019-11-26

Joseph E, Villalobos-Acosta DMÁ, Torres-Ramos MA, et al (2019)

Neuroprotective Effects of Apocynin and Galantamine During the Chronic Administration of Scopolamine in an Alzheimer's Disease Model.

Journal of molecular neuroscience : MN pii:10.1007/s12031-019-01426-5 [Epub ahead of print].

Alzheimer's disease (AD) is one of the most complicated neurodegenerative diseases, and several hypotheses have been associated with its development and progression, such as those involving glucose hypometabolism, the cholinergic system, calcium imbalance, inflammation, oxidative imbalance, microtubule instability, and the amyloid cascade, several of which are related to oxidative stress (free radical generation), which contributes to neuronal death. Therefore, several efforts have been made to establish a sporadic AD model that takes into account these hypotheses. One model that replicates the increase in amyloid beta (Aβ) and oxidative stress in vivo is the scopolamine model. In the present work, the chronic administration (6 weeks) of scopolamine was used to analyze the neuroprotective effects of apocynin and galantamine. The results showed that scopolamine induced cognitive impairment, which was evaluated 24 h after the final dose was administered. In addition, after scopolamine administration, the Aβ and superoxide anion levels were increased, and NADPH oxidase 2 (NOX2), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa B (NFkB) genes were overexpressed. These effects were not observed when either apocynin or galantamine was administered during the last 3 weeks of scopolamine treatment, and although the results from both molecules were related to lower Aβ production and, consequently, lower superoxide anion production, they were likely realized through different pathways. That is, both apocynin and galantamine diminished NADPH oxidase expression, but their effects on transcription factor expression differed. Moreover, experiments in silico showed that galantamine did not interact with the active site of beta secretase, whereas diapocynin, an apocynin metabolite, interacted with the beta-site APP-cleaving enzyme (BACE1) at the catalytic site.

RevDate: 2019-11-26

Santoro SL, Cannon S, Capone G, et al (2019)

Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database.

Genetics in medicine : official journal of the American College of Medical Genetics pii:10.1038/s41436-019-0706-8 [Epub ahead of print].

PURPOSE: An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease.

METHODS: Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls.

RESULTS: We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p < 0.001 for all but externalizing behaviors). Patients with regression had four times as many mental health concerns (p < 0.001), six times as many stressors (p < 0.001), and seven times as many depressive symptoms (p < 0.001). Tiered medical evaluation most often identified abnormalities in vitamin D 25-OH levels, polysomnograms, thyroid peroxidase antibodies, and celiac screens. Analysis of the subset of patients with nondiagnostic medical evaluations reinforced the proposed definition.

CONCLUSIONS: Our case-control evidence supports a proposed definition of unexplained regression in Down syndrome. Establishing this clinical definition supports future research and investigation of an underlying mechanism.

RevDate: 2019-11-26

Corkins MR, COMMITTEE ON NUTRITION (2019)

Aluminum Effects in Infants and Children.

Pediatrics pii:peds.2019-3148 [Epub ahead of print].

Aluminum has no known biological function; however, it is a contaminant present in most foods and medications. Aluminum is excreted by the renal system, and patients with renal diseases should avoid aluminum-containing medications. Studies demonstrating long-term toxicity from the aluminum content in parenteral nutrition components led the US Food and Drug Administration to implement rules for these solutions. Large-volume ingredients were required to reduce the aluminum concentration, and small-volume components were required to be labeled with the aluminum concentration. Despite these rules, the total aluminum concentration from some components continues to be above the recommended final concentration. The concerns about toxicity from the aluminum present in infant formulas and antiperspirants have not been substantiated but require more research. Aluminum is one of the most effective adjuvants used in vaccines, and a large number of studies have documented minimal adverse effects from this use. Long-term, high-concentration exposure to aluminum has been linked in meta-analyses with the development of Alzheimer disease.

RevDate: 2019-11-27

Mendoza-Léon R, Puentes J, Uriza LF, et al (2019)

Single-slice Alzheimer's disease classification and disease regional analysis with Supervised Switching Autoencoders.

Computers in biology and medicine, 116:103527 pii:S0010-4825(19)30386-5 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a difficult to diagnose pathology of the brain that progressively impairs cognitive functions. Computer-assisted diagnosis of AD based on image analysis is an emerging tool to support AD diagnosis. In this article, we explore the application of Supervised Switching Autoencoders (SSAs) to perform AD classification using only one structural Magnetic Resonance Imaging (sMRI) slice. SSAs are revised supervised autoencoder architectures, combining unsupervised representation and supervised classification as one unified model. In this work, we study the capabilities of SSAs to capture complex visual neurodegeneration patterns, and fuse disease semantics simultaneously. We also examine how regions associated to disease state can be discovered by SSAs following a local patch-based approach.

METHODS: Patch-based SSAs models are trained on individual patches extracted from a single 2D slice, independently for Axial, Coronal, and Sagittal anatomical planes of the brain at selected informative locations, exploring different patch sizes and network parameterizations. Then, models perform binary class prediction - healthy (CDR = 0) or AD-demented (CDR > 0) - on test data at patch level. The final subject classification is performed employing a majority rule from the ensemble of patch predictions. In addition, relevant regions are identified, by computing accuracy densities from patch-level predictions, and analyzed, supported by Atlas-based regional definitions.

RESULTS: Our experiments employing a single 2D T1-w sMRI slice per subject show that SSAs perform similarly to previous proposals that rely on full volumetric information and feature-engineered representations. SSAs classification accuracy on slices extracted along the Axial, Coronal, and Sagittal anatomical planes from a balanced cohort of 40 independent test subjects was 87.5%, 90.0%, and 90.0%, respectively. A top sensitivity of 95.0% on both Coronal and Sagittal planes was also obtained.

CONCLUSIONS: SSAs provided well-ranked accuracy performance among previous classification proposals, including feature-engineered and feature learning based methods, using only one scan slice per subject, instead of the whole 3D volume, as it is conventionally done. In addition, regions identified as relevant by SSAs' were, in most part, coherent or partially coherent in regard to relevant regions reported on previous works. These regions were also associated with findings from medical knowledge, which gives value to our methodology as a potential analytical aid for disease understanding.

RevDate: 2019-11-25

Liu Y, Zhong X, Shen J, et al (2019)

Elevated serum TC and LDL-C levels in Alzheimer's disease and mild cognitive impairment: a meta-analysis study.

Brain research pii:S0006-8993(19)30608-0 [Epub ahead of print].

Serum lipid levels such as triglyceride and cholesterol has been reported to play an important role in the pathophysiological process of Alzheimer disease (AD) and mild cognitive impairment (MCI). However, it still remains controversial in different studies. Here, we performed a meta-analysis to assess the importance of serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in AD and MCI patients. PubMed, China National Knowledge Infrastructure (CNKI) system database were used to identify 17 studies(10 AD-only + 4 MCI-only + 3 shared AD/MCI), including 2333 cases and 3615 healthy controls (HC). We found that compared with HC, both the serum TC levels [SMD = 0.58; 95%CI (0.25, 0.90); P =0.001) and the serum LDL-C levels [SMD = 0.7780; 95%CI (0.3940, 1.1521); P = 0.000] were higher in cognitive impairment population (including AD and MCI) than those in HC, respectively. Furthermore, we analyzed the serum TC and LDL-C levels in AD and MCI patients. We found that the serum TC levels [SMD = 0.76; 95% CI (0.13, 1.40); P= 0.019]1 and the LDL-C levels [SMD = 1.40; 95% CI (0.70, 2.10; P= 0.000] were increased in AD patients. In the MCI patients, the serum TC levels [SMD = 0.30; 95%CI (0.01, 0.59); P =0.041] had a significantly upward trend, while the LDL-C levels had no significant change, compared with HC subjects. However, there is no significant changes in HDL-C and TG levels in AD or MCI patients. Therefore, our results suggested that the elevated TC and LDL-C levels may be a potential risk factor for cognitive impairment.

RevDate: 2019-11-25

Anonymous (2019)

Correction to: Causal Effect of Lp(a) [Lipoprotein(a)] Level on Ischemic Stroke and Alzheimer Disease: A Mendelian Randomization Study.

Stroke, 50(12):e439.

RevDate: 2019-11-25

Wessels AM, Tariot PN, Zimmer JA, et al (2019)

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials.

JAMA neurology pii:2755347 [Epub ahead of print].

Importance: Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression.

Objective: To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia.

AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging-Alzheimer's Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study.

Interventions: Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo.

Main Outcomes and Measures: The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale-cognitive subscale. Secondary outcomes included Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population.

Results: Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo.

Conclusions and Relevance: Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline.

Trial Registration: ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573.

RevDate: 2019-11-25

Meng H, Li Y, Zhang W, et al (2019)

The relationship between cognitive impairment and homocysteine in a B12 and folate deficient population in China: A cross-sectional study.

Medicine, 98(47):e17970.

Alzheimer disease (AD) is the most common neurodegenerative disease in the world. The relationship between AD and homocysteine (Hcy) is contradictory.A community-based investigation was conducted to find patients with AD in a vitamin B deficient population (≥55 years old) in Lüliang area in China. Venous blood samples were collected. Serum Hcy, folate, and vitamin B12 were measured. For each case, 4 controls were selected matched with age to evaluate the relationship between Hcy and AD.The crude prevalence of AD among people ages 55 years or older in this area was 8.60%. There were significant differences in serum Hcy and B12 between the case and control groups. We found that the higher level of serum Hcy was associated with a high risk of AD, and higher education level, higher folate and B12 concentration were protective factors to AD.Adjustment of diet structure and supplementation of folate and B12 may offer potential therapeutic measures in this area.

RevDate: 2019-11-25

Lau KF, Chow WN, Ngo JCK, et al (2019)

FE65 serine-610 phosphorylation and its functional implications in Alzheimer disease amyloid precursor protein processing.

Hong Kong medical journal = Xianggang yi xue za zhi, 25 Suppl 7(5):44-47.

RevDate: 2019-11-25

Masdeu JC (2020)

Neuroimaging of Diseases Causing Dementia.

Neurologic clinics, 38(1):65-94.

Neuroimaging provides a window on the biological events underlying dementia. Amyloid PET is positive in Alzheimer disease (AD) and some cases of diffuse Lewy body disease, but negative in the frontotemporal dementias (FTDs). Tau PET using the current tracers shows the greatest signal in AD and a lesser signal in FTD. Quantifying volume loss with MRI and measuring metabolism with fluorodeoxyglucose PET helps separate different causes of dementia and follow their progression. Brain inflammation can be assessed with PET. Some of these techniques, still investigational, are likely to find their clinical niche in the near future.

RevDate: 2019-11-24

Selles MC, Fortuna JTS, Zappa-Villar MF, et al (2019)

Adenovirus-Mediated Transduction of Insulin-Like Growth Factor 1 Protects Hippocampal Neurons from the Toxicity of Aβ Oligomers and Prevents Memory Loss in an Alzheimer Mouse Model.

Molecular neurobiology pii:10.1007/s12035-019-01827-y [Epub ahead of print].

Alzheimer's disease (AD) is the main cause of dementia in the elderly. Although activation of brain insulin signaling has been shown to be neuroprotective, to preserve memory in AD models, and appears beneficial in patients, the role of insulin-like growth factor 1 (IGF1) remains incompletely understood. We found reduced active/inactive IGF1 ratio and increased IGF1R expression in postmortem hippocampal tissue from AD patients, suggesting impaired brain IGF1 signaling in AD. Active/inactive IGF-1 ratio was also reduced in the brains of mouse models of AD. We next investigated the possible protective role of IGF1 in AD models. We used a recombinant adenoviral vector, RAd-IGF1, to drive the expression of IGF1 in primary hippocampal neuronal cultures prior to exposure to AβOs, toxins that accumulate in AD brains and have been implicated in early synapse dysfunction and memory impairment. Cultures transduced with RAd-IGF1 showed decreased binding of AβOs to neurons and were protected against AβO-induced neuronal oxidative stress and loss of dendritic spines. Significantly, in vivo transduction with RAd-IGF1 blocked memory impairment caused by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Our results demonstrate altered active IGF1 and IGF1R levels in AD hippocampi, and suggest that boosting brain expression of IGF1 may comprise an approach to prevent neuronal damage and memory loss in AD.

RevDate: 2019-11-24

Olofsson JK, Larsson M, Roa C, et al (2019)

Interaction Between Odor Identification Deficit and APOE4 Predicts 6-Year Cognitive Decline in Elderly Individuals.

Behavior genetics pii:10.1007/s10519-019-09980-9 [Epub ahead of print].

Olfactory identification impairment might indicate future cognitive decline in elderly individuals. An unresolved question is to what extent this effect is dependent on the ApoE-ε4, a genotype associated with risk of Alzheimer's Disease (AD). Given the current concern about reproducibility in empirical research, we assessed this issue in a large sample (n = 1637) of older adults (60 - 96 years) from the population-based longitudinal Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). A hierarchical regression analysis was carried out to determine if a low score on an odor identification test, and the presence of ApoE-ε4, would predict the magnitude of a prospective 6-year change in the Mini-Mental State Examination (MMSE) after controlling for demographic, health-related, and cognitive variables. We found that overall, lower odor identification performance was predictive of cognitive decline, and, as hypothesized, we found that the effect was most pronounced among ApoE-ε4 carriers. Our results from this high-powered sample suggest that in elderly carriers of the ApoE-ε4 allele, odor identification impairment provides an indication of future cognitive decline, which has relevance for the prognosis of AD.

RevDate: 2019-11-24

Guo Y, Xu W, Li JQ, et al (2019)

Genome-wide association study of hippocampal atrophy rate in non-demented elders.

Aging, 11: pii:102470 [Epub ahead of print].

Hippocampal atrophy rate has been correlated with cognitive decline and its genetic modifiers are still unclear. Here we firstly performed a genome-wide association study (GWAS) to identify genetic loci that regulate hippocampal atrophy rate. Six hundred and two non-Hispanic Caucasian elders without dementia were included from the Alzheimer's Disease Neuroimaging Initiative cohort. Three single nucleotide polymorphisms (SNPs) (rs4420638, rs56131196, rs157582) in the TOMM40-APOC1 region were associated with hippocampal atrophy rate at genome-wide significance and 3 additional SNPs (in TOMM40 and near MIR302F gene) reached a suggestive level of significance. Strong linkage disequilibrium between rs4420638 and rs56131196 was found. The minor allele of rs4420638 (G) and the minor allele of rs157582 (T) showed associations with lower Mini-mental State Examination score, higher Alzheimer Disease Assessment Scale-cognitive subscale 11 score and smaller entorhinal volume using both baseline and longitudinal measurements, as well as with accelerated cognitive decline. Moreover, rs56131196 (P = 1.96 × 10-454) and rs157582 (P = 9.70 × 10-434) were risk loci for Alzheimer's disease. Collectively, rs4420638, rs56131196 and rs157582 were found to be associated with hippocampal atrophy rate. Besides, they were also identified as genetic loci for cognitive decline.

RevDate: 2019-11-24

Mozafari N, Farjadian F, Samani SM, et al (2019)

Simvastatin-chitosan-citicoline conjugates nanoparticles as the co-delivery system in Alzheimer susceptible patients.

International journal of biological macromolecules pii:S0141-8130(19)38302-3 [Epub ahead of print].

The main goal of this study was the preparation and characterization of a chitosan-based system for co-delivery of simvastatin and citicoline to overcome simvastatin unwanted side effects in Alzheimer's disease. This conjugated complex was synthesized in three steps, and 1HNMR, FTIR, and UV-Vis spectroscopy confirmed its success. The simvastatin conjugation rate to chitosan was 1.67 times more than citicoline. X-ray diffraction results showed that the crystalline property of both drugs converted to an amorphous state during the synthesis of the conjugated form. Further, SEM images revealed that the developed nanoparticles have a spherical shape with a size between 100 and 300 nm. Another characterization test was RBC hemolysis, with the lowest value at 6.04% and the highest value at 89.56% and became much lower after preparing nanoparticles using the ionotropic technique. TEM characterized the nanoparticles and showed that the gelation technique stabilized the particles.

RevDate: 2019-11-23

Yu L, Boyle PA, Dawe RJ, et al (2019)

Contribution of TDP and hippocampal sclerosis to hippocampal volume loss in older-old persons.

Neurology pii:WNL.0000000000008679 [Epub ahead of print].

OBJECTIVE: To investigate the contribution of Alzheimer disease (AD) vs non-AD neuropathologies to hippocampal atrophy.

METHODS: The Religious Orders Study and Rush Memory and Aging Project are clinicopathologic cohort studies of aging. The current study included 547 participants who had undergone brain autopsy and postmortem hippocampal volume measurement by November 1, 2018. Hippocampal volume was measured with postmortem MRI via a 3D region of interest applied to the hippocampal formation. Neuropathologies were measured via uniform structured evaluations. Linear regression analyses estimated the proportion of variance of hippocampal volume attributable to AD and non-AD neuropathologies.

RESULTS: The average age at death was 90 years, and the average hippocampal volume was 2.1 mL. AD, transactive response DNA-binding protein 43 (TDP), hippocampal sclerosis (HS), and atherosclerosis were associated with hippocampal volume. After demographics and total hemisphere volume were controlled for, 7.0% of the variance (95% bootstrapped confidence interval [CI] 4.3%-10.5%) of hippocampal volume was attributable to AD pathology. TDP/HS explained an additional 4.5% (95% CI 2.2%-7.6%). Among individuals with Alzheimer dementia (n = 232), 3.1% (95% CI 0.6%-7.7%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 6.1% (95% CI 2.2%-11.6%). Among those without Alzheimer dementia (n = 307), 3.2% (95% CI 0.9%-7.3%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 1.1%, which did not reach statistical significance. Lewy bodies and vascular diseases had modest contribution to the variance of hippocampal volume.

CONCLUSIONS: Both AD and TDP/HS contribute to hippocampal volume loss in older-old persons, with TDP/HS more strongly associated with hippocampal volume than AD in Alzheimer dementia.

RevDate: 2019-11-22

Sun P, Lou W, Liu J, et al (2019)

Mapping the patterns of cortical thickness in single- and multiple-domain amnestic mild cognitive impairment patients: a pilot study.

Aging, 11: pii:102362 [Epub ahead of print].

Amnestic mild cognitive impairment (aMCI) is considered as a transitional stage between the expected cognitive decline of normal aging and Alzheimer's disease (AD). Structural brain difference has shown the potential in cognitive related diagnosis, however cortical thickness patterns transferred from aMCI to AD, especially in the subtypes of aMCI, is still unclear. In this study, we investigated the cortical thickness discrepancies among AD, aMCI and normal control (NC) entities, especially for two subtypes of aMCI - multiple-domain aMCI (aMCI-m) and single-domain aMCI (aMCI-s). Both region of interest (ROI)-based and vertex-based statistical strategies were performed for group-level cortical thickness comparison. Spearman correlation was utilized to identify the correlation between cortical thickness and clinical neuropsychological scores. The result demonstrated that there was a significant cortical thickness decreasing tendency in fusiform gyrus from NC to aMCI-s to aMCI-m to finally AD in both left and right hemispheres. Meanwhile, the two subtypes of aMCI showed cortical thickness difference in middle temporal gyrus in left hemisphere. Spearman correlation indicated that neuropsychological scores had significant correlations with entorhinal, inferior temporal and middle temporal gyrus. The findings suggested that cortical thickness might serve as a potential imaging biomarker for the differential diagnosis of cognitive impairment.

RevDate: 2019-11-22

Zhunina OA, Yabbarov NG, Grechko AV, et al (2019)

Neurodegenerative diseases associated with mitochondrial DNA mutations.

Current pharmaceutical design pii:CPD-EPUB-102531 [Epub ahead of print].

Mitochondrial dysfunction underlies several human chronic pathologies, including cardiovascular disorders, cancers and neurodegenerative diseases. Impaired mitochondrial function associated with oxidative stress can be a result of both nuclear and mitochondrial DNA (mtDNA) mutations. Neurological disorders associated with mtDNA mutations include mitochondrial encephalomyopathy, chronic progressive external ophthalmoplegia, neurogenic weakness, and Leigh syndrome. Moreover, mtDNA mutations were shown to play a role in the development of Parkinson and Alzheimer's diseases. In this review, the discuss the current knowledge on the distribution and possible roles of mtDNA mutations in the onset and development of various neurodegenerative diseases, with special focus on Parkinson and Alzheimer's diseases.

RevDate: 2019-11-26

Schreiber JA, Schepmann D, Frehland B, et al (2019)

A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors.

Communications biology, 2:420.

N-methyl-D-aspartate receptors (NMDARs), especially GluN2B-containing NMDARs, are associated with neurodegenerative diseases like Parkinson, Alzheimer and Huntington based on their high Ca2+ conductivity. Overactivation leads to high intracellular Ca2+ concentrations and cell death rendering GluN2B-selective inhibitors as promising drug candidates. Ifenprodil represents the first highly potent prototypical, subtype-selective inhibitor of GluN2B-containing NMDARs. However, activity of ifenprodil on serotonergic, adrenergic and sigma receptors limits its therapeutic use. Structural reorganization of the ifenprodil scaffold to obtain 3-benzazepines retained inhibitory GluN2B activity but decreased the affinity at the mentioned non-NMDARs. While scaffold optimization improves the selectivity, the molecular inhibitory mechanism of these compounds is still not known. Here, we show a common inhibitory mechanism of ifenprodil and the related 3-benzazepines by mutational modifications of the receptor binding site, chemical modifications of the 3-benzazepine scaffold and subsequent in silico simulation of the inhibitory mechanism.

RevDate: 2019-11-26

Lue LF, Pai MC, Chen TF, et al (2019)

Corrigendum: Age-Dependent Relationship Between Plasma Aβ40 and Aβ42 and Total Tau Levels in Cognitively Normal Subjects.

Frontiers in aging neuroscience, 11:292.

[This corrects the article DOI: 10.3389/fnagi.2019.00222.].

RevDate: 2019-11-26

Klimova B, Novotný M, Kuca K, et al (2019)

Effect Of An Extra-Virgin Olive Oil Intake On The Delay Of Cognitive Decline: Role Of Secoiridoid Oleuropein?.

Neuropsychiatric disease and treatment, 15:3033-3040.

Currently, there is an increase in the number of the world's aging population. This aging process is often connected with cognitive decline of some functions such as memory or speed processing loss. Since Alzheimer's disease cannot be cured yet, considerable efforts are being made to at least delay this cognitive decline among elderly in order to maintain and prolong the quality of their life. This can also be achieved by non-pharmacological approaches such as performing physical activities, cognitive training, or adhering to a Mediterranean Diet (MedDiet). One of the components of MedDiet - extra-virgin olive oil (EVOO) - has considerable health benefits. The purpose of this review is to examine the effect of EVOO intake on the delay of cognitive decline among the elderly. The methodology is based on a literature review of available sources found on the research topic in three acknowledged databases: Web of Science, Scopus, and PubMed. The results of in vitro and in vivo studies indicate that the regular intake of EVOO is associated with enhanced cognitive functions, which means that this oil may have a neuroprotective effect and could positively prevent the development of dementia, especially Alzheimer's dementia. It is believed that secoiridoid oleuropein is responsible for this effectiveness. Furthermore, there is also a need of more randomized controlled studies or longitudinal observational studies to be performed to confirm the efficacy of the beneficial health effect of EVOO on the delay of cognitive decline.

RevDate: 2019-11-22

Wood H (2019)

A single case from Columbia provides insights into Alzheimer disease resistance.

Nature reviews. Neurology pii:10.1038/s41582-019-0293-y [Epub ahead of print].

RevDate: 2019-11-22

Makunts T, Alpatty S, Lee KC, et al (2019)

Proton-pump inhibitor use is associated with a broad spectrum of neurological adverse events including impaired hearing, vision, and memory.

Scientific reports, 9(1):17280 pii:10.1038/s41598-019-53622-3.

Proton-pump inhibitors, PPIs, are considered effective therapy for stomach acid suppression due to their irreversible inhibition of the hydrogen/potassium pump in the gastric parietal cells. They are widely prescribed and are considered safe for over-the-counter use. Recent studies have shown an association between PPI use and Alzheimer dementia, while others have disputed that connection. We analyzed over ten million United States Food and Drug Administration Adverse Event Reporting System reports, including over forty thousand reports containing PPIs, and provided evidence of increased propensity for memory impairment among PPI reports when compared to histamine-2 receptor antagonist control group. Furthermore, we found significant associations of PPI use with a wide range of neurological adverse reactions including, migraine, several peripheral neuropathies, and visual and auditory neurosensory abnormalities.

RevDate: 2019-11-22

Pagoni A, Marinelli L, Di Stefano A, et al (2019)

Novel anti-Alzheimer phenol-lipoyl hybrids: Synthesis, physico-chemical characterization, and biological evaluation.

European journal of medicinal chemistry pii:S0223-5234(19)31032-3 [Epub ahead of print].

To date, drugs that hit a single target are inadequate for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. The development of multitarget ligands, able to interact with the different pathways involved in the progession of these disorders, represents a great challenge for medicinal chemists. In this context, we report here the synthesis and biological evaluation of phenol-lipoyl hybrids (SV1-13), obtained via a linking strategy, to take advantage of the synergistic effect due to the antioxidant portions and anti-amyloid properties of the single constituents present in the hybrid molecule. Biological results showed that SV5 and SV10 possessed the best protective activity against Aβ1-42 induced neurotoxicity in differentiated SH-SY5Y cells. SV9 and SV10 showed remarkable antioxidant properties due to their ability to counteract the damage caused by H2O2 in SHSY-5Y-treated cells. Hovewer, SV5, showing moderate antioxidant and good neuroprotective activities, resulted the best candidate for further experiments since it also resulted stable both simulated and plasma fluids.

RevDate: 2019-11-22

Ming Y, Hsu SW, Yen YY, et al (2019)

Association of oral health-related quality of life and Alzheimer disease: A systematic review.

The Journal of prosthetic dentistry pii:S0022-3913(19)30545-1 [Epub ahead of print].

STATEMENT OF PROBLEM: Oral health-related quality of life (OHRQoL) is a subjective measure that assesses a person's perception of oral health. Patients with Alzheimer disease (AD) suffer from impaired cognitive function and a compromised ability to perform activities of daily living. Further exploration is needed to clarify whether OHRQoL is negatively impacted by cognitive degeneration and oral health conditions among patients with AD.

PURPOSE: The purpose of this systematic review was to increase understanding of OHRQoL among patients with AD and explore factors that may affect OHRQoL.

MATERIAL AND METHODS: Searches were conducted in PubMed, the Cochrane Library database, Medline, EBSCO, ProQuest, and EMBASE until August 30, 2018, with no date restrictions. The initial search targeted quantitative observational studies published in English that included the keywords AD, oral, prosthesis, and OHRQoL. Data extraction was independently conducted by 2 reviewers. OHRQoL was investigated as the outcome. Cognitive status and oral health conditions were treated as exposures. Tools used to measure OHRQoL included the Geriatric Oral Health Assessment Index (GOHAI) and the Oral Health Impact Profile. The research adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

RESULTS: Six studies were included. The sample sizes ranged from 30 to 226 participants, 5 studies used cross-sectional designs, and 1 was a nonrandomized controlled trial. Three studies reported higher OHRQoL scores among participants with AD than those among controls, but only 1 study showed a statistically significant difference. A statistical analysis was conducted with 4 studies that reported GOHAI scores, and no significant differences were found in GOHAI scores between participants with AD and controls (standard mean difference: 0.09; 95% confidence interval: -0.66 to 0.85). All studies that explored factors affecting OHRQoL showed different associations between cognitive impairment, oral health conditions, and OHRQoL. One study showed that cognitive impairment was negatively associated with OHRQoL. Three studies found oral health conditions (including periodontitis, gingival bleeding, probing depth >4 mm, and number of natural teeth) impaired the OHRQoL of participants with AD. Three studies reported that prosthetic type and quality positively affected OHRQoL among participants with AD.

CONCLUSIONS: OHRQoL may not fully represent actual oral health problems of patients with AD. Clinical dentists should evaluate oral problems in this population, preferably by using both subjective and objective examinations, including oral and dental conditions. This will ensure oral problems among patients with AD can be detected early and timely treatment provided.

RevDate: 2019-11-22

Seraji-Bzorgzad N, Paulson H, J Heidebrink (2019)

Neurologic examination in the elderly.

Handbook of clinical neurology, 167:73-88.

Clinical evaluation of neurologic disorders in the elderly requires seeking a thorough history and performing an age-appropriate neurologic examination with special attention to changes that occur with normal aging. The history should be obtained from the patient as well as collateral sources close to the patient to ensure accuracy and should include contextual elements such as medical history, social, economic, and psychological background, as well as an assessment of current functional state beyond activities of daily living. The safety of the patient, including the presence of physical, psychological, and financial threats, should be addressed during the interview. The neurological examination in older adults may need to be modified to circumvent disabilities such as hearing and visual impairment. Some elements of the neurological examination are expected to be affected by the process of aging, including pupillary reactivity, presbyopia, difficulty with ocular pursuit and up-gaze, reduced or absent distal reflexes, slower motor speed, and reduced ability to tandem walk, among others. In addition to a screening neurological assessment, evaluation of older adults with a particular complaint may require additional interview queries and examination manoeuvres. Common symptoms in the elderly include cognitive difficulties, balance and gait disorders, tremors, and neuropathy. A specialized approach to patients with cognitive difficulties must include assessment of each cognitive domain, including attention, executive function, learning and memory, perceptual-motor function, and social cognition. Balance and gait are essential parts of the neurological examination, and in patients with a history of falls or mobility issues, should become a central part of the evaluation. In patient with tremors, careful observation of the tremor quality (amplitude, frequency, and alleviating/exacerbating factors such as rest, movement, and posture) can aid diagnosis. Evaluation of neuropathy includes determining modality (numbness, tingling, pain, and weakness) and the distribution of symptoms in order to localize the site of nerve injury, which can be supplemented with nerve conduction studies/electromyography, to guide further diagnostic workup and treatment. A combination of detailed history and examination often will suggest a likely underlying neurodegenerative disorder and guide further diagnostic workup to establish a specific diagnosis.

RevDate: 2019-11-22

Carr DB, Stowe JD, JC Morris (2019)

Driving in the elderly in health and disease.

Handbook of clinical neurology, 167:563-573.

Driving is a complex, multifaceted instrumental activity of daily living that has an independent influence on multiple health and well-being outcomes among older adults. Therefore, the benefits of driving to the individual must be balanced, through careful assessment and diagnosis, with the potential risk to self and others posed by a medically impaired driver. The influence of dementia changes substantially during the disease progression from very mild to mild, and driving is not advised for those who have progressed to the moderate stage of Alzheimer disease. Fortunately, validated high-quality screening instruments, including modern simulators and other technology aids, can help clinicians trichotomize risk (i.e., high, moderate, or low) and determine which patients need further evaluation by a driving specialist (e.g., those in the moderate range). Moreover, a body of evidence is building regarding the efficacy of certain intervention pathways to maintain current levels of driving performance among individuals with dementia, or at least slow its decline. Even with the progression of advanced driving technologies, understanding driving ability of patients with dementia will remain a critical challenge to clinicians for the foreseeable future.

RevDate: 2019-11-22

Soria Lopez JA, González HM, GC Léger (2019)

Alzheimer's disease.

Handbook of clinical neurology, 167:231-255.

Alzheimer's disease (AD) dementia refers to a particular onset and course of cognitive and functional decline associated with age together with a particular neuropathology. It was first described by Alois Alzheimer in 1906 about a patient whom he first encountered in 1901. Modern clinical diagnostic criteria have been developed, and criteria have also been proposed to recognize preclinical (or presymptomatic) stages of the disease with the use of biomarkers. The primary neuropathology was described by Alzheimer, and in the mid-1980s subsequently evolved into a more specific neuropathologic definition that recognizes the comorbid neuropathologies that frequently contribute to clinical dementia. Alzheimer's disease is now the most common form of neurodegenerative dementia in the United States with a disproportionate disease burden in minority populations. Deficits in the ability to encode and store new memories characterizes the initial stages of the disease. Subsequent progressive changes in cognition and behavior accompany the later stages. Changes in amyloid precursor protein (APP) cleavage and production of the APP fragment beta-amyloid (Aβ) along with hyperphosphorylated tau protein aggregation coalesce to cause reduction in synaptic strength, synaptic loss, and neurodegeneration. Metabolic, vascular, and inflammatory changes, as well as comorbid pathologies are key components of the disease process. Symptomatic treatment offers a modest, clinically measurable effect in cognition, but disease-modifying therapies are desperately needed.

RevDate: 2019-11-21

Nakamura M, Kaneko S, Dickson DW, et al (2019)

Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies.

Journal of neuropathology and experimental neurology pii:5637331 [Epub ahead of print].

BRCA1 plays an important roles in several biological events during the DNA damage response (DDR). Recently, some reports have indicated that BRCA1 dysfunction is involved in the pathogenesis of Alzheimer disease (AD). Furthermore, it has also been reported that BRCA1 accumulates within neurofibrillary tangles (NFTs) in the AD brain. In this study, we examined the immunohistochemical distribution of BRCA1 and another DDR protein, p53-Binding Protein 1 (53BP1), in AD, Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17. In control subjects, neither BRCA1 nor phosphorylated BRCA1 (pBRCA1; Ser1524) immunoreactivity was observed in neurons or glial cells; and that for pBRCA1 (Ser1423) and 53BP1 were slightly detected in neuronal nuclei. The immunoreactivity for both BRCA1 and pBRCA1 (Ser1423) was localized within phosphorylated tau inclusions in all tauopathies, whereas that for pBRCA1 (Ser1524) was mainly associated with Pick bodies in PiD and to a lesser extent with NFTs in AD. On the other hand, 53BP1-immunoreactive deposits tended to be increased in the nucleus of neurons in AD and PSP compared with those in control cases. Our results suggest that DDR dysfunction due to cytoplasmic sequestration of BRCA1 could be involved in the pathogenesis of tauopathies.

RevDate: 2019-11-21

Li B, Liu C, Wan Q, et al (2019)

An integrative review of exercise interventions among community-dwelling adults with Alzheimer's disease.

International journal of older people nursing [Epub ahead of print].

AIMS: To synthesise the current research on exercise interventions and health-related outcomes among community-dwelling adults with Alzheimer's disease (AD).

METHODS: Integrative review of the literature reporting exercise interventions among people with AD living in the communities.

RESULTS: Seventeen studies presented in 24 quantitative papers with 1,068 participants diagnosed with Alzheimer's disease were reviewed. The interventions varied in intervention programme characteristics (e.g. baseline assessments, type of exercise, exercise dose, outcome measurements). Among them, (a) 13 studies appeared beneficial to physical fitness in different areas; (b) 9 studies reported the effects on cognitive ability and two studies showed the positive effects; (c) 12 studies reported the participants' adherence, but only 2 studies reported the participants' adherence using attendance and training intensity.

CONCLUSION: Exercise is proven to be effective in physical fitness among community-dwelling patients with AD. Future studies should verify the effects on cognitive function and possible mechanisms of different exercise types using more sensitive and objective outcome measurements. Additionally, treatment fidelity, cost-effectiveness and long-term effects should be explored.

IMPLICATION FOR PRACTICE: Exercise may be effective and feasible for community-dwelling people with AD, but its effects on cognition need to be verified in the future. This review provided recommendations for assisting nurses and other clinicians in developing, implementing, and/or evaluating exercise interventions for patients with AD.

RevDate: 2019-11-26

Abbastabar H, Bitarafan S, MH Harirchian (2019)

The trend of incidence and burden of neurological disease in Iran between 1990 and 2017: Based on global burden of disease estimations.

Iranian journal of neurology, 18(3):134-142.

Neurological disease contributes significantly to morbidity and mortality in different ages and geographic areas around the world. The purpose of the current study was to investigate the incidence and disability-adjusted life years (DALYs) trend of neurological disease in Iran during 27 years ago. We used the data of the Global Burden of Disease (GBD) Study to estimate the incidence and DALYs of neurological disease in Iran in different age groups between 1990 and 2017. Age groups were defined in 5 groups including < 5 years, 5-14 years, 15-49 years, 50-69 years, and ≥ 70 years. The incidence number of neurological disease during 1990 to 2017 increased from 7.5 million to more than 12 million and the incidence rate grew as much as 1400 per 100000 populations in Iran. Totally, headache, epilepsy, and Alzheimer were the most common neurological diseases according to incidence and had the most values of DALY in Iran. The highest incidence and DALY of neurological disease was observed in the age group of 15-49 years. This study showed that the incidence and burden of neurological diseases had a dramatic increasing trend during 27 years ago in Iran. Consequently, it is necessary to investigate the causes of the growing trend in future studies.

RevDate: 2019-11-26

Honer WG, Ramos-Miguel A, Alamri J, et al (2019)

The synaptic pathology of cognitive life
.

Dialogues in clinical neuroscience, 21(3):271-279.

Prospective, community-based studies allow evaluation of associations between cognitive functioning and synaptic measures, controlled for age-related pathologies. Findings from >400 community-based participants are reviewed. Levels of two presynaptic proteins, complexin-I (inhibitory terminals), and complexin-II (excitatory terminals) contributed to cognitive variation from normal to dementia. Adding the amount of protein-protein interaction between two others, synaptosome-associated protein-25 and syntaxin, explained 6% of overall variance. The presynaptic protein Munc18-1 long variant was localized to inhibitory terminals, and like complexin-I, was positively associated with cognition. Associations depended on Braak stage, with the level of complexin-I contributing nearly 15% to cognitive variation in stages 0-II, while complexin-II contributed 7% in stages V-VI. Non-denaturing gels identified multiple soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein-protein (SNARE) complexes in frontal and in temporal lobes, making specific contributions to cognitive functions. Multiple mechanisms of presynaptic plasticity contribute to cognitive function during aging.
.

RevDate: 2019-11-26

Chung JY, Yoon HJ, Kim H, et al (2019)

Reversion From Mild Cognitive Impairment To Normal Cognition: False-Positive Error Or True Restoration Thanks To Cognitive Control Ability?.

Neuropsychiatric disease and treatment, 15:3021-3032.

Purpose: Relatively little attention has been paid to the meaning of reversion from mild cognitive impairment (MCI) to cognitively normal (CN), compared to MCI progression studies. The purpose of the study was to investigate the characteristics contributing to reversion from MCI to CN and to identify the associated factors with such reversion.

Patients and methods: We retrospectively identified 200 individuals who initially diagnosed as MCI and completed the second visit from the National Research Center for Dementia (NRCD) registry in Korea. Participants underwent comprehensive clinical and neuropsychological assessments. Factors associated with reversion were examined by a independent-samples t-test, χ2 test, and logistic regression. Longitudinal change was examined by a repeated measures analysis of variance (rANOVA).

Results: Based on the second assessment, 78 (39%) individuals were found to have reverted to CN (rMCI) and 118 (59%) remained with MCI (sMCI). Four (2%) progressed to Alzheimer's disease dementia and they were excluded from further analysis. Over a wide range of socio-demographic, clinical, and neuropsychological variables, group difference was significant only in neuropsychological tests of cognitive control. Both groups showed improvement in several neuropsychological tests, implying a practice effect, but the rMCI group showed greater improvement.

Conclusion: Reversion from MCI to CN might not be a false-positive error but a true recovery from cognitive impairment. Our results suggest that cognitive control ability may be a characteristic favorable for the restoration of cognitive function. Therefore, assessment of cognitive control might facilitate the development of appropriate interventions for MCI as well as prognosis evaluation.

RevDate: 2019-11-21

Sgard B, Khalifé M, Bouchut A, et al (2019)

ZTE MR-based attenuation correction in brain FDG-PET/MR: performance in patients with cognitive impairment.

European radiology pii:10.1007/s00330-019-06514-z [Epub ahead of print].

OBJECTIVE: One of the main challenges of integrated PET/MR is to achieve an accurate PET attenuation correction (AC), especially in brain acquisition. Here, we evaluated an AC method based on zero echo time (ZTE) MRI, comparing it with the single-atlas AC method and CT-based AC, set as reference.

METHODS: Fifty patients (70 ± 11 years old, 28 men) underwent FDG-PET/MR examination (SIGNA PET/MR 3.0 T, GE Healthcare) as part of the investigation of suspected dementia. They all had brain computed tomography (CT), 2-point LAVA-flex MRI (for atlas-based AC), and ZTE-MRI. Two AC methods were compared with CT-based AC (CTAC): one based on a single atlas, one based on ZTE segmentation. Impact on brain metabolism was evaluated using voxel and volumes of interest-based analyses. The impact of AC was also evaluated through comparisons between two subgroups of patients extracted from the whole population: 15 patients with mild cognitive impairment and normal metabolic pattern, and 22 others with metabolic pattern suggestive of Alzheimer disease, using SPM12 software.

RESULTS: ZTE-AC yielded a lower bias (3.6 ± 3.2%) than the atlas method (4.5 ± 6.1%) and lowest interindividual (4.6% versus 6.8%) and inter-regional (1.4% versus 2.6%) variabilities. Atlas-AC resulted in metabolism overestimation in cortical regions near the vertex and cerebellum underestimation. ZTE-AC yielded a moderate metabolic underestimation mainly in the occipital cortex and cerebellum. Voxel-wise comparison between the two subgroups of patients showed that significant difference clusters had a slightly smaller size but similar locations with PET images corrected with ZTE-AC compared with those corrected with CT, whereas atlas-AC images showed a notable reduction of significant voxels.

CONCLUSION: ZTE-AC performed better than atlas-AC in detecting pathologic areas in suspected neurodegenerative dementia.

KEY POINTS: • The ZTE-based AC improved the accuracy of the metabolism quantification in PET compared with the atlas-AC method. • The overall uptake bias was 21% lower when using ZTE-based AC compared with the atlas-AC method. • ZTE-AC performed better than atlas-AC in detecting pathologic areas in suspected neurodegenerative dementia.

RevDate: 2019-11-21

Katsumata Y, Fardo DW, Bachstetter AD, et al (2019)

Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene.

Journal of neuropathology and experimental neurology pii:5631811 [Epub ahead of print].

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.

RevDate: 2019-11-25

Barupal DK, Fan S, Wancewicz B, et al (2018)

Generation and quality control of lipidomics data for the alzheimer's disease neuroimaging initiative cohort.

Scientific data, 5(1):180263 pii:10.1038/sdata.2018.263.

Alzheimer's disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/.

RevDate: 2019-11-20

Luo W, Lv JW, Wang T, et al (2019)

Synthesis, in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents.

Bioorganic & medicinal chemistry pii:S0968-0896(19)31182-4 [Epub ahead of print].

A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC50 values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver-Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn't show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer's disease.

RevDate: 2019-11-20

Santabárbara J, Lipnicki DM, Bueno-Notivol J, et al (2019)

Updating the evidence for an association between anxiety and risk of Alzheimer's disease: A meta-analysis of prospective cohort studies.

Journal of affective disorders pii:S0165-0327(19)30807-9 [Epub ahead of print].

OBJECTIVES: Anxiety is postulated to be a modifiable risk factor for Alzheimer's disease (AD). Our primary aim was to conduct a meta-analysis of prospective cohort studies investigating the association between anxiety and AD risk.

DESIGN: We searched multiple scientific databases to identify relevant papers published up to March 2019. Inclusion criteria were: prospective cohort studies with a minimum follow-up period of 1 year, baseline anxiety assessment, absence of dementia at baseline, investigated the association between anxiety and AD incidence, and reporting Relative Risks (RRs), or equivalents (HRs and SHRs), for the association between anxiety and AD risk. We excluded studies that: focused on subjective memory or mild cognitive impairment samples, review and meta-analyses, not reporting original, published peer-reviewed results. We used a random-effects model that accommodated the differences in association statistics.

RESULTS: 7 prospective cohorts (reported in 6 studies), with a total of 24,528 participants, were included in our meta-analysis. A marginally significant association between anxiety and AD risk was found, with a pooled RR of 1.45 (95% CI: 1.00-2.12), and a population attributable fraction for AD of 2.8% (95% CI: 1.2%-4.3%).

LIMITATIONS: There was a high level of heterogeneity across the studies, which may be associated with differences in the covariates adjusted for. Studies also differed considerably in how they measured anxiety.

CONCLUSION: Anxiety is marginally associated with an increased risk of AD in this meta-analysis. Future research is needed to determine the extent to which anxiety might be a cause of AD rather than a prodrome or marker.

RevDate: 2019-11-24

Mehrabadi S, Motevaseli E, Sadr SS, et al (2019)

Hypoxic-conditioned medium from adipose tissue mesenchymal stem cells improved neuroinflammation through alternation of toll like receptor (TLR) 2 and TLR4 expression in model of Alzheimer's disease rats.

Behavioural brain research pii:S0166-4328(19)31469-X [Epub ahead of print].

Microglia have a pivotal role to initiate immune responses in AD brains through toll-like receptors and induce neuroinflammation. Adipose tissue mesenchymal stem cells (ATSCs) secret many neurotrophic and anti-inflammatory factors called conditioned medium (CM). Many studies have demonstrated that CM of mesenchymal stem cells facilitate regeneration and attenuates inflammation in many disorders. To this purpose, the effect of ATSCs-conditioned medium (ATSC-CM) on brain inflammation and the role of toll-like receptors were investigated in this study. Seventy-two rats were randomly divided into 6 groups: control, sham, sham+ATSC-CM: 200μl ATSC-CM once a day intraperitoneally for 8 days, AD group injected the Aβ1-40 intra-hippocampal, AD+ASC-CM, which was injected Aβ1-40 intra-hippocampal and 200μl ATSC-CM once a day intraperitoneally for 8 days and AD+ rivastigmine: was injected Aβ1-40 intra-hippocampal and received rivastigmine (0.6 mg/kg) orally once a day for 2 weeks. Memory and learning were measured by Morris water maze and novel object recognition tests. For detection of beta-amyloid plaque, Congo red staining was used, and neuronal survival was assessed by Nissl staining. Expression of TLR2 and TLR4 was measured by real-time PCR, and finally, to assess inflammation markers (IL-1β and TNF-α) in the hippocampus, ELISA kits were used. In treatment group spatial and recognition memory significantly was improved. ATSC-CM administration decreased beta amyloid plaques and enhanced neuronal survival in AD brain rats. In addition, TLR2 and TLR4 expression decreased in treatment group. Results also showed that ATSC-CM reduced IL-1β and TNF-α as inflammation markers. ATSC-CM improved memory deficit, decreased beta amyloids formation, increased neuron survival, and attenuated inflammation by reducing the expression of TLRs.

RevDate: 2019-11-18

Hong P, Zhang X, Gao S, et al (2019)

Role of monocarboxylate transporter 4 in Alzheimer disease.

Neurotoxicology pii:S0161-813X(19)30133-0 [Epub ahead of print].

The pathological process of Alzheimer disease (AD) is closely related to energy metabolism disorders. In the nervous system, monocarboxylate transporter 4 (MCT4) is expressed in the glial cell membrane and is responsible for transporting intracellular lactic acid. In this study, we found that MCT4 expression was elevated in the cerebrospinal fluid of patients with mild cognitive impairment. Two- and three-month-old APPswe/PS1dE9 (APP/PS1) mice and C57 mice were studied. The APP/PS1 mice began to show cognitive decline at 3 months of age and MCT4 in the hippocampus of 2- and 3-month old APP/PS1 mice was higher than that of C57 mice. This change is similar to that in people with mild cognitive impairment. Subsequently, MCT4 overexpression/siRNA lentiviral particles were used to establish stable primary astrocytes. Overexpression and knockdown of MCT4 had no significant effect on glial cell apoptosis. Transfected astrocytes were co-cultured with neurons. Overexpression of cytoplasmic MCT4 increased the expression of Aβ42, γ-secretase, and CD147 in the co-culture system; in addition, the growth ability of primary neurons decreased significantly, extracellular lactic acid increased, and neuronal apoptosis increased. In AD model mice, siMCT4 injection improved cognitive ability, reduced neuronal apoptosis, and reduced γ-secretase expression. Taken together, these results suggest that MCT4 is involved in energy metabolism during early pathological processes in AD, and suppression of MCT4 represents a new potential neuroprotective factor for AD.

RevDate: 2019-11-18

Seo DO, DM Holtzman (2019)

Gut microbiota: from the forgotten organ to a potential key player in the pathology of Alzheimer disease.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5628721 [Epub ahead of print].

More than three hundred years ago, Antony van Leewenhoeck first described observing single-celled microorganisms, which he termed 'animalcules', examining his saliva under a microscope. Although the idea of the coexistence of microorganisms in our body is not new, we have only recently been able to investigate their ecological relationship to our body, with the development of high throughput molecular techniques. The diverse microorganism communities residing in our guts are established and maintained by complex interactions among microorganisms and their host. Notably, their alteration has been implicated in influencing various diseases including neurological diseases. Alzheimer disease (AD) is the most common cause of dementia characterized by a progressive decline in memory and thinking severe enough to interfere with daily life. Despite the great progress in linking genetic risk factors with AD pathogenesis, treatments targeted at AD pathology and its modifiers have not yet resulted in a disease modifying therapy. There is mounting evidence that the gut microbiota interacts with AD pathogenesis by disrupting neuroinflammation and metabolic homeostasis - the gut microbiota has gone from being the forgotten organ to a potential key player in the AD pathology.

RevDate: 2019-11-18

Schneider LS (2019)

Pragmatic Trials and Repurposed Drugs for Alzheimer Disease.

JAMA neurology pii:2755278 [Epub ahead of print].

RevDate: 2019-11-18

Howard R, Zubko O, Bradley R, et al (2019)

Minocycline at 2 Different Dosages vs Placebo for Patients With Mild Alzheimer Disease: A Randomized Clinical Trial.

JAMA neurology pii:2755279 [Epub ahead of print].

Importance: There are no disease-modifying treatments for Alzheimer disease (AD), the most common cause of dementia. Minocycline is anti-inflammatory, protects against the toxic effects of β-amyloid in vitro and in animal models of AD, and is a credible repurposed treatment candidate.

Objective: To determine whether 24 months of minocycline treatment can modify cognitive and functional decline in patients with mild AD.

Participants were recruited into a double-blind randomized clinical trial from May 23, 2014, to April 14, 2016, with 24 months of treatment and follow-up. This multicenter study in England and Scotland involved 32 National Health Service memory clinics within secondary specialist services for people with dementia. From 886 screened patients, 554 patients with a diagnosis of mild AD (Standardised Mini-Mental State Examination [sMMSE] score ≥24) were randomized.

Interventions: Participants were randomly allocated 1:1:1 in a semifactorial design to receive minocycline (400 mg/d or 200 mg/d) or placebo for 24 months.

Main Outcomes and Measures: Primary outcome measures were decrease in sMMSE score and Bristol Activities of Daily Living Scale (BADLS), analyzed by intention-to-treat repeated-measures regression.

Results: Of 544 eligible participants (241 women and 303 men), the mean (SD) age was 74.3 (8.2) years, and the mean (SD) sMMSE score was 26.4 (1.9). Fewer participants completed 400-mg minocycline hydrochloride treatment (28.8% [53 of 184]) than 200-mg minocycline treatment (61.9% [112 of 181]) or placebo (63.7% [114 of 179]; P < .001), mainly because of gastrointestinal symptoms (42 in the 400-mg group, 15 in the 200-mg group, and 10 in the placebo group; P < .001), dermatologic adverse effects (10 in the 400-mg group, 5 in the 200-mg group, and 1 in the placebo group; P = .02), and dizziness (14 in the 400-mg group, 3 in the 200-mg group, and 1 in the placebo group; P = .01). Assessment rates were lower in the 400-mg group: 68.4% (119 of 174 expected) for sMMSE at 24 months compared with 81.8% (144 of 176) for the 200-mg group and 83.8% (140 of 167) for the placebo group. Decrease in sMMSE scores over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). The combined minocycline group had mean sMMSE scores 0.1 points higher than the placebo group (95% CI, -1.1 to 1.2; P = .90). The decrease in mean sMMSE scores was less in the 400-mg group than in the 200-mg group (3.3 vs 4.7 points; treatment effect = 1.2; 95% CI, -0.1 to 2.5; P = .08). Worsening of BADLS scores over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo groups (treatment effect for minocycline vs placebo = -0.53; 95% CI, -2.4 to 1.3; P = .57; treatment effect for 400 mg vs 200 mg of minocycline = -0.31; 95% CI, -0.2 to 1.8; P = .77). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data.

Conclusions and Relevance: Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. This study also found that 400 mg of minocycline is poorly tolerated in this population.

Trial Registration: isrctn.org Identifier: ISRCTN16105064.

RevDate: 2019-11-18

Tian H, Ding N, Guo M, et al (2019)

Analysis of Learning and Memory Ability in an Alzheimer's Disease Mouse Model using the Morris Water Maze.

Journal of visualized experiments : JoVE.

A Morris water maze (MWM) experiment forces experimental animals to swim and learn to find a platform hidden in the water. It is widely used in scientific research to assess the learning and memory of animals. Due to the extensive use of the MWM test, visual experimental protocols are essential for researchers. This manuscript uses the latest studies to introduce the protocol of the MWM test. Alzheimer' Disease (AD) is characterized by a progressive loss of memory and cognitive function. An alternative and complementary treatment used for AD is Manual Acupuncture (MA). To assess the learning and memory ability of AD model mice, the MWM test was conducted. The visible platform trial, hidden platform trial, probe trial, and reversal trial of MWM were used to evaluate spatial learning and memory ability. In the visible platform trial, the swimming speed and escape latency of mice in different groups was not significantly different. In the hidden platform and reversal trials, the AD group showed a long escape latency. The escape latency decreased significantly after the MA treatment. Low platform crossover number and the proportion of time in the SW quadrant in the probe trial increased after the MA treatment (p < 0.05 or p < 0.01). The results of the MWM tests suggest that MA can effectively improve the spatial learning and memory abilities of AD model mice. Rigorous experimental operations provided assurance of the reliability of the results.

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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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