共查询到20条相似文献，搜索用时 15 毫秒
1.
Jenny U. Johansson William D. Brubaker Harold Javitz Andrew W. Bergen Denise Nishita Abhishek Trigunaite Andrés Crane Justine Ceballos Diego Mastroeni Andrea J. Tenner Marwan Sabbagh Joseph Rogers 《Alzheimer's & dementia》2018,14(11):1438-1449
Introduction
Genome-wide association studies consistently show that single nucleotide polymorphisms (SNPs) in the complement receptor 1 (CR1) gene modestly but significantly alter Alzheimer's disease (AD) risk. Follow-up research has assumed that CR1 is expressed in the human brain despite a paucity of evidence for its function there. Alternatively, erythrocytes contain >80% of the body's CR1, where, in primates, it is known to bind circulating pathogens.Methods
Multidisciplinary methods were employed.Results
Conventional Western blots and quantitative polymerase chain reaction failed to detect CR1 in the human brain. Brain immunohistochemistry revealed only vascular CR1. By contrast, erythrocyte CR1 immunoreactivity was readily observed and was significantly deficient in AD, as was CR1-mediated erythrocyte capture of circulating amyloid β peptide. CR1 SNPs associated with decreased erythrocyte CR1 increased AD risk, whereas a CR1 SNP associated with increased erythrocyte CR1 decreased AD risk.Discussion
SNP effects on erythrocyte CR1 likely underlie the association of CR1 polymorphisms with AD risk. 相似文献2.
William D. Brubaker Andrés Crane Jenny U. Johansson Kevin Yen Kristina Garfinkel Diego Mastroeni Priya Asok Bonnie Bradt Marwan Sabbagh Tanya L. Wallace Courtney Glavis-Bloom Andrea J. Tenner Joseph Rogers 《Alzheimer's & dementia》2017,13(12):1397-1409
Introduction
Although amyloid β peptide (Aβ) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role.Methods
Multidisciplinary methods were used to demonstrate immune adherence capture of Aβ by erythrocytes and its deficiency in Alzheimer's disease (AD).Results
Aβ was shown to be subject to immune adherence at every step in the pathway. Aβ dose-dependently activated serum complement. Complement-opsonized Aβ was captured by erythrocytes via CR1. Erythrocytes, Aβ, and hepatic Kupffer cells were colocalized in the human liver. Significant deficits in erythrocyte Aβ levels were found in AD and mild cognitive impairment patients.Discussion
CR1 polymorphisms elevate AD risk, and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically relevant in AD. 相似文献3.
Hugo Lövheim Fredrik Elgh Anders Johansson Henrik Zetterberg Kaj Blennow Göran Hallmans Sture Eriksson 《Alzheimer's & dementia》2017,13(7):778-782
Introduction
Biomarkers that identify individuals at risk of Alzheimer's disease (AD) development would be highly valuable. Plasma concentration of amyloid β (Aβ)—central in the pathogenesis of AD—is a logical candidate, but studies to date have produced conflicting results on its utility.Methods
Plasma samples from 339 preclinical AD cases (76.4% women, mean age 61.3 years) and 339 age- and sex-matched dementia-free controls, taken an average of 9.4 years before AD diagnosis, were analyzed using Luminex xMAP technology and INNO-BIA plasma Aβ form assays to determine concentrations of free plasma Aβ40 and Aβ42.Results
Plasma concentrations of free Aβ40 and Aβ42 did not differ between preclinical AD cases and dementia-free controls, in the full sample or in subgroups defined according to sex and age group (<60 and ≥ 60 years). The interval between sampling and AD diagnosis did not affect the results. Aβ concentrations did not change in the years preceding AD diagnosis among individuals for whom longitudinal samples were available.Discussion
Plasma concentrations of free Aβ could not predict the development of clinical AD, and Aβ concentrations did not change in the years preceding AD diagnosis in this sample. These results indicate that free plasma Aβ is not a useful biomarker for the identification of individuals at risk of developing clinical AD. 相似文献4.
Journal of NeuroVirology - In patients infected with the human immunodeficiency virus (HIV), the HIV-Tat protein may be continually produced despite adequate antiretroviral therapy. As the... 相似文献
5.
6.
Niklas Mattsson Colin Groot Willemijn J. Jansen Susan M. Landau Victor L. Villemagne Sebastiaan Engelborghs Mark M. Mintun Alberto Lleo José Luis Molinuevo William J. Jagust Giovanni B. Frisoni Adrian Ivanoiu Gaël Chételat Catarina Resende de Oliveira Karen M. Rodrigue Johannes Kornhuber Anders Wallin Aleksandra Klimkowicz-Mrowiec Rik Ossenkoppele 《Alzheimer's & dementia》2018,14(7):913-924
Introduction
Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.Methods
We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location.Results
The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.Discussion
The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location. 相似文献7.
8.
Jon B. Toledo Matthias Arnold Gabi Kastenmüller Rui Chang Rebecca A. Baillie Xianlin Han Madhav Thambisetty Jessica D. Tenenbaum Karsten Suhre J. Will Thompson Lisa St. John-Williams Siamak MahmoudianDehkordi Daniel M. Rotroff John R. Jack Alison Motsinger-Reif Shannon L. Risacher Colette Blach Joseph E. Lucas Rima Kaddurah-Daouk 《Alzheimer's & dementia》2017,13(9):965-984
Introduction
The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.Methods
Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.Results
Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1–42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.Discussion
Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. 相似文献9.
William Jagust Clifford R. Jack David A. Bennett Kaj Blennow Samantha Budd Haeberlein David M. Holtzman Frank Jessen Jason Karlawish Enchi Liu Jose Luis Molinuevo Thomas Montine Creighton Phelps Katherine P. Rankin Christopher C. Rowe Philip Scheltens Eric Siemers Reisa Sperling 《Alzheimer's & dementia》2019,15(1):153-157
10.
Jason Karlawish Clifford R. Jack Walter A. Rocca Heather M. Snyder Maria C. Carrillo 《Alzheimer's & dementia》2017,13(4):374-380
In the history of medicine, one means to progress is when we make the decision that our assumptions and definitions of disease are no longer consistent with the scientific evidence, and no longer serve our health care needs. The arc of scientific progress is now requiring a change in how we diagnose Alzheimer's disease. Both the National Institute on Aging—Alzheimer's Association (NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable measures of biological changes in the brain, commonly known as biological markers, or biomarkers, as part of the diagnosis. This Special Report examines how the development and validation of Alzheimer's disease biomarkers—including those detectable in the blood or cerebral spinal fluid, or through neuroimaging—is a top research priority. This has the potential to markedly change how we diagnose Alzheimer's disease and, as a result, how we count the number of people with this disease. As research advances a biomarker-based method for diagnosis and treatment at the earliest stages of Alzheimer's disease, we envision a future in which Alzheimer's disease is placed in the same category as other chronic diseases, such as cardiovascular disease or diabetes, which can be readily identified with biomarkers and treated before irrevocable disability occurs. 相似文献
11.
12.
13.
Petroula Proitsi Min Kim Luke Whiley Andrew Simmons Martina Sattlecker Latha Velayudhan Michelle K. Lupton Hillka Soininen Iwona Kloszewska Patrizia Mecocci Magda Tsolaki Bruno Vellas Simon Lovestone John F. Powell Richard J.B. Dobson Cristina Legido-Quigley 《Alzheimer's & dementia》2017,13(2):140-151
Introduction
The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer's disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex).Methods
We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods.Results
We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with >70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R2 = 0.10, test data set) and brain atrophy (R2 ≥ 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines.Discussion
Blood lipids are promising AD biomarkers that may lead to new treatment strategies. 相似文献14.
15.
Min Shi Lu Tang Jon B. Toledo Carmen Ginghina Hua Wang Patrick Aro Poul H. Jensen Daniel Weintraub Alice S. Chen-Plotkin David J. Irwin Murray Grossman Leo McCluskey Lauren B. Elman David A. Wolk Edward B. Lee Leslie M. Shaw John Q. Trojanowski Jing Zhang 《Alzheimer's & dementia》2018,14(8):1052-1062
Introduction
The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1–42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α-synuclein [α-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis.Methods
CSF total α-syn, phosphorylated α-syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays in 367 participants, followed by validation in 74 different neuropathologically confirmed cases.Results
CSF total α-syn, when combined with amyloid β peptide 1–42 and either total tau or phosphorylated tau, improved the differential diagnosis of AD versus frontotemporal dementia, Lewy body disorders, or other neurological disorders. The diagnostic accuracy of the combined models attained clinical relevance (area under curve ～0.9) and was largely validated in neuropathologically confirmed cases.Discussion
Combining CSF biomarkers representing AD and Lewy body pathologies may have clinical value in the differential diagnosis of AD. 相似文献16.
Melanie D. Sweeney Axel Montagne Abhay P. Sagare Daniel A. Nation Lon S. Schneider Helena C. Chui Michael G. Harrington Judy Pa Meng Law Danny J.J. Wang Russell E. Jacobs Fergus N. Doubal Joel Ramirez Sandra E. Black Maiken Nedergaard Helene Benveniste Martin Dichgans Costantino Iadecola Berislav V. Zlokovic 《Alzheimer's & dementia》2019,15(1):158-167
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. 相似文献
17.
Sonia Moreno–Grau Octavio Rodríguez-Gómez Ángela Sanabria Alba Pérez-Cordón Domingo Sánchez-Ruiz Carla Abdelnour Sergi Valero Isabel Hernández Maitée Rosende-Roca Ana Mauleón Liliana Vargas Asunción Lafuente Silvia Gil Miguel Ángel Santos-Santos Montserrat Alegret Ana Espinosa Gemma Ortega Marina Guitart A. Vivas 《Alzheimer's & dementia》2018,14(5):634-643
Introduction
Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored.Methods
We evaluated apolipoprotein E (APOE) ε4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta-analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts.Results
Analysis of the FACEHBI cohort and the meta-analysis demonstrated SCD individuals presented higher allelic frequencies of APOE ε4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels.Discussion
The FACEHBI sample presents APOE ε4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this AD endophenotype. 相似文献18.
Introduction
Neurodegenerative disorders have been a graveyard for hundreds of well-intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimer's disease (AD) share many overlapping pathologies and possible clinical links.Methods
We searched the literature since 1995 using MEDLINE and Google Scholar for the terms concussion, AD, and shared neuropathologies. We also studied a TBI animal model as a supplement to transgenic (Tg) mouse AD models for evaluating AD drug efficacy by preventing neuronal losses. To evaluate TBI/AD pathologies and neuronal self-induced cell death (apoptosis), we are studying brain extracellular vesicles in plasma and (-)-phenserine pharmacology to probe, in animal models of AD and humans, apoptosis and pathways common to concussion and AD.Results
Neuronal cell death and a diverse and significant pathological cascade follow TBIs. Many of the developing pathologies are present in early AD. The use of an animal model of concussion as a supplement to Tg mice provides an indication of an AD drug candidate's potential for preventing apoptosis and resulting progression toward dementia in AD. This weight drop supplementation to Tg mouse models, the experimental drug (-)-phenserine, and plasma-derived extracellular vesicles enriched for neuronal origin to follow biomarkers of neurodegenerative processes, each and in combination, show promise as tools useful for probing the progression of disease in AD, TBI/AD pathologies, apoptosis, and drug effects on rates of apoptosis both preclinically and in humans. (-)-Phenserine both countered many subacute post-TBI pathologies that could initiate clinical AD and, in the concussion and other animal models, showed evidence consistent with direct inhibition of neuronal preprogrammed cell death in the presence of TBI/AD pathologies.Discussion
These findings may provide support for expanding preclinical Tg mouse studies in AD with a TBI weight drop model, insights into the progression of pathological targets, their relations to apoptosis, and timing of interventions against these targets and apoptosis. Such studies may demonstrate the potential for drugs to effectively and safely inhibit preprogrammed cell death as a new drug development strategy for use in the fight to defeat AD. 相似文献19.
20.
Dominik Wolf Martina Bocchetta Gregory M. Preboske Marina Boccardi Michel J. Grothe 《Alzheimer's & dementia》2017,13(8):893-902