共查询到20条相似文献，搜索用时 15 毫秒
1.
Gyungah R. Jun Jaeyoon Chung Jesse Mez Robert Barber Gary W. Beecham David A. Bennett Joseph D. Buxbaum Goldie S. Byrd Minerva M. Carrasquillo Paul K. Crane Carlos Cruchaga Philip De Jager Nilufer Ertekin-Taner Denis Evans M. Danielle Fallin Tatiana M. Foroud Robert P. Friedland Alison M. Goate Lindsay A. Farrer 《Alzheimer's & dementia》2017,13(7):727-738
Introduction
Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.Methods
We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.Results
Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10?8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10?6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10?6).Discussion
Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci. 相似文献2.
Clifford R. Jack Heather J. Wiste Stephen D. Weigand Terry M. Therneau Val J. Lowe David S. Knopman Jeffrey L. Gunter Matthew L. Senjem David T. Jones Kejal Kantarci Mary M. Machulda Michelle M. Mielke Rosebud O. Roberts Prashanthi Vemuri Denise A. Reyes Ronald C. Petersen 《Alzheimer's & dementia》2017,13(3):205-216
Introduction
Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness.Methods
We examined five methods for determining cut points.Results
The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal.Discussion
In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method. 相似文献3.
Clifford R. Jack David A. Bennett Kaj Blennow Maria C. Carrillo Billy Dunn Samantha Budd Haeberlein David M. Holtzman William Jagust Frank Jessen Jason Karlawish Enchi Liu Jose Luis Molinuevo Thomas Montine Creighton Phelps Katherine P. Rankin Christopher C. Rowe Philip Scheltens Eric Siemers Nina Silverberg 《Alzheimer's & dementia》2018,14(4):535-562
In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people. 相似文献
4.
Jordi Pegueroles Eduard Vilaplana Victor Montal Frederic Sampedro Daniel Alcolea Maria Carmona-Iragui Jordi Clarimon Rafael Blesa Alberto Lleó Juan Fortea 《Alzheimer's & dementia》2017,13(5):499-509
Introduction
Brain structural changes in preclinical Alzheimer's disease (AD) are poorly understood.Methods
We compared the changes in cortical thickness in the ADNI cohort during a 2-year follow-up between the NIA-AA preclinical AD stages defined by cerebrospinal fluid (CSF) biomarker levels. We also analyzed the correlation between baseline CSF biomarkers and cortical atrophy rates.Results
At follow-up, stage 1 subjects showed reduced atrophy rates in medial frontal areas and precuneus compared to stage 0 subjects, whereas stage 2/3 subjects presented accelerated atrophy in medial temporal structures. Low CSF Aβ1–42 levels were associated with reduced atrophy rates in subjects with normal tau levels and high CSF tau levels with accelerated atrophy only in subjects with low Aβ1–42 levels.Discussion
Our longitudinal data confirm a biphasic trajectory of changes in brain structure in preclinical AD. These have implications in AD trials, both in patient selection and the use of MRI as a surrogate marker of efficacy. 相似文献5.
6.
The new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease has been developed to accelerate drug discovery and offer a common structure and language to construct new Alzheimer's disease conceptual models. However, as a “complex” disease, a model based on systems-level understanding is needed to accommodate the complex, interacting etiologic pathways and the system-level changes associated with Alzheimer's disease pathogenesis and interventions that are currently known and which will be identified in the future. To accomplish this, the evolution of the structure of the research framework itself should be encouraged. 相似文献
7.
Jaeyoon Chung Xulong Wang Toru Maruyama Yiyi Ma Xiaoling Zhang Jesse Mez Richard Sherva Haruko Takeyama Kathryn L. Lunetta Lindsay A. Farrer Gyungah R. Jun 《Alzheimer's & dementia》2018,14(5):623-633
Introduction
Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.Methods
We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ42 and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study.Results
In CN subjects, study-wide significant (P < 8.3 × 10?9) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls.Discussion
Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes. 相似文献8.
Suzanne E. Schindler Yan Li Kaitlin W. Todd Elizabeth M. Herries Rachel L. Henson Julia D. Gray Guoqiao Wang Danielle L. Graham Leslie M. Shaw John Q. Trojanowski Jason J. Hassenstab Tammie L.S. Benzinger Carlos Cruchaga Mathias Jucker Johannes Levin Jasmeer P. Chhatwal James M. Noble John M. Ringman Anne M. Fagan 《Alzheimer's & dementia》2019,15(5):655-665
IntroductionFour less well-studied but promising “emerging” cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40).MethodsCSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations.ResultsThe four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15–19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset.DiscussionEarly abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation. 相似文献
9.
Karen Ritchie Michael Ropacki Bruce Albala John Harrison Jeffrey Kaye Joel Kramer Christopher Randolph Craig W. Ritchie 《Alzheimer's & dementia》2017,13(2):186-195
The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease. 相似文献
10.
Introduction
Many previous studies have been limited by self- or proxy-reported injury or short follow-up. We investigated whether head or brain injuries are associated with Alzheimer's disease (AD), possible modifying factors and dose-response relationship.Methods
Nested register-based case-control study of all community dwellers who received clinically verified AD diagnosis in Finland in 2005 to 2011 (n = 70,719) and one to four matched controls for each case (n of controls = 282,862).Results
The magnitude of association between hospital-treated head and/or brain injuries was strongly dependent on the lag time between exposure and outcome. With a 5-year lag time, head injury (adjusted odds ratio; 95% confidence interval 1.19; 1.15–1.23) or brain injury (1.23; 1.18–1.29) was associated with higher risk of AD. Dose-response relationship with number and severity of injuries was observed. Associations were stronger in those with earlier onset of AD.Conclusions
Stronger associations with shorter lag times indicate that head and/or brain injuries may also reflect the ongoing AD disease process. 相似文献11.
Sirwan K.L. Darweesh Frank J. Wolters M. Arfan Ikram Frank de Wolf Daniel Bos Albert Hofman 《Alzheimer's & dementia》2018,14(11):1450-1459
Introduction
Inflammatory markers are often elevated in patients with dementia, including Alzheimer's disease (AD). However, it remains unclear whether inflammatory markers are associated with the risk of developing dementia.Methods
We searched PubMed, Embase, and Cochrane library for prospective population-based studies reporting associations between inflammatory markers and all-cause dementia or AD. We used random effects meta-analyses to obtain pooled hazard ratios (HRs) and 95% confidence intervals of inflammatory markers (highest vs. lowest quantile) for all-cause dementia and AD.Results
Fifteen articles from 13 studies in six countries reported data that could be meta-analyzed. C-reactive protein (HR = 1.37 [1.05; 1.78]), interleukin-6 (HR = 1.40 [1.13; 1.73]), α1-antichymotrypsin (HR = 1.54 [1.14; 2.80]), lipoprotein-associated phospholipase A2 activity (HR = 1.40 [1.03; 1.90]), and fibrinogen were each associated with all-cause dementia, but neither was significantly associated with AD.Discussion
Several inflammatory markers are associated with an increased risk of all-cause dementia; however, these markers are not specific for AD. Whether inflammatory markers closely involved in AD pathology are associated with the risk of AD remains to be elucidated. 相似文献12.
Yang An Vijay R. Varma Sudhir Varma Ramon Casanova Eric Dammer Olga Pletnikova Chee W. Chia Josephine M. Egan Luigi Ferrucci Juan Troncoso Allan I. Levey James Lah Nicholas T. Seyfried Cristina Legido-Quigley Richard O&#x;Brien Madhav Thambisetty 《Alzheimer's & dementia》2018,14(3):318-329
Introduction
It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis.Methods
Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose.Results
Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations.Discussion
Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms. 相似文献13.
Silvia Rios-Romenets Hugo Lopez Liliana Lopez Liliana Hincapie Amanda Saldarriaga Lucia Madrigal Francisco Piedrahita Alex Navarro Juliana Acosta-Uribe Laura Ramirez Margarita Giraldo Natalia Acosta-Baena Sebastián Sánchez Claudia Ramos Claudia Muñoz Ana Baena Diana Alzate Paula Ospina Francisco Lopera 《Alzheimer's & dementia》2017,13(5):602-605
14.
韦维 《中国实用神经疾病杂志》2017,20(5)
目的 评价阿尔茨海默病(Alzheimer's disease,AD)患者应用淡漠评估量表临床医师评定版(apathy evaluation scale-clinician administered,AES-C)评估的价值,探讨阿尔茨海默病患者淡漠症状的影响因素.方法 选取26例阿尔茨海默病患者为研究组(n=26),同时选择26例正常对照组(n=26).对2组分别进行以淡漠评估量表(AES-C)为主的多个量表评定.收集患者年龄、性别、文化程度等一般资料,评估AES-C量表的内部一致性.通过单因素分析相关影响因素,探讨AES-C得分和认知功能损害的联系.结果 年龄、文化程度相关系数分别为0.169和-0.162(P<0.05),表明AES-C与年龄呈弱正相关,与文化程度呈弱负相关;研究组患者中淡漠症状的存在与认知功能的定向力、记忆力、执行能力及总体水平呈负相关(P<0.05);研究组和对照组AES-C与GDS得分之间的相关系数为0.423,二者存在弱相关,差异具有统计学意义(r=0.423,P<0.05).结论 淡漠评估量表可靠性较好,可用于评估阿尔茨海默病淡漠症状.淡漠在阿尔茨海默病患者中普遍存在,淡漠症状的严重程度与认知功能损害呈显著相关,这些患者的认知功能损害程度也越严重.阿尔茨海默病患者的淡漠发生可能与认知功能减退、年龄和抑郁症状等多种因素相关. 相似文献
15.
Objective
We explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide a rational framework for incorporating recent and seemingly independent findings on the antimicrobial role of β-amyloid and emerging experimental, genetic, and epidemiological data, suggesting innate immune-mediated inflammation propagates AD neurodegeneration.Background
AD pathology is characterized by cerebral deposition of amyloid-β protein (Aβ) as β-amyloid. Genetic studies have confirmed the key role of Aβ in AD, revealing that mutation-mediated shifts in the peptides generation lead to early onset familial Alzheimer's disease. However, Aβ generation appears normal for the majority of AD patients, who lack early onset familial Alzheimer's disease mutations. In prevailing models of nonfamilial AD, individual genetics and age-associated changes in brain milieu promote an intrinsically abnormal propensity of Aβ for self-association. However, emerging findings are increasingly inconsistent with characterization of Aβ oligomerization as a nonphysiological and exclusively pathological activity. Recent studies suggest Aβ is an ancient, highly conserved effector molecule of innate immunity. Moreover, Aβ oligomerization and β-amyloid generation appear to be important innate immune pathways that mediate pathogen entrapment and protect against infection.New AD amyloidogenesis model
Recent findings on inflammation-mediated neurodegeneration and the role of Aβ in immunity have led to emergence of the “Antimicrobial Protection Hypothesis” of AD. In this model, β-amyloid deposition is an early innate immune response to genuine, or mistakenly perceived, immunochallenge. Aβ first entraps and neutralizes invading pathogens in β-amyloid. Aβ fibrillization drives neuroinflammatory pathways that help fight the infection and clear β-amyloid/pathogen deposits. In AD, chronic activation of this pathway leads to sustained inflammation and neurodegeneration. Mounting data link elevated brain microbe levels with AD. The Antimicrobial Protection Hypothesis reveals how increased brain microbial burden may directly exacerbate β-amyloid deposition, inflammation, and AD progression.Amyloid cascade hypothesis
In the antimicrobial protection model, the modality of Aβ's pathophysiology is shifted from abnormal stochastic behavior toward dysregulated innate immune response. However, β-amyloid deposition in AD still leads to neurodegeneration. Thus, the new model extends but remains broadly consistent with the Amyloid Cascade Hypothesis and overwhelming data showing the primacy of Aβ in AD pathology. 相似文献16.
17.
Heather M. Snyder William R. Perlman Robert Egge Maria C. Carrillo 《Alzheimer's & dementia》2018,14(4):522-531
Introduction
The National Plan to Address Alzheimer's Disease stresses the need for public-private partnerships to be coordinated and cooperative to accelerate the state of research and reach the ultimate goal of preventing and effectively treating Alzheimer's disease by the year 2025.Methods
The Alzheimer's Association, in collaboration with the International Alzheimer's disease Research Funder Consortium, compiles this annually updated compendium to centralize this inventory of partnerships in an effort to synergize these activities.Results
This article reflects the 2017 landscape of nonprofit organizations who engage in public-private partnerships to promote and support dementia research.Discussion
The private-public partnerships in the Alzheimer's disease community continue to increase, addressing much needed complex challenges in the field. 相似文献18.
Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease
María Carmona-Iragui Mircea Balasa Bessy Benejam Daniel Alcolea Susana Fernández Laura Videla Isabel Sala María Belén Sánchez-Saudinós Estrella Morenas-Rodriguez Roser Ribosa-Nogué Ignacio Illán-Gala Sofía Gonzalez-Ortiz Jordi Clarimón Frederick Schmitt David K. Powell Beatriz Bosch Albert Lladó Michael S. Rafii Juan Fortea 《Alzheimer's & dementia》2017,13(11):1251-1260
Introduction
We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]).Methods
Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68).Results
CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA.Discussion
CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD. 相似文献19.
Heather M. Snyder Tim Ahles Stuart Calderwood Maria C. Carrillo Honglei Chen Chung-Chou H. Chang Suzanne Craft Philip De Jager Jane A. Driver Howard Fillit David Knopman Michael Lotze Mary C. Tierney Suzana Petanceska Andrew Saykin Sudha Seshadri Diana Shineman Mary Ganguli 《Alzheimer's & dementia》2017,13(3):267-273
Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one-day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action. 相似文献
20.
Dallas P. Veitch Michael W. Weiner Paul S. Aisen Laurel A. Beckett Nigel J. Cairns Robert C. Green Danielle Harvey Clifford R. Jack William Jagust John C. Morris Ronald C. Petersen Andrew J. Saykin Leslie M. Shaw Arthur W. Toga John Q. Trojanowski 《Alzheimer's & dementia》2019,15(1):106-152