Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Salloway S
PROVIDER: S-EPMC5536824 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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Performance of [<sup>18</sup>F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease.
Salloway Stephen S Gamez Jose E JE Singh Upinder U Sadowsky Carl H CH Villena Teresa T Sabbagh Marwan N MN Beach Thomas G TG Duara Ranjan R Fleisher Adam S AS Frey Kirk A KA Walker Zuzana Z Hunjan Arvinder A Escovar Yavir M YM Agronin Marc E ME Ross Joel J Bozoki Andrea A Akinola Mary M Shi Jiong J Vandenberghe Rik R Ikonomovic Milos D MD Sherwin Paul F PF Farrar Gill G Smith Adrian P L APL Buckley Christopher J CJ Thal Dietmar Rudolf DR Zanette Michelle M Curtis Craig C
Alzheimer's & dementia (Amsterdam, Netherlands) 20170701
<h4>Introduction</h4>Performance of the amyloid tracer [<sup>18</sup>F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines).<h4>Methods</h4>After [<sup>18</sup>F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five inde ...[more]
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Project description:IntroductionNeuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used.MethodsFifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change.ResultsCurrent practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable.DiscussionAD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.
| S-EPMC4562409 | biostudies-literature
Project description: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 ? 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 ?-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.
| S-EPMC5958625 | biostudies-literature
Project description:While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques.To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait.Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers.A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on ?-amyloid load by immunocytochemistry, and replication with fibrillar ?-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir.Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P?=?.02) and CD2AP (rs9349407; P?=?.03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P?=?3.3?×?10-6). This polymorphism was associated with postmortem ?-amyloid load as well as fibrillar ?-amyloid in 2 independent cohorts of adults with normal cognition.These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.
| S-EPMC3773291 | biostudies-literature
Project description:BACKGROUND:A long dynamic scanning protocol may be required to accurately measure longitudinal changes in amyloid load. However, such a protocol results in a lower patient comfort and scanning efficiency compared to static scans. A compromise can be achieved by implementing dual-time-window protocols. This study aimed to optimize these protocols for quantitative [18F]flutemetamol and [18F]florbetaben studies. METHODS:Rate constants for subjects across the Alzheimer's disease spectrum (i.e., non-displaceable binding potential (BPND) in the range 0.02-0.77 and 0.02-1.04 for [18F]flutemetamol and [18F]florbetaben, respectively) were established based on clinical [18F]flutemetamol (N?=?6) and [18F]florbetaben (N?=?20) data, and used to simulate tissue time-activity curves (TACs) of 110?min using a reference tissue and plasma input model. Next, noise was added (N?=?50) and data points corresponding to different intervals were removed from the TACs, ranging from 0 (i.e., 90-90?=?full-kinetic curve) to 80 (i.e., 10-90) minutes, creating a dual-time-window. Resulting TACs were fitted using the simplified reference tissue method (SRTM) to estimate the BPND, outliers (??1.5?×?BPND max) were removed and the bias was assessed using the distribution volume ratio (DVR?=?BPND?+?1). To this end, acceptability curves, which display the fraction of data below a certain bias threshold, were generated and the area under those curves were calculated. RESULTS:[18F]Flutemetamol and [18F]florbetaben data demonstrated an increased bias in amyloid estimate for larger intervals and higher noise levels. An acceptable bias (??3.1%) in DVR could be obtained with all except the 10-90 and 20-90-min intervals. Furthermore, a reduced fraction of acceptable data and most outliers were present for these two largest intervals (maximum percentage outliers 48 and 32 for [18F]flutemetamol and [18F]florbetaben, respectively). CONCLUSIONS:The length of the interval inversely correlates with the accuracy of the BPND estimates. Consequently, a dual-time-window protocol of 0-30 and 90-110?min (=maximum of 60?min interval) allows for accurate estimation of BPND values for both tracers. [18F]flutemetamol: EudraCT 2007-000784-19, registered 8 February 2007, [18F]florbetaben: EudraCT 2006-003882-15, registered 2006.
| S-EPMC6437225 | biostudies-literature
Project description:The Centiloid (CL) is a method for standardizing amyloid beta (A?) quantification through different ligands and methods. To find the most appropriate reference region to reduce the variance in the A? CL unit between 18F-florbetaben (FBB) and 18F-flutemetamol (FMM), we conducted head-to-head comparisons from 56 participants using the direct comparison of FBB-FMM CL (dcCL) method with four reference regions: cerebellar gray (CG), whole cerebellum (WC), WC with brainstem (WC?+?B), and pons. The FBB and FMM dcCL units were highly correlated in four reference regions: WC (R2?=?0.97), WC?+?B (R2?=?0.98), CG (R2?=?0.92), and pons (R2?=?0.98). WC showed the largest effect size in both FBB and FMM. Comparison of the variance of the dcCL values within the young control group showed that with FBB, WC?+?B had the smallest variance and with FMM, the WC had the smallest variance. Additionally, WC?+?B showed the smallest absolute difference between FBB and FMM, followed by the WC, pons, and CG. We found that it would be reasonable to use the WC or WC?+?B as the reference region when converting FBB and FMM SUVRs into dcCL, which can increase the accuracy of standardizing FBB and FMM PET results.
| S-EPMC7486392 | biostudies-literature
Project description:Recommendations for the diagnosis of preclinical Alzheimer disease (AD) have been formulated by a workgroup of the National Institute on Aging and Alzheimer's Association. Three stages of preclinical AD were described. Stage 1 is characterized by abnormal levels of ?-amyloid. Stage 2 represents abnormal levels of ?-amyloid and evidence of brain neurodegeneration. Stage 3 includes the features of stage 2 plus subtle cognitive changes. Stage 0, not explicitly defined in the criteria, represents subjects with normal biomarkers and normal cognition. The ability of the recommended criteria to predict progression to cognitive impairment is the crux of their validity.Using previously developed operational definitions of the 3 stages of preclinical AD, we examined the outcomes of subjects from the Mayo Clinic Study of Aging diagnosed as cognitively normal who underwent brain MRI or [(18)F]fluorodeoxyglucose and Pittsburgh compound B PET, had global cognitive test scores, and were followed for at least 1 year.Of the 296 initially normal subjects, 31 (10%) progressed to a diagnosis of mild cognitive impairment (MCI) or dementia (27 amnestic MCI, 2 nonamnestic MCI, and 2 non-AD dementias) within 1 year. The proportion of subjects who progressed to MCI or dementia increased with advancing stage (stage 0, 5%; stage 1, 11%; stage 2, 21%; stage 3, 43%; test for trend, p < 0.001).Despite the short follow-up period, our operationalization of the new preclinical AD recommendations confirmed that advancing preclinical stage led to higher proportions of subjects who progressed to MCI or dementia.
| S-EPMC3348848 | biostudies-other
Project description:The National Institute of Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of ?-amyloid (CSF A?1-42 and positron emission tomography imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural magnetic resonance imaging) with longitudinal clinical follow-up. Participants were classified in preclinical AD stage 1 (?-amyloidosis) or preclinical AD stage 2+ (?-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer disease pathophysiology group (neuronal injury without ?-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based on neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury and has important implications for clinical trials using biomarkers for enrollment or as surrogate end point measures.
| S-EPMC4913039 | biostudies-literature
Project description:BackgroundBetween 30% and 80% of survivors of critical illness experience cognitive impairment, but the underlying mechanisms remain unknown.ObjectiveTo determine whether intensive care unit (ICU) delirium biomarkers align with the National Institute on Aging-Alzheimer's Association (NIA-AA) research framework for diagnostic biomarkers for Alzheimer disease and other related dementias (ADRD).MethodsOvid MEDLINE, PsycInfo, Embase, and the Cochrane Library were systematically searched for articles published between January 1, 2000, and February 20, 2020, on the relationship between delirium and biomarkers listed in the NIA-AA framework. Only studies that addressed delirium in the ICU setting and fluid biomarkers were included in these analyses.ResultsOf 61 256 records screened, 38 studies met inclusion criteria, 8 of which were suitable for meta-analysis. In pooled analysis, significant associations were found between ICU delirium and amyloid β-peptide 1-40 (standard mean difference [SMD], 0.42; 95% CI, 0.09-0.75), interleukin (IL)-1 receptor antagonist (SMD, 0.58; 95% CI, 0.21-0.94), and IL-6 (SMD, 0.31; 95% CI, 0.06-0.56). No significant association was observed in pooled analyses between ICU delirium and the other biomarkers. Few studies have examined ICU delirium and pathologic tau or neurodegeneration biomarkers.ConclusionsInflammatory biomarkers and amyloid β are associated with ICU delirium and point to potential overlapping mechanisms between delirium and ADRD. Critical care providers should consider integrating diagnostic approaches used in ADRD in their assessment of post-ICU cognitive dysfunction.
| S-EPMC8897570 | biostudies-literature
Project description:ObjectivesTo identify whether delirium biomarkers aligned with the National Institute on Aging-Alzheimer's Association (NIA-AA) research framework, a conceptual model that describes the use of diagnostic biomarkers for Alzheimer's disease and other related dementias (ADRD).DesignSystematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.SettingAcute care and outpatient settings.ParticipantsAdults diagnosed with delirium.Methods and measurementsMEDLINE, PsycInfo, Embase, and the Cochrane Library were searched for English-language studies published from January 2010 to February 2020. Studies included adults older than 18 years, identified delirium with a standardized assessment tool, and measured an ADRD biomarker. Independent reviewers determined whether an association between delirium and ADRD biomarker was found, the quality of biomarker data based on the REMARK (REporting recommendations for tumor MARKer prognostic studies) checklist, and the study bias based on the Newcastle-Ottawa Scale.ResultsA total of 61,256 citations were identified; 113 studies were included. Most studies did not examine amyloid, tau, or neurodegeneration biomarkers. Delirium may be associated with neurodegeneration biomarkers, but few to no studies found an association with amyloid and tau biomarkers. Delirium was not consistently associated with inflammatory biomarkers. The quality of biomarker data was moderate, and the risk of bias was moderate to high. Studies often did not collect prehospital and posthospital cognitive data.ConclusionMost delirium diagnostic biomarker studies did not measure amyloid, tau, and/or neurodegenerative biomarkers, making characterization of the relationship between delirium and ADRD difficult. Future delirium biomarker diagnostic studies could improve the understanding of pathophysiologic links between delirium with other conditions affecting cognition.
| S-EPMC7923964 | biostudies-literature
Project description:Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aβ plaques in Alzheimer's disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aβ plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2-/- mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2+/- mice had significantly more plaque-associated microglia than 5XFAD × TREM2-/- mice. Nonetheless, AD-tau injected 5XFAD × TREM2+/- mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2+/+ mice. Expression profiling revealed that 5XFAD × TREM2+/- mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2+/+ and 5XFAD × TREM2-/- mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2+/- and 5XFAD × TREM2-/- mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2+/- and TREM2-/- mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.
| S-EPMC8428059 | biostudies-literature