Age dependence of brain β-amyloid deposition in Down syndrome

Jennings, Danna; Seibyl, John; Sabbagh, Marwan N.; Lai, Florence; Hopkins, William E.; Bullich, Santi; Gimenez, Monica; Reininger, Cornelia; Pütz, Barbara; Stephens, Andrew; Catafau, Ana M.; Marek, Kenneth

doi:10.1212/wnl.0000000000001212

Cited by 63 publications

(49 citation statements)

References 36 publications

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“…The relationship of visual interpretations to quantitative values was also consistent with prior reports (6,14), indicating high concordance between visual positivity and negativity and the composite SUVR using a quantitative cutoff for positive and negative scans. There were only a few cases (10 for e-trained and 9 for in-person-trained of 81 case evaluations) in which there was discordance between visual and quantitative assessments.…”

Section: Discussionsupporting

confidence: 86%

Impact of Training Method on the Robustness of the Visual Assessment of ¹⁸F-Florbetaben PET Scans: Results from a Phase-3 Study

et al. 2016

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Training for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT). Methods: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n 5 3 expert interpreters) or an electronic training method (n 5 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques. Results: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS 1 immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person-trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss k) was excellent (0.89) for in-person-trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both inperson-trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-persontrained interpreters and in 87.7% of scans for e-trained interpreters. Conclusion: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments. Fl orbetaben is an 18 F-labeled b-amyloid tracer developed for PET. In 2014, florbetaben was approved by the U.S. Food and Drug Administration, the European Medicines Agency, and the Korean Ministry of Food and Drug Safety to detect or exclude the presence of neuritic b-amyloid plaques in the brain (1,2). In a phase-3 study, high sensitivity and specificity were demonstrated for florbetaben in the detection of b-amyloid aggregates comparing PET with postmortem histopathology (3).The current clinical method for interpretation of florbetaben b-amyloid PET scans...

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Section: Discussionsupporting

confidence: 86%

Impact of Training Method on the Robustness of the Visual Assessment of ¹⁸F-Florbetaben PET Scans: Results from a Phase-3 Study

et al. 2016

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“…Nonetheless, most individuals with DS have amyloid-positive PET scans by the age of 50 (REFS 45,96,99,100). Amyloid load, as measured by PET, does not correlate well with cognitive function in adults who have DS in cross-sectional studies 45,99 , highlighting the importance of factors other than amyloid in the development of dementia. However, longitudinal imaging studies in this population have yet to be undertaken and may be highly informative 45,99 .…”

Section: Neuropathological Changes In Ad-dsmentioning

confidence: 89%

“…Amyloid load, as measured by PET, does not correlate well with cognitive function in adults who have DS in cross-sectional studies 45,99 , highlighting the importance of factors other than amyloid in the development of dementia. However, longitudinal imaging studies in this population have yet to be undertaken and may be highly informative 45,99 .No NFTs have been reported in AD-DS in the absence of dense-core plaque pathology, which is consistent with the predictions of the amyloid cascade hypothesis. The density of NFTs triples between the fourth and fifth decade of life in AD-DS 77 , mirroring the onset of dementia, and NFT formation rather than amyloid deposition correlates best with cognitive decline 34 , which is consistent with similar findings in LOAD.…”

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confidence: 89%

“…These 'non-cognitive' changes (also referred to as behavioural and psychological symptoms of dementia (BPSDs)) 38-42 are associated with deficits in executive functioning and with the frontal atrophy that is visible on MRI scans, which may indicate frontal lobe dysfunction 40,43 . These changes may be related to preexisting deficits in the integrity of the frontal tracts that have been observed in individuals with DS 44 and that may be worsened by Aβ deposition in the frontal lobes 45 . Although BPSDs are very prominent in early AD-DS, this presentation is not unique to these individuals -it also occurs, albeit at lower rates, during the early stages of LOAD 46 and EOAD 47 , particularly in cases arising from mutations in the AD risk gene presenilin 1 (PSEN1; which maps to chromosome 14).…”

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confidence: 99%

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A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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“…Visual reads yielded a sensitivity and specificity of 80 % and 91 %, respectively [40]. Another phase II study was able to detect amyloid in patients with Down syndrome without clinical evidence of dementia, suggesting the utility of imaging in high-risk patients [41].…”

Section: [ 18 F]-av-1 or [F-18]-bay94-9172 Or Florbetabenmentioning

confidence: 98%

Amyloid Imaging: Poised for Integration into Medical Practice

Anand

Sabbagh

2017

Neurotherapeutics

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Amyloid imaging represents a significant advance as an adjunct in the diagnosis of Alzheimer's disease (AD) because it is the first imaging modality that identifies in vivo changes known to be associated with the pathogenesis. Initially, 11 C-PIB was developed, which was the prototype for many 18 F compounds, including florbetapir, florbetaben, and flutemetamol, among others. Despite the high sensitivity and specificity of amyloid imaging, it is not commonly used in clinical practice, mainly because it is not reimbursed under current Center for Medicare and Medicaid Services guidelines in the USA. To guide the field in who would be most appropriate for the utility of amyloid positron emission tomography, current studies are underway [Imaging Dementia Evidence for Amyloid Scanning (IDEAS) Study] that will inform the field on the utilization of amyloid positron emission tomography in clinical practice. With the advent of monoclonal antibodies that specifically target amyloid antibody, there is an interest, possibly a mandate, to screen potential treatment recipients to ensure that they are suitable for treatment. In this review, we summarize progress in the field to date.

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Age dependence of brain β-amyloid deposition in Down syndrome

Abstract: Brain β-amyloid binding, as measured by [(18)F]florbetaben, increases with age in DS. Subjects with DS who have no evidence of dementia demonstrate brain β-amyloid binding in vivo, suggesting that [(18)F]florbetaben PET imaging may detect β-amyloid in this at-risk population.

Cited by 63 publications

References 36 publications

Impact of Training Method on the Robustness of the Visual Assessment of ¹⁸F-Florbetaben PET Scans: Results from a Phase-3 Study

Impact of Training Method on the Robustness of the Visual Assessment of ¹⁸F-Florbetaben PET Scans: Results from a Phase-3 Study

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Amyloid Imaging: Poised for Integration into Medical Practice

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Age dependence of brain β-amyloid deposition in Down syndrome

Abstract: Brain β-amyloid binding, as measured by [(18)F]florbetaben, increases with age in DS. Subjects with DS who have no evidence of dementia demonstrate brain β-amyloid binding in vivo, suggesting that [(18)F]florbetaben PET imaging may detect β-amyloid in this at-risk population.

Cited by 63 publications

References 36 publications

Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study

Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Amyloid Imaging: Poised for Integration into Medical Practice

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Product

Resources

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Impact of Training Method on the Robustness of the Visual Assessment of ¹⁸F-Florbetaben PET Scans: Results from a Phase-3 Study

Impact of Training Method on the Robustness of the Visual Assessment of ¹⁸F-Florbetaben PET Scans: Results from a Phase-3 Study