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Cited by 71Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMedical Imaging Techniques and Applications

Early detection of amyloid load using 18F-florbetaben PET

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Bullich, Santiago, Roé-Vellvé, Núria, Marquié, Marta, Landau, Susan M., Barthel, Henryk, Villemagne, Victor L., Sanabria, Ángela, Tartari, Juan Pablo +13 more·2021·Alzheimer's Research & Therapy
DOI 10.1186/s13195-021-00807-6PMC PMC8005243
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Abstract

Background: A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18 F-florbetaben PET. Quantitative thresholds for the early (SUVR early) and established (SUVR estab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).

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  • The 12-Centiloid threshold is the optimal cut-off validated in neuropathology to detect CERAD moderate-to-frequent neuritic plaque scores, early detection of Aβ abnormalities by PET, and agreement against CSF AD biomarkers.

    “The 12-Centiloid threshold is the optimal cut-off validated in neuropathology to detect CERAD moderate-to-frequent, neuritic plaque scores19, early detection of Aβ abnormalities by PET22 and agreement against CSF AD biomarkers18.”

    From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [22]

    The citation to this paper is attached to early detection of Aβ abnormalities by PET. The Abstract Results and Conclusions report an early PET cutoff of 13.5 Centiloids, not an optimal cutoff of exactly 12; the Discussion places early cutoffs in an approximate 11–17 Centiloid range. The neuropathology and CSF portions of the citing sentence have separate citations. (LLM, conf=0.88)

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  • 35.7 Centiloids is a cut-off for established Aβ abnormalities in PET.

    “and with the 35.7 Centiloid cut-off for established Aβ abnormalities in PET described by Bullic et al.22.”

    From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [22]

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Authors
Bullich, S., Roé-Vellvé, N., Marquié, M., Landau, S. M., Barthel, H., Villemagne, V. L., Sanabria, Á., Tartari, J. P., Sotolongo-Grau, O., Doré, V., Koglin, N., Müller, A., Perrotin, A., Jovalekic, A., De Santi, S., Tárraga, L., Stephens, A. W., Rowe, C. C., Sabri, O., Seibyl, J. P., & Boada, M.
Affiliations
  • Instituto de Salud Carlos III (ES)
  • Lawrence Berkeley National Laboratory (US)
  • University Hospital Leipzig (DE)
  • The University of Melbourne (AU)
  • Universitat Internacional de Catalunya (ES)
  • Commonwealth Scientific and Industrial Research Organisation (AU)
  • Invicro (United States) (US)
Corresponding author
Bullich, Santiago
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-03-27
Volume
13
Issue
1
Pages
67-67
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-021-00807-6
PMC
PMC8005243
OpenAlex
W3143545452
Cited by
71
References
5
Citations by year
2026: 11 · 2025: 13 · 2024: 18 · 2023: 14 · 2022: 14 · 2021: 1
FWCI
8.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Bayer Pharma AG or Piramal Imaging
  • Fundació ACE Institut Català de Neurociències Aplicades, Grifols, Life Molecular Imaging, Araclon Biotech, Alkahest, Laboratorio de análisis Echevarne and IrsiCaixa
  • EU-EFPIA Innovative Medicines Initiatives 2 Joint Undertaking (115952)
  • Alzheimer's Disease Neuroimaging Initiative (National Institutes of Health Grant U01 AG024904, Department of Defense award number W81XWH-12-2-0012)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Keywords
amyloid PET, 18F-florbetaben, amyloid burden, gray zone, mild cognitive impairment, Alzheimer's disease progression, subjective cognitive decline, tau deposition, standardized uptake value ratio, amyloid PET quantification, cingulate cortex, precuneus, temporal cortex
MeSH terms
Alzheimer Disease, Aniline Compounds, Humans, Stilbenes, Amyloid beta-Peptides, Positron-Emission Tomography, Cognitive Dysfunction

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