Centiloid scaling for quantification of brain amyloid with [18F]flutemetamol using multiple processing methods

Battle, Mark; Pillay, Lovena Chedumbarum; Lowe, Val J.; Knopman, David S.; Kemp, Bradley J.; Rowe, Christopher C.; Doré, Vincent; Villemagne, Victor L.; Buckley, Christopher

doi:10.1186/s13550-018-0456-7

Cited by 65 publications

(62 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1) in part due to occasional intracellular APP/Aβ immunoreactivity. It is worth noting that the scaling factor between cyanoflutemetamol and cyano-PiB positive histological plaque burdens in tissue sections analyzed in the current study is similar to that in a recently reported Centiloid analysis of paired [ 18 F]flutemetamol and [ 11 C]PiB scans from 74 subjects [3]. In support of the idea that both ligands' fluorescence intensity is influenced by Aβ fibril density, our current study shows that cyano-labeled derivatives of the two ligands exhibited bright fluorescence in cored plaques, characterized by high Aβ fibril packing density in the core region, and dimmer fluorescence in diffuse plaques, characterized by loosely organized Aβ fibrils.…”

Section: Discussionsupporting

confidence: 85%

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer’s disease

et al. 2020

Self Cite

View full text Add to dashboard Cite

Specificity and sensitivity of positron emission tomography (PET) radiopharmaceuticals targeting fibrillar amyloid-β (Aβ) deposits is high for detection of neuritic Aβ plaques, a mature form of Aβ deposits which often have dense Aβ core (i.e., cored plaques). However, imaging-to-autopsy validation studies of amyloid PET radioligands have identified several false positive cases all of which had mainly diffuse Aβ plaques (i.e., plaques without neuritic pathology or dense amyloid core), and high amyloid PET signal was reported in the striatum where diffuse plaques predominate in Alzheimer’s disease (AD). Relative contributions of different plaque types to amyloid PET signal is unclear, particularly in neocortical areas where they are intermixed in AD. In vitro binding assay and autoradiography were performed using [3H]flutemetamol and [3H]Pittsburgh Compound-B (PiB) in frozen brain homogenates from 30 autopsy cases including sporadic AD and non-AD controls with a range of brain Aβ burden and plaque density. Fixed tissue sections of frontal cortex and caudate from 10 of the AD cases were processed for microscopy using fluorescent derivatives of flutemetamol (cyano-flutemetamol) and PiB (cyano-PiB) and compared to Aβ immunohistochemistry and pan-amyloid (X-34) histology. Using epifluorescence microscopy, percent area coverage and fluorescence output values of cyano-PiB- and cyano-flutemetamol-labeled plaques in two-dimensional microscopic fields were then calculated and combined to obtain integrated density measurements. Using confocal microscopy, we analysed total fluorescence output of the entire three-dimensional volume of individual cored plaques and diffuse plaques labeled with cyano-flutemetamol or cyano-PiB. [3H]Flutemetamol and [3H]PiB binding values in tissue homogenates correlated strongly and their binding pattern in tissue sections, as seen on autoradiograms, overlapped the pattern of Aβ-immunoreactive plaques on directly adjacent sections. Cyano-flutemetamol and cyano-PiB fluorescence was prominent in cored plaques and less so in diffuse plaques. Across brain regions and cases, percent area coverage of cyano-flutemetamol-labeled plaques correlated strongly with cyano-PiB-labeled and Aβ-immunoreactive plaques. For both ligands, plaque burden, calculated as percent area coverage of all Aβ plaque types, was similar in frontal cortex and caudate regions, while integrated density values were significantly greater in frontal cortex, which contained both cored plaques and diffuse plaques, compared to the caudate, which contained only diffuse plaques. Three-dimensional analysis of individual plaques labeled with either ligand showed that total fluorescence output of a single cored plaque was equivalent to total fluorescence output of approximately three diffuse plaques of similar volume. Our results indicate that [18F]flutemetamol and [11C]PiB PET signal is influenced by both diffuse plaques and cored plaques, and therefore is likely a function of plaque size and density of Aβ fibrils in plaques. Brain areas with large volumes/frequencies of diffuse plaques could yield [18F]flutemetamol and [11C]PiB PET retention levels comparable to brain regions with a lower volume/frequency of cored plaques.

show abstract

Section: Discussionsupporting

confidence: 85%

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer’s disease

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…PET images were not corrected for partial volume correction. All Aβ PET scans were quantified using CapAIBL 24 and the Aβ level was expressed in Centiloids (CL) as described by Klunk et al 12 and Bourgeat et al 25 [12][13][14][15][16][17][18] Consequently we set <15 CL as negative, 15-25 as uncertain and then, to reflect categories…”

Section: Imaging Methods and Analysismentioning

confidence: 99%

Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals

et al. 2021

Self Cite

View full text Add to dashboard Cite

Objective:To determine the effect of Aβ level on progression risk to MCI or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals.Methods:All CN from the Australian Imaging Biomarkers and Lifestyle study (AIBL) with Aβ PET and ≥3 years follow-up were included (n=534; age 72±6 yrs; 27% Aβ positive; follow-up 5.3±1.7 yrs). Aβ level was divided using the standardised 0-100 Centiloid scale: <15 CL negative, 15-25 CL uncertain, 26-50 CL moderate, 51-100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline.Results:Aβ levels in 63% were negative, 10% uncertain, 10% moderate, 14% high and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aβ, the hazard ratio for progression for moderate Aβ was 3.2 (95% CI 1.3-7.6; p<0.05), for high was 7.0 (95% CI 3.7-13.3; p<0.001) and for very high was 11.4 (95% CI 5.1-25.8; p<0.001). Decline in cognitive composite score was minimal in the moderate group (-0.02 SD/year, p=0.05) while the high and very high declined substantially (high -0.08 SD/year, p<0.001; very high -0.35 SD/year p<0.001).Conclusion:The risk of MCI or dementia over 5 years in older CN is related to Aβ level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26-50 CL to 28% if 51-100 CL and 50% if >100 CL. This information may be useful for dementia risk counselling and aid design of preclinical AD trials.

show abstract

“…This is why there has been an ongoing development to standardise quantitative Aβ imaging measures using the "centiloid scale" [34]. Work is now ongoing to validate centiloid scaling between various tracers and against other biomarkers [35][36][37]. Standardisation such as centiloid scaling has yet to be applied in tau imaging to a greater extent [38].…”

Section: Amyloid-β Petmentioning

confidence: 99%

Imaging biomarkers in neurodegeneration: current and future practices

et al. 2020

View full text Add to dashboard Cite

There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.

show abstract

Centiloid scaling for quantification of brain amyloid with [18F]flutemetamol using multiple processing methods

Cited by 65 publications

References 22 publications

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer’s disease

Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer’s disease

Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals

Imaging biomarkers in neurodegeneration: current and future practices

Contact Info

Product

Resources

About