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Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. (Nuklearmedicin och PET)
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2015 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 121, 184-192 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: The amyloid imaging PET tracer [(18)F]flutemetamol was recently approved by regulatory authorities in the US and EU for estimation of β-amyloid neuritic plaque density in cognitively impaired patients. While the clinical assessment in line with the label is a qualitative visual assessment of 20min summation images, the aim of this work was to assess the performance of various parametric analysis methods and standardized uptake value ratio (SUVR), in comparison with arterial input based compartment modeling.

METHODS: The cerebellar cortex was used as reference region in the generation of parametric images of binding potential (BPND) using multilinear reference tissue methods (MRTMo, MRTM, MRTM2), basis function implementations of the simplified reference tissue model (here called RPM) and the two-parameter version of SRTM (here called RPM2) and reference region based Logan graphical analysis. Regionally averaged values of parametric results were compared with the BPND of corresponding regions from arterial input compartment modeling. Dynamic PET data were also pre-filtered using a 3D Gaussian smoothing of 5mm FWHM and the effect of the filtering on the correlation was investigated. In addition, the use of SUVR images was evaluated. The accuracy of several kinetic models were also assessed through simulations of time-activity curves based on clinical data for low and high binding adding different levels of statistical noise representing regions and individual voxels.

RESULTS: The highest correlation was observed for pre-filtered reference Logan, with correction for individual reference region efflux rate constant k2' (R(2)=0.98), or using a cohort mean k2' (R(2)=0.97). Pre-processing filtered MRTM2, unfiltered SUVR over the scanning window 70-90min and unfiltered RPM also demonstrated high correlations with arterial input compartment modeling (MRTM2 R(2)=0.97, RPM R(2)=0.96 and SUVR R(2)=0.95) Poorest agreement was seen with MRTM without pre-filtering (R(2)=0.68).

CONCLUSIONS: Parametric imaging allows for quantification without introducing bias due to selection of anatomical regions, and thus enables objective statistical voxel-based comparisons of tracer binding. Several parametric modeling approaches perform well, especially after Gaussian pre-filtering of the dynamic data. However, the semi-quantitative use of SUVR between 70 and 90min has comparable agreement with full kinetic modeling, thus supporting its use as a simplified method for quantitative assessment of tracer uptake.

Place, publisher, year, edition, pages
2015. Vol. 121, 184-192 p.
Keyword [en]
PET; Amyloid imaging; [F-18]flutemetamol; Parametric imaging
National Category
Radiology, Nuclear Medicine and Medical Imaging Medical and Health Sciences
URN: urn:nbn:se:uu:diva-261034DOI: 10.1016/j.neuroimage.2015.07.037ISI: 000363122000017PubMedID: 26209803OAI: oai:DiVA.org:uu-261034DiVA: diva2:849543
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2015-11-20Bibliographically approved
In thesis
1. Characterization of [18F]flutemetamol binding properties: A β-amyloid PET imaging ligand
Open this publication in new window or tab >>Characterization of [18F]flutemetamol binding properties: A β-amyloid PET imaging ligand
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The criteria for diagnosing Alzheimer’s disease (AD) have recently been revised to include the use of biomarkers for the in vivo presence of β-amyloid, one of the neuropathological hallmarks of AD. Examples of such biomarkers are positron emission tomography (PET) β-amyloid specific ligands, including [18F]flutemetamol. The aim of this thesis was to characterize the binding properties of [18F]flutemetamol from a tracer kinetic perspective as well as by validating binding measures through comparison with tissue pathology assessments. The applicability of previously developed kinetic models of tracer binding for voxel-based analysis was examined and compared to arterial input compartment modelling, the “gold standard” for PET quantification. Several voxel-based methods were found to exhibit high correlations with compartment modelling, including the semi-quantitative standardized uptake value ratio (SUVR). The kinetic components of [18F]flutemetamol uptake were also investigated without model assumptions using the data driven method spectral analysis, with binding to β-amyloid shown to relate to a slow kinetic component. The same component was also found to predominate in the uptake of white matter, known to be free of β-amyloid accumulation. White matter uptake was however possible to separate from β-amyloid binding based on the relative contribution of the slow component to the total volume of distribution. Uptake of [18F]flutemetamol as quantified using SUVR or assessed visually was found to correlate well with tissue pathology assessments. Classifying the brains of 68 deceased subjects who had undergone [18F]flutemetamol PET scanning ante mortem, based on the spatial distribution of β-amyloid according to pre-defined phases, revealed that abnormal uptake patterns of [18F]flutemetamol were only certain to be found in the last phase of β-amyloid accumulation. In the same cohort however, [18F]flutemetamol was also shown to accurately distinguish between subjects with AD and non-AD dementia. While this supports the use of [18F]flutemetamol in clinical settings for ruling out AD, the association of abnormal [18F]flutemetamol uptake to late phases of β-amyloid accumulation may limit the detection of early accumulation and pre-clinical stages of AD. It remains to be investigated whether application of voxel-based methods and slow component filtering may increase sensitivity, particularly in the context of clinical trials.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 74 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1139
Positron emission tomography (PET), molecular imaging, amyloid, tracer validation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
urn:nbn:se:uu:diva-262019 (URN)978-91-554-9356-1 (ISBN)
Public defence
2015-11-19, Skoogsalen, Akademiska Sjukhuset, Ingång 79, Uppsala, 09:15 (English)
Available from: 2015-10-28 Created: 2015-09-07 Last updated: 2015-11-10

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