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Characterization of [18F]flutemetamol binding properties: A β-amyloid PET imaging ligand
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. (Nuklearmedicin och PET)
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1139
Keyword [en]
Positron emission tomography (PET), molecular imaging, amyloid, tracer validation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Radiology
Identifiers
URN: urn:nbn:se:uu:diva-262019ISBN: 978-91-554-9356-1 (print)OAI: oai:DiVA.org:uu-262019DiVA: diva2:858097
Public defence
2015-11-19, Skoogsalen, Akademiska Sjukhuset, Ingång 79, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-10-28 Created: 2015-09-07 Last updated: 2015-11-10
List of papers
1. Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.
Open this publication in new window or tab >>Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.
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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.

Keyword
PET; Amyloid imaging; [F-18]flutemetamol; Parametric imaging
National Category
Radiology, Nuclear Medicine and Medical Imaging Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-261034 (URN)10.1016/j.neuroimage.2015.07.037 (DOI)000363122000017 ()26209803 (PubMedID)
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-12-04Bibliographically approved
2. Separation of β-amyloid binding and white matter uptake of [18F]flutemetamol using spectral analysis
Open this publication in new window or tab >>Separation of β-amyloid binding and white matter uptake of [18F]flutemetamol using spectral analysis
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(English)Article in journal (Other academic) In press
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-262077 (URN)
Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2015-11-10
3. An exploratory efficacy study of the amyloid imaging agent [F-18]flutemetamol in Japanese Subjects
Open this publication in new window or tab >>An exploratory efficacy study of the amyloid imaging agent [F-18]flutemetamol in Japanese Subjects
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2015 (English)In: Annals of Nuclear Medicine, ISSN 0914-7187, E-ISSN 1864-6433, Vol. 29, no 5, 391-399 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the study presented was to investigate the brain uptake properties of the amyloid PET agent [F-18]flutemetamol in Japanese healthy controls and clinically probable Alzheimer's disease (AD) patients, and to make a comparison with the results of a previously performed study on Caucasian subjects. [F-18]flutemetamol was recently approved by the American Food and Drug Administration and the European Medicines Agency for visualization of amyloid in vivo. Since the first clinical study of [F-18]flutemetamol-an F-18 derivative of the PET tracer 11C-Pittsburgh Compound B targeting beta-amyloid--took place, several clinical studies have been performed, but few focusing on a Japanese population. In the Step A, three elderly healthy volunteers and three AD subjects underwent dynamic PET scanning 0-30 and 60-150 min after injection of 185 MBq [F-18]flutemetamol. The brain volume of distribution (V-T) was quantified using Logan's linear graphical analysis and as standardized uptake value ratios (SUVR) with a cerebellar reference. The optimal acquisition window was determined from brain time activity curves for Step B. In the Step B, 5 AD and 5 elderly healthy volunteers were scanned from 80 to 140 min after intravenous injection of [F-18]flutemetamol. The data from the two parts were pooled for estimation of overall efficacy. [F-18]Flutemetamol injection was shown to be safe-no serious adverse events were reported during this study. A simplified SUVR estimate of the uptake of [F-18]flutemetamol using a time window of 85-115 min post injection successfully discriminated AD cases from healthy volunteers. AD subjects showed an elevated tracer uptake in prefrontal cortex, the lateral temporal cortex and precuneus amongst other regions. No significant [F-18]flutemetamol PET differences could be seen between the Japanese AD cases in this study and those from an earlier Caucasian study, or between control subjects in Japanese and Caucasian studies. This study supports the use of [F-18]flutemetamol PET in Japanese population as a marker of the presence of fibrillar beta-amyloid. The lack of differences between the Japanese cohort and those from a previous Caucasian cohort supports the extrapolation of results from other Caucasian [F-18]flutemetamol PET studies to the Japanese population.

Keyword
[F-18] flutemetamol, Alzheimer's disease, Amyloid beta, Japanese population, Positron emission tomography
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-258778 (URN)10.1007/s12149-015-0957-7 (DOI)000356938000001 ()25874747 (PubMedID)
Available from: 2015-07-20 Created: 2015-07-20 Last updated: 2017-12-04Bibliographically approved
4. Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.
Open this publication in new window or tab >>Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.
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2013 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 20, no 7, 1043-52 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-β measured by immunohistochemical and histochemical staining in a frontal cortical biopsy.

METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-β was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain.

RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-β levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003).

CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-β in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-β pathology, both in patients with possible NPH and among the wider population.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-261037 (URN)10.1111/ene.12102 (DOI)23398333 (PubMedID)
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-12-04
5. Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.
Open this publication in new window or tab >>Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.
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2014 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 2, 46- p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies.

RESULTS: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result.

CONCLUSION: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-261036 (URN)10.1186/2051-5960-2-46 (DOI)24755237 (PubMedID)
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-05-10
6. [(18)F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid-β pathology.
Open this publication in new window or tab >>[(18)F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid-β pathology.
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2015 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 8, 975-85 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Amyloid positron emission tomography (PET) has become an important tool to identify amyloid-β (Aβ) pathology in Alzheimer's disease (AD) patients. Here, we determined the diagnostic value of the amyloid PET tracer [(18)F]flutemetamol in relation to Aβ pathology at autopsy.

METHODS: [(18)F]flutemetamol PET was carried out in a cohort of 68 patients included in a [(18)F]flutemetamol amyloid PET imaging end-of-life study (GE067-007). At autopsy, AD pathology was determined and Aβ plaque pathology was classified into phases of its regional distribution (0-5).

RESULTS: [(18)F]flutemetamol PET was universally positive in cases with advanced stage postmortem Aβ pathology (Aβ phases 4 and 5). Negative amyloid PET was universally observed in nondemented or non-AD dementia cases with initial Aβ phases 1 and 2, whereas 33.3% of the phase 3 cases were positive.

CONCLUSIONS: [(18)F]flutemetamol amyloid PET detects primarily advanced stages of Aβ pathology in preclinical and symptomatic AD cases.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-261035 (URN)10.1016/j.jalz.2015.05.018 (DOI)000360912300009 ()26141264 (PubMedID)
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-12-04Bibliographically approved

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