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Tracer kinetic analysis of (S)-18F-THK5117 as a PET tracer for assessing tau pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, Med Phys, Uppsala, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Uppsala Hosp, PET Ctr, Uppsala, Sweden.
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Translat Alzheimer Neurobiol, S-14157 Huddinge, Sweden.
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2016 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 4, p. 574-581Article in journal (Refereed) Published
Abstract [en]

Because a correlation between tau pathology and the clinical symptoms of Alzheimer's disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-(18)F-THK5117.

METHODS: 9 subjects (5 with AD, 4 with mild cognitive impairment) received a 90 min dynamic (S)-(18)F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. VOI-based analysis was performed using plasma-input models; single-tissue and two-tissue (2TCM) compartment models and plasma-input Logan, and reference tissue models; simplified reference tissue model (SRTM), reference Logan and standardised uptake value ratio (SUVr). Cerebellum grey matter was used as reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan and SUVr. Regionally averaged voxel values were compared to VOI-based values from the optimal reference tissue model and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40 and 60 min data were analysed.

RESULTS: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R2=0.99, slope=0.96). SRTM binding potential (BPND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R2=1.00, slope≈1.00) while SUVr70-90-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R2=0.99, slope=1.03). SUVr70-90-1 values were almost 3 times higher than BPND values in white matter and 1.5 times higher in grey matter. Simulations showed poorer accuracy and precision for SUVr70-90-1 values than for the other reference methods. SRTM BPND and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min.

CONCLUSION: SRTM BPND and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-(18)F-THK5117 DVR-1 parametric images with the greatest accuracy and precision, and with a much lower white matter signal than seen with SUVr-1 images.

Place, publisher, year, edition, pages
2016. Vol. 57, no 4, p. 574-581
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-281917DOI: 10.2967/jnumed.115.158519ISI: 000373627800025PubMedID: 26795290OAI: oai:DiVA.org:uu-281917DiVA, id: diva2:915974
Funder
Swedish Research Council, 05817Stockholm County CouncilStiftelsen Gamla TjänarinnorThe Karolinska Institutet's Research FoundationThe Swedish Brain FoundationSwedish Foundation for Strategic Research EU, FP7, Seventh Framework ProgrammeAvailable from: 2016-03-31 Created: 2016-03-31 Last updated: 2018-02-15Bibliographically approved
In thesis
1. Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases
Open this publication in new window or tab >>Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders worldwide. Positron emission tomography (PET), together with suitable biomarkers, can aid in the clin-ical evaluation as well as in research investigations of these diseases. Straightforward and quantitative assessments of the parameters of inter-est estimated on a voxel-level, as parametric images, are possible when PET data is acquired over time. Prerequisites to facilitate clinical use of dynamic PET are simplified analysis methods and scan protocols suita-ble for clinical routine.

The aim of this thesis was to validate simplified analysis methods, suitable for clinical use, for quantification of dopamine transporter (DAT) availability in patients with parkinsonism using [11C]PE2I PET and tau accumulation in AD patients with [18F]THK5317 PET.

The included subjects comprised of both healthy controls and pa-tients with parkinsonism, AD or mild cognitive impairment and each subject underwent a dynamic PET scan with either [11C]PE2I or [18F]THK5317. Models for quantitative voxel-based analysis, resulting in parametric images of tracer binding and overall brain function, were validated in both patients and controls. These parametric methods were compared to region-based values acquired using both plasma- and refer-ence-input models. Clinically feasible scan durations were evaluated for both [11C]PE2I and [18F]THK5317, and a clustering method to obtain a reference time activity curve directly from the dynamic PET data was validated. Furthermore, images of DAT availability and overall brain functional activity, generated from one single dynamic [11C]PE2I PET scan, were compared to a dual-scan approach using [123I]FP-CIT single photon emission computed tomography (SPECT) and [18F]FDG PET, for differential diagnosis of patient with parkinsonism.

Study I-III supply valuable information on the feasibility of dynamic [11C]PE2I in a clinical setting for differential diagnosis of parkinsonian disorders, by having easily accessible images of DAT availability and overall brain functional activity. The work in study IV-V showed that reference methods can be used for quantification of tau accumulation, and suggests that simplified analysis methods and shorter scan durations can be applied to further facilitate applications of dynamic [18F]THK5317 PET.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1429
Keywords
Positron emission tomography, PET, Molecular imaging, Quantification, Kinetic modelling, Parametric images, Alzheimer’s disease, Parkinson’s disease
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Radiology
Identifiers
urn:nbn:se:uu:diva-341786 (URN)978-91-513-0238-6 (ISBN)
Public defence
2018-04-06, Skoogsalen, Akademiska Sjukhuset, Ing 79, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-03-14 Created: 2018-02-15 Last updated: 2018-04-24

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Jonasson, MyWall, AndersThibblin, AlfEriksson, JonasSörensen, JensAntoni, GunnarLubberink, Mark

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