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Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. (Nuklearmedicin och PET)
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. , s. 55
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1429
Emneord [en]
Positron emission tomography, PET, Molecular imaging, Quantification, Kinetic modelling, Parametric images, Alzheimer’s disease, Parkinson’s disease
HSV kategori
Forskningsprogram
Radiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-341786ISBN: 978-91-513-0238-6 (tryckt)OAI: oai:DiVA.org:uu-341786DiVA, id: diva2:1182886
Disputas
2018-04-06, Skoogsalen, Akademiska Sjukhuset, Ing 79, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-03-14 Laget: 2018-02-15 Sist oppdatert: 2018-04-24
Delarbeid
1. Validation of parametric methods for [(11)C]PE2I positron emission tomography
Åpne denne publikasjonen i ny fane eller vindu >>Validation of parametric methods for [(11)C]PE2I positron emission tomography
Vise andre…
2013 (engelsk)Inngår i: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 74, s. 172-178Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

OBJECTIVES

The radioligand [(11)C]PE2I is highly selective for dopamine transporter (DAT) and can be used in vivo for investigation of changes in DAT concentration, progression of disease and validation of treatment using positron emission tomography (PET). DAT is an important protein for regulation of central dopamine concentration and DAT deficiency has been associated with several neurodegenerative and neuropsychiatric disorders. Accurate parametric images are a prerequisite for clinical application of [(11)C]PE2I. The purpose of this study was to evaluate different methods for producing [(11)C]PE2I parametric images, showing binding potential (BPND) and relative delivery (R1) at the voxel level, using clinical data as well as simulations.

METHODS

Investigations were made in twelve subjects either with social anxiety disorder (n=6) or parkinsonian syndrome (n=6), each receiving an 80min dynamic PET scan. All subjects underwent a T1-weighted MRI scan which was co-registered to the PET images and used for definition of regions of interest using a probabilistic template (PVElab). Two basis function implementations (receptor parametric mapping: RPM, RPM2) of the simplified reference tissue model (SRTM) and three multilinear reference tissue models (MRTMo, MRTM and MRTM2) were used for computation of parametric BPND and R1 images. In addition, reference Logan and standard uptake value ratio (SUVr) were investigated. Evaluations of BPND and R1 images were performed using linear regression to compare the parametric methods to region-based analyses with SRTM and cerebellar gray matter as reference region. Accuracy and precision of each method were assessed by simulations.

RESULTS

Correlation and slope of linear regression between parametric and region-based BPND and R1 values in both striatum and extra-striatal regions were optimal for RPM (R(2)=0.99 for both BPND and R1; slopes 0.99 and 0.98 for BPND and R1, respectively, in striatum). In addition, accuracy and precision were best for RPM and RPM2.

CONCLUSION

The basis function methods provided more robust estimations of the parameters compared to the other models and performed best in simulations. RPM, a basis function implementation of SRTM, is the preferred method for voxel level analysis of [(11)C]PE2I PET studies.

HSV kategori
Forskningsprogram
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-197228 (URN)10.1016/j.neuroimage.2013.02.022 (DOI)000317441300018 ()23435214 (PubMedID)
Tilgjengelig fra: 2013-03-22 Laget: 2013-03-19 Sist oppdatert: 2018-02-15bibliografisk kontrollert
2. Use of C-11-PE2I PET in Differential Diagnosis of Parkinsonian Disorders
Åpne denne publikasjonen i ny fane eller vindu >>Use of C-11-PE2I PET in Differential Diagnosis of Parkinsonian Disorders
Vise andre…
2015 (engelsk)Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, nr 2, s. 234-242Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using I-123-FP-CIT (I-123-N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane, or I-123-ioflupane) SPECT and F-18-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic C-11-PE2I (N-(3-iodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(4-methyl-phenyl) nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R-1]) at voxel level. This study aimed to evaluate the validity of C-11-PE2I PET against the dual-modality approach using I-123-FP-CIT SPECT and F-18-FDG PET.

Methods: Sixteen patients with parkinsonian disorders had a dual examination with F-18-FDG PET and I-123-FP-CIT SPECT following clinical routines and additionally an experimental C-11-PE2I PET scan. Parametric BPND and R-1 images were generated using receptor parametric mapping with the cerebellum as a reference. T1-weighted MR imaging was used for automated definition of volumes of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examined using VOIs across the brain. BPND and R-1 values were compared with normalized I-123-FP-CIT and F-18-FDG uptake values, respectively, using Pearson correlations and regression analyses. In addition, 2 masked interpreters evaluated the images visually, in both the routine and the experimental datasets, for comparison of patient diagnoses.

Results: Parametric C-11-PE2I BPND and R-1 images showed high consistency with I-123-FP-CIT SPECT and F-18-FDG PET images. Correlations between C-11-PE2I BPND and I-123-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, respectively. Regional C-11-PE2I R-1 values were moderately to highly correlated with normalized F-18-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between C-11-PE2I BPND and I-123-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using I-123-FP-CIT and F-18-FDG images. Substantial differences were found between clinical diagnosis and both neuro-imaging diagnoses.

Conclusion: A single, dynamic C-11-PE2I PET investigation is a powerful alternative to a dual examination with I-123-FP-CIT SPECT and F-18-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathologic patterns in overall brain functional activity for various parkinsonian disorders.

Emneord
parkinsonism, dopamine transporter, DAT, overall brain functional activity, PET, SPECT
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-247403 (URN)10.2967/jnumed.114.148619 (DOI)000349324300024 ()25593112 (PubMedID)
Tilgjengelig fra: 2015-03-20 Laget: 2015-03-18 Sist oppdatert: 2018-02-15bibliografisk kontrollert
3. Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.
Åpne denne publikasjonen i ny fane eller vindu >>Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.
Vise andre…
2017 (engelsk)Inngår i: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, nr 6, s. 263-274Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum reference region defined on a co-registered MRI, as well as a supervised cluster analysis (SVCA)-based reference. Initial 20, 30 and 40 min of the scans were extracted and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based reference. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extraction of a reference region. These outcomes will support routine applications of [11C]PE2I PET in clinical settings.

Emneord
PET, [11C]PE2I, parametric images, parkinsonism, supervised clustering
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-340790 (URN)000419593300003 ()29348981 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilSwedish Society for Medical Research (SSMF)
Tilgjengelig fra: 2018-02-02 Laget: 2018-02-02 Sist oppdatert: 2018-02-21bibliografisk kontrollert
4. Tracer kinetic analysis of (S)-18F-THK5117 as a PET tracer for assessing tau pathology.
Åpne denne publikasjonen i ny fane eller vindu >>Tracer kinetic analysis of (S)-18F-THK5117 as a PET tracer for assessing tau pathology.
Vise andre…
2016 (engelsk)Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, nr 4, s. 574-581Artikkel i tidsskrift (Fagfellevurdert) 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.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-281917 (URN)10.2967/jnumed.115.158519 (DOI)000373627800025 ()26795290 (PubMedID)
Forskningsfinansiär
Swedish Research Council, 05817Stockholm County CouncilStiftelsen Gamla TjänarinnorThe Karolinska Institutet's Research FoundationThe Swedish Brain FoundationSwedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme
Tilgjengelig fra: 2016-03-31 Laget: 2016-03-31 Sist oppdatert: 2018-02-15bibliografisk kontrollert
5. Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET
Åpne denne publikasjonen i ny fane eller vindu >>Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET
Vise andre…
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Emneord
Alzheimer’s disease, PET, Parametric images, Supervised clustering, Tau imaging
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-341785 (URN)
Tilgjengelig fra: 2018-02-14 Laget: 2018-02-14 Sist oppdatert: 2018-02-15

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