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Abdominal Aortic Aneurysm: Molecular Imaging Studies of Pathophysiology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pathological process behind abdominal aortic aneurysm (AAA) formation is poorly understood and difficult to study. The aim of the thesis was to study the pathophysiology of AAA formation with positron emission tomography (PET) technology, a molecular imaging technique, allowing in vivo studies of pathophysiological changes.

In study I 18F-FDG, a glucose analogue, was tested. It had previously been reported as a useful tracer studying inflammation in AAAs. These studies included, however, foremost large, symptomatic, and inflammatory AAAs. In the present study on five small and seven large asymptomatic AAAs, no increase in 18F-FDG uptake could be revealed in vivo.

In study II 11C-PK11195, a macrophage tracer, and 11C-D-deprenyl, an unspecific inflammatory tracer, previously never tested on asymptomatic AAAs, were tested in vivo on five and 10 AAA-patients respectively, without signs of increased levels of inflammatory activity in the aorta.

In study III several tracers were screened in vitro through autoradiography on AAA tissue. [18F]fluciclatide, targeting the integrin αVβ3 receptor upregulated in angiogenesis, was the only tracer with an increased uptake.

In study IV [18F]fluciclatide-autoradiography was performed on AAA tissue from five patients and non-aneurysmal aortic tissue obtained from five age and sex matched organ donors. The study showed a 56% increased specific uptake in AAA, although not significant (P=0.136). Immunohistochemical revealed inflammatory cell foci in close relation to the vessels.

In conclusion, PET has potential to elucidate the pathophysiology of AAA formation. For the large group of small asymptomatic AAAs, 18F-FDG is not suitable, as the chronic inflammation in asymptomatic AAA is not sufficiently metabolically active. Furthermore, 11C-PK11195 and 11C-D-deprenyl were unable to show the chronic inflammation seen in asymptomatic AAA.

The interesting finding with uptake of [18F]fluciclatide showed that angiogenesis may be imaged in large asymptomatic AAAs in vitro, through the integrin αVβ3 receptor. Thus, it is likely that future studies of the role of angiogenesis in AAA formation in vivo, in small AAAs, could use this target site. The development of an integrin αVβ3 receptor tracer, preferably with higher affinity, is in progress for further in vitro and in vivo studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 111 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 899
Keyword [en]
Abdominal aortic aneurysm, AAA, Positron emission tomography, PET, Molecular Imaging, Pathophysiology, Autoradiography, Angiogenesis, integrin alphaVbeta3, FDG, 18F-FDG, 11C-PK11195, 11C-D-deprenyl, [18F]fluciclatide, Fluciclatide
Keyword [sv]
Bukaortaaneurysm, Molekylär bilddiagnostik, Patofysiologi, PET, Autoradiografi, Angiogenes
National Category
Medical and Health Sciences Surgery Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Surgery; Medical Radiophysics
Identifiers
URN: urn:nbn:se:uu:diva-194663ISBN: 978-91-554-8656-3 (print)OAI: oai:DiVA.org:uu-194663DiVA: diva2:615542
Public defence
2013-05-31, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-08 Created: 2013-02-18 Last updated: 2013-08-30Bibliographically approved
List of papers
1. Inflammation in the walls of asymptomatic abdominal aortic aneurysms is not associated with increased metabolic activity detectable by 18-fluorodeoxglucose positron-emission tomography
Open this publication in new window or tab >>Inflammation in the walls of asymptomatic abdominal aortic aneurysms is not associated with increased metabolic activity detectable by 18-fluorodeoxglucose positron-emission tomography
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2012 (English)In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 56, no 3, 802-807 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

We hypothesized that the general inflammation observed in the wall of large, asymptomatic abdominal aortic aneurysms (AAAs) could be detected in vivo by 18-fluorodeoxglucose (FDG) positron-emission tomography (PET) and, if so, that this method could be used to study if active inflammation is an early pathogenetic finding in small AAAs detected by screening.

METHODS:

In this prospective clinical study, 12 men were examined with FDG-PET computed tomography. Seven had large asymptomatic AAAs (range, 52-66 mm) that required surgery, and five had small AAAs (range, 34-40 mm) under surveillance. In the surgery group, biopsy specimens were taken from the aneurysm wall for histologic examinations.

RESULTS:

Compared with normal segments of the aorta, liver, and blood and compared with healthy controls matched for age and sex, no increased FDG uptake, measured as standardized uptake value, was detected in any of the large or small AAAs. The SUVmean difference between infrarenal aorta and blood was -0.3 for cases and -0.1 for controls (P = .06). The corresponding differences between the infrarenal aorta and liver was -0.8 and -0.8 (P = .91) and between infrarenal aorta and suprarenal aorta was -0.2 and -0.1 for cases and controls, respectively (P = .20). The histologic examination of the aneurysm walls showed high inflammatory cell infiltration with T lymphocytes, B lymphocytes, and macrophages.

CONCLUSIONS:

The chronic inflammation observed in the wall of asymptomatic AAAs was not sufficiently metabolically active to result in an increased glucose metabolism detectable by FDG-PET by means of this standard protocol. To study the importance of inflammation in the pathogenesis of AAAs in vivo, PET tracers other than FDG need to be developed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-181755 (URN)10.1016/j.jvs.2012.02.024 (DOI)000308085500029 ()22854268 (PubMedID)
Available from: 2012-09-28 Created: 2012-09-28 Last updated: 2017-12-07Bibliographically approved
2. 4D-PET/CT with [11C]-PK11195 and [11C]-D-deprenyl does not identify the chronic inflammation in asymptomatic abdominal aortic aneurysms
Open this publication in new window or tab >>4D-PET/CT with [11C]-PK11195 and [11C]-D-deprenyl does not identify the chronic inflammation in asymptomatic abdominal aortic aneurysms
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2013 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 45, no 4, 351-356 p.Article in journal (Refereed) Published
Abstract [en]

Objectives

The aim of this study was to investigate the relevance of inflammation in the pathogenesis of abdominal aortic aneurysm (AAA) in vivo with two novel positron emission tomography (PET) tracers: [11C]-PK11195 which targets the translocator protein (18 kDa) expressed on macrophages and [11C]-d-deprenyl with a yet unknown target receptor expressed in chronic inflammation.

Design

Prospective clinical study.

Materials/methods

Five patients were examined with [11C]-PK11195-positron emission tomography/computed tomography (PET/CT) and 10 with [11C]-d-deprenyl-PET/CT. Nine large AAAs (54–66 mm) scheduled for repair and six small AAA (35–44 mm). All 15 patients were male and the AAAs were all asymptomatic. Regional activity was measured as standardised uptake values (SUVs) and retention index was calculated. Biopsies were taken from the aneurysm wall for histological examinations, in the nine patients operated on.

Results

No aortic uptake was recorded on the visual inspection, neither with [11C]-PK11195 nor with [11C]-d-deprenyl. For [11C]-PK11195 the median SUV of the AAA wall was 0.9 (range 0.8–1.0) and for [11C]-d-deprenyl, 0.7 (range 0.4–1.2). No increased uptake was seen in the aneurysmal infrarenal aorta compared with the non-aneurysmal suprarenal aorta. Histological examination of the aneurysm wall showed high inflammatory cell infiltration with lymphocytes and macrophages.

Conclusions

The chronic inflammation observed in the vessel wall was not detectable with [11C]-PK11195 and [11C]-d-deprenyl. In order to study the relevance of the inflammation in the pathogenesis of AAA in vivo other PET tracers need to be investigated.

Keyword
AAA, PET, 11C-PK1195, 11C-D-deprenyl, pathophysiology
National Category
Surgery Physiology Other Medical Biotechnology
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-197429 (URN)10.1016/j.ejvs.2013.01.011 (DOI)000316924900007 ()23394769 (PubMedID)
Available from: 2013-03-25 Created: 2013-03-25 Last updated: 2017-12-06Bibliographically approved
3. Autoradiography screening of potential positron emission tomography tracers for asymptomatic abdominal aortic aneurysms
Open this publication in new window or tab >>Autoradiography screening of potential positron emission tomography tracers for asymptomatic abdominal aortic aneurysms
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2014 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 3, 229-235 p.Article in journal (Refereed) Published
Abstract [en]

Objective. The aetiology and early pathophysiological mechanisms of aortic aneurysm formation are still unknown and challenging to study in vivo. Positron emission tomography (PET) is a potentially valuable instrument for non-invasive in vivo pathophysiological studies. No specific tracer to identify the pathophysiological process of aneurysmal dilatation is yet available, however. The aim of this study was to explore if different PET tracers could be useful to image aneurysmal disease. Methods and results. Human aneurysmal aortic tissue, collected during elective resection of abdominal aortic aneurysm (AAA) of asymptomatic patients, was investigated in vitro by means of autoradiography with [Ga-68]CRP-binder targeting C-reactive protein, [C-11]DAA1106 targeting translocator protein (18 kDa), [C-11]D-deprenyl with unknown target receptor, [C-11] deuterium-L-deprenyl targeting astrocytes, [F-18]fluciclatide targeting integrin alpha(V)beta(3), [Ga-68]IMP461 and bi-specific antibody TF2 052107 targeting carcinoembryonic antigen, [F-18]F-metomidate targeting mitochondrial cytochrome P-450 species in the adrenal cortex, and [F-18]vorozole targeting aromatase. Of the investigated tracers, only [F-18]fluciclatide exhibited specific binding, whereas the other PET tracers failed to show specific uptake in the investigated tissue and are probably not useful for the intended purpose. Conclusion. It seems likely that alpha(V)beta(3) integrin expression in AAA can be visualized with PET and that the alpha(V)beta(3) selective tracer, [F-18]fluciclatide, may be suitable for in vivo molecular imaging of asymptomatic AAA. Additional evaluation of [F-18]fluciclatide and alpha(V)beta(3) integrin expression in AAA will be performed in vitro as well as in vivo.

Keyword
AAA, PET tracers, pathophysiology
National Category
Surgery Physiology Other Medical Biotechnology
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-197428 (URN)10.3109/03009734.2014.894157 (DOI)000340110800003 ()
Funder
Swedish Research Council, K2013-64X-20406-07-3
Available from: 2013-03-25 Created: 2013-03-25 Last updated: 2017-12-06Bibliographically approved
4. [18F]fluciclatide- Autoradiography study of angiogenesis in abdominal aortic aneurysm
Open this publication in new window or tab >>[18F]fluciclatide- Autoradiography study of angiogenesis in abdominal aortic aneurysm
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2013 (English)Manuscript (preprint) (Other academic)
Keyword
AAA, PET, 18F-Fluciclatide, integrin alfaVbeta3, angiogenesis, pathophysiology
National Category
Surgery Physiology Other Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-197432 (URN)
Available from: 2013-03-25 Created: 2013-03-25 Last updated: 2015-09-24

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