| 1. |
- Alhuseinalkhudhur, Ali
(författare)
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HER2-receptor quantification in breast cancer patients by imaging with ABY-025 Affibody and PET
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common malignancy in women worldwide. Human epidermal growth factor receptor type 2 (HER2) is overexpressed in up to 20% of breast cancer cases and is considered an important prognostic factor and a therapeutic target. With the introduction of HER2-targeted therapy, it was important to recognize patients who will likely benefit from such treatment. Immunohistochemistry staining performed on a tumor biopsy, with in situ hybridization to detect gene amplification if needed, is the current gold standard method for HER2 receptor quantification. However, in cases with multiple metastases, it is both unfeasible and impractical to perform multiple biopsies without risking higher morbidity. Molecular imaging with tracers specifically targeting HER2 receptors provides a non-invasive approach, which allows full body quantification without the serious side effects associated with invasive biopsies. The molecule of focus in this thesis work is Affibody ZHER2:2891 (ABY-025) molecule that has a high affinity and selectivity towards HER2 receptors.This thesis is based on four original articles. The first part focused on the aspect of breast cancer imaging using HER2-targeting gallium-labeled tracer 68Ga-ABY-025 in positron emission tomography (PET) and its role in predicting breast cancer outcome. The second part was to investigate the effect of different risk factors on developing brain metastasis, the overall survival and the effect of HER2-targeted treatment on breast cancer brain metastasis based on Uppsala County cancer registry.We demonstrated that HER2-binding Affibody PET kinetics can be explained using a two-tissue compartment model and SUV values correlated well with the influx rates calculated using kinetic modeling, supporting its use to measure actual HER2 receptor binding. Phase II study demonstrated the potential of 68Ga-ABY-025 PET to predict the treatment outcome more accurately compared to biopsy HER2-status that uses the traditional immunohistochemistry staining and in situ hybridization techniques. 68Ga-ABY-025 PET provided accurate staging and reduced false positive 18F-FDG PET results in HER2-positive cases. HER2-positive molecular subtypes were associated with an increased risk of developing brain metastasis. Yet, longer survival times were observed in HER2-positive subtypes receiving HER2-targeted therapy.
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| 2. |
- Andersson, Jonathan
(författare)
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Water–fat separation in magnetic resonance imaging and its application in studies of brown adipose tissue
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Virtually all the magnetic resonance imaging (MRI) signal of a human originates from water and fat molecules. By utilizing the property chemical shift the signal can be separated, creating water- and fat-only images. From these images it is possible to calculate quantitative fat fraction (FF) images, where the value of each voxel is equal to the percentage of its signal originating from fat. In papers I and II methods for water–fat signal separation are presented and evaluated.The method in paper I utilizes a graph-cut to separate the signal and was designed to perform well even for a low signal-to-noise ratio (SNR). The method was shown to perform as well as previous methods at high SNRs, and better at low SNRs.The method presented in paper II uses convolutional neural networks to perform the signal separation. The method was shown to perform similarly to a previous method using a graph-cut when provided non-undersampled input data. Furthermore, the method was shown to be able to separate the signal using undersampled data. This may allow for accelerated MRI scans in the future.Brown adipose tissue (BAT) is a thermogenic organ with the main purpose of expending chemical energy to prevent the body temperature from falling too low. Its energy expending capability makes it a potential target for treating overweight/obesity and metabolic dysfunctions, such as type 2 diabetes. The most well-established way of estimating the metabolic potential of BAT is through measuring glucose uptake using 18F-fludeoxyglucose (18F-FDG) positron emission tomography (PET) during cooling. This technique exposes subjects to potentially harmful ionizing radiation, and alternative methods are desired. One alternative method is measuring the BAT FF using MRI.In paper III the BAT FF in 7-year olds was shown to be negatively associated with blood serum levels of the bone-specific protein osteocalcin and, after correction for adiposity, thigh muscle volume. This may have implications for how BAT interacts with both bone and muscle tissue.In paper IV the glucose uptake of BAT during cooling of adult humans was measured using 18F-FDG PET. Additionally, their BAT FF was measured using MRI, and their skin temperature during cooling near a major BAT depot was measured using infrared thermography (IRT). It was found that both the BAT FF and the temperature measured using IRT correlated with the BAT glucose uptake, meaning these measurements could be potential alternatives to 18F-FDG PET in future studies of BAT.
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| 3. |
- Fahlström, Markus
(författare)
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On potentials and limitations of perfusion MRI in neurological disorders
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cerebral perfusion outlines several parameters which describe the status of cerebral haemodynamics. Numerous neurological diseases affect cerebral perfusion, thus the importance of diagnostic measurements. Perfusion magnetic resonance imaging (MRI) is a collection of non-ionizing magnetic resonance-based perfusion measurement techniques that can be used for clinical assessment of cerebral perfusion. The aim of this thesis was to investigate potentials and limitations of perfusion MRI used for clinical assessment of patients with neurological disorders. Patients with glioblastoma were examined with dynamic susceptibility contrast MRI (DSC-MRI) and dynamic contrast enhanced MRI (DCE-MRI) before/after treatment with fractionated radiotherapy (FRT). Radiation-induced changes in normal-appearing brain tissue were found in the form of decreased cerebral blood volume (CBV) and cerebral blood flow (CBF) measured with DSC-MRI and increased vascular permeability and increased fraction of the extravascular extracellular space measured with DCE-MRI. Papers I–II provide valuable information regarding the possibility that radiation-induced changes could be a confounder in DSC-MRI and that DCE-MRI could potentially act as a biomarker for vascular damage secondary to radiation exposure. Additionally, CBF derived from arterial spin labelling (ASL) was compared to the reference standard 15O-water positron emission tomography (PET). Simultaneous measurements were acquired with an integrated PET/MR scanner using arterial blood sampling and zero-echo time-based attenuation correction in healthy subjects and patients with epilepsy. Correlation- and Bland–Altman analysis showed fair correlation and a negative relationship with wide limits of agreement in several cortical and subcortical regions. Thus, agreement with 15O-water is insufficient for absolute quantification with ASL, but ASL provides reliable relative measures that could potentially be rescaled to absolute values. Moyamoya disease (MMD) is characterized by progressive stenosis/occlusion in large brain arteries. A limitation of ASL is the sensitivity to prolonged arterial transit times, which is common in the collateral vessels of the brain in patients with MMD. Given the non-invasiveness and non-ionizing exposure, ASL has a pronounced potential for use in diagnostic imaging in patients with MMD. ASL was performed before and after administration of acetazolamide; CBF and cerebrovascular reserve capacity were derived for large vascular regions. Artefacts originating from prolonged arterial transit times were found to have negligible effects on CBF and cerebrovascular reserve capacity derived from ASL. This thesis adds to the understanding of potential and limitations of perfusion MRI in neurological diseases.
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| 4. |
- Fällmar, David, 1980-
(författare)
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Visual assessment of perfusion and metabolism in neurodegenerative dementia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A worldwide demographic shift is currently occurring, with rapidly increasing numbers of elderly individuals. Since the incidence of neurodegenerative disease generally increases with age, this entails an increase in dementia prevalence. There are several strong incentives for establishing robust and widely available imaging methods for the early diagnosis of these diseases. Atrophy patterns are evident only late in the disease process, and the distinction from healthy ageing can often be elusive. For early diagnosis, physiologic parameters such as perfusion or metabolism must be assessed. The available modalities all have restricted clinical usefulness. The main aim of this thesis was to advance the clinical usefulness of perfusion and metabolism imaging in patients with neurodegenerative dementia, with a focus on visual assessment.A cohort of patients with neurodegenerative dementia was included, along with an age-matched control group. All subjects underwent MRI, including a pseudocontinuous ASL sequence and FDG-PET. In papers II and III, a subgroup containing both patients and controls underwent a second FDG-PET with reduced dose. In paper IV, the material was combined with a similar cohort from Amsterdam.Paper I showed that spatial smoothing increased the correlation between visually assessed perfusion and metabolism levels as displayed with FDG-PET. However, the distinction between patients and healthy controls was less satisfactory due to false positives.Paper II showed that differences in regional standard uptake value ratios between normal- and low-dose FDG-PET were small and without clinically significant bias.Paper III showed that the diagnostic performance of Z-score maps showing regions of significant deficits in metabolism was highly similar in normal- and low-dose FDG-PET images. Paper IV showed that ASL perfusion-based Z-score maps can be used for diagnostic purposes with high specificity, but inferior sensitivity, compared to FDG-PET.In conclusion, the included studies address aspects of the visual assessment of perfusion and metabolism neuroimaging, with a focus on clinical usefulness in diagnosing neurodegenerative dementia.
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| 5. |
- Heurling, Kerstin, 1982-
(författare)
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Characterization of [18F]flutemetamol binding properties : A β-amyloid PET imaging ligand
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 6. |
- Ilan, Ezgi
(författare)
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Theranostics in Neuroendocrine Tumors : Somatostatin Receptor Imaging and Therapy
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroendocrine tumors (NETs) are characterized by cellular overexpression of somatostatin receptors (SSTR), which allows for the use of radiolabeled somatostatin analogs (SSA) for both imaging and therapy. Because NETs often are diagnosed at a metastatic stage, curative surgery is not possible. Monthly long-acting SSA preparation constitutes first-line therapy for low-grade small-intestinal NETs and pancreatic NETs. Peptide receptor radionuclide therapy (PRRT), with radiolabeled SSAs such as 177Lu-DOTATATE, has been shown to be an effective therapeutic alternative for NETs, improving symptoms and quality of life. The gold-standard method for SSTR imaging and diagnosis of NETs is positron emission tomography (PET) using Gallium-68 (68Ga)-labeled SSAs, such as 68Ga-DOTATOC and 68Ga-DOTATATE. The tumor standardized uptake value (SUV) has been proposed both as a marker of SSTR tumor density and a tool for evaluating therapy response. Changes of tumor SUV on 68Ga-DOTATOC- and DOTATATE-PET have, however, not been shown to correlate with the patient outcome.This thesis is based on five original papers, evaluating the relation between tumor-absorbed dose and tumor shrinkage and developing novel theranostic methods in which quantitative PET imaging with 68Ga-DOTATATE and 68Ga-DOTATOC is used to optimize PRRT with 177Lu-DOTATATE in NET patients.A high and significant positive correlation was found between tumor-absorbed dose and tumor shrinkage in pancreatic NETs treated with 177Lu-DOTATATE. Furthermore, it was found that tumor SUV in 68Ga-DOTATATE and 68Ga-DOTATOC failed to correlate linearly with the net influx rate (Ki), assumed to reflect the SSTR density, due to low tracer availability in blood for high Ki values. SUV blood was significantly higher in tumors with high Ki (>0.2) than in tumors with low Ki, and it was found that the tumor-to-blood ratio (TBR) correlates linearly with Ki. Thus, both Ki and TBR may be used as tools to monitor NET therapy response rather than SUV. It was also found that parametric Ki images, illustrating Ki at the voxel level, provide higher tumor-to-liver contrast than static whole-body PET images. Further, it was found that administration of a single dose of cold peptide pre-PRRT with 177Lu-DOTATATE gave rise to faster recycling of SSTRs in tumors than in normal organs. A linear relation was found for tumor SUV and early Ki, between 68Ga-DOTATATE-PET and 177Lu-DOTATE-SPECT; however, the kinetics for 68Ga-DOTATAE could not be used for predicting that of 177Lu-DOTATATE because of tumor clearance of 177Lu-DOTATATE at late time interval.In conclusion, quantitative PET imaging with 68Ga-DOTATATE and 68Ga-DOTATOC shows great potential for both evaluating therapy response and optimizing PRRT with 177Lu-DOTATATE.
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| 7. |
- Jahn, Ulrika
(författare)
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Peptide Receptor Radionuclide Therapy in Neuroendocrine Neoplasms : Aspects of tumour characteristics, receptor recycling and peptide mass
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroendocrine neoplasm (NEN) can arise in any part of the body, but most commonly in the lungs, bronchi, and the gastrointestinal tract including the pancreas. They combine neuroendocrine and tissue-of-origin-specific characteristics; explaining different symptoms depending on the organ of origin. NEN is divided into slow-growing neuroendocrine tumours (NETs) and the rarer aggressive neuroendocrine cancers (NECs). Some hormone producing NETs give rise to symptoms (functioning), generally detected earlier than the non-functioning NETs, which often are larger and metastatic at diagnosis. NETs commonly express an abundance of somatostatin receptors (SSTR). Synthetic copies of somatostatin (somatostatin analogues, SSA), supress hormonal symptoms such as diarrhoea and flush. The SSA-SSTR ligand-receptor complex interaction instantly internalises into the cells, separate, and the SSTR re-surface. Gallium-68 (68Ga)-labelled SSAs are used for PET/CT-camera visualisation of NETs, and SSA labelled with a therapeutic radionuclide, provide a means for internal radio-therapy, peptide receptor radionuclide therapy (PRRT).The aim of the thesis was to compare the tumour response to PRRT in small intestinal NET (SI-NET) and pancreatic NET (P-NET). Study I, II and IV are retrospective and include patients who underwent PRRT with 177Lu-DOTA-TATE at the Uppsala University Hospital. Study I, quantified and related the radiation dose in 25 SI-NETs to tumour shrinkage using two- and three-dimensional measurements, although no dose-response relationship was demonstrated. A relationship between tumour shrinkage and the total administered activity was however found. Study II compared the tumour response between SI-NETs from study I with P-NETs included in an earlier report, now re-evaluated by adding more tumour parameters, and with longer observation time. There radiation dose in P-NETs was the same as in SI-NETs. The radiation dose in P-NETs was highest at the first PRRT cycles, and then decreased significantly in consecutive cycles, which was not observed in SI-NETs.The prospective study III, mapped the recirculation time of SSTR in SI-NETs and normal organs. Twelve tumours were measured at repeated 68Ga-DOTA-SSA-PET examinations. Larger tumours (>4 cm) showed a faster SSTR turn-over rate than small tumours, demonstrating a turnover resembling that in the normal organs. These results open the possibility that pre-treatment could protect normal tissues during PRRT, and probably increase radioactivity tumour uptake and hence, the radiation dose.The retrospective study IV investigated the effects of various amounts of SSA delivered in the PRRT preparation, although the absorbed radiation dose to tumours and normal tissues, was unrelated to the amount of peptide and to the patient’s total tumour burden.
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| 8. |
- Jonasson, My
(författare)
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Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 9. |
- Kero, Tanja
(författare)
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Methodological aspects of quantitative cardiac molecular imaging
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The objective of this research was to facilitate the use of quantitative cardiac molecular imaging by developing and validating methods and applications. More specifically:we determined the optimal tracer kinetic model for analysis of 11C-PIB and evaluated the performance of two simpler measures, retention index (RI) and standardized uptake value (SUV), in the quantification of cardiac 11C-PIB uptake in amyloidosis. An irreversible two-tissue (2Tirr) model best described the 11C-PIB uptake in cardiac amyloidosis. RI and SUV showed high correlation with quantitative results from this kinetic model and also a better discrimination between amyloidosis patients and controls than a 2Tirr model with population averaged metabolite correction. RI and SUV are furthermore more feasible for use in clinical routine and therefore the preferred measure to use in PET diagnosis of cardiac amyloidosis. We also tested the feasibility of a semiautomatic software to analyze RI and visualize cardiac uptake of 11C-PIB in amyloidosis. The RI values were comparable with RI based on manual segmentation, showing significantly higher 11C-PIB RI in amyloidosis patients than in healthy volunteers. A fast and accurate semiautomatic analysis process is thus feasible to use for PET in cardiac amyloidosis instead of the laborious manual analyses that were used so far.Furthermore, we assessed the quantitative accuracy of cardiac perfusion measurements with 15O-water PET in a digital time-of-flight PET-MR scanner. A high correlation and agreement between PET-MR based and PET-CT based MBF was found; cardiac perfusion measurements with 15O-water can therefore be performed accurately with the fully integrated Signa PET-MR scanner. Finally, we assessed the quantitative accuracy of cardiac perfusion measurements using dynamic contrast-enhanced MRI with simultaneous 15O-water PET as reference at rest and during adenosine-induced hyperemia with a fully integrated PET-MR scanner. The correlations between global and regional MRI- and PET-based MBF values were good and the biases were negliable for both global and regional MBF comparisons, but the limits of agreement were wide for both global and regional MBF, with larger variability for high MBF-values indicating that MRI-based quantitative MBF measurement based on widely available acquisition protocols is not yet ready for clinical introduction.
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| 10. |
- Lilja, Johan, 1977-
(författare)
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[18F]Flutemetamol PET image processing, visualization and quantification targeting clinical routine
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is the leading cause of dementia and is alone responsible for 60-70% of all cases of dementia. Though sharing clinical symptoms with other types of dementia, the hallmarks of AD are the abundance of extracellular depositions of β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles of hyper phosphorylated tau proteins and synaptic depletion. The onset of the physiological hallmarks may precede clinical symptoms with a decade or more, and once clinical symptoms occur it may be difficult to separate AD from other types of dementia based on clinical symptoms alone. Since the introduction of radiolabeled Aβ tracer substances for positron emission tomography (PET) imaging it is possible to image the Aβ depositions in-vivo, strengthening the confidence in the diagnosis. Because the accumulation of Aβ may occur years before the first clinical symptoms are shown and even reach a plateau, Aβ PET imaging may not be feasible for disease progress monitoring. However, a negative scan may be used to rule out AD as the underlying cause to the clinical symptoms. It may also be used as a predictor to evaluate the risk of developing AD in patients with mild cognitive impairment (MCI) as well as monitoring potential effects of anti-amyloid drugs.Though currently validated for dichotomous visual assessment only, there is evidence to suggest that quantification of Aβ PET images may reduce inter-reader variability and aid in the monitoring of treatment effects from anti-amyloid drugs.The aim of this thesis was to refine existing methods and develop new ones for processing, quantification and visualization of Aβ PET images to aid in the diagnosis and monitoring of potential treatment of AD in clinical routine. Specifically, the focus for this thesis has been to find a way to fully automatically quantify and visualize a patient’s Aβ PET image in such way that it is presented in a uniform way and show how it relates to what is considered normal. To achieve the aim of the thesis registration algorithms, providing the means to register a patient’s Aβ PET image to a common stereotactic space avoiding the bias of different uptake patterns for Aβ- and Aβ+ images, a suitable region atlas and a 3-dimensional stereotactic surface projections (3D SSP) method, capable of projecting cortical activity onto the surface of a 3D model of the brain without sampling white matter, were developed and evaluated.The material for development and testing comprised 724 individual amyloid PET brain images from six distinct cohorts, ranging from healthy volunteers to definite AD. The new methods could be implemented in a fully automated workflow and were found to be highly accurate, when tested by comparisons to Standards of Truth, such as defining regional uptake from PET images co-registered to magnetic resonance images, post-mortem histopathology and the visual consensus diagnosis of imaging experts.
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