Kinetic modeling and parameter estimation of TSPO PET imaging in the human brain

PURPOSE: Translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET) is widely used in research studies of brain diseases that have a neuro-immune component. Quantification of TSPO PET images, however, is associated with several challenges, such as the lack of a reference region, a genetic polymorphism affecting the affinity of the ligand for TSPO, and a strong TSPO signal in the endothelium of the brain vessels. These challenges have created an ongoing debate in the field about which type of quantification is most useful and whether there is an appropriate simplified model. METHODS: This review focuses on the quantification of TSPO radioligands in the human brain. The various methods of quantification are summarized, including the gold standard of compartmental modeling with metabolite-corrected input function as well as various alternative models and non-invasive approaches. Their advantages and drawbacks are critically assessed. RESULTS AND CONCLUSIONS: Researchers employing quantification methods for TSPO should understand the advantages and limitations associated with each method. Suggestions are given to help researchers choose between these viable alternative methods

A hybrid deconvolution approach for estimation of in vivo non-displaceable binding for brain PET targets without a reference region

Background and aim Estimation of a PET tracer’s non-displaceable distribution volume (VND) is required for quantification of specific binding to its target of interest. VND is generally assumed to be comparable brain-wide and is determined either from a reference region devoid of the target, often not available for many tracers and targets, or by imaging each subject before and after blocking the target with another molecule that has high affinity for the target, which is cumbersome and involves additional radiation exposure. Here we propose, and validate for the tracers [11C]DASB and [11C]CUMI-101, a new data-driven hybrid deconvolution approach (HYDECA) that determines VND at the individual level without requiring either a reference region or a blocking study. Methods HYDECA requires the tracer metabolite-corrected concentration curve in blood plasma and uses a singular value decomposition to estimate the impulse response function across several brain regions from measured time activity curves. HYDECA decomposes each region’s impulse response function into the sum of a parametric non-displaceable component, which is a function of VND, assumed common across regions, and a nonparametric specific component. These two components differentially contribute to each impulse response function. Different regions show different contributions of the two components, and HYDECA examines data across regions to find a suitable common VND. HYDECA implementation requires determination of two tuning parameters, and we propose two strategies for objectively selecting these parameters for a given tracer: using data from blocking studies, and realistic simulations of the tracer. Using available test-retest data, we compare HYDECA estimates of VND and binding potentials to those obtained based on VND estimated using a purported reference region. Results For [11C]DASB and [11C]CUMI-101, we find that regardless of the strategy used to optimize the tuning parameters, HYDECA provides considerably less biased estimates of VND than those obtained, as is commonly done, using a non-ideal reference region. HYDECA test-retest reproducibility is comparable to that obtained using a VND determined from a non-ideal reference region, when considering the binding potentials BPP and BPND. Conclusions HYDECA can provide subject-specific estimates of VND without requiring a blocking study for tracers and targets for which a valid reference region does not exist

[11C]flumazenil Binding Is Increased in a Dose-Dependent Manner with Tiagabine-Induced Elevations in GABA Levels

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [11C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [11C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [11C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [11C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [11C]flumazenil VT in Group II in association cortices (6.8±0.8 mL g−1 vs. 7.3±0.4 mL g−1;p = 0.03), sensory cortices (6.7±0.8 mL g−1 vs. 7.3±0.5 mL g−1;p = 0.02) and limbic regions (5.2±0.6 mL g−1 vs. 5.7±0.3 mL g−1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [11C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA

Kinetic Modelling in Human Brain Imaging

Geneeskunde en GesondheidswetenskappeKerngeneeskundePlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]

지연가역 신경수용체 결합 파라메트릭 영상화를 위한 동적 뇌 PET 기반 비침습적 이중도표분석법

학위논문 (박사)-- 서울대학교 대학원 : 뇌인지과학과, 2016. 2. 이재성.Tracer kinetic modeling in dynamic positron emission tomography (PET) has been widely used to investigate characteristic distribution pattern or dysfunction of neuroreceptors in brain diseases, by offering a unique tool for generating images of quantitative parameters (or parametric imaging) of neuroreceptor binding. Graphical analysis (GA) is a major technique of parametric imaging, and is based on a simple linear regression model that is linearized and further simplified from a more complex general compartment model. Although each simple model of various GA methods enables very desirable parametric imaging, it depends on several assumptions that are commonly hard to satisfy simultaneously in parametric imaging for slow kinetic tracers, leading to error in parameter estimates. A combination of two GA methods, a bi-graphical analysis, may improve such intrinsic limitation of GA approaches by taking full advantage of spatiotemporal information captured in dynamic PET data and diverse strengths of individual GA methods. This thesis focuses on a bi-graphical analysis for parametric imaging of reversible neuroreceptor binding. Firstly, I provide an overview of GA-based parametric image generation with dynamic neuroreceptor PET data. The associated basic concepts in tracer kinetic modeling are presented, including commonly used compartment models and major parameters of interest. Then, technical details of GA approaches for reversible and irreversible radioligands are described considering both arterial-plasma-input-based (invasive) and reference-region-input-based (noninvasive) modelstheir underlying assumptions and statistical properties are described in view of parametric imaging. Next, I present a novel noninvasive bi-graphical analysis for the quantification of a reversible radiotracer binding that may be too slow to reach relative equilibrium (RE) state during PET scans. The proposed method indirectly implements the conventional noninvasive Logan plot, through arithmetic combination of the parameters of two other noninvasive GA methods and the apparent tissue-to-plasma efflux rate constant for the reference region (k_2^'). I investigate its validity and statistical properties, by performing a simulation study with various noise levels and k_2^' values, and also evaluate its feasibility for [18F]FP-CIT PET in human brain. The results reveal that the proposed approach provides a binding-parameter estimation comparable to the Logan plot at low noise levels while improving underestimation caused by non-RE state differently depending on k_2^'. Furthermore, the proposed method is able to avoid noise-induced bias of the Logan plot at high noise levels, and the variability of its results is less dependent on k_2^' than the Logan plot. In sum, this approach, without issues related to arterial blood sampling if a pre-estimated k_2^' is given, could be useful in parametric image generation for slow kinetic tracers staying in a non-RE state within a PET scan.Chapter 1 Introduction 1 1.1 Tracer Kinetic Modeling in PET 1 1.2 Regional versus Voxel-wise Quantification 2 1.3 Requirements for Parametric Imaging 3 1.4 Graphical Analysis 4 1.5 Thesis Statement and Contributions 5 1.6 Organization of the Thesis 6 Chapter 2 Basic Theory in Tracer Kinetic Modeling 8 2.1 Dynamic PET Acquisition 8 2.2 Compartmental Models 11 2.3 Parameters of Interest in Neuroreceptor Study 14 2.4 Limitations in Parametric Image Generation 18 Chapter 3 Overview of Graphical Analysis 20 3.1 General Characteristics 20 3.2 Reversible Radioligand Models 25 3.2.1 Logan Plot 25 3.2.2 Relative Equilibrium-based Graphical Plot 31 3.2.3 Ito Plot 36 3.3 Irreversible Radioligand Models 39 3.3.1 Invasive Gjedde-Patlak Plot 39 3.3.2 Noninvasive Gjedde-Patlak Approaches 40 Chapter 4 Noninvasive Bi-graphical Analysis for the Quantification of Slowly Reversible Radioligand Binding 43 4.1 Background 43 4.2 Materials and Methods 45 4.2.1 Invasive RE-GP Plots 45 4.2.2 Noninvasive GA Approaches 47 4.2.3 Noninvasive RE-GP Plots 49 4.2.4 Computer Simulations 51 4.2.5 Human [18F]FP-CIT PET Data 52 4.3 Results 54 4.3.1 Regional Time-activity Curves and Graphical Plots 54 4.3.2 Simulation Results 59 4.3.3 Application to Human Data 60 4.4 Discussion 66 4.4.1 Characteristics of [18F]FP-CIT PET Data 67 4.4.2 Kinetic Methods for [18F]FP-CIT PET 67 4.4.3 Correction for NRE Effects 68 4.4.4 Linearity Condition 69 4.4.5 Advantages over the Noninvasive Logan plot 69 4.4.6 Comparison with the SRTM 71 4.4.7 Simulation Settings 72 4.4.8 Noninvasiveness 74 Chapter 5 Summary and Conclusion 76 Bibliography 77 초 록 97Docto

Positron emission tomography : development, evaluation and application of quantification methods

Positron Emission Tomography (PET) is an imaging technique that allows for in vivo quantification of biochemical and physiological processes in the brain. Examples of targets in the brain that can be imaged using PET are dopamine receptors and the translocator protein 18kDa (TSPO). Following intravenous injection of a radio-labeled ligand and the ensuing PET examination of a subject, kinetic models are often used to estimate parameters of interest. Example of such parameters are binding potential or distribution volume, which are estimates of the availability of receptors in a specific region or volume-element of the brain. These parameters can then be inserted into statistical models to infer e.g. differences in target availability between patients and controls or relationships to behavioral traits. In order to detect effects of interest, it is important that the estimation of these parameters is precise, reliable and valid. The aim of this thesis was to evaluate different methods for estimating such parameters, and apply them on clinical data. The thesis consists of two different themes. The focus of theme I was the quantification of dopamine receptor in striatum and the cortex, and their relationship to normal and dysfunctional social behavior. Study I and Study II examined the relationship between dopamine D1 receptor availability and self-rated pro and anti-social behavior in healthy subjects. Study I found a positive correlation between striatal D1 receptor availability and Social Desirability, and a negative correlation to Trait Aggression. Study II did however fail to replicate these results. In Study III, dopamine D2 receptor availability in limbic and cortical regions in patients with social anxiety disorder and healthy controls were compared. Exploratory analyses suggested that patients had higher D2 receptor availability in the lateral and orbitofrontal cortex, although the results warrant replication in a larger sample. The focus of theme II was the quantification of TSPO in patients with psychosis and healthy subjects. The level of TSPO in the brain has been hypothesized to function as an index of microglial cell activity, which in turn is believed to be a proxy for immune activation in the central nervous system. In Study IV, [11C]PBR28 binding in the whole grey-matter in patients with first-episode psychosis and healthy controls were compared. Contrary to the hypothesis of elevated microglia activity, patients were found to have lower TSPO levels. Study V evaluated the test-retest reliability and convergent validity of different methods to measure TSPO levels using [11C]PBR28. Distribution volume ratios and standardized uptakes value ratios, derived using pseudo-reference regions, showed both poor reliability and convergent validity. Study VI carried out a meta-analysis of TSPO in patients with schizophrenia and psychotic disorders compared to healthy controls. Again, contrary to the hypothesis of higher microglia activity, strong evidence was found in favor of patients having lower TSPO levels in both cortical and subcortical regions. In Study VII, the test-retest reliability and convergent validity of different methods to estimate TSPO levels using (R)-[11C]PK11195 were evaluated. Outcomes derived using pseudo-reference region approaches were unreliable and showed no convergent validity to outcomes derived using arterial input function. Finally, Study VIII evaluated the reliability and accuracy of a new modeling method, applied to [11C]PBR28 data, in order to estimate specific binding without requiring a reference region. Simulations, a pharmacological challenge and test-retest analysis showed that non-displaceable distribution volume, and ensuing specific distribution volume values, derived using this method were accurate, precise and reliable. Taken together, the results of the studies illustrate the importance of evaluating quantification methods prior to applying them on clinical data. The thesis also shows how robust kinetic and statistical modeling, and the use of direct replications or multi-center collaborations, can yield more trustworthy and reliable findings in PET

Kinetics of protein-based in vivo Imaging tracers for positron emission tomography

Within the framework of the “Sel-tag imaging project”, a novel method was used to rapidly label protein tracers and the in vivo targeting abilities of these tracers were studied in animal models of cancer using a preclinical positron emission tomography (PET) camera. To first evaluate and optimize preclinically the use of PET tracers can facilitate their translation to and implementation in human patient studies. The ultimate goal of the different projects within the Sel-tag imaging project was to find imaging biomarkers that could potentially be used for individualizing cancer treatment and thereby improve the therapeutic results. This thesis focuses on methods employed to describe the distribution of these protein-based tracers in human xenografts. Many of the techniques used had been developed for other imaging circumstances. Therefore verification for these imaging applications was an important aspect of these papers. Paper I examined the distribution in a tumour of a medium-sized AnnexinA5-based tracer that targeted phosphatidylserine externalised during cell death in tumours in two cases; first, with no pre-treatment (baseline) and, second, after pre-treatment with a chemotherapeutic agent. Small differences between tracer uptakes in the two cases required a macro parameter analysis method for quantifications. Evaluations of the influence of the enhanced permeability and retention effect by using a size-matched control were introduced. The AnnexinA5 results were compared to those of the metabolic tracer [18F]FDG and complemented with circulating serum markers to increase sensitivity. Paper II extended the analysis in paper I to incorporate more verifications that were also more thorough. The choice of input (blood or reference tissue) and the statistical significance of intergroup comparisons when using conventional uptake measurements and the more involved macro parameter analyses like in paper I were compared. We also proposed that distribution volume ratio was a more appropriate quantification parameter concept for these protein-based tracers with relatively large non-specific uptake. Paper III assessed the smaller Affibody™ tracer ZHER2:342 as an imaging biomarker for human epidermal growth factor 2 (HER2), whose overexpressions are associated with a poor prognosis for breast cancer patients. In order to demonstrate specific binding to HER2, pre-treatment of the tumour with unlabelled protein and uptake in xenografts with low HER2 expression was evaluated. Ex vivo immunohistochemistry of expression levels supported the imaging results. Paper IV examined a radiopharmaceutical that targeted the epidermal growth factor receptor (EGFR), whose overexposure in tumours is associated with a negative prognosis. Again an Affibody™ molecule, (ZEGFR:2377), was used and, as in in paper I, a size-matched control was also used to estimate the non-specific uptake. Uptakes, quantified by conventional uptake methods, varied in tumours with different EGFR expression levels. Ex vivo analyses of expression levels were also performed. Paper V addressed the non-uniform (heterogeneous) uptake of different tracers in a tumour tissue. An algorithm was written that aimed at incorporating all relevant aspects that will influence non-uniformity. Histograms were generated that visualized how the frequency and spread of deviations contributed to the heterogeneity. These aspects could not always be attended in a direct manner, but instead had to be handled in an indirect way. The effect of varying imaging parameters was examined as part of the validation procedure. The method developed is a robust, user-friendly tool for comparing heterogeneity in similar volume preclinical tumor tissues

The longitudinal biology of depression : PET studies of the dopamine and serotonin systems

The involvement of monoamine neurotransmission in the pathophysiology of depression was established already in the 1960s. However despite an abundance of research, the exact role of the serotonin (5-HT) and dopamine systems in depression have remained elusive. Positron emission tomography (PET) is a nuclear imaging technique that makes the study of the living human brain possible at a molecular level. In this thesis, PET methods were validated (study I) and applied to study aspects of the serotonin and dopamine systems in depression. This was done through patient and control comparisons (study II and III), through examining correlations between key 5-HT proteins (study IV), and through a longitudinal approach testing patients before and after treatments with known efficacy (study II and III). In study I, binding characteristics of the D2 dopamine receptor (D2R) radioligand [11C]raclopride was evaluated in brain regions where D2R density is low (i.e., outside striatum). In most extrastriatal brain regions, little or no decrease in binding was observed after administration of a pharmacological competitor, lending no support for valid quantification. Further, extrastriatal test-retest repeatability was poor. The results indicate that [11C]raclopride PET is not suitable for D2R quantification in extrastriatal brain regions. The aim of study II was to investigate D2R availability in patients with severe depression, compared with healthy controls at baseline and before and after electroconvulsive treatment. Nine patients hospitalized for depression were examined using [11C]raclopride PET before and after a series of electroconvulsive therapy treatments, and nine healthy, matched controls were examined twice. Lower striatal D2R availability was observed in patients compared with controls. No significant change in [11C]raclopride binding was observed in the patient group following treatment. The results suggest that low D2R is associated with severe depression. In Study III, [11C]MADAM PET was used to quantify the 5-HT transporter (5-HTT) in 17 patients with depression before and after treatment with cognitive behavioral therapy. Matched healthy controls were examined once with [11C]MADAM PET. Depression severity decreased and 5-HTT availability increased significantly in patients following the treatment. No significant difference in [11C]MADAM binding was observed between controls and patients at baseline. The results indicate that previous findings of 5-HT dysregulation in patients with depression reflect a temporary state rather than a permanent trait. The aim of study IV was to evaluate the correlation between 5-HTT availability and 5-HT 1B receptor (5-HT1B) availability in the human brain. [11C]MADAM and [11C]AZ10419369 PET was used to quantify 5-HTT and 5-HT1B respectively. 17 healthy individuals were examined with both radioligands. Strong correlations were observed in cortical regions while very weak correlations were observed in most subcortical regions. The results could be indicative of a strong transsynaptic regulation of the 5-HT system in cortical regions. However, the analysis was exploratory and [11C]MADAM signal to noise ratio is poor in cortex so the results should be interpreted with caution

Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [ 11 C]NMPB and PET

Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examined the feasibility of utilizing [ 11 C]N-methyl-4-piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes associated with cholinergic dysfunction. Based on prior data describing the accuracy of various kinetic methods, we examined the concentration of muscarinic receptors with [ 11 C]NMPB and PET using two- and three-compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was associated with a reduction in muscarinic receptor binding in neocortical regions and thalamus. In AD patients, the three-compartment model appeared capable of dissociating changes in tracer transport from changes in receptor binding, but suffered from statistical uncertainty, requiring normalization to a reference region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concentrations were observed in AD. Synapse 39:275–287, 2001. © 2001 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34992/1/1010_ftp.pd

Molecular imaging of depressive disorders

This chapter summarizes findings of a large number of molecular imaging studies in the field of unipolar and bipolar depression (BD). Brain metabolism in depressed unipolar and bipolar patients is generally hypoactive in the middle frontal gyri, the pregenual and posterior anterior cingulate, the superior temporal gyrus, the insula, and the cerebellum, while hyperactivity exists in subcortical (caudate nucleus, thalamus), limbic (amygdala, anterior hippocampus), and medial and inferior frontal regions. Interestingly, after depletion of serotonin or noradrenalin/dopamine in vulnerable (recovered) major depressive disorder (MDD) patients, a similar response pattern in metabolism occurs. Findings on the pre-and postsynaptic dopaminergic system show indications that, at least in subgroups of retarded MDD patients, presynaptic dopaminergic markers may be decreased, while postsynaptic markers may be increased. The findings regarding serotonin synthesis, pre-and postsynaptic imaging can be integrated to a presumable loss of serotonin in MDD, while this remains unclear in BD. This reduction of serotonin and dopamine in MDD was recently summarized in a revised version of the monoamine hypothesis, which focuses more on a dysfunction at the level of the MAO enzyme. This should be addressed further in future studies. Nevertheless, it should be acknowledged that the serotonergic and dopaminergic systems appear adaptive; therefore, it remains difficult to distinguish state and trait abnormalities. Therefore, future longitudinal molecular imaging studies in the same subjects at different clinical mood states (preferably with different tracers and imaging modalities) are needed to clarify whether the observed changes in transporters and receptors are compensatory reactions or reflect different, potentially causal mechanisms. Several suggestions for future developments are also provided at the end of this chapter.</p