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

Simulations to benchmark time-varying connectivity methods for fMRI

Published: May 29, 2018There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance.WHT acknowledges support from the Knut och Alice Wallenbergs Stiftelse (SE) (grant no. 2016.0473, http://kaw.wallenberg.org). PR acknowledges support from the Swedish Research Council (Vetenskapsrådet) (grants no. 2016-03352 and 773 013-61X-08276-26-4) (http://vr.se) and the Swedish e-Science Research Center (http://e- science.se/). CGR acknowledges financial support from the Spanish Ministry of Economy and Competitiveness, through the ªSevero Ochoaº Programme for Centres/Units of Excellence in R&Dº (SEV-2015-490, http://csic.es/)

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Abstract Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia

Kinetic models for estimating occupancy from single-scan PET displacement studies

The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [11C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.</p

[11C]FLB457 binding in drug-naive psychosis

Examine difference in [11C]FLB457 BPND (an index of dopamine D2-R availability) between drug-naive patients with psychotic disorders and healthy controls in the thalamus