Optimally Stabilized PET Image Denoising Using Trilateral Filtering

Low-resolution and signal-dependent noise distribution in positron emission tomography (PET) images makes denoising process an inevitable step prior to qualitative and quantitative image analysis tasks. Conventional PET denoising methods either over-smooth small-sized structures due to resolution limitation or make incorrect assumptions about the noise characteristics. Therefore, clinically important quantitative information may be corrupted. To address these challenges, we introduced a novel approach to remove signal-dependent noise in the PET images where the noise distribution was considered as Poisson-Gaussian mixed. Meanwhile, the generalized Anscombe's transformation (GAT) was used to stabilize varying nature of the PET noise. Other than noise stabilization, it is also desirable for the noise removal filter to preserve the boundaries of the structures while smoothing the noisy regions. Indeed, it is important to avoid significant loss of quantitative information such as standard uptake value (SUV)-based metrics as well as metabolic lesion volume. To satisfy all these properties, we extended bilateral filtering method into trilateral filtering through multiscaling and optimal Gaussianization process. The proposed method was tested on more than 50 PET-CT images from various patients having different cancers and achieved the superior performance compared to the widely used denoising techniques in the literature.Comment: 8 pages, 3 figures; to appear in the Lecture Notes in Computer Science (MICCAI 2014

TSPO expression in brain tumours: is TSPO a target for brain tumour imaging?

Positron emission tomography (PET) alone or in combination with MRI is increasingly assuming a central role in the development of diagnostic and therapeutic strategies for brain tumours with the aim of addressing tumour heterogeneity, assisting in patient stratification, and contributing to predicting treatment response. The 18 kDa translocator protein (TSPO) is expressed in high-grade gliomas, while its expression is comparatively low in normal brain. In addition, the evidence of elevated TSPO in neoplastic cells has led to studies investigating TSPO as a transporter of anticancer drugs for brain delivery and a selective target for tumour tissue. The TSPO therefore represents an ideal candidate for molecular imaging studies. Knowledge of the biology of TSPO in normal brain cells, in-depth understanding of TSPO functions and biodistribution in neoplastic cells, accurate methods for quantification of uptake of TSPO tracers and pharmacokinetic data regarding TSPO-targeted drugs are required before introducing TSPO PET and TSPO-targeted treatment in clinical practice. In this review, we will discuss the impact of preclinical PET studies and the application of TSPO imaging in human brain tumours, the advantages and disadvantages of TSPO imaging compared to other imaging modalities and other PET tracers, and pathology studies on the extent and distribution of TSPO in gliomas. The suitability of TSPO as molecular target for treatment of brain tumours will also be the appraised

A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling

The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in neuronal cytotoxicity

Test-retest analysis of a non-invasive method of quantifying [C-11]-PBR28 binding in Alzheimer's disease

Purpose: In order to maximise the utility of [11C]-PBR28 for use in longitudinal studies and clinical trials in Alzheimer’s disease (AD), there is a need to develop non-invasive metrics of tracer binding that do not require arterial cannulation. Recent work has suggested that standardised uptake value (SUV)-based methods may be sensitive to changes in translocator protein (TSPO) levels associated with neurodegeneration. However, the test-retest reliability of these approaches in AD over a time period relevant for clinical trials is unknown. In this study, the test-retest reliability of three SUV-based metrics was assessed in AD patients over 12 weeks. Methods: Five patients with mild AD and the high-affinity binding TSPO genotype underwent two [11C]-PBR28 PET scans approximately 12 weeks apart. The test-retest reliability (TRR) of the unadjusted SUV, SUV relative to cerebellar grey matter (SUVRC) and SUV normalised to whole brain activity (SUVRWB) in nine cortical and limbic regions of interest was assessed using the absolute variability and the intraclass correlation coefficient. Results: Of the three measures, SUVRWB performed best overall, showing low absolute variability (mean −0.13 %, SD 2.47 %) and high reliability (mean ICC = 0.83). Unadjusted SUV also performed well, with high reliability (ICC = 0.94) but also high variability (mean −1.24 %, SD 7.28 %). By comparison, the SUVRC showed higher variability (mean −3.98 %, SD 7.07 %) and low reliability (ICC = 0.65). Conclusions: In this AD sample, we found that SUV-derived metrics of [11C]-PBR28 binding showed high stability over 12 weeks. These results compare favourably with studies reporting TRR of absolute quantification of [11C]-PBR28. Pending further validation of SUV-based measures of [11C]-PBR28, semi-quantitative methods of [11C]-PBR28 analysis may prove useful in longitudinal studies of AD

Active acquisition for multimodal neuroimaging

In many clinical and scientific situations the optimal neuroimaging sequence may not be known prior to scanning and may differ for each individual being scanned, depending on the exact nature and location of abnormalities. Despite this, the standard approach to data acquisition, in such situations, is to specify the sequence of neuroimaging scans prior to data acquisition and to apply the same scans to all individuals. In this paper, we propose and illustrate an alternative approach, in which data would be analysed as it is acquired and used to choose the future scanning sequence: Active Acquisition. We propose three Active Acquisition scenarios based around multiple MRI modalities. In Scenario 1, we propose a simple use of near-real time analysis to decide whether to acquire more or higher resolution data, or acquire data with a different field-of-view. In Scenario 2, we simulate how multimodal MR data could be actively acquired and combined with a decision tree to classify a known outcome variable (in the simple example here, age). In Scenario 3, we simulate using Bayesian optimisation to actively search across multiple MRI modalities to find those which are most abnormal. These simulations suggest that by actively acquiring data, the scanning sequence can be adapted to each individual. We also consider the many outstanding practical and technical challenges involving normative data acquisition, MR physics, statistical modelling and clinical relevance. Despite these, we argue that Active Acquisition allows for potentially far more powerful, sensitive or rapid data acquisition, and may open up different perspectives on individual differences, clinical conditions, and biomarker discovery

Mean expression of the X-chromosome is associated with neuronal density

peer reviewedBackground: Neurodegenerative diseases are characterized by key features such as loss of neurons, astrocytosis, and microglial activation/proliferation. These changes cause differences in the density of cell types between control and disease subjects, confounding results from gene expression studies. Chromosome X (ChrX) is known to be specifically important in the brain. We hypothesized the existence of a chromosomal signature of gene expression associated with the X-chromosome for neurological conditions not normally associated with that chromosome. The hypothesis was investigated using publicly available microarray datasets from studies on Parkinson's disease, Alzheimer's disease, and Huntington's disease. Data were analyzed using Chromowave, an analytical tool for detecting spatially extended expression changes along chromosomes. To examine associations with neuronal density and astrocytosis, the expression of cell specific reporter genes was extracted. The association between these genes and the expression patterns extracted by Chromowave was then analyzed. Further analyses of the X:Autosome ratios for laser dissected neurons, microglia cultures and whole tissue were performed to detect cell specific differences. Results: We observed an extended pattern of low expression of ChrX consistent in all the neurodegenerative disease brain datasets. There was a strong correlation between mean ChrX expression and the pattern extracted from the autosomal genes representing neurons, but not with mean autosomal expression. No chromosomal patterns associated with the neuron specific genes were found on other chromosomes. The chromosomal expression pattern was not present in datasets from blood cells. The X:Autosome expression ratio was also higher in neuronal cells than in tissues with a mix of cell types. Conclusions: The results suggest that neurological disorders show as a reduction in mean expression of many genes along ChrX. The most likely explanation for this finding relates to the documented general up-regulation of ChrX in brain tissue which, this work suggests, occurs primarily in neurons. If validated, this cell specific ChrX expression warrants further research as understanding the biological reasons and mechanisms for this expression, may help to elucidate a connection with the development of neurodegenerative disorders

The Blind Psychological Scientists and the Elephant: Reply to Sherlock and Zietsch

The Commentary by Sherlock and Zietsch (2018) raises important questions about how the science of human psychological development moves forward as researchers make dramatic strides in understanding the role of genetics. In this response, we return to these larger questions, but we begin by addressing Sherlock and Zietsch’s specific argument that “genetic contributions should almost always be considered when dealing with associations between parents’ behavior and their children’s behavior” (p. 156). In our 60-year study of the association between warmth of the childhood family environment and late-life security of attachment (Waldinger & Schulz, 2016), we did not mention the potential influence of genetic factors, and we regret this omission. Moreover, we acknowledge that in some places in the article, we used causal language that was not justified by the design of the study. Although we explicitly stated that the association between warmth of the childhood family environment and late-life security of attachment is correlational and not causal, we went on to interpret these findings as indications of support for the influence of childhood environment on well-being in adulthood. Although this is a plausible interpretation, Sherlock and Zietsch are justified in arguing that genetic influences could contribute to this link and that our article should have noted this. The editorial review process encourages investigators to highlight the implications of their work, and in our enthusiasm to convey the importance of an association that spans six decades, we did not adequately address possible alternative explanations for this association. Waldinger, R. J., & Schulz, M. S. (2016). The long reach of nurturing family environments: links with midlife emotion-regulatory styles and late-life security in intimate relationships. Psychological Science. 27.11. http://doi.org/10.1177/095679761666155

The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative PET and MRI study

Background: Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signalling vary depending on where within the striatum the dysfunction occurs. Positron emission tomography (PET) allows for the quantification of dopamine function across the striatum. In the current study we use a novel method to investigate the relationship between spatial variability in dopamine synthesis capacity and psychotic symptoms. Methods: We used a multimodal imaging approach combining 18F-DOPA PET and resting state MRI in 29 patients with first episode psychosis and 21 healthy controls. In each participant, resting state functional connectivity maps were used to quantify the functional connectivity of each striatal voxel to well-established cortical networks. Network-specific striatal dopamine synthesis capacity(Kicer) was then calculated for the resulting connectivity defined parcellations. Results: The connectivity defined parcellations generated Kicer values with equivalent reliability, and significantly greater orthogonality to standard anatomical parcellation methods. As a result, dopamine-symptom associations were significantly different from one another for different subdivisions, whereas no unique subdivision relationships were found when using an anatomical parcellation. In particular, dopamine function within striatal areas connected to the default mode network was strongly associated with negative symptoms(p<0.001). Conclusion: These findings suggest that individual differences in the topography of dopamine dysfunction within the striatum contribute to shaping psychotic symptomatology. Further validation of the novel approach in future studies is necessary

Microglial activity in people at ultra high risk of psychosis and in schizophrenia; an [11C]PBR28 PET brain imaging study

Objective: The purpose of this study was to determine whether microglial activity, measured using translocator-protein positron emission tomography (PET) imaging, is increased in unmedicated persons presenting with subclinical symptoms indicating that they are at ultra high risk of psychosis and to determine whether microglial activity is elevated in schizophrenia after controlling for a translocator-specific genetic polymorphism. Method: The authors used the second-generation radioligand [11C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis. Participants were recruited from early intervention centers. The authors also imaged a cohort of patients with schizophrenia and matched healthy subjects for comparison. In total, 56 individuals completed the study. At screening, participants were genotyped to account for the rs6971 polymorphism in the gene encoding the 18Kd translocator protein. The main outcome measure was total gray matter [11C]PBR28 binding ratio, representing microglial activity. Results: [11C]PBR28 binding ratio in gray matter was elevated in ultra-high-risk participants compared with matched comparison subjects (Cohen’s d >1.2) and was positively correlated with symptom severity (r=0.730). Patients with schizophrenia also demonstrated elevated microglial activity relative to matched comparison subjects (Cohen’s d >1.7). Conclusions: Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity. These findings suggest that neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms