Biomedical subjects

F E Turkheimer

Publications and source records attributed to F E Turkheimer.

12 recordsLinked to original sources

PubMed2006

Multi-resolution Bayesian regression in PET dynamic studies using wavelets.

In the kinetic analysis of dynamic PET data, one usually posits that the variation of the data through one dimension, time, can be described by a mathematical model encapsulating the relevant physiological features of the radioactive tracer. In this work, we posit that the remaining dimension, space, can also be modeled as a physiological feature, and we introduce this concept into a new computational procedure for the production of parametric maps. An organ and, in the instance considered here, the brain presents similarities in the physiological properties of its elements across scales: computationally, this similarity can be implemented in two stages. Firstly, a multi-scale decomposition of the dynamic frames is created through the wavelet transform. Secondly, kinetic analysis is performed in wavelet space and the kinetic parameters estimated at low resolution are used as priors to inform estimates at higher resolutions. Kinetic analysis in the above scheme is achieved by extension of the Patlak analysis through Bayesian linear regression that retains the simplicity and speed of the original procedure. Application to artificial and real data (FDG and FDOPA) demonstrates the ability of the procedure to reduce remarkably the variance of parametric maps (up to 4-fold reduction) without introducing sizeable bias. Significance of the methodology and extension of the procedure to other data (fMRI) and models are discussed.

Bayes Theorem↗

PubMed2004

Towards a transcriptome definition of microglial cells.

This study provides an expression signature of interferon-gamma (IFN-gamma)-activated microglia. Microglia are macrophage precursor cells residing in the brain and spinal cord. The microglial phenotype is highly plastic and changes in response to numerous pathological stimuli. IFN-gamma has been established as a strong immunological activator of microglial cells both in vitro and in vivo. Affymetrix RG_U34A microarrays were used to determine the effect of IFN-gamma stimulation on migroglia cells isolated from newborn Lewis rat brains. More than 8,000 gene sequences were examined, i.e., 7,000 known genes and 1,000 expressed sequence tag (EST) clusters. Under baseline conditions, microglia expressed 326 of 8,000 genes examined (approximately 4% of all genes, 182 known and 144 ESTs). Transcription of only 34 of 7,000 known genes and 8 of 1,000 ESTs was induced by IFN-gamma stimulation. The majority of the newly expressed genes encode pro-inflammatory cytokines and components of the MHC-mediated antigen presentation pathway. The expression of 60 of 182 identified genes and of 9 of 144 ESTs was increased by IFN-gamma, whereas 29 of 182 known genes and 7 of 144 ESTs were down-regulated or undetectable in IFN-gamma-stimulated cultures. Overall, the activating effect of IFN-gamma on the microglial transcriptome showed restriction to pathways involved in antigen presentation, protein degradation, actin binding, cell adhesion, apoptosis, and cell signaling. In comparison, down-regulatory effects of IFN-gamma stimulation appeared to be confined to pathways of growth regulation, remodeling of the extracellular matrix, lipid metabolism, and lysosomal processing. In addition, transcriptomic profiling revealed previously unknown microglial genes that were de novo expressed, such as calponin 3, or indicated differential regulatory responses, such as down-regulation of cathepsins that are up-regulated in response to other microglia stimulators.

Animals↗

PubMed2004

Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study.

Microglial activation is implicated in the pathogenesis of ALS and can be detected in animal models of the disease that demonstrate increased survival when treated with anti-inflammatory drugs. PK11195 is a ligand for the "peripheral benzodiazepine binding site" expressed by activated microglia. Ten ALS patients and 14 healthy controls underwent [(11)C](R)-PK11195 PET of the brain. Volumes of interest were defined to obtain [(11)C](R)-PK11195 regional binding potential values for motor and "extra-motor" regions. Significantly increased binding was found in motor cortex (P = 0.003), pons (P = 0.004), dorsolateral prefrontal cortex (P = 0.010) and thalamus (P = 0.005) in the ALS patients, with significant correlation between binding in the motor cortex and the burden of upper motor neuron signs clinically (r = 0.73, P = 0.009). These findings indicate that cerebral microglial activation can be detected in vivo during the evolution of ALS, and support the previous observations that cerebral pathology is widespread. They also argue for the development of therapeutic strategies aimed at inflammatory pathways.

Adult↗

PubMed2002

Kinetic modeling in positron emission tomography.

Most PET kinetic modeling approaches have at their basis a compartmental model that has first-order, constant coefficients. The present article outlines the one-, two-, and three-compartment models used to measure cerebral blood flow, cerebral glucose metabolism, and receptor binding, respectively. The number of compartments of each model is based on specific knowledge of the physiological and/or biochemical compartments into which the tracer distributes. Additional physical and biochemical properties of the tracer distribution are considered in specifying the use of first-order rate constants. For example, in cerebral blood flow and receptor binding studies transport across the blood-brain barrier by diffusion can be modeled as a first-order process. A saturable carrier-mediated process or saturable enzyme catalyzed reaction, when tracer doses of the labeled substrate are used and the natural substrate is in steady-state, also results in first-order rate constants, as in glucose metabolism studies. The rate of ligand binding, on the other hand, depends on the concentrations of both substrate and available receptors. In order to appropriately model the reaction as pseudo first-order during a specified experimental interval, protocols are carefully designed to assure that the number of available binding sites remains approximately constant throughout the given interval. A broad array of scanning protocols is employed for kinetic analyses. These include single-scan approaches, which function like their autoradiographic counterparts in animal studies and are often called "autoradiographic" methods, which allow estimation of a single parameter. Dynamic scanning to obtain the time course of tissue activity allows simultaneous estimation of multiple parameters. Scanning may be conducted during a period of tracer uptake or after attainment of steady-state conditions. All quantitative modeling approaches share the common requirement that an arterial input function be measured or an appropriate surrogate be found. A vast array of methods is available for estimation of model parameters, both micro and macro. In the final analysis, it is the interaction among all elements of the PET study, including careful tracer selection, model specification, experimental protocol design, and sound parameter estimation methods, that determines the quantitative accuracy of the estimates of the physiological or biochemical process under study.

Animals↗

PubMed2001

In-vivo measurement of activated microglia in dementia.

BACKGROUND: Activated microglia have a key role in the brain's immune response to neuronal degeneration. The transition of microglia from the normal resting state to the activated state is associated with an increased expression of receptors known as peripheral benzodiazepine binding sites, which are abundant on cells of mononuclear phagocyte lineage. We used brain imaging to study expression of these sites in healthy individuals and patients with Alzheimer's disease. METHODS: We studied 15 normal individuals (age 32-80 years), eight patients with Alzheimer's disease, and one patient with minimal cognitive impairment. Quantitative in-vivo measurements of glial activation were obtained with positron emission tomography (PET) and carbon-11-labelled (R)-PK11195, a specific ligand for the peripheral benzodiazepine binding site. FINDINGS: In normal individuals, regional [11C](R)-PK11195 binding did not significantly change with age, except in the thalamus, where an age-dependent increase was found. By contrast, patients with Alzheimer's disease showed significantly increased regional [11C](R)-PK11195 binding in the entorhinal, temporoparietal, and cingulate cortex. INTERPRETATION: In-vivo detection of increased [11C](R)-PK11195 binding in Alzheimer-type dementia, including mild and early forms, suggests that microglial activation is an early event in the pathogenesis of the disease.

Adult↗

PubMed2001

Estimation of the number of "true" null hypotheses in multivariate analysis of neuroimaging data.

The repeated testing of a null univariate hypothesis in each of many sites (either regions of interest or voxels) is a common approach to the statistical analysis of brain functional images. Procedures, such as the Bonferroni, are available to maintain the Type I error of the set of tests at a specified level. An initial assumption of these methods is a "global null hypothesis," i.e., the statistics computed on each site are assumed to be generated by null distributions. This framework may be too conservative when a significant proportion of the sites is affected by the experimental manipulation. This report presents the development of a rigorous statistical procedure for use with a previously reported graphical method, the P plot, for estimation of the number of "true" null hypotheses in the set. This estimate can then be used to sharpen existing multiple comparison procedures. Performance of the P plot method in the multiple comparison problem is investigated in simulation studies and in the analysis of autoradiographic data.

Anesthesia, General↗

PubMed2000

Modeling dynamic PET-SPECT studies in the wavelet domain.

This work develops a theoretical framework and corresponding algorithms for the modeling of dynamic PET-SPECT studies both in time and space. The problem of estimating the spatial dimension is solved by applying the wavelet transform to each scan of the dynamic sequence and then performing the kinetic modeling and statistical analysis in the wavelet domain. On reconstruction through the inverse wavelet transform, one obtains parametric images that are consistent estimates of the spatial patterns of the kinetic parameter of interest. The theoretical setup allows the use of linear techniques currently used in PET-SPECT for kinetic analysis. The method is applied to artificial and real data sets. The application to dynamic PET-SPECT studies was performed both for validation purposes, when the spatial patterns are known, and for illustration of the advantages offered by the technique in case of tracers with an unknown pattern of distribution.

Benzamides↗

PubMed2000

Statistical modeling of positron emission tomography images in wavelet space.

A new method is introduced for the analysis of multiple studies measured with emission tomography. Traditional models of statistical analysis (ANOVA, ANCOVA and other linear models) are applied not directly on images but on their correspondent wavelet transforms. Maps of model effects estimated from these models are filtered using a thresholding procedure based on a simple Bonferroni correction and then reconstructed. This procedure inherently represents a complete modeling approach and therefore obtains estimates of the effects of interest (condition effect, difference between conditions, covariate of interest, and so on) under the specified statistical risk. By performing the statistical modeling step in wavelet space. the procedure allows the direct estimation of the error for each wavelet coefficient; hence, the local noise characteristics are accounted for in the subsequent filtering. The method was validated by use of a null dataset and then applied to typical examples of neuroimaging studies to highlight conceptual and practical differences from existing statistical parametric mapping approaches.

Artifacts↗

PubMed1999

[11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis.

This study was designed to explore the feasibility of PET using [11C](R)-PK11195 as an in vivo marker of activated microglia/brain macrophages for the assessment of neuroinflammation in Rasmussen's encephalitis (RE). [11C](R)-PK11195 PET was carried out in four normal subjects, two patients with histologically confirmed RE, and three patients with clinically stable hippocampal sclerosis and low seizure frequency. Binding potential maps showing specific binding of [11C](R)-PK11195 were generated for each subject. Regional binding potential values were calculated for anatomically defined regions of interest after coregistration to and spatial transformation into the subjects' own MRI. In one patient with RE who underwent hemispherectomy, the resected, paraffin-embedded brain tissue was stained with an antibody (CR3/43) that labels activated human microglia. Whereas specific binding of [11C](R)-PK11195 in clinically stable hippocampal sclerosis was similar to that in normal brain, patients with RE showed a focal and diffuse increase in binding throughout the affected hemisphere. In RE, [11C](R)-PK11195 PET can reveal in vivo the characteristic, unilateral pattern known from postmortem neuropathologic study. PET imaging of activated microglia/brain macrophages offers a tool for investigation of a range of brain diseases where neuroinflammation is a component and in which conventional MRI does not unequivocally indicate an inflammatory tissue reaction. [11C](R)-PK11195 PET may help in the choice of appropriate biopsy sites and, further, may allow assessment of the efficacy of antiinflammatory disease-modifying treatment.

Adolescent↗

PubMed1999

Redefining the functional organization of working memory processes within human lateral prefrontal cortex.

It is widely held that the frontal cortex plays a critical part in certain aspects of spatial and non-spatial working memory. One unresolved issue is whether there are functionally distinct subdivisions of the lateral frontal cortex that subserve different aspects of working memory. The present study used positron emission tomography (PET) to demonstrate that working memory processes within the human mid-dorsolateral and mid-ventrolateral frontal regions are organized according to the type of processing required rather than according to the nature (i.e. spatial or non-spatial), of the information being processed, as has been widely assumed. Two spatial working memory tasks were used which varied in the extent to which they required different executive processes. During a 'spatial span' task that required the subject to hold a sequence of five previously remembered locations in working memory a significant change in blood-flow was observed in the right mid-ventrolateral frontal cortex, but not in the anatomically and cytoarchitectonically distinct mid-dorsolateral frontal-lobe region. By contrast, during a '2-back' task that required the subject to continually update and manipulate an ongoing sequence of locations within working memory, significant blood flow increases were observed in both mid-ventrolateral and mid-dorsolateral frontal regions. When the two working memory tasks were compared directly, the one that emphasized manipulation of information within working memory yielded significantly greater activity in the right mid-dorsolateral frontal cortex only. This dissociation provides unambiguous evidence that the mid-dorsolateral and mid-ventrolateral frontal cortical areas make distinct functional contributions to spatial working memory and corresponds with a fractionation of working memory processes in psychological terms.

Adult↗

PubMed1999

Multiresolution analysis of emission tomography images in the wavelet domain.

This article develops a theoretical framework for the use of the wavelet transform in the estimation of emission tomography images. The solution of the problem of estimation addresses the equivalent problems of optimal filtering, maximum compression, and statistical testing. In particular, new theory and algorithms are presented that allow current wavelet methodology to deal with the two main characteristics of nuclear medicine images: low signal-to-noise ratios and correlated noise. The technique is applied to synthetic images, phantom studies, and clinical images. Results show the ability of wavelets to model images and to estimate the signal generated by cameras of different resolutions in a wide variety of noise conditions. Moreover, the same methodology can be used for the multiscale analysis of statistical maps. The relationship of the wavelet approach to current hypothesis-testing methods is shown with an example and discussed. The wavelet transform is shown to be a valuable tool for the numerical treatment of images in nuclear medicine. It is envisaged that the methods described here may be a starting point for further developments in image reconstruction and image processing.

Algorithms↗

PubMedDate not supplied

Microglia in culture: what genes do they express?

The cell culture model utilized in this study represents one of the most widely used paradigms of microglia in vitro. After 14 days, microglia harvested from the neonatal rat brain are considered 'mature'. However, it is clear that this represents a somewhat arbitrary definition. In this paper, we provide a transcriptome definition of such microglial cells. More than 7,000 known genes and 1,000 expressed sequence tag clusters were analysed. 'Microglia genes' were defined as sequences consistently expressed in all microglia samples tested. Accordingly, 388 genes were identified as microglia genes. Another 1,440 sequences were detected in a subset of the cultures. Genes consistently expressed by microglia included genes known to be involved in the cellular immune response, brain tissue surveillance, microglial migration as well as proliferation. The expression profile reported here provides a baseline against which changes of microglia in vitro can be examined. Importantly, expression profiling of normal microglia will help to provide the presently purely operational definition of 'microglial activation' with a molecular biological correlate. Furthermore, the data reported here add to our understanding of microglia biology and allow projections as to what functions microglia may exert in vivo, as well as in vitro.

Animals↗