Biomedical subjects

Richard B Banati

Publications and source records attributed to Richard B Banati.

16 recordsLinked to original sources

PubMed2006

Evaluation of transmission methodology and attenuation correction for the microPET Focus 220 animal scanner.

An accurate, low noise estimate of photon attenuation in the subject is required for quantitative microPET studies of molecular tracer distributions in vivo. In this work, several transmission-based measurement techniques were compared, including coincidence mode with and without rod windowing, singles mode with two different energy sources ((68)Ge and (57)Co), and postinjection transmission scanning. In addition, the effectiveness of transmission segmentation and the propagation of transmission bias and noise into the emission images were examined. The (57)Co singles measurements provided the most accurate attenuation coefficients and superior signal-to-noise ratio, while (68)Ge singles measurements were degraded due to scattering from the object. Scatter correction of (68)Ge transmission data improved the accuracy for a 10 cm phantom but over-corrected for a mouse phantom. (57)Co scanning also resulted in low bias and noise in postinjection transmission scans for emission activities up to 20 MBq. Segmentation worked most reliably for transmission data acquired with (57)Co but the minor improvement in accuracy of attenuation coefficients and signal-to-noise may not justify its use, particularly for small subjects. We conclude that (57)Co singles transmission scanning is the most suitable method for measured attenuation correction on the microPET Focus 220 animal scanner.

Algorithms↗

PubMed2005

Small animal SPECT and its place in the matrix of molecular imaging technologies.

Molecular imaging refers to the use of non-invasive imaging techniques to detect signals that originate from molecules, often in the form of an injected tracer, and observe their interaction with a specific cellular target in vivo. Differences in the underlying physical principles of these measurement techniques determine the sensitivity, specificity and length of possible observation of the signal, characteristics that have to be traded off according to the biological question under study. Here, we describe the specific characteristics of single photon emission computed tomography (SPECT) relative to other molecular imaging technologies. SPECT is based on the tracer principle and external radiation detection. It is capable of measuring the biodistribution of minute (<10(-10) molar) concentrations of radio-labelled biomolecules in vivo with sub-millimetre resolution and quantifying the molecular kinetic processes in which they participate. Like some other imaging techniques, SPECT was originally developed for human use and was subsequently adapted for imaging small laboratory animals at high spatial resolution for basic and translational research. Its unique capabilities include (i) the ability to image endogenous ligands such as peptides and antibodies due to the relative ease of labelling these molecules with technetium or iodine, (ii) the ability to measure relatively slow kinetic processes (compared with positron emission tomography, for example) due to the long half-life of the commonly used isotopes and (iii) the ability to probe two or more molecular pathways simultaneously by detecting isotopes with different emission energies. In this paper, we review the technology developments and design tradeoffs that led to the current state-of-the-art in SPECT small animal scanning and describe the position SPECT occupies within the matrix of molecular imaging technologies.

Animals↗

PubMed2005

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release.

Aged↗

PubMed2005

[Microglia--biology and relevance to disease].

Microglia, the resting macrophage population in the brain and spinal cord, has a central role in inflammatory processes and in acute and chronic degenerative diseases of the central nervous system. The possibility of utilizing microglia diagnostically has emerged with the prospect of visualization of reactive microgliosis via positron emission tomography. Microglia might also have a therapeutic potential by way of recruitment of microglial precursors from the blood with the opportunity to introduce genetically modified cells lesion-specifically into the central nervous system via the bloodstream. Knowledge about microglial function has preferentially been obtained via studies in experimental animal models of the pathological central nervous system. In spite of the rather extensive knowledge regarding the pathophysiological implications of these cells, their function in the normal central nervous system remains rather unknown.

Animals↗

PubMed2005

Ligands for peripheral benzodiazepine binding sites in glial cells.

Within the diseased brain, glial cells and in particular, microglia, express a multimeric protein complex termed "peripheral benzodiazepine binding sites (PBBS)" or "peripheral benzodiazepine receptor (PBR)". The expression of the PBBS is dependent on the functional state of the cell and in glial cells is triggered by a wide range of activating stimuli. In the healthy brain, the PBBS are nearly absent with the notable exception of the choroid plexus, ependymal layer, perivascular cells, central canal, possibly certain nuclei in the brainstem and layers in the cerebellum where a constitutive presence of the PBBS is found. Likewise, areas that due to the absence of the blood-brain barrier contain more active glial cells, such as the pituitary gland, or the area postrema at floor of the 4th ventricle show a degree of constitutive expression. The tight correlation of the parenchymal de novo expression of the PBBS with the presence of activated glial cells, that in turn are usually only found in tissue affected by progressive disease, establishes the PBBS as a generic marker for the detection and measurement of active disease processes in the brain. Specific radioligands of the PBBS for use in positron emission tomography (PET) may thus provide a sensitive in vivo index of neuropathological activity. Whilst prototype ligands for the PBBS are available, future research needs to focus on the development of new ligands with improved pharmacodynamic properties and the ability to discriminate between the different, still insufficiently understood functional states of the peripheral benzodiazepine receptor complex.

Animals↗

PubMed2004

[11C]vinpocetine: a prospective peripheral benzodiazepine receptor ligand for primate PET studies.

Vinpocetine, a synthetic derivative of the Vinca minor alkaloid vincamine, is a widely used drug in neurological practice. We tested the hypothesis that vinpocetine binds to peripheral benzodiazepine binding sites (PBBS) and is therefore a potential ligand of PBBS. Positron emission tomography (PET) measurements in two cynomolgous monkeys showed that pretreatment with vinpocetine markedly reduced the brain uptake of [11C]PK11195, a known PBBS radioligand. On the other hand, whereas pretreatment with PK11195 increased the brain uptake of [11C]vinpocetine due to the blockade of PBBS in the periphery, it significantly reduced the binding potential (BP) values of [11C]vinpocetine in the whole brain and in individual brain structures to PK11195. These findings indicate that, whereas the two ligands have different affinities to PBBS, vinpocetine is a potent ligand of PBBS, which in turn suggests that the pharmacological activity of vinpocetine may involve the regulation of glial functions.

Animals↗

PubMed2004

Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study.

We obtained [11C](R)-PK11195 PET scans in six patients at different time points between 3 and 150 days after onset of ischemic stroke in order to measure the time course of microglial activation. Increased [11C](R)-PK11195 binding around the lesion was observed as early as 3 days. Scans at later time points showed ongoing changes in the distribution of the [11C](R)-PK11195 signal, involving the area of the primary lesion and areas distant from the primary lesion site. Our data suggest that [11C](R)-PK11195 PET can be used to investigate both the primary lesion and remote pathological changes following Wallerian degeneration.

Adult↗

PubMed2004

In vivo detection of microglial activation in frontotemporal dementia.

Using positron emission tomography and [(11)C](R)-PK11195, a marker of "peripheral benzodiazepine sites" that is upregulated on activated microglia during progressive tissue pathology, we show increased binding of [(11)C](R)-PK11195 in frontotemporal lobar degeneration in the typically affected frontotemporal brain regions. This implies the presence of an active glial response reflecting progressive neuronal degeneration. It also suggests that increased [(11)C](R)-PK11195 binding, previously demonstrated for Alzheimer's disease, may occur independently from increased amyloid plaque formation, given that it is not a characteristic feature of frontotemporal lobar degeneration.

Aged↗

PubMed2004

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration.

Corticobasal degeneration (CBD) is a neurodegenerative parkinsonian disorder of unknown cause that shows considerable clinical heterogeneity. In CBD, activated microglia have been shown to be associated closely with the extensive tau pathology found in the affected basal ganglia, brainstem nuclei, and cortical regions. We report on the use of [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) (PK11195) positron emission tomography (PET), a marker of peripheral benzodiazepine binding sites (PBBS) that are expressed by activated microglia, to demonstrate in vivo the degree and distribution of glial response to the degenerative process in 4 patients with CBD. Compared with normal age-matched controls, the CBD patient group showed significantly increased mean [(11)C](R)-PK11195 binding in the caudate nucleus, putamen, substantia nigra, pons, pre- and postcentral gyrus, and the frontal lobe. [11C](R)-PK11195 PET reveals a pattern of increased microglial activation in CBD patients involving cortical regions and the basal ganglia that corresponds well with the known distribution of neuropathological changes, which may therefore help to characterize in vivo the underlying disease activity in CBD.

Aged↗

PubMed2004

Mitochondria in activated microglia in vitro.

In the CNS, microglia become activated, i.e. change their functional state and phenotype, in response to a wide variety of pathological stimuli. Since this activation is triggered at a very low threshold and at the same time remains territorially restricted, the spatial distribution of activated microglia can be used as a sensitive, generic measure of the anatomical localisation of ongoing disease processes. One protein complex, undetectable in resting microglia but highly up-regulated upon activation in vivo and in vitro, is the 'peripheral benzodiazepine binding site', as measured by binding of the isoquinoline derivate PK11195. Particularly numerous in the outer membrane of mitochondria, this binding site has also been referred to as the 'mitochondrial benzodiazepine receptor'. The de novo expression of this receptor by activated microglia suggests that the process of activation may be associated with important qualitative changes in the state of mitochondria. Here, we provide confocal light- and electron microscopic evidence that the activation of microglia indeed entails conspicuous mitochondrial alterations. In cultured rat microglia stained with the fluorescent probe, JC-1, a sensitive indicator of mitochondrial membrane potential, we demonstrate that stimulation by bacterial lipopolysaccharide and interferon-gamma increases the number of microglial mitochondrial profiles and leads to marked changes in their morphology. Prominent elongated, "needle-like" mitochondria are a characteristic feature of activated microglia in vitro. Electron microscopically, an abundance of abnormal profiles, including circular cristae or ring- and U-shaped membranes, are found. Our observations support the notion that the previously reported increase in microglial binding of PK11195, that labelled with carbon-11 ([11C] (R)-PK11195) has clinical use for the visualisation of activated microglia in vivo by positron emission tomography, may at least in part relate to an increased number and altered functional state of microglial mitochondria.

Animals↗

PubMed2004

Cyclooxygenase-2 (Cox-2) in injured human nerve and a rat model of nerve injury.

Inflammation associated with nerve injury produces a number of pathogenic chemical mediators of which prostanoids are a potent component. Cyclooxygenases (Cox-1 and Cox-2) are the enzymes responsible for prostanoid production. We have investigated Cox-2 immunoreactivity (Cox-2-IR) and glial activation in human injured (n = 16) and uninjured (n = 8) nerves and in the chronic constriction injury (CCI) model of nerve injury in the rat, using immunohistological and autoradiographic methods. Tissues were immunostained with antibodies to Cox-2, CD-68 (human macrophage marker), OX42 (rat microglial marker), or incubated with tritiated PK11195 (marker of glial activation), prior to image analysis. In human nerves, Cox-2-IR was detected in cells with morphology and distribution similar to macrophages/microglia - these were increased significantly in human nerve proximal to injury (p < 0.002), reaching a peak at 4-6 weeks after injury. In the rat CCI model, at 40 days after injury, microglia-like cells with Cox-2-IR were increased significantly in the injured nerve (p < 0.004) and ipsilateral dorsal spinal cord (p < 0.008). PK11195-binding results were similar for Cox-2-IR in chronic injured human nerve and rat tissues. These findings suggest that Cox-2-immunoreactive cells could play a role in processes associated with Wallerian degeneration, nerve regeneration, and the development of persistent pain. Selection of patients 4-6 weeks after nerve injury would be more likely to show any efficacy of Cox-2 inhibitors.

Adult↗

PubMed2003

Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain.

Glial cells form a structural and functional network with complex cell-cell communication pathways that enable fast and slow signalling amongst themselves as well as with neurons. They exert regulatory influence on normal synaptic transmission and alter it in disease. It is becoming increasingly clear that an understanding of brain function in disease conditions requires a better account of the highly plastic, disease-associated changes in glial physiology in vivo. Particularly, microglia, the brain's ubiquitous but normally inconspicuous immune effector cell, are prominently involved in many brain diseases. They respond rapidly and in a territorially highly confined way to subtle, acute and chronic pathological stimuli. Detection of microglial activation provides diagnostically useful formal parameters of disease, such as the accurate spatial localisation, disease progression and the secondary neurodegenerative or adaptive changes remote from the primary site of disease. The latter has potential relevance for the understanding of disease-induced brain plasticity. Systematic attempts are now undertaken, using positron emission tomography and a ligand with relative selectivity for activated microglia, to develop generic imaging tools for a cellular in vivo neuropathology.

Benzodiazepines↗

PubMed2003

A linear wavelet filter for parametric imaging with dynamic PET.

This paper describes a new filter for parametric images obtained from dynamic positron emission tomography (PET) studies. The filter is based on the wavelet transform following the heuristics of a previously published method that are here developed into a rigorous theoretical framework. It is shown that the space-time problem of modeling a dynamic PET sequence reduces to the classical one of estimation of a normal multivariate vector of independent wavelet coefficients that, under least-squares risk, can be solved by straightforward application of well established theory. From the study of the distribution of wavelet coefficients of PET images, it is inferred that a James-Stein linear estimator is more suitable for the problem than traditional nonlinear procedures that are incorporated in standard wavelet filters. This is confirmed by the superior performance of the James-Stein filter in simulation studies compared to a state-of-the-art nonlinear wavelet filter and a nonstationary filter selected from literature. Finally, the formal framework is interpreted for the practitioner's point of view and advantages and limitations of the method are discussed.

Aged↗

PubMed2002

Visualising microglial activation in vivo.

In health, microglia reside as quiescent guardian cells ubiquitously, but isolated without any cell-cell contacts amongst themselves, throughout the normal CNS. In disease, however, they act as swift "sensors" for pathological events, including subtle ones without any obvious structural damage. Once activated, microglia show a territorially highly restricted involvement in the disease process. This property, peculiar to microglia, confers to them diagnostic value for the accurate spatial localisation of any active disease process, acute or chronic. In the brain, the isoquinoline PK11195, a ligand for the peripheral benzodiazepine binding site (PBBS), binds with relative cellular selectivity to activated, but not resting, microglia. Labelled with carbon-11, (R)-PK11195 and positron emission tomography (PET) have been used for the study of inflammatory and neurodegenerative brain disease in vivo. These studies demonstrate meaningfully distributed patterns of regional [(11)C](R)-PK11195 signal increases that correlate with clinically observed loss of function. Increased [(11)C](R)-PK11195 binding closely mirrors the histologically well-described activation of microglia in the penumbra of focal lesions, as well as in the distant, anterograde, and retrograde projection areas of the lesioned neural pathway. There is also some indication that in long-standing alterations of a neural network with persistent abnormal input, additional signals of glial activation may also emerge in transsynaptic areas. These data suggest that the injured brain is less static than commonly thought and shows subtle glial responses even in macroanatomically stable appearing regions. This implies that glial activation is not solely a sign of tissue destruction, but possibly of disease-induced adaptation or plasticity as well. Whilst further technological and methodological advances are necessary to achieve routine clinical value and feasibility, a systematic attempt to image glial cells in vivo is likely to furnish valuable information on the cellular pathology of CNS diseases and their progression within the distributed neural architecture of the brain.

Animals↗

PubMed2002

In vivo imaging of neuroinflammation.

We briefly outline the rationale for employing positron emission tomography (PET), using the ligand [11C](R)-PK11195, the binding site for which is highly expressed by activated microglia, in order (a) to detect in vivo neuroinflammatory changes occurring in a variety of brain diseases and at different disease stages and (b) to monitor the progression of neuroinflammation as a generic in vivo marker of 'disease activity'. The use of [11C](R)-PK11195 PET is described as a systematic attempt at measuring the emerging phenomenology of tissue pathology itself-as opposed to measuring, for example, the loss of neuronal function or structure-and as a proof of principle for the clinical utility of imaging glial cells in vivo.

Animals↗

PubMedDate not supplied

Brain plasticity and microglia: is transsynaptic glial activation in the thalamus after limb denervation linked to cortical plasticity and central sensitisation?

Microglia are a subset of tissue-macrophages that are ubiquitously distributed throughout the entire CNS. In health, they remain largely dormant until activated by a pathological stimulus. The availability of more sensitive detection techniques has allowed the early measurement of the cell responses of microglia in areas with few signs of active pathology. Subtle neuronal injury can induce microglial activation in retrograde and anterograde projection areas remote from the primary lesion focus. There is also evidence that in cases of long-standing abnormal neuronal activity, such as in patients after limb amputation with chronic pain and phantom sensations, glial activation may occur transsynaptically in the thalamus. Such neuronally driven glial responses may be related to the emergence central sensitisation in chronic pain states or plasticity phenomena in the cerebral cortex. It is suggested, that such persistent low-level microglial activation is not adequately described by the traditional concept of phagocyte-mediated tissue damage that largely evolved from studies of acute brain lesion models or acute human brain pathology. Due to the presence of signal molecules that can act on neurons and microglia alike, the communication between neurons and microglia is likely to be bi-directional. Persistent subtle microglial activity may modulate basal synaptic transmission and thus neuronal functioning either directly or through the interaction with astrocytes. The activation of microglia leads to the emergence of microstructural as well as functional compartments in which neurokines, interleukins and other signalling molecules introduce a qualitatively different, more open mode of cell-cell communication that is normally absent from the healthy adult brain. This 'neo-compartmentalisation', however, occurs along predictable neuronal pathways within which these glial changes are themselves under the modulatory influence of neurons or other glial cells and are subject to the evolving state of the pathology. Depending on the disease state, yet relatively independent of the specific disease cause, fluctuations in the modulatory influence by non-neuronal cells may form the cellular basis for the variability of brain plasticity phenomena, i.e. the plasticity of plasticity.

Animals↗