Henri Tochon-Danguy

The fate of hypoxic tissue on 18F-fluoromisonidazole positron emission tomography after ischemic stroke.

We studied 24 patients up to 51 hours after ischemic stroke using 18F‐fluoromisonidazole positron emission tomography to determine the fate of hypoxic tissue likely to represent the ischemic penumbra. Areas of hypoxic tissue were detected on positron emission tomography in 15 patients, and computed tomography was available in 12 patients, allowing comparison with the infarct volume to determine the proportions of the hypoxic tissue volume that infarcted and survived. The proportion of patients with hypoxic tissue and the amount of hypoxic tissue detected declined with time. On average, 45% of the total hypoxic tissue volume survived and 55% infarcted. Up to 68% (mean, 17.5%) of the infarct volume was initially hypoxic. Most of the tissue “initially affected” proceeded to infarction. We correlated hypoxic tissue volumes with neurological and functional outcome assessed using the National Institutes of Health Stroke Scale, Barthel Index, and Rankin Score. Initial stroke severity correlated significantly with the “initially affected” volume, neurological deterioration during the first week after stroke with the proportion of the “initially affected” volume that infarcted, and functional outcome with the infarct volume. Significant reductions in the size of the infarct and improved clinical outcomes might be achieved if hypoxic tissue can be rescued. Ann Neurol 2000;48:228–235

Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study.

BACKGROUND This study examined cerebral function in posttraumatic stress disorder (PTSD) during the updating of working memory to trauma-neutral, verbal information. METHODS Ten PTSD and matched control subjects completed a visuoverbal target detection task involving continuous updating (Variable target condition) or no updating (Fixed target condition) of target identity, with updating activity estimated by condition comparison. RESULTS Normal updating activity using this paradigm involved bilateral activation of the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobe. The PTSD group lacked this activation in the left hemisphere and was significantly different from control subjects in this regard, but showed additional activation in the superior parietal lobe, bilaterally. CONCLUSIONS The pattern of parietal activation suggests a dependence on visuospatial coding for working memory representation of trauma-neutral, verbal information. Group differences in the relative involvement of the DLPFC indicate less dependence in PTSD on the executive role normally attributed to the left DLPFC for monitoring and manipulation of working memory content in posterior regions of the brain.

Updating working memory for words: A PET activation study

A PET study of 10 normal individuals was carried out to investigate the cerebral regions involved in the controlled updating of verbal working memory. Subjects viewed single concrete words on a computer monitor and detected occasional target words in an attended color. In the activating condition, a target was defined as a word that was identical to the previous word presented in the attended color. In the control condition, the target was a predesignated word. The same word lists, target probabilities, and target response demands were used for both conditions, with interword intervals constrained to ensure equivalence in the demand for target rehearsal. A comparison of the conditions found bilateral activation of dorsolateral prefrontal (middle frontal gyrus; MFG) and inferior parietal (supramarginal gyrus; SMG) cortical regions. Activation of the MFG is taken to reflect executive control by prefrontal regions over the working memory updating process linking posterior representations of the anticipated target stimulus to anterior representations of the planned response. It is proposed that the updating of the stimulus link is mediated via connections between the MFG and SMG. The role of the SMG as an amodal region binding the various modal representations in posterior association cortex of the word being retained in working memory is considered and reviewed. It is suggested that the combined activation of these regions is related to the executive control of goal‐setting in planned behavior. Hum. Brain Mapping 9:42–54, 2000.

Topography and Temporal Evolution of Hypoxic Viable Tissue Identified by 18F-Fluoromisonidazole Positron Emission Tomography in Humans After Ischemic Stroke

Background and Purpose— We sought to characterize the spatial and temporal evolution of human cerebral infarction. Using a novel method of quantitatively mapping the distribution of hypoxic viable tissue identified by 18F-fluoromisonidazole (18F-FMISO) PET relative to the final infarct, we determined its evolution and spatial topography in human stroke. Methods— Patients with acute middle cerebral artery territory stroke were imaged with 18F-FMISO PET (n=19; <6 hours, 4; 6 to 16 hours, 4; 16 to 24 hours, 5; 24 to 48 hours, 6). The hypoxic volume (HV) comprised voxels with significant (P <0.05; >1 mL) uptake on statistical parametric mapping compared with 15 age-matched controls. Central, peripheral, and external zones of the corresponding infarct on the anatomically coregistered delayed CT were defined according to voxel distance from the infarct center and subdivided into 24 regions by coronal, sagittal, and axial planes. Maps (“penumbragrams”) displaying the percentage of HV in each region were generated for each time epoch. Results— Higher HV was observed in the central region of the infarct in patients studied within 6 hours of onset (analysis of covariance [ANCOVA]; P <0.05) compared with those studied later, in whom the HV was mainly in the periphery or external to the infarct. HV was maximal in the superior, mesial, and posterior regions of the infarct (ANCOVA; P <0.05). Conclusions— These observations suggest that infarct expansion occurs at the expense of hypoxic tissue from the center to the periphery of the ischemic region in humans, similar to that seen in experimental animal models. These findings have important pathophysiological and therapeutic implications.

The resistance to ischemia of white and gray matter after stroke

A contributing factor to the failure of trials of neuroprotectants in acute ischemic stroke may be the differing vulnerability to ischemia of white compared with gray matter. To address this issue, we determined to establish the existence of potentially viable tissue in white matter and its evolution to infarction or salvage in both gray and white matter compartments in patients with ischemic stroke. Twenty‐seven patients (mean age, 73.4 years) at a median of 16.5 hours after symptom onset were studied using the hypoxic marker 18F‐misonidazole with positron emission tomography (PET). Tissue was segmented using an magnetic resonance probabilistic map. Although there was a greater volume of initially “at‐risk tissue” in gray matter (58.3cm3, 29.9–93.0cm3) than white matter (42.0cm3, 15.8–74.0cm3; p < 0.001) at the time of PET imaging, a higher proportion of this was still potentially viable in white matter (41.4%, 4.6–74.5%) than in gray matter (23.6%, 3.2–61.1%; p < 0.05). However, a similar proportion in each compartment spontaneously survived. These data provide evidence for the existence of potentially salvageable tissue in human white matter and is consistent with it having a similar or even greater resistance to ischemia than gray matter. For the latter possibility, alternative therapeutic strategies may be required for its salvage. Ann Neurol 2004;56:695–701

Second Order Components of Moving Plaids Activate Extrastriate Cortex: A Positron Emission Tomography Study

A moving plaid is a composite pattern produced by superimposing two sinusoidal gratings which differ in orientation and motion direction. The perceived drift direction of a plaid appears to be determined partly by a binocular mechanism, which follows intersection of constraint rules (Burke and Wenderoth, 1993b), and partly by a monocular mechanism, which tracks the dark and bright intersects of the plaid, the contrast envelopes. The first neurones that respond to plaids as patterns rather than component gratings are found in area V5, also known as MT, which is exclusively binocular. Therefore, the psychophysical evidence suggesting that the contrast envelope tracking mechanism is monocular is surprising but has been obtained consistently. We aimed to localize the contrast envelope tracking mechanism by undertaking a positron emission tomography (PET) activation experiment in which the subjects were presented with alternating plaid components during the control scan and with the moving plaid resulting from the superposition of these components as the activation scan. The results showed differential activation in area V3. Recent results from macaque single cell recordings have also demonstrated increased sensitivity to moving plaid stimuli compared to the plaid component gratings in V3 neurones.

The relationship between nicotinic receptors and cognitive functioning in healthy aging: An in vivo positron emission tomography (PET) study with 2‐[18F]fluoro‐A‐85380

Extensive experimental and neuropathological evidence supports the general hypothesis that decline in the basal forebrain cholinergic system contributes significantly to age‐related cognitive impairment. Postmortem studies suggest reductions in neuronal nicotinic acetylcholine receptors (nAChRs, particularly the α4β2 subtype) with aging. This study aimed to determine the distribution of α4β2‐subtype nAChRs in vivo by 2‐FA PET in healthy subjects (aged 21–83) and to establish whether there is an age‐related decline in nAChRs. Furthermore, the relationship between PET measures of 2‐FA binding and neurobehavioral measures of cognitive function was investigated. All participants were nonsmokers and underwent extensive cognitive testing and a PET scan after injection of 2‐FA (200 MBq). Brain regional 2‐FA binding was assessed through a simplified estimation of distribution volume (DVS). As expected, increasing age was associated with poorer cognitive performance, particularly on tasks assessing episodic memory and attentional processes. No significant age‐related differences in regional nAChR DVS were found. Furthermore, no significant correlations were found between cognitive measures and nAChR DVS. These results are consistent with recent studies suggesting the stability of cholinergic markers during senescence. It is plausible that changes in α4β2 nAChRs do occur with advancing age, but are beyond detection by the clinical 2‐FA PET approach adopted here. However, this approach may be appropriate for use in pathologies considered to undergo extensive nAChR loss such as Alzheimers disease and Parkinsons disease. Synapse 63:752–763, 2009.

Is planar thallium-201/fluorine-18 fluorodeoxyglucose imaging a reasonable clinical alternative to positron emission tomographic myocardial viability scanning?

This comparative study was performed to determine whether a conventional planar gamma camera optimised for 511-keV imaging can reliably assess myocardial viability using the fluorine-18 fluorodeoxyglucose (FDG) metabolic tracer previously developed for positron emission tomography (PET). Twenty-seven patients with severe ischaemic cardiomyopathy (mean left ventricular ejection fraction: 20%±9%) having clinically indicated nitrogen-13 ammonia/FDG PET myocardial viability studies consented to resting, four-view, planar myocardial thallium-201 perfusion and FDG metabolism imaging. The resultant PET and planar perfusion/metabolism images (PPI) were independently assessed for FDG defect size and perfusion/metabolism mismatch, using a four-point scale, in each of four vascular regions: apex, circumflex, left anterior and posterior descending coronary artery territories. Of 108 regions, 106 were evaluable (two not assessed by PET). There was complete agreement in 70% of coronary vascular territories, giving an unweighted kappa score of 0.56. Moreover, in 94% of segments agreement was within one grade. Interestingly, six of the seven differences of more than one grade occurred in the circumflex coronary territory, which was also the only region for which planar positron imaging underestimated FDG defect size. Three of four moderate areas of perfusion/metabolism mismatch seen with PET were also seen on PPI. PPI showed three small regions of mismatch not seen on PET, whilst the reverse occurred with one other small region of mismatch. Thus, for this PET protocol, PPI provides very similar information on the extent of regional FDG uptake and occurrence of mismatch. This suggests that perfusion/FDG imaging using an adequately collimated conventional planar gamma camera may be used instead of a formal PET viability study for the clinical detection of viable myocardium, making this form of metabolic assessment more widely available throughout the community.

Implementation of a solid target production facility

The desire to utilize long-lived PET isotopes in Australia has significantly increased over the years and several research projects for labelling of peptides, proteins and biomolecules, including labelling of recombinant antibodies has been restricted due to the limited availability of suitable isotopes. This need has led to the recent installation and commissioning of a new facility dedicated to fully automated solid target isotope production, including 24I, 64Cu, 89Zr and 86Y at the Austin Health Centre for PET.

IC-03-03: The Australian Biomarker, Imaging and Lifestyle Study: Preliminary PIB results

Kathryn A. Ellis, Victor L. Villemagne, David Ames, Nat Lenzo, Kerryn E. Pike, Graeme O’Keefe, Henri Tochon-Danguy, Roger Price, Gareth Jones, Mira Rimajova, Pierrick Bourgeat, Parnesh Raniga, Jurgen Fripp, Oscar Acosta, Olivier Salvado, Ralph Martins, Colin L. Masters, Christopher C. Rowe, University of Melbourne, Melbourne, VIC, Australia; Austin Hospital, Melbourne, VIC, Australia; The Mental Health Research Institute of Victoria, Melbourne, VIC, Australia; National Ageing Research Institute, Melbourne, VIC, Australia; WA PET Centre, Perth, WA, Australia; Edith Cowan University, Perth, WA, Australia; Sir Charles Gairdner Hospital, Perth, WA, Australia; CSIRO ICT Centre, Brisbane, QLD, Australia. Contact e-mail: kellis@unimelb.edu.au