Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

IMPORTANCE Combined oxygen 15-labeled positron emission tomography (15O PET) and brain tissue oximetry have demonstrated increased oxygen diffusion gradients in hypoxic regions after traumatic brain injury (TBI). These data are consistent with microvascular ischemia and are supported by pathologic studies showing widespread microvascular collapse, perivascular edema, and microthrombosis associated with selective neuronal loss. Fluorine 18-labeled fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings. OBJECTIVE To combine [18F]FMISO and 15O PET to demonstrate the relative burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia in early TBI. DESIGN, SETTING, AND PARTICIPANTS This case-control study included 10 patients who underwent [18F]FMISO and 15O PET within 1 to 8 days of severe or moderate TBI. Two cohorts of 10 healthy volunteers underwent [18F]FMISO or 15O PET. The study was performed at the Wolfson Brain Imaging Centre of Addenbrooke's Hospital. Cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism (CMRO2), oxygen extraction fraction, and brain tissue oximetry were measured in patients during [18F]FMISO and 15O PET imaging. Similar data were obtained from control cohorts. Data were collected from November 23, 2007, to May 22, 2012, and analyzed from December 3, 2012, to January 6, 2016. MAIN OUTCOMES AND MEASURES Estimated ischemic brain volume (IBV) and hypoxic brain volume (HBV) and a comparison of their spatial distribution and physiologic signatures. RESULTS The 10 patients with TBI (9 men and 1 woman) had a median age of 59 (range, 30-68) years; the 2 control cohorts (8 men and 2 women each) had median ages of 53 (range, 41-76) and 45 (range, 29-59) years. Compared with controls, patients with TBI had a higher median IBV (56 [range, 9-281] vs 1 [range, 0-11] mL; P < .001) and a higher median HBV (29 [range, 0-106] vs 9 [range, 1-24] mL; P = .02). Although both pathophysiologic tissue classes were present within injured and normal appearing brains, their spatial distributions were poorly matched. When compared with tissue within the IBV compartment, the HBV compartment showed similar median cerebral blood flow (17 [range, 11-40] vs 14 [range, 6-22] mL/100 mL/min), cerebral blood volume (2.4 [range, 1.6- 4.2] vs 3.9 [range, 3.4-4.8] mL/100 mL), and CMRO2 (44 [range, 27-67] vs 71 [range, 34-88] μmol/100 mL/min) but a lower oxygen extraction fraction (38% [range, 29%-50%] vs 89% [range, 75%-100%]; P < .001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with brain tissue oximetry monitoring suggested that the threshold for increased [18F]FMISO trapping is probably 15 mm Hg or lower. CONCLUSIONS AND RELEVANCE Tissue hypoxia after TBI is not confined to regions with structural abnormality and can occur in the absence of conventional macrovascular ischemia. This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.

OBJECTIVE:To determine if functional imaging using 11C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment. DESIGN/METHODS:Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied. RESULTS:Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS. CONCLUSIONS:In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).

Background: Positron emission tomography (PET) imaging of atherosclerosis with 18F-fluorodeoxyglucose (FDG) gives a non-invasive surrogate of inflammation. FDG PET can be used to track the response...

Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.

Sub-striatal regions of interest (ROIs) are widely used in PET studies to investigate the role of dopamine in the modulation of neural networks implicated in emotion, cognition and motor function. One common approach is that of Mawlawi et al. (2001) and Martinez et al. (2003), where each striatum is divided into five sub-regions. This study focuses on the use of two spatial normalization-based alternatives to manual sub-striatal ROI delineation per subject: manual ROI delineation on a template brain and the production of probabilistic ROIs from a set of subject-specific manually delineated ROIs. Two spatial normalization algorithms were compared: SPM5 unified segmentation and ART. The ability of these methods to quantify sub-striatal regional non-displaceable binding potential (BPND) and BPND % change (following methylphenidate) was tested on 32 subjects (16 controls and 16 ADHD patients) scanned with the dopamine D2/D3 ligand [18F]fallypride. Probabilistic ROIs produced by ART provided the best results, with similarity index values against subject-specific manual ROIs of 0.75–0.89 (mean 0.84) compared to 0.70–0.85 (mean 0.79) for template ROIs. Correlations (r) for BPND and BPND % change between subject-specific manual ROIs and these probabilistic ROIs of 0.90–0.98 (mean 0.95) and 0.98–1.00 (mean 0.99) respectively were superior overall to those obtained with template ROIs, although only marginally so for BPND % change. The significance of relationships between BPND measures and both behavioural tasks and methylphenidate plasma levels was preserved with ART combined with both probabilistic and template ROIs. SPM5 virtually matched the performance of ART for BPND % change estimation but was inferior for BPND estimation in caudate sub-regions. ART spatial normalization combined with probabilistic ROIs and to a lesser extent template ROIs provides an efficient and accurate alternative to time-consuming manual sub-striatal ROI delineation per subject, especially when the parameter of interest is BPND % change.

No study so far has attempted to map the 3D topography of brain hypoxia in the individual rat in vivo following middle cerebral artery occlusion (MCAo). In a previous microPET study, we reported that 18F-fluoromisonidazole (18F-MISO) trapping in the brain after MCAo was specific for the hypoxic viable tissue. Here, we used 18F-MISO microPET to map the 3D topography of brain hypoxia in the acute stage of permanent distal MCAo in individual spontaneously hypertensive rats. Normal rats were also studied. 18F-MISO was intravenously injected approximately 1h after clip placement and PET data were acquired for 2 hours. Animals were sacrificed and the brains harvested 48h later for infarct mapping using standard histopathology. As expected, continuous 18F-MISO trapping was found over the affected relative to unaffected and control MCA cortex. Using single-subject voxel-based statistical mapping, tracer accumulation 90–120 min after injection was consistently significantly higher in the anterior MCA cortex (proximal relative to clip site) and gradually decreased towards posterior areas, a pattern consistent with the classic penumbra concept. The data also suggested that (i) a portion of the significant 18F-MISO trapping area may sit outside the contours of the final infarct despite the permanent MCAo, suggesting that 18F-MISO may be a marker not only of severe (penumbral) but also of milder (oligemic) hypoxia, and (ii) small portions of the final infarct may not exhibit early tracer trapping, suggesting that by the time the tracer was administered this tissue had already progressed to irreversible damage. This study shows the feasibility of single-subject mapping of brain hypoxia following MCAo in the rat, which has potential applications in pathophysiological investigations.

In this study, we show a basis function method (BAFPIC) for voxelwise calculation of kinetic parameters (K(1), k(2), k(3), K(i)) and blood volume using an irreversible two-tissue compartment model. BAFPIC was applied to rat ischaemic stroke micro-positron emission tomography data acquired with the hypoxia tracer [(18)F]fluoromisonidazole because irreversible two-tissue compartmental modelling provided good fits to data from both hypoxic and normoxic tissues. Simulated data show that BAFPIC produces kinetic parameters with significantly lower variability and bias than nonlinear least squares (NLLS) modelling in hypoxic tissue. The advantage of BAFPIC over NLLS is less pronounced in normoxic tissue. K(i) determined from BAFPIC has lower variability than that from the Patlak-Gjedde graphical analysis (PGA) by up to 40% and lower bias, except for normoxic tissue at mid-high noise levels. Consistent with the simulation results, BAFPIC parametric maps of real data suffer less noise-induced variability than do NLLS and PGA. Delineation of hypoxia on BAFPIC k(3) maps is aided by low variability in normoxic tissue, which matches that in K(i) maps. BAFPIC produces K(i) values that correlate well with those from PGA (r(2)=0.93 to 0.97; slope 0.99 to 1.05, absolute intercept <0.00002 mL/g per min). BAFPIC is a computationally efficient method of determining parametric maps with low bias and variance.

In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. Previous human studies using 18F-fluoromisonidazole and positron emission tomography (18F-FMISO PET) have shown high tracer retention indicative of tissue hypoxia, which had normalized at repeat scan >48 h later. In the only validation study of 18F-FMISO, using ex vivo autoradiography in thread middle cerebral artery occluded (MCAo) rats, there was unexpected high uptake as late as 22 h after reperfusion, raising questions about the use of 18F-FMISO as a hypoxia tracer. Here we report a pilot study of 18F-FMISO PET in experimental stroke. Spontaneous hypertensive rats were subjected to distal clip MCAo. Three-hour dynamic PET was performed in 7 rats: 3 normals, 1 with permanent MCAo (two sessions: 30 mins and 48 h after clip), and 3 with temporary MCAo (45 mins, n=1; 120 mins, n=2; scanning started 30 mins after clip removal). Experiments were terminated by perfusion-fixation for standard histopathology. Late tracer retention was assessed by both compartmental modelling and simple side-to-side ratios. In the initial PET session of the permanent MCAo rat, striking trapping of 18F-FMISO was observed in the affected cortex, which had normalized 48 h later; histopathology revealed pannecrosis. In contrast, there was no demonstrable tracer retention in either temporary MCAo models, and histopathology showed ischemic changes only. These results document elevated 18F-FMISO uptake in the stroke area only in the early phase of MCAo, but not after early reperfusion nor when tissue necrosis has developed. These findings strongly support the validity of 18F-FMISO as a marker of viable hypoxic tissue/penumbra after stroke.