Joel Dunn

Attenuation of Insulin-Evoked Responses in Brain Networks Controlling Appetite and Reward in Insulin Resistance The Cerebral Basis for Impaired Control of Food Intake in Metabolic Syndrome?

The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [18F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 ± 5.2 and 23.2 ± 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P < 0.001), relative to global brain. Insulin’s effect was less in ventral striatum and prefrontal cortex in the insulin-resistant subjects (mean ± SD for right ventral striatum 3.2 ± 3.9 vs. 7.7 ± 1.7, P = 0.017). We conclude that brain insulin resistance exists in peripheral insulin resistance, especially in regions subserving appetite and reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.

Attenuation of Amydgala and Frontal Cortical Responses to Low Blood Glucose Concentration in Asymptomatic Hypoglycemia in Type 1 Diabetes: A New Player in Hypoglycemia Unawareness?

OBJECTIVE—Loss of ability to recognize hypoglycemia (hypoglycemia unawareness) increases risk of severe hypoglycemia threefold in insulin-treated diabetes. We set out to investigate the cerebral correlates of unawareness in type 1 patients. RESEARCH DESIGN AND METHODS—Regional changes in brain glucose kinetics were measured using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), in 13 men with type 1 diabetes—6 with hypoglycemia awareness and 7 with hypoglycemia unawareness—at euglycemia (5 mmol/l) and hypoglycemia (2.6 mmol/l), in random order. RESULTS—Epinephrine responses to hypoglycemia were reduced in hypoglycemia unawareness (P < 0.0003), as were symptoms. Statistical parametric mapping (SPM) of FDG uptake using SPM2 at a statistical threshold of P < 0.005 showed increased FDG uptake in left amygdala in hypoglycemia awareness, but not in hypoglycemia unawareness (region of interest analysis −0.40 ± 1.03 vs. 3.66 ± 0.42, respectively; P = 0.007), and robust increase in bilateral ventral striatum during hypoglycemia (region of interest analysis hypoglycemia unawareness 3.52 ± 1.02 vs. awareness 6.1 ± 0.53; P = 0.054). Further analysis at the statistical threshold of P < 0.01 showed bilateral attenuated activation of brain stem regions and less deactivation in lateral orbitofrontal cortex in hypoglycemia unawareness. CONCLUSIONS—Ventral striatal, amygdala, brain stem, and orbitofrontal responses to hypoglycemia indicate engagement of appetitive motivational networks, associated with integrated behavioral responses to hypoglycemia. Reduced responses in these networks in hypoglycemia unawareness, particularly failure of amygdala and orbifrontal cortex responses, suggest habituation of higher behavioral responses to hypoglycemia as a basis for unawareness. New approaches may be needed to restore awareness effectively in practice.

Differential effects of teriparatide on regional bone formation using 18F-fluoride positron emission tomography

Teriparatide increases skeletal mass, bone turnover markers, and bone strength, but local effects on bone tissue may vary between skeletal sites. We used positron emission tomography (PET) to study 18F‐fluoride plasma clearance (Ki) at the spine and standardized uptake values (SUVs) at the spine, pelvis, total hip, and femoral shaft in 18 postmenopausal women with osteoporosis. Subjects underwent a 1‐hour dynamic scan of the lumbar spine and a 10‐minute static scan of the pelvis and femurs at baseline and after 6 months of treatment with 20 µg/day teriparatide. Blood samples were taken to derive the arterial input function and lumbar spine Ki values evaluated using a three‐compartment model. SUVs were calculated for the spine, pelvis, total hip, and femoral shaft. After 6 months treatment with teriparatide, spine Ki values increased by 24% (p = .0003), while other model parameters were unchanged except for the fraction of tracer going to bone mineral (k3/[k2 + k3]), which increased by 23% (p = .0006). In contrast to Ki, spine SUVs increased by only 3% (p = .84). The discrepancy between changes in Ki and SUVs was explained by a 20% decrease in 18F− plasma concentration. SUVs increased by 37% at the femoral shaft (p = .0019), 20% at the total hip (p = .032), and 11% at the pelvis (p = .070). Changes in bone turnover markers and BMD were consistent with previous trials. We conclude that the changes in bone formation rate during teriparatide treatment as measured by 18F− PET differ at different skeletal sites, with larger increases in cortical bone than at trabecular sites.

Phase 2 Study of Sorafenib in Malignant Mesothelioma Previously Treated with Platinum-Containing Chemotherapy

Introduction: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data. Methods: Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon’s two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively. Results: Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome. Conclusions: Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.

Regional cerebral blood flow and FDG uptake in asymptomatic HIV‐1 men

Despite advances in the treatment of patients with human immunodeficiency virus (HIV), HIV‐associated neurocognitive disorder occurs in 15–50% of HIV‐infected individuals, and may become more apparent as ageing advances. In the present study we investigated regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose uptake (rCMRglc) in medically and psychiatrically stable HIV‐1‐infected participants in two age‐groups. Positron emission tomography (PET) and magnetic resonance imaging (MRI)‐based arterial spin labeling (ASL) were used to measure rCMRglc and rCBF, respectively, in 35 HIV‐infected participants and 37 HIV‐negative matched controls. All participants were currently asymptomatic with undetectable HIV‐1 viral loads, without medical or psychiatric comorbidity, alcohol or substance misuse, stable on medication for at least 6 months before enrolment in the study. We found significant age effects on both ASL and PET with reduced rCBF and rCMRglc in related frontal brain regions, and consistent, although small, reductions in rCBF and rCMRglc in the anterior cingulate cortex (ACC) in HIV, a finding of potential clinical significance. There was no significant interaction between HIV status and the ageing process, and no significant HIV‐related changes elsewhere in the brain on PET or ASL. This is the first paper to combine evidence from ASL and PET method in HIV participants. These finding provide evidence of crossvalidity between the two techniques, both in ageing and a clinical condition (HIV). Hum Brain Mapp 34:2484–2493, 2013.

Establishing Test–Retest Reliability of an Adapted [18F]Fallypride Imaging Protocol in Older People

[ 18 F]fallyprlde is a high-affinity dopamine D2/3 receptor tracer with the ability to reliably quantify D2/3 receptor sites in both striatal and corticolimbic regions. The translational potential of [ 18 F]fallypride imaging is, however, limited by the lengthy scanning sessions (60–80 minutes duration over a total of 3–4 hours) required by current protocols. The aims of our study were to adapt [ 18 F]fallypride imaging for use in clinical populations with neurological and neuropsychiatric disorders, by reducing the duration of individual scanning sessions;and to establish the reproducibility and reliability of our adapted protocol in healthy older people. Eight participants (five male and three female;mean age = 75.87 ± 4.39 years) were scanned twice, 4–6 weeks apart. [ 18 F]fallypride binding potential was determined from image data collected during three sampling times: 0-30;60-90;and 210–240 minutes post injection. High reproducibility and reliability (test-retest variability <8%;intraclass correlation coefficient >0.8) were observed in all but the prefrontal regions, and remained so when sampling times were reduced to 20 minutes (0-20;70-90;220-240 minutes). The adapted protocol is feasible for use across neuropsychiatric disorders in which dopamine has been implicated and is sufficiently sensitive to detect within-subject changes between 2.7% and 5.5% in striatal and limbic regions.

PET Imaging of Copper Trafficking in a Mouse Model of Alzheimer Disease

Alzheimer disease (AD) is a fatal neurodegenerative disorder characterized by progressive neuronal loss and cognitive decline. The lack of reliable and objective diagnostic markers for AD hampers early disease detection and treatment. Growing evidence supports the existence of a dysregulation in brain copper trafficking in AD. The aim of this study was to investigate brain copper trafficking in a transgenic mouse model of AD by PET imaging with 64Cu, to determine its potential as a diagnostic biomarker of the disorder. Methods: Brain copper trafficking was evaluated in 6- to 8-mo-old TASTPM transgenic mice and age-matched wild-type controls using the 64Cu bis(thiosemicarbazone) complex 64Cu-GTSM (glyoxalbis(N4-methyl-3-thiosemicarbazonato) copper(II)), which crosses the blood–brain barrier and releases 64Cu bioreductively into cells. Animals were intravenously injected with 64Cu-GTSM and imaged at 0–30 min and 24–25 h after injection. The images were analyzed by atlas-based quantification and texture analysis. Regional distribution of 64Cu in the brain 24 h after injection was also evaluated via ex vivo autoradiography and compared with amyloid-β plaque deposition in TASTPM mice. Results: Compared with controls, in TASTPM mice PET image analysis demonstrated significantly increased (by a factor of ∼1.3) brain concentration of 64Cu at 30 min (P < 0.01) and 24 h (P < 0.05) after injection of the tracer and faster (by a factor of ∼5) 64Cu clearance from the brain (P < 0.01). Atlas-based quantification and texture analysis revealed significant differences in regional brain uptake of 64Cu and PET image heterogeneity between the 2 groups of mice. Ex vivo autoradiography showed that regional brain distribution of 64Cu at 24 h after injection did not correlate with amyloid-β plaque distribution in TASTPM mice. Conclusion: The trafficking of 64Cu in the brain after administration of 64Cu-GTSM is significantly altered by AD-like pathology in the TASTPM mouse model, suggesting that 64Cu-GTSM PET imaging warrants clinical evaluation as a diagnostic tool for AD and possibly other neurodegenerative disorders.

Role of 18F-FDG PET imaging in paediatric primary dystonia and dystonia arising from neurodegeneration with brain iron accumulation

PurposeNo current neuroimaging modality offers mechanistic or prognostic information to guide management in paediatric dystonia. We assessed 18F-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) brain imaging in childhood primary dystonia (PDS) and neurodegeneration with brain iron accumulation (NBIA) to determine whether it would identify altered metabolism and hence constitute a potentially useful ‘biomarker’ indicating functional disturbances associated with dystonia and severity of the disease. Materials and methodsA total of 27 children (15 PDS and 12 NBIA) underwent brain 18F-FDG PET/CT imaging under anaesthesia during acquisition. The images were assessed visually and the two groups were compared quantitatively with statistical parametric mapping. PET/CT images were spatially transformed to Montreal Neurological Institute standard space. Voxelwise 18F-FDG uptake was normalized to whole-brain uptake. Data of both groups were correlated separately with duration and severity of dystonia as assessed using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). ResultsVisual inspection did not identify any abnormalities in 18F-FDG uptake within the cerebral cortex, basal ganglia, or thalami in either group. Quantitative analysis identified higher uptake in the posterior cingulate and bilateral posterior putamina but decreased uptake in the occipital cortex and cerebellum in NBIA compared with PDS. The NBIA group had more severe dystonia scores compared with the PDS group. BFMDRS was negatively correlated with age but not with duration of dystonia. ConclusionCompared with PDS, NBIA is dominated by relative overactivity in the putamen and by cerebellar underactivity, patterns that may reflect the increased severity of dystonia in NBIA cases. Hence, there is a potential role for 18F-FDG PET/CT imaging in paediatric dystonia, particularly in the NBIA group.

Correction for the effect of rising plasma glucose levels on quantification of MRglc with FDG-PET

Positron emission tomography (PET) using the tracer [18F]-fluorodeoxyglucose (FDG) is commonly used for measuring metabolic rate of glucose (MRglc) in the human brain. Conventional PET methods (e.g., the Patlak method) for quantifying MRglc assume the tissue transport and phosphorylation mechanisms to be in steady state during FDG uptake. As FDG and glucose use the same transporters and phosphorylation enzymes, changing blood glucose levels can change the rates of FDG transport and phosphorylation. Compartmental models were used to simulate the effect of rising arterial glucose, from normal to hyperglycemic levels on FDG uptake for a typical PET protocol. The subsequent errors on the values of MRglc calculated using the Patlak method were investigated, and a correction scheme based on measured arterial glucose concentration (Gp) was evaluated. Typically, with a 40% rise in Gp over the duration of the PET study, the true MRglc varied by only 1%; however, the Patlak method overestimated MRglc by 15%. The application of the correction reduced this error to −2%. In general, the application of the correction resulted in values of MRglc consistently significantly closer to the true steady state calculation of MRglc independently of changes to the parameters defining the model.

Towards a therapeutic window of D2/3 occupancy for treatment of psychosis in Alzheimer's disease, with [18F]fallypride positron emission tomography

Dopamine D2/3 receptor positron emission tomography tracers have guided antipsychotic prescribing in young people with schizophrenia by establishing a ‘therapeutic window’ of striatal D2/3 receptor occupancy. Older people, particularly those with dementia, are highly susceptible to motor side effects and may benefit from the appropriate application of imaging techniques. The study aimed to adapt [18F]fallypride imaging for use in occupancy studies in Alzheimers disease (AD) and to investigate whether data acquisition could be made more tolerable by piloting the protocol in a small sample.