Weiguo Ye

In Vivo Imaging of Amyloid Deposition in Alzheimer Disease Using the Radioligand 18F-AV-45 (Flobetapir F 18)

An 18F-labeled PET amyloid-β (Aβ) imaging agent could facilitate the clinical evaluation of late-life cognitive impairment by providing an objective measure for Alzheimer disease (AD) pathology. Here we present the results of a clinical trial with (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine (18F-AV-45 or flobetapir F 18). Methods: An open-label, multicenter brain imaging, metabolism, and safety study of 18F-AV-45 was performed on 16 patients with AD (Mini-Mental State Examination score, 19.3 ± 3.1; mean age ± SD, 75.8 ± 9.2 y) and 16 cognitively healthy controls (HCs) (Mini-Mental State Examination score, 29.8 ± 0.45; mean age ± SD, 72.5 ± 11.6 y). Dynamic PET was performed over a period of approximately 90 min after injection of the tracer (370 MBq [10 mCi]). Standardized uptake values and cortical-to-cerebellum standardized uptake value ratios (SUVRs) were calculated. A simplified reference tissue method was used to generate distribution volume ratio (DVR) parametric maps for a subset of subjects. Results: Valid PET data were available for 11 AD patients and 15 HCs. 18F-AV-45 accumulated in cortical regions expected to be high in Aβ deposition (e.g., precuneus and frontal and temporal cortices) in AD patients; minimal accumulation of the tracer was seen in cortical regions of HCs. The cortical-to-cerebellar SUVRs in AD patients showed continual substantial increases through 30 min after administration, reaching a plateau within 50 min. The 10-min period from 50 to 60 min after administration was taken as a representative sample for further analysis. The cortical average SUVR for this period was 1.67 ± 0.175 for patients with AD versus 1.25 ± 0.177 for HCs. Spatially normalized DVRs generated from PET dynamic scans were highly correlated with SUVR (r = 0.58–0.88, P < 0.005) and were significantly greater for AD patients than for HCs in cortical regions but not in subcortical white matter or cerebellar regions. No clinically significant changes in vital signs, electrocardiogram, or laboratory values were observed. Conclusion: 18F-AV-45 was well tolerated, and PET showed significant discrimination between AD patients and HCs, using either a parametric reference region method (DVR) or a simplified SUVR calculated from 10 min of scanning 50–60 min after 18F-AV-45 administration.

Sex Differences in Striatal Dopamine Release in Healthy Adults

BACKGROUND Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings. METHODS Using positron emission tomography (PET) scans with high-specific-activity [11C] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined. RESULTS Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, mens ratings of the positive effects of amphetamine were greater than womens. We found no sex difference in neuroendocrine hormone responses. CONCLUSIONS We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum.

Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB

Objective: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Aβ) deposition in vivo in individuals without dementia. Method: [11C]PiB images were obtained to measure fibrillar Aβ burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [11C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. Results: [11C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. Conclusions: Higher Aβ deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Aβ deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-Rs), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DArel) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DArel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D2-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS-OCD). In three subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DArel and 5-HT2A BP, when compared with TS–OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DArel is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT2AR in individuals with TS who had increased DArel, suggest a condition of increased phasic DArel modulated by low 5-HT in concomitant OCD.

Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

Impulsivity and chronic stress are associated with amphetamine-induced striatal dopamine release

A challenging question that continues to plague the field of addiction is why some individuals are more vulnerable for substance use disorders than others. Several important risk factors for substance abuse have been identified in clinical studies, including trait impulsivity and environmental stress. However, the neurobiological mechanisms that underlie the relationships remain poorly understood. The purpose of this study was to examine associations among impulsivity, stress, and striatal dopamine (DA) responses to amphetamine (AMPH) in humans. Forty healthy M, F adults, ages 18-29 years, completed self-report measures of trait impulsivity, life events stress, and perceived stress. Subjects subsequently underwent two consecutive 90-min positron emission tomography (PET) studies with high specific activity [11C]raclopride. The first scan was preceded by an intravenous injection of saline; the second was preceded by 0.3 mg/kg AMPH. Findings showed that high impulsivity was associated with blunted right ventral striatal DA release. However, effects were modified by a significant interaction with life events stress. Dopamine release was greater in low vs. high impulsivity subjects under conditions of low or moderate stress. Under conditions of high stress, both groups had low DA release. Subjects with high impulsivity reported more pleasant effects with AMPH than subjects with low impulsivity. In contrast, stress was negatively associated with pleasant drug effects. No associations were observed between impulsivity or stress and cortisol responses to AMPH. The findings are consistent with notions that blunted DA responses represent an endophenotype for substance use disorders.

A consistent and efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies

The widely used Logan plot in radioligand receptor dynamic PET studies produces marked noise-induced negative biases in the estimates of total distribution volume (DV(T)) and binding potential (BP). To avoid the inconsistencies in the estimates from the Logan plot, a new graphical analysis method was proposed and characterized in this study. The new plot with plasma input and with reference tissue input was first derived to estimate DV(T) and BP. A condition was provided to ensure that the estimate from the new plot equals DV(T) or BP. It was demonstrated theoretically that 1) the statistical expectations of the estimates from the new plot with given input are independent of the noise of the target tissue concentration measured by PET; and 2) the estimates from the time activity curves of regions of interest are identical to those from the parametric images for the new plot. The theoretical results of the new plot were also confirmed by computer simulations and fifty-five human [(11)C]raclopride dynamic PET studies. By contrast, the marked noise-induced underestimation in the DV(T) and BP images and noise-induced negative bias in the estimates from the Logan plot were demonstrated by the same data sets used for the new plot. The computational time for generating DV(T) or BP images in the human studies was reduced by 80% on average by the new plot in contrast to the Logan plot. In conclusion, the new plot is a consistent and computationally efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies.

Multi-graphical analysis of dynamic PET

In quantitative dynamic PET studies, graphical analysis methods including the Gjedde-Patlak plot, the Logan plot, and the relative equilibrium-based graphical plot (RE plot) (Zhou Y., Ye W., Brasić J.R., Crabb A.H., Hilton J., Wong D.F. 2009b. A consistent and efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies. Neuroimage 44(3):661-670) are based on the theory of a compartmental model with assumptions on tissue tracer kinetics. If those assumptions are violated, then the resulting estimates may be biased. In this study, a multi-graphical analysis method was developed to characterize the non-relative equilibrium effects on the estimates of total distribution volume (DV(T)) from the RE plot. A novel bi-graphical analysis method using the RE plot with the Gjedde-Patlak plot (RE-GP plots) was proposed to estimate DV(T) for the quantification of reversible tracer kinetics that may not be at relative equilibrium states during PET study period. The RE-GP plots and the Logan plot were evaluated by 19 [(11)C]WIN35,428 and 10 [(11)C]MDL100,907 normal human dynamic PET studies with brain tissue tracer kinetics measured at both region of interest (ROI) and pixel levels. A 2-tissue compartment model (2TCM) was used to fit ROI time activity curves (TACs). By applying multi-graphical plots to the 2TCM fitted ROI TACs which were considered as the noise-free tracer kinetics, the estimates of DV(T) from the RE-GP plots, the Logan plot, and the 2TCM fitting were equal to each other. For the measured ROI TACs, there was no significant difference between the estimates of the DV(T) from the RE-GP plots and those from 2TCM fitting (p=0.77), but the estimates of the DV(T) from the Logan plot were significantly (p<0.001) lower, 2.3% on average, than those from 2TCM fitting. There was a highly linear correlation between the ROI DV(T) from the parametric images (Y) and those from the ROI kinetics (X) by using the RE-GP plots (Y=1.01X+0.23, R(2)=0.99). For the Logan plot, the ROI estimates from the parametric images were 13% to 83% lower than those from ROI kinetics. The computational time for generating parametric images was reduced by 69% on average by the RE-GP plots in contrast to the Logan plot. In conclusion, the bi-graphical analysis method using the RE-GP plots was a reliable, robust and computationally efficient kinetic modeling approach to improve the quantification of dynamic PET.

Lack of association between 11C-PiB and longitudinal brain atrophy in non-demented older individuals

Amyloid-β plaques (Aβ) are a hallmark of Alzheimers disease (AD), begin deposition decades before the incipient disease, and are thought to be associated with neuronal loss, brain atrophy and cognitive impairment. We examine associations between (11)C-PiB-PET measurement of Aβ burden and brain volume changes in the preceding years in 57 non-demented individuals (age 64-86; M=78.7). Participants were prospectively followed through the Baltimore Longitudinal Study of Aging, with up to 10 consecutive MRI scans (M=8.1) and an (11)C-PiB scan approximately 10 years after the initial MRI. Linear mixed effects models were used to determine whether mean cortical (11)C-PiB distribution volume ratios, estimated by fitting a reference tissue model to the measured time activity curves, were associated with longitudinal regional brain volume changes of the whole brain, ventricular CSF, frontal, temporal, parietal, and occipital white and gray matter, the hippocampus, orbito-frontal cortex, and the precuneus. Despite significant longitudinal declines in the volumes of all investigated regions (p<0.05), no associations were detected between current Aβ burden and regional brain volume decline trajectories in the preceding years, nor did the regional volume trajectories differ between those with highest and lowest Aβ burden. Consistent with a threshold model of disease, our findings suggest that Aβ load does not seem to affect brain volume changes in individuals without dementia.

An extended simplified reference tissue model for the quantification of dynamic PET with amphetamine challenge

BACKGROUND Equilibrium analysis to quantify dynamic positron emission tomography (PET) with bolus followed by continuous tracer infusion and acute amphetamine challenge assumes that all tissue kinetics attain steady states during pre- and post-challenge phases. Violations of this assumption may result in unreliable estimation of the amphetamine-induced percent change in the binding potential (DeltaBP%). METHOD We derived an extended simplified reference tissue model (ESRTM) for modeling tracer kinetics in the pre- and post-challenge phases. Ninety-minute [11C]raclopride PET studies with bolus injection followed by continuous tracer infusion were performed on 18 monkeys and 2 baboons. Forty minutes after the bolus injection, a single acute intravenous amphetamine administration was given of 2.0 mg/kg to monkeys and of 0.05, 0.1, 0.5, and 1.5 mg/kg to baboons. Computer simulations further evaluated and characterized the ESRTM. RESULTS In monkey studies, the DeltaBP% estimated by the ESRTM was 32+/-11, whereas, the DeltaBP% obtained using the equilibrium methods was 32% to 81% lower. In baboon studies, the DeltaBP% values estimated with the ESRTM showed a linear relationship between the DeltaBP% and the natural logarithm of amphetamine dose (R2=0.96), where the DeltaBP%=10.67Ln(dose)+33.79 (0.05<or=dose in mg/kg<or=1.5). At 1.5 mg/kg amphetamine, the DeltaBP% estimates from equilibrium methods were 18% to 40% lower than those estimated by the ESRTM. Results showed that the nonsteady state of tracer kinetics produced an underestimation of the DeltaBP% from the equilibrium analysis. The accuracy of the DeltaBP% estimates from the equilibrium analysis was significantly improved by the ESRTM. The DeltaBP% estimated by the ESRTM in the study was consistent with that from previous [11C] raclopride PET with amphetamine challenge. CONCLUSION In conclusion, the ESRTM is a robust kinetic modeling approach and is proposed for the quantification of dynamic PET with acute amphetamine stimulation.