Cortical ß-amyloid burden, gray matter, and memory in adults at varying APOE ε4 risk for Alzheimer's disease.

Models of preclinical Alzheimer's disease (AD) propose that cerebral amyloidosis leads to neurodegeneration and subsequent cognitive decline. This study investigated whether APOE genotype is related to ß-amyloid (Aß) burden in brain regions preferentially affected by AD and whether Aß burden is associated with gray-matter (GM) fraction (as a marker of neurodegeneration) and episodic memory performance in cognitively normal middle-aged individuals at varying genetic risk for AD. Three groups of cognitively normal participants aged 50-65 years with a first-degree family history of AD (APOE genotype ε4ε4 [n = 15], ε3ε4 [n = 15], and ε3ε3 [n = 15]) underwent [11C]PiB positron emission tomography scans to quantify cortical Aß, brain magnetic resonance imaging, and neuropsychological testing. APOE ε4ε4 participants demonstrated significantly higher cortical Aß burden than APOE ε3ε3 (p < 0.001). Furthermore, cortical Aß burden was inversely associated with cortical GM fraction (p = 0.017) but not episodic memory performance. In cognitively normal, middle-aged individuals, Aß burden is significantly associated with GM fraction but not episodic memory performance. These findings are consistent with models of preclinical AD in which neurodegeneration occurs before manifest cognitive decline.

Serotonin 1B receptor imaging in pathological gambling.

Abstract Objectives. Although serotonergic mechanisms have been implicated in pathological gambling (PG), no ligand-based imaging studies have assessed serotonin receptors in individuals with PG. Given its role in substance addictions and its abundance in brain regions implicated in PG, we evaluated serotonin 1B receptors (5-HT1BRs) in PG. Methods. Ten medication-free subjects with PG (mean ± SD age = 36.3 ± 9.4 years, nine men) and ten control comparison (CC) subjects (mean ± SD age = 35.8 ± 9.9 years, nine men) underwent [(11)C]P943 positron emission scanning on a high resolution research tomograph. Results. 5-HT1BR BPND values were similar in PG and CC subjects (P > 0.1). Among PG subjects, scores on the South Oaks Gambling Screen (SOGS) correlated positively with 5-HT1BR BPND values in the ventral striatum (r = 0.66; P = 0.04), putamen (r = 0.67; P = 0.03) and anterior cingulate cortex (r = 0.73; P = 0.02). Conclusions. These findings provide the first evidence that PG severity in humans is linked to increased levels of 5-HT1BRs in regions previously implicated in functional neuroimaging studies of PG. These findings indicate a potential role for serotonergic function in the ventral striatum and anterior cingulate cortex contributing to problem gambling severity and warrant further studies to investigate whether numbers of available 5-HT1BRs might represent a vulnerability factor for PG or develop in relationship to problem gambling.

Age effects on serotonin receptor 1B as assessed by PET.

UNLABELLED: Previous imaging studies have suggested that there is an age-related decline in brain serotonin (5-hydroxytryptamine) measures in healthy subjects. This paper addresses whether the availability of 5-hydroxytryptamine receptor 1B (5-HT(1B)) is seen to decrease with aging via PET imaging. METHODS: Forty-eight healthy control subjects (mean age ± SD, 30 ± 10 y; age range, 18-61 y; 33 men, 15 women) underwent (11)C-P943 scanning on a high-resolution PET tomograph. Regions were examined with and without gray matter masking, the latter in an attempt to control for age-related gray matter atrophy on nondisplaceable binding potential (BP(ND)) as determined by a validated multilinear reference tissue model. RESULTS: 5-HT(1B) BP(ND) decreased in the cortex at an average rate of 8% per decade without and 9% with gray matter masking. A negative association with age was also observed in all individual cortical regions. Differences in the putamen and pallidum (positive association) were significant after adjustment for multiple comparisons. No sex- or race-related effects on 5-HT(1B) BP(ND) were found in any regions. CONCLUSION: These findings indicate that age is a relevant factor for 5-HT(1B) in the cortex of healthy adults.

Direct 4-D PET list mode parametric reconstruction with a novel EM algorithm.

The production of images of kinetic parameters is often the ultimate goal of positron emission tomography (PET) imaging. The indirect method of PET parametric imaging, also called the frame-based method (FM), is performed by fitting the time-activity curve (TAC) for each voxel with an appropriate compartment model after image reconstruction. The indirect method is simple and easily implemented, however, it usually leads to some loss of accuracy or precision, due to the use of two separate steps. This paper presents a direct 4-D method for producing 3-D images of kinetic parameters from list mode PET data. In this application, the TAC for each voxel is described by a one-tissue compartment model (1T). Extending previous EM algorithms, a new spatiotemporal complete data space was introduced to optimize the maximum likelihood function. This leads to a straightforward closed-form parametric image update equation. This method was implemented by extending the current list mode platform MOLAR to produce a parametric algorithm PMOLAR-1T. Using an ordered subset approach, qualitative and quantitative evaluations were performed using 2-D (x, t) and 4-D (x, y, z, t) simulated list mode data based on brain receptor tracers and also with a human brain study. Comparisons with the indirect method showed that the proposed direct method can lead to accurate estimation of the parametric image values with reduced variance, especially at low count levels. In the 2-D test, the direct method showed similar bias to the frame-based method but with variance reduction of 23%-60%. In the 4-D test, bias values of both methods were no more than 4% and the direct method had lower variability (coefficient of variation reduction of 0%-64% compared to the frame-based method) at the normal count level. The direct method had a larger reduction in variability (27%-81%) and lower bias (1%-5% for 4-D and 1%-19% for FM) at low count levels. The results in the human brain study are similar with PMOLAR-1T showing lower noise than FM.

Glucose metabolism in the insula and cingulate is affected by systemic inflammation in humans.

UNLABELLED: Depression is associated with systemic inflammation, and the systemic inflammation caused by endotoxin administration elicits mild depressive symptoms such as fatigue and reduced interest. The neural correlates of depressive symptoms that result from systemic inflammation are poorly defined. The aim of this study was to use (18)F-FDG PET to identify brain regions involved in the response to endotoxin administration in humans. METHODS: Nine healthy subjects received double-blind endotoxin (0.8 ng/kg) and placebo on different days. (18)F-FDG PET was used to measure differences in the cerebral metabolic rate of glucose in the following regions of interest: insula, cingulate, and amygdala. Serum levels of tumor necrosis factor-α and interleukin-6 were used to gauge the systemic inflammatory response, and depressive symptoms were measured with the Montgomery-Åsberg Depression Rating Scale and other scales. RESULTS: Endotoxin administration was associated with an increase in Montgomery-Åsberg Depression Rating Scale, increased fatigue, reduced social interest, increased levels of inflammatory cytokines, higher normalized glucose metabolism (NGM) in the insula, and, at a trend level, lower NGM in the cingulate. Secondary analyses of insula and cingulate subregions indicated that these changes were driven by the right anterior insula and the right anterior cingulate. There was a negative correlation between peak cytokine levels and change in social interest and between peak cytokine levels and change in insula NGM. There was a positive correlation between the change in NGM in the insula and change in social interest. CONCLUSION: Systemic inflammation in humans causes an increase in depressive symptoms and concurrent changes in glucose metabolism in the insula and cingulate-brain regions that are involved in interoception, positive emotionality, and motivation.

The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding.

CONTEXT: Serotonergic dysfunction is implicated in the pathogenesis of posttraumatic stress disorder (PTSD), and recent animal models suggest that disturbances in serotonin type 1B receptor function, in particular, may contribute to chronic anxiety. However, the specific role of the serotonin type 1B receptor has not been studied in patients with PTSD. OBJECTIVE: To investigate in vivo serotonin type 1B receptor expression in individuals with PTSD, trauma-exposed control participants without PTSD (TC), and healthy (non-trauma-exposed) control participants (HC) using positron emission tomography and the recently developed serotonin type 1B receptor selective radiotracer [(11)C]P943. DESIGN: Cross-sectional positron emission tomography study under resting conditions. SETTING: Academic and Veterans Affairs medical centers. PARTICIPANTS: Ninety-six individuals in 3 study groups: PTSD (n = 49), TC (n = 20), and HC (n = 27). Main Outcome Measure  Regional [(11)C]P943 binding potential (BP(ND)) values in an a priori-defined limbic corticostriatal circuit investigated using multivariate analysis of variance and multiple regression analysis. RESULTS: A history of severe trauma exposure in the PTSD and TC groups was associated with marked reductions in [(11)C]P943 BP(ND) in the caudate, the amygdala, and the anterior cingulate cortex. Participant age at first trauma exposure was strongly associated with low [(11)C]P943 BP(ND). Developmentally earlier trauma exposure also was associated with greater PTSD symptom severity and major depression comorbidity. CONCLUSIONS: These data suggest an enduring effect of trauma history on brain function and the phenotype of PTSD. The association of early age at first trauma and more pronounced neurobiological and behavioral alterations in PTSD suggests a developmental component in the cause of PTSD.

Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder.

RATIONALE: Although serotonin (5-HT) dysregulation is implicated in the pathophysiology of major depressive disorder (MDD), the role of specific receptor subtypes remains to be elucidated. Emerging preclinical research suggests an important role for the 5-HT(1B) receptor in behavioral regulation and depressive phenotypes. In particular, 5-HT(1B) heteroreceptors located within the striatum have been shown to play an essential role in antidepressant action. OBJECTIVES: The objective of this study was to determine 5-HT(1B) receptor binding potential (BP (ND)) in the region of the ventral striatum/ventral pallidum (VS/VP) in individuals with MDD and healthy control participants. METHODS: Ten participants with MDD (30.8 ± 9.5 years, five men/five women) in a current major depressive episode (MDE) and ten healthy control participants (30.7 ± 10.5 years, five men/five women) underwent positron emission tomography (PET) scanning with the selective 5-HT(1B) receptor radioligand [(11)C]P943. RESULTS: Within the VS/VP region of interest, [(11)C]P943 BP (ND) was significantly reduced in the MDD group compared with the healthy control group (1.37 ± 0.13 and 1.68 ± 0.16, respectively; 18.7% between-group difference; p < 0.001). CONCLUSIONS: Consistent with preclinical and postmortem data, our findings suggest abnormally reduced function of VS/VP 5-HT(1B) receptors in humans with MDD. Abnormal 5-HT(1B) heteroreceptor function may contribute to dysfunctional reward signaling within the striatum, including the nucleus accumbens, via interaction with dopamine, γ-amino-butyric acid, or glutamate systems. Our findings suggest reduced 5-HT(1B) receptor signaling in the VS/VP in MDD and contribute to the therapeutic rationale for testing 5-HT(1B) agonists as a novel class of antidepressants.

Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo.

BACKGROUND: Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate, the most common treatment for attention deficit hyperactivity disorder, is unclear. In vitro, the affinity of methylphenidate for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylphenidate in vivo in humans. METHODS: We used (S,S)-[¹¹C] methylreboxetine ([¹¹C]MRB) to determine the effective dose 50 (ED50) of methylphenidate for NET. In a within-subject design, healthy subjects (n = 11) received oral, single-blind placebo and 2.5, 10, and 40 mg of methylphenidate 75 min before [¹¹C]MRB injection. Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable (BP(ND)) in the thalamus and other NET-rich regions. RESULTS: BP(ND) was reduced by methylphenidate in a dose-dependent manner in thalamus and other NET-rich regions. The global ED50 was estimated to be .14 mg/kg; therefore, the average clinical maintenance dose of methylphenidate (.35-.55 mg/kg) produces 70% to 80% occupancy of NET. CONCLUSIONS: For the first time in humans, we demonstrate that oral methylphenidate significantly occupies NET at clinically relevant doses. The ED50 is lower than that for DAT (.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in attention-deficit/hyperactivity disorder.

Arterial transit time effects in pulsed arterial spin labeling CBF mapping: insight from a PET and MR study in normal human subjects.

Arterial transit time (ATT), a key parameter required to calculate absolute cerebral blood flow in arterial spin labeling (ASL), is subject to much uncertainty. In this study, ASL ATTs were estimated on a per-voxel basis using data measured by both ASL and positron emission tomography in the same subjects. The mean ATT increased by 260 +/- 20 (standard error of the mean) ms when the imaging slab shifted downwards by 54 mm, and increased from 630 +/- 30 to 1220 +/- 30 ms for the first slice, with an increase of 610 +/- 20 ms over a four-slice slab when the gap between the imaging and labeling slab increased from 20 to 74 mm. When the per-slice ATTs were employed in ASL cerebral blood flow quantification and the in-slice ATT variations ignored, regional cerebral blood flow could be significantly different from the positron emission tomography measures. ATT also decreased with focal activation by the same amount for both visual and motor tasks (approximately 80 ms). These results provide a quantitative relationship between ATT and the ASL imaging geometry and yield an assessment of the assumptions commonly used in ASL imaging. These findings should be considered in the interpretation of, and comparisons between, different ASL-based cerebral blood flow studies. The results also provide spatially specific ATT data that may aid in optimizing the ASL imaging parameters.

Kinetic modeling of the serotonin 5-HT(1B) receptor radioligand [(11)C]P943 in humans.

[(11)C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT(1B)) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [(11)C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BP(ND) binding potential estimates were computed. [(11)C]P943 BP(ND) estimates were significantly correlated with in vitro measurements of the density of 5-HT(1B) receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [(11)C]P943 could be computed using both MA1 and MRTM2. The results show that [(11)C]P943 provides quantitative measurements of 5-HT(1B) binding potential.

PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S,S)-[(11)C]O-methylreboxetine and HRRT.

OBJECTIVES: The role of the norepinephrine transporter (NET) in cocaine dependence has never been demonstrated via in vivo imaging due to the lack of suitable NET radioligands. Here we report our preliminary studies evaluting the NET in individuals with cocaine dependence (COC) in comparison to healthy controls (HC) using (S,S)-[(11)C]methylreboxetine ([(11)C]MRB), the most promising C-11 labeled positron-emission tomography (PET) radioligand for NET developed to date. METHODS: Twenty two human volunteers (10 COC and 12 HC) underwent dynamic (11)C-MRB-PET acquisition using a High Resolution Research Tomograph (HRRT). Binding potential (BP(ND)) parametric images were computed using the simplified reference tissue model (SRTM2) with occipital cortex as reference region. BP(ND) values were compared between the two groups. RESULTS: Locus coeruleus (LC), hypothalamus, and pulvinar showed a significant inverse correlation with age among HC (age range = 25-54 years; P = 0.04, 0.009, 0.03 respectively). The BP(ND) was significantly increased in thalamus (27%; P < 0.02) and dorsomedial thalamic nuclei (30%; P < 0.03) in COC as compared to HC. Upon age normalization, the upregulation of NET in COC also reached significance in LC (63%, P < 0.01) and pulvinar (55%, P < 0.02) regions. CONCLUSION: Our results suggest that (a) brain NET concentration declines with age in HC, and (b) there is a significant upregulation of NET in thalamus and dorsomedial thalamic nucleus in COC as compared to HC. Our results also suggest that the use of [(11)C]MRB and HRRT provides an effective strategy for studying alterations of the NET system in humans.

Initial Evaluation of Direct 4D Parametric Reconstruction with Human PET Data.

Previously, we presented a direct EM method for producing kinetic parameter images from list mode PET data, where the time-activity curve for each voxel is described by a one-tissue compartment model (1T). The initial evaluations were performed with simulations, without motion, randoms, or scatter effects included. By extension of our previous frame-based physics correction methods, a practical direct 4D parametric reconstruction algorithm is now proposed and implemented for human data. Initial evaluations were performed using 3 human subjects with the serotonin transporter tracer [(11)C]AFM. Comparisons with the 2-step approach (frame-based reconstruction followed by voxel-by-voxel parameter estimation) provided encouraging initial results. Regional analysis showed that the 2-step and 4D methods have similar K(1) and V(T) values, but with a consistent difference. Visual analysis showed some noise reduction in 4D. These initial results suggest that direct 4D parametric reconstruction can be performed with real data, and offers the potential for improved accuracy and precision over the 2-step frame method.

A Multimodal Approach to Image-Derived Input Functions for Brain PET.

Many methods have been proposed for generating an image-derived input function (IDIF) exclusively from PET images. The purpose of this study was to assess the viability of a multimodality approach utilizing registered MR images. 3T-MR and HRRT-PET data were acquired from human subjects. Segmentation of both the left and right carotid arteries was performed in MR images using a 3D level sets method. Vessel centerlines were extracted by parameterization of the segmented voxel coordinates with either a single polynomial curve or a B-spline curve fitted to the segmented data. These centerlines were subsequently re-registered to static PET data to maximize the accurate classification of PET voxels in the ROI. The accuracy of this approach was assessed by comparison of the area under the curve (AUC) of the IDIF to that measured from conventional automated arterial blood sampling.Our method produces curves similar in shape to that of blood sampling. The mean AUC ratio of the centerline region was 0.40±0.19 before re-registration and 0.69±0.26 after re-registration. Increasing the diameter of the carotid ROI produced a smooth reduction in AUC. Thus, even with the high resolution of the HRRT, partial volume correction is still necessary. This study suggests that the combination of PET information with MR segmented regions will demonstrate an improvement over regions based solely on MR or PET alone.

Accuracy of Head Motion Compensation for the HRRT: Comparison of Methods.

Motion correction in PET has become more important as system resolution has improved. The purpose of this study was to evaluate the accuracy of three motion compensation methods, event-by-event motion compensation with list-mode reconstruction (MOLAR), frame-based motion correction, and post-reconstruction image registration. Motion compensated image reconstructions were carried out with simulated HRRT data, using a range of motion information based on human motion data. ROI analyses in high contrast regions were performed to evaluate the accuracy of all the motion compensation methods, with particular attention to within-frame motion.Our study showed that MOLAR with list-mode based motion correction using accurate motion data can reliably correct for all reasonable head motions. Over all motions, the average ROI count was within 0.1±4.2% and 0.7±0.9% of the reference, no-motion value for two different ROIs. The location of the ROI centroid was found to be within 0.7±0.3mm of that of the reference image for the raphe nucleus. Frame-based motion compensation and post-reconstruction image registration were able to correct for small (<5mm), but the ROI intensity begins to deteriorate for medium motions (5-10mm), especially for small brain structures such as the raphe nucleus. For large (>10mm) motions, the average centroid locations of the raphe nucleus ROI had an offset error of 1.5±1.8mm and 1.8±1.8mm for each of the frame-based methods. For each frame-based method, the decrease in the average ROI intensity was 16.9±4.3% and 20.2±9.9% respectively for the raphe nucleus, and was 5.5±2.2% and 7.4±0.2% for putamen. Based on these data, we conclude that event-by-event based motion correction works accurately for all reasonable motions, whereas frame-based motion correction is accurate only when the within-frame motion is less than 10mm.

Quantitative Accuracy of HRRT List-mode Reconstructions: Effect of Low Statistics.

Previous studies showed that iterative image reconstruction algorithms may produce overestimations of activity in low-activity regions in low-count frames. The purpose of this study was (1) to evaluate the quantitative accuracy of the MOLAR list-mode iterative reconstruction method in the context of ligand-receptor PET studies in low counts, and (2) to determine the minimum noise equivalent counts (NEC) per frame to avoid bias. Evaluation of clinical data was performed for 4 tracers using dynamic brain PET studies. True activity was estimated from high-statistics frames (300s) and ROI analysis was performed to evaluate bias in low-activity regions in short acquisition frames (10-30s) from matching times. Bias in the ROI mean values was analyzed as function of NEC. In addition, accuracy was assessed using Hoffman phantom data and simulated list mode data based on human data, but without scatter and randoms.Unlike previous results, small biases of -3±3% for low statistics region across the 4 tracers were found for NEC >100K in each frame. Very similar results were found in the phantom and simulation data. We conclude that the MOLAR iterative reconstruction method provides accurate results even in very low-count frames. This improved performance may be attributed to some of the unique characteristics of MOLAR including randoms estimation from singles, iterative estimation of scatter within the algorithm, component-based normalization, and incorporation of a line-spread function model in the reconstruction.

Direct 4D List Mode Parametric Reconstruction for PET with a Novel EM Algorithm.

We present a direct method for producing images of kinetic parameters from list mode PET data. The time-activity curve for each voxel is described by a one-tissue compartment, 2-parameter model. Extending previous EM algorithms, a new spatiotemporal complete data space was introduced to optimize the maximum likelihood function. This leads to a straightforward parametric image update equation with moderate additional computation requirements compared to the conventional algorithm. Qualitative and quantitative evaluations were performed using 2D (x,t) and 4D (x,y,z,t) simulated list mode data for a brain receptor study. Comparisons with the two-step approach (frame-based reconstruction followed by voxel-by-voxel parameter estimation) show that the proposed method can lead to accurate estimation of the parametric image values with reduced variance, especially for the volume of distribution (V(T)).

Cerebral metabolic effects of intravenous glycine in healthy human subjects.

Enhancing N-methyl-D-aspartate (NMDA) receptor function via increasing synaptic concentrations of glycine is currently investigated as a novel approach to treat schizophrenia. The neural correlates of enhanced NMDA receptor function in humans, however, are unclear to date. The present study determines the effects of intravenous administration of the glycine on regional cerebral metabolic rate of glucose (rCMRGlu) in healthy control subjects by using [18F]fluorodeoxyglucose and positron emission tomography and on neuropsychological behavioral measures. Thirteen healthy volunteers were recruited, and 12 subjects completed the protocol. These individuals participated in 1 magnetic resonance imaging study and 2 [18F]fluorodeoxyglucose positron emission tomography studies. In a double-blind, randomized, controlled, crossover design, participants received on one test day an intravenous glycine infusion and on the other test day a placebo infusion. There were no significant behavioral and neuropsychological effects of glycine compared with placebo. However, there was a significant reduction of whole-brain CMRGlu during administration of glycine compared with placebo (t = 2.60, df = 11, P = 0.023). In the a priori-selected regions of interest, there was a significant reduction in the cerebellum (t = -3.18, df = 11, P = 0.009) and the dorsolateral prefrontal cortex (t = -2.31, df = 11, P = 0.041). When corrected for whole-brain CMRGlu, rCMRGlu differences were not significant. This study suggests that studies of whole-brain cerebral metabolism may be useful for studying glycine-related mechanisms in healthy humans because there is not a clear cognitive or behavioral signal related to glycine administration at doses thought to be important clinically in patient populations.