Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans.

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.

Human Cognitive Ability Is Modulated by Aromatase Availability in the Brain in a Sex-Specific Manner.

The enzyme aromatase catalyzes the final step in estrogen biosynthesis, converting testosterone to estradiol, and is expressed in the brain of all mammals. Estrogens are thought to be important for maintenance of cognitive function in women, whereas testosterone is thought to modulate cognitive abilities in men. Here, we compare differences in cognitive performance in relation to brain aromatase availability in healthy men and women. Twenty-seven healthy participants were administered tests of verbal learning and memory and perceptual/abstract reasoning. In vivo images of brain aromatase availability were acquired in this sample using positron emission tomography (PET) with the validated aromatase radiotracer [11C]vorozole. Regions of interest were placed bilaterally on the amygdala and thalamus where aromatase availability is highest in the human brain. Though cognitive performance and aromatase availability did not differ as a function of sex, higher availability of aromatase in the amygdala was associated with lower cognitive performance in men. No such relationship was found in women; and the corresponding regression slopes were significantly different between the sexes. Thalamic aromatase availability was not significantly correlated with cognitive performance in either sex. These findings suggest that the effects of brain aromatase on cognitive performance are both region- and sex-specific and may explain some of the normal variance seen in verbal and nonverbal cognitive abilities in men and women as well as sex differences in the trajectory of cognitive decline associated with Alzheimer's disease.

Assessment of metastatic lymph nodes in head and neck squamous cell carcinomas using simultaneous 18F-FDG-PET and MRI.

In this study, we investigate the feasibility of using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), diffusion weighted imaging (DWI), and dynamic positron emission tomography (PET) for detection of metastatic lymph nodes in head and neck squamous cell carcinoma (HNSCC) cases. Twenty HNSCC patients scheduled for lymph node dissection underwent DCE-MRI, dynamic PET, and DWI using a PET-MR scanner within one week prior to their planned surgery. During surgery, resected nodes were labeled to identify their nodal levels and sent for routine clinical pathology evaluation. Quantitative parameters of metastatic and normal nodes were calculated from DCE-MRI (ve, vp, PS, Fp, Ktrans), DWI (ADC) and PET (Ki, K1, k2, k3) to assess if an individual or a combination of parameters can classify normal and metastatic lymph nodes accurately. There were 38 normal and 11 metastatic nodes covered by all three imaging methods and confirmed by pathology. 34% of all normal nodes had volumes greater than or equal to the smallest metastatic node while 4 normal nodes had SUV > 4.5. Among the MRI parameters, the median vp, Fp, PS, and Ktrans values of the metastatic lymph nodes were significantly lower (p = <0.05) than those of normal nodes. ve and ADC did not show any statistical significance. For the dynamic PET parameters, the metastatic nodes had significantly higher k3 (p value = 8.8 × 10-8) and Ki (p value = 5.3 × 10-8) than normal nodes. K1 and k2 did not show any statistically significant difference. Ki had the best separation with accuracy = 0.96 (sensitivity = 1, specificity = 0.95) using a cutoff of Ki = 5.3 × 10-3 mL/cm3/min, while k3 and volume had accuracy of 0.94 (sensitivity = 0.82, specificity = 0.97) and 0.90 (sensitivity = 0.64, specificity = 0.97) respectively. 100% accuracy can be achieved using a multivariate logistic regression model of MRI parameters after thresholding the data with Ki < 5.3 × 10-3 mL/cm3/min. The results of this preliminary study suggest that quantitative MRI may provide additional value in distinguishing metastatic nodes, particularly among small nodes, when used together with FDG-PET.

Relationship of estrogen synthesis capacity in the brain with obesity and self-control in men and women.

Gonadal hormones are linked to mechanisms that govern appetitive behavior and its suppression. Estrogens are synthesized from androgens by the enzyme aromatase, highly expressed in the ovaries of reproductive-aged women and in the brains of men and women of all ages. We measured aromatase availability in the amygdala using positron emission tomography (PET) with the aromatase inhibitor [11C]vorozole in a sample of 43 adult, normal-weight, overweight, or obese men and women. A subsample of 27 also completed personality measures to examine the relationship between aromatase and personality traits related to self-regulation and inhibitory control. Results indicated that aromatase availability in the amygdala was negatively associated with body mass index (BMI) (in kilograms per square meter) and positively correlated with scores of the personality trait constraint independent of sex or age. Individual variations in the brain's capacity to synthesize estrogen may influence the risk of obesity and self-control in men and women.

Expectation effects on brain dopamine responses to methylphenidate in cocaine use disorder.

The response to drugs of abuse is affected by expectation, which is modulated in part by dopamine (DA), which encodes for a reward prediction error. Here we assessed the effect of expectation on methylphenidate (MP)-induced striatal DA changes in 23 participants with an active cocaine use disorder (CUD) and 23 healthy controls (HC) using [11C]raclopride and PET both after placebo (PL) and after MP (0.5 mg/kg, i.v.). Brain dopamine D2 and D3 receptor availability (D2R: non-displaceable binding potential (BPND)) was measured under four conditions in randomized order: (1) expecting PL/receiving PL, (2) expecting PL/receiving MP, (3) expecting MP/receiving PL, and (4) expecting MP/receiving MP. Expecting MP increased pulse rate compared to expecting PL. Receiving MP decreased D2R in striatum compared to PL, indicating MP-induced striatal DA release, and this effect was significantly blunted in CUD versus HC consistent with prior findings of decreased striatal dopamine responses both in active and detoxified CUD. There was a group × challenge × expectation effect in caudate and midbrain, with expectation of MP increasing MP-induced DA release in HC but not in CUD, and expectation of PL showing a trend to increase MP-induced DA release in CUD but not in HC. These results are consistent with the role of DA in reward prediction error in the human brain: decreasing DA signaling when rewards are less than expected (blunted DA increases to MP in CUD) and increasing them when greater than expected (for PL in CUD reflecting conditioned responses to injection). Our findings also document disruption of the expectation of drug effects in dopamine signaling in participants with CUD compared to non-addicted individuals.

Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.

BACKGROUND AND PURPOSE: Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [11 C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials. METHODS: The sample consisted of 20 participants with PD and 19 HVs. Two independent teams analyzed the data to compare the volume of distribution calculated using image-derived input functions (IDIFs), and binding potentials calculated using the Logan reference region model. RESULTS: With all methods, the higher signal-to-background in patients resulted in lower variability and better repeatability than in controls. We were able to use noninvasive techniques showing significantly increased uptake of PK in multiple brain regions of participants with PD compared to HVs. CONCLUSION: Although not necessarily reflecting absolute values, these noninvasive image analysis methods can discriminate between PD patients and HVs. We see a difference of 24% in the substantia nigra between PD and HV with a repeatability coefficient of 13%, showing that it will be possible to estimate responses in longitudinal, within subject trials of novel neuroprotective drugs.

The rationale for a role for diet and nutrition in the prevention and treatment of cancer.

There is considerable evidence to support dietary recommendations for prevention of cancer as well as for patients undergoing or recovering from cancer treatment. We consider here implications from human, animal and in-vitro studies of the effects of dietary factors (macronutrients and micronutrients-phytochemicals) on cancer. An important epidemiology study, the China Project found a significant correlation between disease incidence and markers of animal product consumption. Evidence of the role of animal protein in the promotion of cancer also comes from animal studies. Food restriction has been shown in human and animal studies to slow cancer progression. Phytochemicals from whole plant foods are protective against oxidative stress, inhibit cell proliferation, induce cell-cycle arrest, and apoptosis, act as antiangiogenesis factors, and inhibit cyclooxygenase-2, which has been related to metastasis. Some mechanisms that mediate the effect of diet on cancer involve cell signaling through insulin factors and mammalian target of rapamycin, a nutrient sensing complex related to growth, altered gene expression through epigenetics, and the effects of microbial metabolites produced by the gut microbiota that is strongly influenced by dietary factors. The evidence accumulating for many years indicates that diet, what we eat every day, can affect disease. Besides preventing the development of cancer, this could also be harnessed to positively influence treatment outcomes as well as prevent recurrence. As research strategies developed for drug studies are not appropriate, it is important that new methodologies be developed to study these effects.

On the potential for RF heating in MRI to affect metabolic rates and 18 FDG signal in PET/MR: simulations of long-duration, maximum normal mode heating.

PURPOSE: To examine the possibility that MR-induced RF power deposition (SAR) and the resulting effects on temperature-dependent metabolic rates or perfusion rates might affect observed 18FDG signal in PET/MR. METHODS: Using numerical simulations of the SAR, consequent temperature increase, effect on rates of metabolism or perfusion, and [18FDG] throughout the body, we simulated the potential effect of maximum-allowable whole-body SAR for the entire duration of an hour-long PET/MR scan on observed PET signal for two different 18FDG injection times: one hour before onset of imaging and concurrent with the beginning of imaging. This was all repeated three times with the head, the heart, and the abdomen (kidneys) at the center of the RF coil. RESULTS: Qualitatively, little effect of MR-induced heating is observed on simulated PET images. Maximum relative increases in PET signal (26% and 31% increase, respectively, for the uptake models based on metabolism and the perfusion) occur in regions of low baseline metabolic rate (also associated with low perfusion and, thus, greater potential temperature increase due to high local SAR), such that PET signal in these areas remains comparatively low. Maximum relative increases in regions of high metabolic rate (and also high perfusion: heart, thyroid, brain, etc.) are affected mostly by the relatively small increase in core body temperature and thus are not affected greatly (10% maximum increase). CONCLUSIONS: Even for worst-case heating, little effect of MR-induced heating is expected on 18FDG PET images during PET/MR for many clinically relevant applications. For quantitative, dynamic MR/PET studies requiring high SAR for extended periods, it is hoped that methods like those introduced here can help account for such potential effects in design of a given study, including selection of reference locations that should not experience notable increase in temperature.

The Effect of Body Posture on Brain Glymphatic Transport.

The glymphatic pathway expedites clearance of waste, including soluble amyloid ß (Aß) from the brain. Transport through this pathway is controlled by the brain's arousal level because, during sleep or anesthesia, the brain's interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency. We used dynamic-contrast-enhanced MRI and kinetic modeling to quantify CSF-ISF exchange rates in anesthetized rodents' brains in supine, prone, or lateral positions. To validate the MRI data and to assess specifically the influence of body posture on clearance of Aß, we used fluorescence microscopy and radioactive tracers, respectively. The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position, in which the rat's head was in the most upright position (mimicking posture during the awake state), transport was characterized by "retention" of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels. The optical imaging and radiotracer studies confirmed that glymphatic transport and Aß clearance were superior in the lateral and supine positions. We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans. SIGNIFICANCE STATEMENT: The rodent brain removes waste better during sleep or anesthesia compared with the awake state. Animals exhibit different body posture during the awake and sleep states, which might affect the brain's waste removal efficiency. We investigated the influence of body posture on brainwide transport of inert tracers of anesthetized rodents. The major finding of our study was that waste, including Aß, removal was most efficient in the lateral position (compared with the prone position), which mimics the natural resting/sleeping position of rodents. Although our finding awaits testing in humans, we speculate that the lateral position during sleep has advantage with regard to the removal of waste products including Aß, because clinical studies have shown that sleep drives Aß clearance from the brain.

Recovery of dopamine transporters with methamphetamine detoxification is not linked to changes in dopamine release.

Methamphetamine's widepread abuse and concerns that it might increase Parkinson's disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [(11)C]cocaine to measure DAT, and with [(11)C]raclopride to measure dopamine release (assessed as changes in specific binding of [(11)C]raclopride between placebo and methylphenidate), which was used as a marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when compared to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.

Kinetic Analysis and Quantification of [¹¹C]Martinostat for in Vivo HDAC Imaging of the Brain.

Epigenetic mechanisms mediated by histone deacetylases (HDACs) have been implicated in a wide-range of CNS disorders and may offer new therapeutic opportunities. In vivo evaluation of HDAC density and drug occupancy has become possible with [(11)C]Martinostat, which exhibits selectivity for a subset of class I/IIb HDAC enzymes. In this study, we characterize the kinetic properties of [(11)C]Martinostat in the nonhuman primate (NHP) brain in preparation for human neuroimaging studies. The goal of this work was to determine whether classic compartmental analysis techniques were appropriate and to further determine if arterial plasma is required for future NHP studies. Using an arterial plasma input function, several analysis approaches were evaluated for robust outcome measurements. [(11)C]Martinostat showed high baseline distribution volume (VT) ranging from 29.9 to 54.4 mL/cm(3) in the brain and large changes in occupancy (up to 99%) with a blocking dose approaching full enzyme saturation. An averaged nondisplaceable tissue uptake (VND) of 8.6 ± 3.7 mL/cm(3) suggests high specific binding of [(11)C]Martinostat. From a two-tissue compartment model, [(11)C]Martinostat exhibits a high K1 (averaged K1 of 0.65 mL/cm(3)/min) and a small k4 (average of 0.0085 min(-1)). Our study supports that [(11)C]Martinostat can be used to detect changes in HDAC density and occupancy in vivo and that simplified analysis not using arterial blood could be appropriate.

Aromatase imaging with [N-methyl-11C]vorozole PET in healthy men and women.

UNLABELLED: Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aimed to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathologic situations can be studied. METHODS: (11)C-vorozole (111-296 MBq/subject) was injected intravenously in 13 men and 20 women (age range, 23-67 y). PET data were acquired over a 90-min period. Each subject had 4 scans, 2 per day separated by 2-6 wk, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned after pretreatment with a clinical dose of the aromatase inhibitor letrozole. Time-activity curves were obtained, and standardized uptake values (SUV) were calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone, and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole-body radiation exposures were calculated using OLINDA software. RESULTS: Liver uptake was higher than uptake in any other organ but was not blocked by pretreatment with letrozole. Mean SUVs were higher in men than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than SUVs in any other organ (ranging from 0.48 ± 0.05 in lungs to 1.5 ± 0.13 in kidneys). Mean ovarian SUVs (3.08 ± 0.7) were comparable to brain levels and higher than in any other organ. Furthermore, ovarian SUVs in young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, whereas aging and cigarette smoking reduced (11)C-vorozole uptake. CONCLUSION: PET with (11)C-vorozole is useful for assessing physiologic changes in estrogen synthesis capacity in the human body. Baseline levels in breasts, lungs, and bones are low, supporting further investigation of this tracer as a new tool for detection of aromatase-overexpressing primary tumors or metastases in these organs and optimization of treatment in cancer and other disorders in which aromatase inhibitors are useful.

Monoamine oxidase: radiotracer chemistry and human studies.

Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serotonin, norepinephrine, and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson's disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 years since the first radiotracers were developed and the first positron emission tomography (PET) images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variables that have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe the following: (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological, and psychiatric disorders; and (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers that are currently used and possible new applications.

Quantitative graphical analysis of simultaneous dynamic PET/MRI for assessment of prostate cancer.

PURPOSE: Dynamic FDG imaging for prostate cancer characterization is limited by generally small size and low uptake in prostate tumors. Our aim in this pilot study was to explore feasibility of simultaneous PET/MRI to guide localization of prostate lesions for dynamic FDG analysis using a graphical approach. METHODS: Three patients with biopsy-proven prostate cancer underwent simultaneous FDG PET/MRI, incorporating dynamic prostate imaging. Histology and multiparametric MRI findings were used to localize tumors, which in turn guided identification of tumors on FDG images. Regions of interest were manually placed on tumor and benign prostate tissue. Blood activity was extracted from a region of interest placed on the femoral artery on PET images. FDG data were analyzed by graphical analysis using the influx constant Ki (Patlak analysis) when FDG binding seemed irreversible and distribution volume VT (reversible graphical analysis) when FDG binding seemed reversible given the presence of washout. RESULTS: Given inherent coregistration, simultaneous acquisition facilitated use of MRI data to localize small lesions on PET and subsequent graphical analysis in all cases. In 2 cases with irreversible binding, tumor had higher Ki than benign using Patlak analysis (0.023 vs 0.006 and 0.019 vs 0.008 mL/cm3 per minute). In 1 case appearing reversible, tumor had higher VT than benign using reversible graphical analysis (0.68 vs 0.52 mL/cm3). CONCLUSIONS: Simultaneous PET/MRI allows localization of small prostate tumors for dynamic PET analysis. By taking advantage of inclusion of the femoral arteries in the FOV, we applied advanced PET data analysis methods beyond conventional static measures and without blood sampling.

Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors.

Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and Positron emission tomography in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal, and premotor cortices and insula and disengaged cuneus and default mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. These findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues.

Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain.

Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson's disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared with equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using positron emission tomography and the MAO-A radiotracer [(11)C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11-70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9-68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.

A pilot study of the value of 18F-fluoro-deoxy-thymidine PET/CT in predicting viable lymphoma in residual 18F-FDG avid masses after completion of therapy.

BACKGROUND: Despite its success in diagnosing and staging lymphoma, F-FDG PET/CT can be falsely positive in areas of posttreatment inflammation. 3'-F-fluoro-3'-deoxy-l-thymidine (F-FLT) is a structural analog of the DNA constituent thymidine; its uptake correlates with cellular proliferation. This pilot study evaluates the ability of F-FLT PET/CT to distinguish viable lymphoma from posttreatment inflammatory changes in F-FDG avid residual masses. METHODS: Twenty-one patients with lymphoma with at least 1 F-FDG avid residual mass after therapy underwent F-FLT PET/CT imaging. F-FDG and F-FLT uptake values were compared, including quantitative pharmacokinetic parameters extracted from the F-FLT time activity curves generated from dynamic data using graphical and nonlinear compartmental modeling. RESULTS: The true nature of the residual mass was confirmed by biopsy in 12 patients (8 positive and 4 negative for viable lymphoma and by follow-up CT and/or repeat F-FDG PET/CT imaging over 1 year); among the remaining 9 patients, 7 lesions resolved or decreased and 2 showed growth indicative of lymphoma. F-FLT PET SUVest.max was significantly higher in tumors than in benign lesions (5.5 [2.2] vs 1.7 [0.6]; P < 0.0001), whereas the difference in F-FDG SUVs was not significant (malignant, 7.8 [3.8] vs benign, 5.4 [2.4]; P = 0.11). All of the benign lesions had an F-FLT SUVest.max of less than 3.0. CONCLUSIONS: F-FLT shows improved specificity over F-FDG in distinguishing residual lymphoma from posttreatment inflammation and may be useful in the evaluation of patients with residual F-FDG-positive masses after completing therapy.

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity.

Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [(11)C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [(11)C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BPND)] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BPND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.

BMI modulates calorie-dependent dopamine changes in accumbens from glucose intake.

OBJECTIVE: Dopamine mediates the rewarding effects of food that can lead to overeating and obesity, which then trigger metabolic neuroadaptations that further perpetuate excessive food consumption. We tested the hypothesis that the dopamine response to calorie intake (independent of palatability) in striatal brain regions is attenuated with increases in weight. METHOD: We used positron emission tomography with [11C]raclopride to measure dopamine changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose) devoid of calories to that of glucose to assess their association with body mass index (BMI) in nineteen healthy participants (BMI range 21-35). RESULTS: Neither the measured blood glucose concentrations prior to the sucralose and the glucose challenge days, nor the glucose concentrations following the glucose challenge vary as a function of BMI. In contrast the dopamine changes in ventral striatum (assessed as changes in non-displaceable binding potential of [11C]raclopride) triggered by calorie intake (contrast glucose - sucralose) were significantly correlated with BMI (r = 0.68) indicating opposite responses in lean than in obese individuals. Specifically whereas in normal weight individuals (BMI <25) consumption of calories was associated with increases in dopamine in the ventral striatum in obese individuals it was associated with decreases in dopamine. CONCLUSION: These findings show reduced dopamine release in ventral striatum with calorie consumption in obese subjects, which might contribute to their excessive food intake to compensate for the deficit between the expected and the actual response to food consumption.

Kinetic analysis of [11C]vorozole binding in the human brain with positron emission tomography.

Using positron emission tomography, we investigated the kinetics of [11C]vorozole ([11C]VOR), a radiotracer for the enzyme aromatase that catalyzes the last step in estrogen biosynthesis. Six subjects were scanned under baseline conditions followed by retest 2 weeks later. The retest was followed by a blocking study with 2.5 mg of the aromatase inhibitor letrozole. The binding potential (BP(A)ND) was estimated from a Lassen plot using the total tissue distribution volume (VT) for baseline and blocked. for the thalamus was found to be 15 times higher than that for the cerebellum. From the letrozole studies, we found that [11C]VOR exhibits a slow binding compartment (small k4) that has a nonspecific and a blockable component. Because of the sensitivity of VT to variations in k4, a common value was used for the four highest binding regions. We also considered the tissue uptake to plasma ratio for 60 to 90 minutes as an outcome measure. Using the ratio method, the difference between the highest and lowest was 2.4 compared to 3.5 for the VT. The ratio method underestimates the high regions but is less variable and may be more suitable for patient studies. Because of its kinetics and distribution, this tracer is not a candidate for a bolus infusion or reference tissue methods.