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.