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The purpose of this study was to evaluate the consistency of 3'-deoxy-3'[(18)F]fluorothymidine (FLT) standardized uptake values (SUVs) over the time course of imaging in head and neck cancer. Thirteen (13) subjects (all male; age: 56.9 +/- 6.7 years) with squamous cell head and neck cancer, stage III/IV, were administered FLT and imaged dynamically for 1 hour over the tumor and then underwent whole-body (WB) imaging commencing at 74 +/- 6 minutes. Imaging was repeated after 5 days of radiotherapy (10 Gy) and a single course of platinum-based chemotherapy. Volumes-of-interest (VOIs) were created on the last dynamic frame (SUV(60)). The pretherapy WB and midtherapy images were coregistered to the dynamic sequence and VOIs were applied. Mean and maximum SUVs (SUV(60) and SUV(WB)) and the change with treatment were evaluated. The correlations (Spearman's rho) between SUV(60) and SUV(WB) for all VOIs (pre- and midtherapy, n = 108 data pairs) were 0.98 for mean and 0.97 for maximum SUVs (p < 0.0001). Average absolute differences between SUV(60) and SUV(WB) were 0.18 +/- 0.15 and 0.29 +/- 0.32 SUV units, respectively. Correlations (Spearman's rho) between the change in SUV with therapy were 0.90 for mean and 0.89 for maximum SUV (p < 0.0001), with differences in the change values averaging 0.03 +/- 0.36 and -0.17 +/- 0.57 units, respectively. FLT SUVs are stable and comparable for images initiated between 55 and 100 minutes postinjection whether acquired pre- or midtherapy in head and neck cancer. [ABSTRACT FROM AUTHOR]

Objective: Extraversion, a trait associated with individual differences in approach motivation and the experience of positive emotional states, is negatively correlated with certain psychiatric disorders, including depression and social phobia. The authors examined the correlation between extraversion and regional cerebral blood flow (rCBF) while participants were exposed to olfactory stimuli in order to further characterize individual differences in hedonic processing associated with this trait. Method: Twelve healthy participants were exposed to pleasant and unpleasant odors while rCBF was measured using [(15)O] water PET. The NEO Five-Factor Inventory was used to assess extraversion. Associations between extraversion scores and rCBF in each olfactory stimulus condition were assessed by correlational analysis. Results: During the pleasant smell condition, extraversion was correlated with rCBF in the amygdala and occipital cortex. During the unpleasant smell condition, extraversion was correlated with rCBF in the occipital cortex and inferior temporal gyrus. Conclusions: These results provide important evidence for the biological basis of extraversion and indicate that there are systematic individual differences in patterns of brain activation in response to affective stimuli. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to quantify the relationship of bone marrow response to radiation dose, using 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT)-labeled uptake quantified in positron-emission tomography (PET) scans.Methods and Materials: Pre- and post-Week 1 treatment [(18)F]FLT PET images were registered to the CT images used to create the radiation treatment plan. Changes in [(18)F]FLT uptake values were measured using profile data of standardized uptake values (SUVs) and doses along the vertebral bodies located at a field border where a range of radiation doses were present for 10 patients. Data from the profile measurements were grouped into 1 Gy dose bins from 1 to 9 Gy to compare SUV changes for all patients. Additionally, the maximum pretreatment, the post-Week 1 treatment, and the dose values located within the C6-T7 vertebrae that straddled the field edge were measured for all patients.Results: Both the profile and the individual vertebral data showed a strong correlation between SUV change and radiation dose. Relative differences in SUVs between bins >1 Gy and <7 Gy were statistically significant (p < 0.01, two-sample t test). The reduction in SUV was approximately linear until it reached a reduction threshold of 75%-80% in SUV for doses greater than 6 Gy/week for both the dose-binned data and the vertebral maximum SUVs.Conclusions: The change in SUV observed in head and neck cancer patients treated with chemoradiation shows the potential for using [(18)F]FLT PET images for identifying active bone marrow and monitoring changes due to radiation dose. Additionally, the change in [(18)F]FLT uptake observed in bone marrow for different weekly doses suggests potential dose thresholds for reducing bone marrow toxicity. [ABSTRACT FROM AUTHOR]

Post-COVID-19 syndrome (PCS) fatigue is typically most severe <6 months post-infection. Combining magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging with the glucose analog [ 18 F]-Fluorodeoxyglucose (FDG) provides a comprehensive overview of the effects of PCS on regional brain volumes and metabolism, respectively. The primary purpose of this exploratory study was to investigate differences in MRI/PET outcomes between people < 6 months (N = 18, 11 female) and > 6 months (N = 15, 6 female) after COVID-19. The secondary purpose was to assess if any differences in MRI/PET outcomes were associated with fatigue symptoms. Subjects > 6 months showed smaller volumes in the putamen, pallidum, and thalamus compared to subjects < 6 months. In subjects > 6 months, fatigued subjects had smaller volumes in frontal areas compared to non-fatigued subjects. Moreover, worse fatigue was associated with smaller volumes in several frontal areas in subjects > 6 months. The results revealed no brain metabolism differences between subjects > 6 and < 6 months. However, both groups exhibited both regional hypo- and hypermetabolism compared to a normative database. These results suggest that PCS may alter regional brain volumes but not metabolism in people > 6 months, particularly those experiencing fatigue symptoms.

Common symptoms of multiple sclerosis (MS) include motor impairments of the lower extremities, particularly gait disturbances. Loss of balance and muscle weakness, representing some peripheral effects, have been shown to influence these symptoms, however, the individual role of cortical and subcortical structures in the central nervous system is still to be understood. Assessing [ 18 F]fluorodeoxyglucose (FDG) uptake in the CNS can assess brain activity and is directly associated with regional neuronal activity. One potential modality to increase cortical excitability and improve motor function in patients with MS (PwMS) is transcranial direct current stimulation (tDCS). However, tDCS group outcomes may not mirror individual subject responses, which impedes our knowledge of the pathophysiology and management of diseases like MS. Three PwMS randomly received both 3 mA tDCS and SHAM targeting the motor cortex (M1) that controls the more-affected leg for 20 min on separate days before walking on a treadmill. The radiotracer, FDG, was injected at minute two of the 20 min walk and the subjects underwent a Positron emission tomography (PET) scan immediately after the task. Differences in relative regional metabolism of areas under the tDCS anode and the basal ganglia were calculated and investigated. The results indicated diverse and individualized responses in regions under the anode and consistent increases in some basal ganglia areas (e.g., caudate nucleus). Thus, anodal tDCS targeting the M1 that controls the more-affected leg of PwMS might be capable of affecting remote subcortical regions and modulating the activity (motor, cognitive, and behavioral functions) of the circuitry connected to these regions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rudroff, Fietsam, Deters, Workman and Boles Ponto.)

Neurodegenerative diseases (NDDs) are characterized by progressive neuronal loss, leading to dementia and movement disorders. NDDs broadly include Alzheimer's disease, frontotemporal lobar degeneration, parkinsonian syndromes, and prion diseases. There is an ever-increasing prevalence of mild cognitive impairment and dementia, with an accompanying immense economic impact, prompting efforts aimed at early identification and effective interventions. Neuroimaging is an essential tool for the early diagnosis of NDDs in both clinical and research settings. Structural, functional, and metabolic imaging modalities, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are widely available. They show encouraging results for diagnosis, monitoring, and treatment response evaluation. The current review focuses on the complementary role of various imaging modalities in relation to NDDs, the qualitative and quantitative utility of newer MRI techniques, novel radiopharmaceuticals, and integrated PET/MRI in the setting of NDDs.

Objective: The pathological cascades associated with the development of Alzheimer's disease (AD) have a common element: acidosis. T 1 rho MRI is a pH-sensitive measure, with higher values associated with greater neuropathological burden. The authors investigated the relationship between T 1 rho imaging and AD-associated pathologies as determined by available diagnostic imaging techniques., Methods: Twenty-seven participants (men, N=13, women, N=14; ages 55-90) across the cognitive spectrum (healthy control subjects [HCs] with normal cognition, N=17; participants with mild cognitive impairment [MCI], N=7; participants with mild AD, N=3) underwent neuropsychological testing, MRI (T 1 -weighted and T 1 rho [spin-lattice relaxation time in the rotating frame]), and positron emission tomography imaging ([ 11 C]Pittsburg compound B for amyloid burden [N=26] and [ 18 F]fluorodeoxyglucose for cerebral glucose metabolism [N=12]). The relationships between global T 1 rho values and neuropsychological, demographic, and imaging measures were explored., Results: Global mean and median T 1 rho were positively associated with age. After controlling for age, higher global T 1 rho was associated with poorer cognitive function, poorer memory function (immediate and delayed memory scores), higher amyloid burden, and more abnormal cerebral glucose metabolism. Regional T 1 rho values, when controlling for age, significantly differed between HCs and participants with MCI or AD in select frontal, cingulate, and parietal regions., Conclusions: Higher T 1 rho values were associated with greater cognitive impairment and pathological burden. T 1 rho, a biomarker that varies according to a feature common to each cascade rather than one that is unique to a particular pathology, has the potential to serve as a metric of neuropathology, theoretically providing a measure for assessing pathological status and for monitoring the neurodegeneration trajectory.

This exploratory pilot study investigated the effects of chronic Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on cerebral glucose metabolism in people with multiple sclerosis (PwMS). Compared with nonusers, THC users had hypermetabolism of 3 regions ( p < 0.039, d >1.17) in left temporal areas, while CBD users had hypometabolism of 5 regions ( p < 0.032, d > 1.31) in left temporal areas. This study highlights the need to discriminate between THC and CBD in future cannabis studies. Novelty Chronic THC and CBD use had disparate effects on cerebral glucose metabolism in PwMS.

Radiomics is an image analysis approach for extracting large amounts of quantitative information from medical images using a variety of computational methods. Our goal was to evaluate the utility of radiomic feature analysis from 18 F-fluorothymidine positron emission tomography (FLT PET) obtained at baseline in prediction of treatment response in patients with head and neck cancer. Thirty patients with advanced-stage oropharyngeal or laryngeal cancer, treated with definitive chemoradiation therapy, underwent FLT PET imaging before treatment. In total, 377 radiomic features of FLT uptake and feature variants were extracted from volumes of interest; these features variants were defined by either the primary tumor or the total lesion burden, which consisted of the primary tumor and all FLT-avid nodes. Feature variants included normalized measurements of uptake, which were calculated by dividing lesion uptake values by the mean uptake value in the bone marrow. Feature reduction was performed using clustering to remove redundancy, leaving 172 representative features. Effects of these features on progression-free survival were modeled with Cox regression and P -values corrected for multiple comparisons. In total, 9 features were considered significant. Our results suggest that smaller, more homogenous lesions at baseline were associated with better prognosis. In addition, features extracted from total lesion burden had a higher concordance index than primary tumor features for 8 of the 9 significant features. Furthermore, total lesion burden features showed lower interobserver variability.

Greater aortic stiffness and pulse pressure are associated with cerebrovascular remodeling, reduced white matter microstructure, and cognitive performance with aging in humans. However, it is unclear whether aortic stiffness and pulse pressure are associated with reduced basal global cerebral blood flow (CBF) and cerebrovascular reserve among older adults. Global CBF was quantified in 205 adults (range, 19-87 years; mean±SE: 30.6±1.3 years) using quantitative [ 15 O]water brain positron emission tomography imaging. In a subset of older adults (n=24; 70.0±2.0 years), aortic stiffness (carotid femoral pulse wave velocity) and cerebrovascular reserve (change in global CBF after intravenous infusion of acetazolamide) were assessed. In the entire cohort, global CBF was lower in older compared with young adults (36.5±1.1 versus 50.5±0.7 mL/min per 100 mL; P <0.001). Global CBF was higher in young women compared with young men (51.0±0.30 versus 47.4±0.03 mL/min per 100 mL; P <0.001) but did not differ between older women and men ( P =0.63). In older adults, greater carotid femoral pulse wave velocity was associated with lower cerebrovascular reserve ( r =-0.68; P =0.001 adjusted for age, sex, and mean arterial pressure) but not global CBF ( r =0.13; P =0.60). Brachial pulse pressure was not associated with lower cerebrovascular reserve ( r =-0.37; P =0.159) when adjusted for age and sex. These data indicate that the age-related increases in aortic stiffness may contribute, in part, to the brain's impaired ability to augment blood flow in response to a stimulus with aging in humans., (© 2018 American Heart Association, Inc.)

The medical use of marijuana is increasing, yet little is known about the exposure-response relationship for its psychoactive effects. It is well known that the plasma concentrations of the principal psychoactive component of marijuana, Δ 9 -tetrahydrocannabinol (THC), do not directly correlate to the observed psychoactive effects. The purpose of this research was to use an effect-compartment modeling approach to predict and relate the concentrations of the psychoactive components (THC and its active metabolite) in the "hypothetical" effect-site compartment to the observed psychoactive effects. A "hypothetical" effect-compartment model was developed using literature data to characterize the observed delay in peak "highness" ratings compared with plasma concentrations of the psychoactive agents following intravenous administration of THC. A direct relationship was established between the reported psychoactive effects ("highness" or intoxication) and the predicted effect-site concentrations of THC. The differences between estimated equilibration half-lives for THC and THC-OH in the effect-compartment model indicated the differential equilibration of parent drug and the active metabolite between plasma and the effect-site. These models contribute to the understanding of the pharmacokinetic-pharmacodynamic relationships associated with marijuana use and are important steps in the prediction of pharmacodynamic effects related to the psychoactive components in marijuana., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to determine whether preoperative [ 18 F]fludeoxyglucose (FDG)-positron emission tomography (PET) asymmetry in temporal lobe metabolism predicts neuropsychological and seizure outcomes after temporal lobectomy (TL)., Methods: An archival sample of 47 adults with unilateral temporal lobe epilepsy who underwent TL of their language-dominant (29 left, 1 right) or nondominant (17 right) hemisphere were administered neuropsychological measures pre- and postoperatively. Post-TL seizure outcomes were measured at 1year. Regional FDG uptake values were defined by an automated technique, and a quantitative asymmetry index (AI) was calculated to represent the relative difference in the FDG uptake in the epileptic relative to the nonepileptic temporal lobe for four regions of interest: medial anterior temporal (MAT), lateral anterior temporal (LAT), medial posterior temporal (MPT), and lateral posterior temporal (LPT) cortices., Results: In language-dominant TL, naming outcomes were predicted by FDG uptake asymmetry in the MAT (r=-0.38) and LPT (r=-0.45) regions. For all patients, visual search and motor speed outcomes were predicted by FDG uptake asymmetry in all temporal regions (MPT, r=0.42; MAT, r=0.34; LPT, r=0.47; LAT, r=0.51). Seizure outcomes were predicted by FDG uptake asymmetry in the MAT (r=0.36) and MPT (r=0.30) regions. In all of these significant associations, greater hypometabolism in regions of the epileptic temporal lobe was associated with better postoperative outcomes., Conclusions: Our results support the conclusion that FDG uptake asymmetry is a useful clinical tool in assessing risk for cognitive changes in patients being considered for TL., (Published by Elsevier Inc.)

The brain-specific isoform of renin (Ren-b) has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-b Null mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-b Null mice are unknown. Fluid intake was similar in control and Ren-b Null mice at baseline and both exhibited an equivalent dipsogenic response to deoxycorticosterone acetate-salt. Dehydration promoted increased water intake in Ren-b Null mice, particularly after deoxycorticosterone acetate-salt. Ren-b Null and control mice exhibited similar body weight when fed a chow diet. However, when fed a high-fat diet, male Ren-b Null mice gained significantly less weight than control mice, an effect blunted in females. This difference was not because of changes in food intake, energy absorption, or physical activity. Ren-b Null mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue, suggesting increased thermogenesis. Ren-b Null mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased brown adipose tissue glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS., (© 2017 American Heart Association, Inc.)

Purpose: The purpose of the present prospective clinical trial was to determine the efficacy of [(18)F]fluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the FLT uptake change during and after chemoradiation therapy with hematologic toxicity., Methods and Materials: Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose response of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity., Results: IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P<.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P<.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received >35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P<.05, paired t test)., Conclusions: IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses >35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This study aimed to examine global and regional cerebral blood flow and amyloid burden in combat veterans with and without traumatic brain injury (TBI). Cerebral blood flow (in milliliters per minute per 100 mL) was measured by quantitative [(15)O]water, and amyloid burden was measured by [(11)C]PIB imaging. Mean global cerebral blood flow was significantly lower in veterans with TBI compared with non-TBI veterans. There were essentially no differences between groups for globally normalized regional cerebral blood flow. Amyloid burden did not differ between TBI and non-TBI veterans. Veterans who have suffered a TBI have significantly lower cerebral blood flow than non-TBI controls but did not manifest increased levels of amyloid, globally or regionally.

Pharmacological ascorbate (AscH(-)) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells compared with normal cells. Positron emission tomography (PET) with the thymidine analog 3'-deoxy-3'-((18)F) fluorothymidine (FLT) enables noninvasive imaging and quantification of the proliferation fraction of tumors. We hypothesized that the rate of tumor proliferation determined by FLT-PET imaging, would be inversely proportional to tumor susceptibility to pharmacological AscH(-)-based treatments. Indeed, there was decreased FLT uptake in human pancreatic cancer cells treated with AscH(-) in vitro, and this effect was abrogated by co-treatment with catalase. In separate experiments, cells were treated with AscH(-), ionizing radiation or a combination of both. These studies demonstrated that combined AscH(-) and radiation treatment resulted in a significant decrease in FLT uptake that directly correlated with decreased clonogenic survival. MicroPET (18)F-FLT scans of mice with pre-established tumors demonstrated that AscH(-) treatment induced radiosensitization compared to radiation treatment alone. These data support testing of pharmacological ascorbate as a radiosensitizer in pancreatic cancer as well as the use of FLT-PET to monitor response to therapy.

Melanocortin 4 receptor (MC4R) signaling mediates diverse physiological functions, including energy balance, glucose homeostasis, and autonomic activity. Although the lateral hypothalamic area (LHA) is known to express MC4Rs and to receive input from leptin-responsive arcuate proopiomelanocortin neurons, the physiological functions of MC4Rs in the LHA are incompletely understood. We report that MC4R(LHA) signaling regulates glucose tolerance and sympathetic nerve activity. Restoring expression of MC4Rs specifically in the LHA improves glucose intolerance in obese MC4R-null mice without affecting body weight or circulating insulin levels. Fluorodeoxyglucose-mediated tracing of whole-body glucose uptake identifies the interscapular brown adipose tissue (iBAT) as a primary source where glucose uptake is increased in MC4R(LHA) mice. Direct multifiber sympathetic nerve recording further reveals that sympathetic traffic to iBAT is significantly increased in MC4R(LHA) mice, which accompanies a significant elevation of Glut4 expression in iBAT. Finally, bilateral iBAT denervation prevents the glucoregulatory effect of MC4R(LHA) signaling. These results identify a novel role for MC4R(LHA) signaling in the control of sympathetic nerve activity and glucose tolerance independent of energy balance., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Purpose: The term "chemobrain" is sometimes used to denote deficits in neuropsychological functioning that may occur as a result of cancer treatment. As breast cancer survivors now commonly reach late life, it is not known whether previous exposure to chemotherapy may affect long-term risk for cognitive impairment. To help address this concern, this study tested whether successfully surviving chemotherapy earlier in life was associated with later differences in brain metabolic function as an older adult compared to controls. This question was examined using positron emission tomography measures of brain glucose metabolism in elderly women cancer survivors., Methods: Breast cancer survivors (N = 10), currently free of recurrent cancer and without a diagnosis of a cognitive disorder, were compared to matched healthy controls (N = 10). All subjects were imaged at rest with [(18)F]fluorodeoxyglucose. Images were analyzed semi-quantitatively using the Alzheimer's Discrimination Tool and a volume of interest-based approach derived from co-registered magnetic resonance imaging., Results: Relative [(18)F]fluorodeoxyglucose uptake (normalized to global) was significantly lower in the survivors compared with control subjects in bilateral orbital frontal regions, consistent with differences between the groups in cognition and executive function (i.e., Trail Making Test, Part B and mini-mental state examination) and despite no significant differences with respect to age, education, intelligence, or working memory. None of the survivors and only one control manifested a global positron emission tomography score consistent with an Alzheimer's disease metabolic pattern., Conclusion: Breast cancer survivors treated with chemotherapy may manifest long-term changes in brain glucose metabolism indicative of subtle frontal hypometabolism, a finding consistent with results from neuropsychological testing and other imaging modalities., (Copyright © 2014 John Wiley & Sons, Ltd.)

Introduction: The goal of this study was to define the kinetics of glucose transport from maternal blood to placenta to fetus using real time imaging., Methods: Positron emission tomography (PET) imaging of the glucose-tracer [(18)F]fluorodeoxyglucose (FDG) was used to temporally and spatially define, in vivo, the kinetics of glucose transport from maternal blood into placentae and fetuses, in the late gestational gravid rat. Computed tomography (CT), with intravenous contrast, co-registered to the PET images allowed anatomic differentiation of placentae from fetal and maternal tissues., Results: FDG was rapidly taken up by placentae and subsequently appeared in fetuses with minimal temporal lag. FDG standardized uptake values in placentae and fetuses approached that of maternal brain. In both anesthetized and awake dams, one quarter of the administered FDG ultimately was accrued in the collective fetuses and placentae. Accordingly, kinetic modeling demonstrated that the placentae had very high avidity for FDG, 2-fold greater than that of the fetus and maternal brain, when accounting for the fact that fetal FDG necessarily must first be taken up by placentae. Consistent with this, placental expression of glucose transporter 1 exceeded that of all other tissues., Discussion: Fetal and placental tissues place a substantial glucose metabolic burden on the mother, owing to very high avidity of placentae for glucose coupled with the large relative mass of fetal and placental tissues., Conclusions: The placenta has a tremendous capacity to uptake and transport glucose. PET/CT imaging is an ideal means to study metabolite transport kinetics in the fetoplacental unit., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

(18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc(ΔEμ) gene insertion and the widely expressed H2-L(d)-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.

Objective: To evaluate the repeatability of gallium-68 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic (DOTA)-D-Phe1-Try3-octreotide (68Ga-DOTATOC) positron emission tomography (PET) in neuroendocrine tumors., Methods: Five patients with neuroendocrine tumors were imaged with 68Ga-DOTATOC PET twice within 5 days. Maximum and mean standardized uptake values (SUVmax and SUVmean) and kinetic parameters (K-Patlak and K-influx) of target lesions were measured. The repeatability of these measurements was investigated., Results: Forty-seven target lesions were identified on whole-body PET and 21 lesions on dynamic images. There was excellent repeatability with intraclass correlation coefficient of 0.99 for SUVmax, SUVmean, and K-Patlak, and 0.85 for K-influx. The median absolute percent differences and the interquartile ranges (IQR) between 2 scans for SUVmax and SUVmean were 7.4% (IQR, 14.1%) and 9.3% (IQR, 10.6%), respectively. The median absolute percent differences for K-Patlak and K-influx were 12.5% (IQR, 12.6%) and 29.9% (IQR, 22.4%), respectively. The SUVmax of target lesions did not differ by more than 25% between the 2 scans., Conclusions: 68Ga-DOTATOC PET imaging of neuroendocrine tumors is highly reproducible. A difference of more than 25% in SUVmax represents a change that is larger than the measurement error observed on repeated studies and should reflect a significant change in the biological character of the tumor.

Biological differences between signed and spoken languages may be most evident in the expression of spatial information. PET was used to investigate the neural substrates supporting the production of spatial language in American Sign Language as expressed by classifier constructions, in which handshape indicates object type and the location/motion of the hand iconically depicts the location/motion of a referent object. Deaf native signers performed a picture description task in which they overtly named objects or produced classifier constructions that varied in location, motion, or object type. In contrast to the expression of location and motion, the production of both lexical signs and object type classifier morphemes engaged left inferior frontal cortex and left inferior temporal cortex, supporting the hypothesis that unlike the location and motion components of a classifier construction, classifier handshapes are categorical morphemes that are retrieved via left hemisphere language regions. In addition, lexical signs engaged the anterior temporal lobes to a greater extent than classifier constructions, which we suggest reflects increased semantic processing required to name individual objects compared with simply indicating the type of object. Both location and motion classifier constructions engaged bilateral superior parietal cortex, with some evidence that the expression of static locations differentially engaged the left intraparietal sulcus. We argue that bilateral parietal activation reflects the biological underpinnings of sign language. To express spatial information, signers must transform visual-spatial representations into a body-centered reference frame and reach toward target locations within signing space.

ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [(18) F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non-distractible in a competing reward environment, (3) significantly increased messenger RNA (mRNA) expressions of ADAR2, serotonin 2C receptor (5HT2C R), D1, D2 and mu opioid receptors and no change in corticotropin-releasing hormone mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal-oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward-related mRNAs and hyperactive brain mesolimbic region., (Genes, Brain and Behavior © 2013 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.)

Eyeblink conditioning is a paradigm commonly used to investigate the neural mechanisms underlying motor learning. It involves the paired presentation of a tone-conditioning stimulus which precedes and co-terminates with an airpuff unconditioned stimulus. Following repeated paired presentations a conditioned eyeblink develops which precedes the airpuff. This type of learning has been intensively studied and the cerebellum is known to be essential in both humans and animals. The study presented here was designed to investigate the role of the cerebellum during eyeblink conditioning in humans using positron emission tomography (PET). The sample includes 20 subjects (10 male and 10 female) with an average age of 29.2 years. PET imaging was used to measure regional cerebral blood flow (rCBF) changes occurring during the first, second, and third blocks of conditioning. In addition, stimuli-specific rCBF to unpaired tones and airpuffs ("pseudoconditioning") was used as a baseline level that was subtracted from each block. Conditioning was performed using three, 15-trial blocks of classical eyeblink conditioning with the last five trials in each block imaged. As expected, subjects quickly acquired conditioned responses. A comparison between the conditioning tasks and the baseline task revealed that during learning there was activation of the cerebellum and recruitment of several higher cortical regions. Specifically, large peaks were noted in cerebellar lobules IV/V, the frontal lobes, and cingulate gyri.

This study was designed to determine the relationships between positron emission tomography (PET)-based quantitative measures of cerebral blood flow and cerebrovascular reserve and neuropsychological functioning in elderly individuals with atherosclerotic vascular disease. It was hypothesized that cerebrovascular function would be significantly associated with neuropsychological functioning. Results showed that both baseline global cerebral blood flow and cerebrovascular reserve were significantly associated with global neuropsychological functioning, when controlling for age and sex. Cerebrovascular reserve was additionally associated with performance on measures of memory and attention. Additional research is needed to determine whether measures of cerebral blood flow can be used to predict cognitive decline.

Background and Purpose: The purpose of this study was to design a radiation therapy treatment planning approach that would spare hematopoietically active bone marrow using [(18)F]FLT PET imaging., Materials and Methods: We have developed an IMRT planning methodology to incorporate functional PET imaging using [(18)F]FLT scans. Plans were generated for two simulated cervical cancer patients, where pelvic active bone marrow regions were incorporated as avoidance regions based on the ranges: SUV4 ≥ 4; 4>SUV3 ≥ 3; and 3 > SUV2 ≥ 2. Dose objectives were set to reduce bone marrow volume that received 10 (V(10)) and 20 (V(20))Gy., Results: Active bone marrow regions identified by [(18)F]FLT with an SUV ≥ 2, SUV ≥ 3, and SUV ≥ 4 represented an average of 43.0%, 15.3%, and 5.8%, respectively of the total osseous pelvis for the two cases studied. Improved dose-volume histograms for all identified bone marrow SUV volumes and decreases in V(10), and V(20) were achieved without clinically significant changes to PTV or OAR doses., Conclusions: Incorporation of [(18)F]FLT PET in IMRT planning provides a methodology to reduce radiation dose to active bone marrow without compromising PTV or OAR dose objectives in pelvic malignancies., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Stroke of the right MCA is common. Such strokes often have consequences for emotional experience, but these can be subtle. In such cases diagnosis is difficult because emotional awareness (limiting reporting of emotional changes) may be affected. The present study sought to clarify the mechanisms of altered emotion experience after right MCA stroke. It was predicted that after right MCA stroke the anterior cingulate cortex (ACC), a brain region concerned with emotional awareness, would show reduced neural activity. Brain activity during presentation of emotional stimuli was measured in 6 patients with stable stroke, and in 12 age- and sex-matched nonlesion comparisons using positron emission tomography and the [(15)O]H(2)O autoradiographic method. MCA stroke was associated with weaker pleasant experience and decreased activity ipsilaterally in the ACC. Other regions involved in emotional processing including thalamus, dorsal and medial prefrontal cortex showed reduced activity ipsilaterally. Dorsal and medial prefrontal cortex, association visual cortex and cerebellum showed reduced activity contralaterally. Experience from unpleasant stimuli was unaltered and was associated with decreased activity only in the left midbrain. Right MCA stroke may reduce experience of pleasant emotions by altering brain activity in limbic and paralimbic regions distant from the area of direct damage, in addition to changes due to direct tissue damage to insula and basal ganglia. The knowledge acquired in this study begins to explain the mechanisms underlying emotional changes following right MCA stroke. Recognizing these changes may improve diagnoses, management and rehabilitation of right MCA stroke victims., (Copyright © 2011 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

We investigated the functional organization of neural systems supporting language production when the primary language articulators are also used for meaningful, but non-linguistic, expression such as pantomime. Fourteen hearing non-signers and 10 deaf native users of American Sign Language (ASL) participated in an H(2) (15)O-PET study in which they generated action pantomimes or ASL verbs in response to pictures of tools and manipulable objects. For pantomime generation, participants were instructed to "show how you would use the object." For verb generation, signers were asked to "generate a verb related to the object." The objects for this condition were selected to elicit handling verbs that resemble pantomime (e.g., TO-HAMMER (hand configuration and movement mimic the act of hammering) and non-handling verbs that do not (e.g., POUR-SYRUP, produced with a "Y" handshape). For the baseline task, participants viewed pictures of manipulable objects and an occasional non-manipulable object and decided whether the objects could be handled, gesturing "yes" (thumbs up) or "no" (hand wave). Relative to baseline, generation of ASL verbs engaged left inferior frontal cortex, but when non-signers produced pantomimes for the same objects, no frontal activation was observed. Both groups recruited left parietal cortex during pantomime production. However, for deaf signers the activation was more extensive and bilateral, which may reflect a more complex and integrated neural representation of hand actions. We conclude that the production of pantomime versus ASL verbs (even those that resemble pantomime) engage partially segregated neural systems that support praxic versus linguistic functions.

The growing fetus depends upon transfer of glucose from maternal blood to fetal tissues. Insulin and glucocorticoid impact maternal glucose metabolism, but the effects of these hormones on fetal glucose assimilation in vivo are understudied. We thus used positron emission tomography imaging to determine the disposition of [(18)F]fluorodeoxyglucose (FDG) in rats on gestational d 20, quantifying the kinetic competition of maternal tissues and fetus for glucose. Three fasting maternal states were studied: after 2-d dexamethasone (DEX), during euglycemic hyperinsulinemic clamp insulin receiving (INS), and control (CON). In CON and DEX mothers, FDG accumulation in fetuses and placentae was substantial, rivaling that of maternal brain. By contrast, FDG accumulation was reduced in INS fetuses, placentae, and maternal brain by approximately 2-fold, despite no diminution in FDG extraction kinetics from maternal blood into these structures. The reduced FDG accumulation was due to more rapid clearance of FDG from the circulation in INS mothers, related to increased FDG avidity in INS select maternal tissues, including skeletal muscle, brown adipose tissue, and heart. DEX treatment of mothers reduced fetal weight by nearly 10%. Nonetheless, the accumulation of FDG into placentae and fetuses was similar in DEX and CON mothers. In our rat model, fetal growth restriction induced by DEX does not involve diminished glucose transport to the fetus. Maternal insulin action has little effect on the inherent avidity of the fetal-placental unit for glucose but increases glucose utilization by maternal tissues, thus indirectly reducing the glucose available to the fetus.

Background: Complex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat., Methodology and Principal Findings: We hypothesized that glucose infused into the arterial supply of one uterine horn would more highly expose fetuses in the ipsilateral versus contralateral uterine horn. To test this, the glucose tracer [18F]fluorodeoxyglucose (FDG) was infused via the left uterine artery. Regional glucose uptake into maternal tissues and fetuses was quantified using positron emission tomography (PET). Upon infusion, FDG accumulation began in the left-sided placentae, subsequently spreading to the fetuses. Over two hours after completion of the infusion, FDG accumulation was significantly greater in left compared to right uterine horn fetuses, favoring the left by 1.9+/-0.1 and 2.8+/-0.3 fold under fasted and hyperinsulinemic conditions (p<10(-11) n=32-35 and p<10(-12) n=27-45) respectively. By contrast, centrally administered [3H]-2-deoxyglucose accumulated equally between the fetuses of the two uterine horns. Induction of significant hyperglycemia (10(3) mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained., Conclusions and Significance: This approach exposes selected fetuses to localized hyperglycemia in vivo, minimizing exposure of the mother and thus secondary effects. Additionally, a set of less exposed internal control fetuses are maintained for comparison, allowing direct study of the in vivo fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health.

Introduction: The kinetics of the bone marrow uptake of 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) before and early after initiation of chemoradiation therapy was investigated in patients with head and neck cancer., Methods: Fourteen subjects with head and neck cancer underwent FLT positron emission tomography (PET) at baseline and after 10 Gy of radiation therapy. Thirteen subjects also received one cycle of platinum-based chemotherapy before the second FLT PET. Kinetic parameters, including the flux constant based on compartmental analysis (K(FLT)) and the Patlak constant (K(Patlak)) for cervical marrow, were calculated. Standardized uptake values (SUVs) for the cervical marrow (inside the radiation field) and lumbar spine marrow (outside the radiation field) were also determined., Results: There was a significant drop in FLT uptake in the bone marrow inside the radiation field. Mean pretreatment uptake values for the cervical spine were SUV=3.08+/-0.66, K(FLT)=0.045+/-0.016 min(-1) and K(Patlak)=0.039+/-0.013 min(-1). After treatment, these values were SUV=0.74+/-0.19, K(FLT)=0.011+/-0.005 min(-1) and K(Patlak)=0.005+/-0.002 min(-1). Compartmental analysis revealed a significant drop in k(3) in irradiated cervical marrow. FLT uptake in the bone marrow outside the radiation field exhibited a significantly smaller decrease., Conclusions: There is a marked decrease in FLT uptake in irradiated bone marrow after 10 Gy of radiation therapy to the head and neck. The drop in FLT uptake in irradiated marrow is due to a significant decrease in the net phosphorylation rate of FLT., ((c( 2010 Elsevier Inc. All rights reserved.)

Unlabelled: The purpose of this study was to investigate the kinetic behavior of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) before and early after initiation of chemoradiation therapy in patients with squamous cell head and neck cancer., Methods: A total of 8 patients with head and neck cancer underwent (18)F-FLT PET scans (7 patients at baseline and after 5 d [10 Gy] of radiation therapy given with concomitant chemotherapy and 1 patient only at baseline). Dynamic PET images were obtained with concurrent arterial or venous blood sampling. Kinetic parameters including the flux constant of (18)F-FLT based on compartmental analysis (K-FLT), the Patlak influx constant (K-Patlak), and standardized uptake value (SUV) were calculated for the primary tumor and (18)F-FLT-avid cervical lymph nodes for all scans., Results: Mean pretreatment values of uptake for the primary tumor and cervical nodes were 0.075 +/- 0.006 min(-1), 0.042 +/- 0.004 min(-1), and 3.4 +/- 0.5 (mean +/- SD) for K-FLT, K-Patlak, and SUV, respectively. After 10 Gy of radiation therapy, these values were 0.040 +/- 0.01 min(-1), 0.018 +/- 0.016 min(-1), and 1.8 +/- 1.1 for K-FLT, K-Patlak, and SUV, respectively. For all lesions seen on pretherapy and midtherapy scans, the correlation was 0.90 between K-FLT and K-Patlak, 0.91 between K-FLT and SUV, and 0.99 between K-Patlak and SUV., Conclusion: The initial (18)F-FLT uptake and change early after treatment in squamous head and neck tumors can be adequately characterized with SUV obtained at 45-60 min, which demonstrates excellent correlation with influx parameters obtained from compartmental and Patlak analyses.

Background: This study evaluated brain volumes in healthy older subjects without dementia who presented with memory complaints. The objective was to examine cortical volumes in relation to cognitive performance among patients who do not have dementia, but who do have mild cognitive deficits., Methods: Fifteen participants were evaluated (mean age = 71.8 +/- 6.2). Brain structure was measured via high-resolution magnetic resonance imaging to quantify gray and white matter volumes. Volumetric measures were assessed relative to cognitive function in separate regression models controlling for total cerebral volume. Reported here are measures of global cognitive performance using the Mattis Dementia Rating Scale (DRS) in relation to volumetric measures., Results: Baseline MMSE scores ranged from 27 to 30 (mean = 29.3; SD = 0.9). After controlling for total cerebral volume, we observed that lower white matter volume in the temporal lobe [F(1,14) = 5.72, p = 0.03] was associated with lower performance on the Mattis Dementia Rating Scale (DRS)., Conclusions: Structural imaging may help provide useful clinical information in the context of mild cognitive decline. Currently, the diagnosis of dementia relies on longitudinal measures of cognition. Future studies will help determine whether the addition of brain imaging may enhance diagnostic certainty as well as predict long-term outcome.

Psychiatric disorders, including disorders of emotion control, are common in Huntington's disease. The neurobiological mechanism of the increased rate of disorders of emotion control are not known. Emotion perception deficits have been reported in Huntington's disease, but studies of emotional experience have been limited. In the present study we aim to expand the research in emotion in Huntington's disease by examining the neural bases of induced dysphoria at an early stage of Huntington's disease. Ten Huntington's disease patients and 12 demographically matched healthy volunteers underwent [(15)O] water positron emission tomography while in a transient state of dysphoria induced by viewing negatively charged affect-laden stimuli. Both groups experienced dysphoric mood, but Huntington's disease patients responded to the stimuli with greater arousal, anger and fear than healthy controls. Induced dysphoric mood was associated with a widespread reduction of activity within the frontal and parietal lobes, thalamus, and cerebellum. These differences could not be explained based on the smaller gray matter volumes of the corresponding regions, although in Huntington's disease patients smaller caudate nucleus volumes predicted lower dorsal-lateral prefrontal activity. Areas of increased activity included the striate and extrastriate cortex, the left thalamus, the transverse temporal gyrus, and the posterior hippocampus. This study elucidates possible mechanisms contributing to psychiatric disturbances of emotion often found in patients with Huntington's disease.

Objectives: Although electroconvulsive therapy (ECT) is a very effective treatment of depression and psychosis, the mechanisms by which this occurs are not fully delineated. The objective of this study was to investigate the functional alterations in brain metabolism in response to ECT through the use of positron emission tomography assessment of cerebral glucose metabolism before and after a course of ECT., Methods: Ten subjects with psychotic depression were studied with positron emission tomography using [F]fluorodeoxyglucose before and between 2 and 3 weeks after a course of ECT. Statistical parametric mapping and region of interest analyses of the anterior cingulate cortex (ACC) subregions (dorsal, rostral, subcallosal, and subgenual) and hippocampus were used to determine glucose metabolic changes from ECT. The Hamilton Depression Rating Scale and the Scale for Assessing Positive Symptoms were the primary measures used for assessing clinical changes from ECT., Results: Electroconvulsive therapy led to significant increases in the left subgenual ACC and hippocampal metabolism, which were directly correlated with each other and to a reduction in depression as measured by total Hamilton Depression Rating Scale scores. Better antidepressant responders had increased, whereas poorer responders had a decreased left subgenual ACC and hippocampal metabolism. The decrease in positive symptoms was also correlated with increased left hippocampal metabolism., Conclusions: The antidepressant effect of ECT was correlated with increased metabolism in the left subgenual ACC and hippocampus, whereas the antipsychotic effect of ECT was only correlated with increased left hippocampal metabolism. This finding has implications to better understand the mechanism of antidepressant and antipsychotic effects of ECT.

Twenty-seven schizophrenia spectrum patients and 25 healthy controls performed a probabilistic version of the serial reaction time task (SRT) that included sequence trials embedded within random trials. Patients showed diminished, yet measurable, sequence learning. Postexperimental analyses revealed that a group of patients performed above chance when generating short spans of the sequence. This high-generation group showed SRT learning that was similar in magnitude to that of controls. Their learning was evident from the very 1st block; however, unlike controls, learning did not develop further with continued testing. A subset of 12 patients and 11 controls performed the SRT in conjunction with positron emission tomography. High-generation performance, which corresponded to SRT learning in patients, correlated to activity in the premotor cortex and parahippocampus. These areas have been associated with stimulus-driven visuospatial processing. Taken together, these results suggest that a subset of patients who showed moderate success on the SRT used an explicit stimulus-driven strategy to process the sequential stimuli. This adaptive strategy facilitated sequence learning but may have interfered with conventional implicit learning of the overall stimulus pattern., (PsycINFO Database Record (c) 2007 APA, all rights reserved.)

The anterior cingulate cortex (ACC) is thought to be the neuroanatomical interface between emotion and cognition. Because effective emotion-cognition interactions are essential to optimal decision making, clarifying how the functionality of the ACC changes in older age using functional imaging holds great promise for ultimately understanding what contributes to the psychological changes occurring in late life. However, the interpretation of functional imaging studies is complicated by the fact that aging is associated with changes in grey matter volume and in the cerebral vasculature. In the present study, we obtained high-resolution structural magnetic resonance (MR) imaging data and quantitative blood flow images to examine the association between aging, blood flow, and grey matter volume in the ACC. Twenty-six healthy individuals between 25 and 79 years of age underwent quantitative [15O]water positron emission tomography (PET) imaging. The ACC was traced onto tissue-classified images derived from T1- and T2-weighted MRIs using previously defined methods. The ACC was divided into dorsal, rostral, and subgenual regions. Age was negatively correlated with blood flow in dorsal and rostral ACC regions. Effects were weaker but in a similar direction for the subgenual ACC. While older age and lower blood flow were both associated with smaller rostral ACC grey matter volumes, mediation analysis revealed that grey matter volume only partially mediated the effect of age on blood flow in the rostral ACC. Neural alterations not detectable on MR images may lead to reduced blood flow due to fewer and/or less metabolically active neurons. Alternatively, lower blood flow may be a cause, rather than a consequence, of smaller grey matter volume in the ACC.

While the role of the cerebellum in motor coordination is widely accepted, the notion that it is involved in emotion has only recently gained popularity. To date, functional neuroimaging has not been used in combination with lesion studies to elucidate the role of the cerebellum in the processing of emotional material. We examined six participants with cerebellar stroke and nine age and education matched healthy volunteers. In addition to a complete neuropsychological, neurologic, and psychiatric examination, participants underwent [15O]water positron emission tomography (PET) while responding to emotion-evoking visual stimuli. Cerebellar lesions were associated with reduced pleasant experience in response to happiness-evoking stimuli. Stroke patients reported an unpleasant experience to frightening stimuli similar to healthy controls, yet showed significantly lower activity in the right ventral lateral and left dorsolateral prefrontal cortex, amygdala, thalamus, and retrosplenial cingulate gyrus. Frightening stimuli led to increased activity in the ventral medial prefrontal, anterior cingulate, pulvinar, and insular cortex. This suggests that alternate neural circuitry became responsible for maintaining the evolutionarily critical fear response after cerebellar damage.

Purpose: This study was undertaken to explore the mechanisms underlying cognitive reserve in subjects with mild memory deficits by using positron emission tomography (PET)., Methods: Global cerebral blood flow (gCBF) and cerebrovascular reserve (CVR) measurements were performed in 15 elders (5 men, 10 women, 62-84, 71.8 +/- 6.2 years) meeting criteria for mild cognitive impairment (MCI). PET consisted of quantitative [(15)O]water determinations of CBF, two at baseline and one postadministration of acetazolamide (ACZ)., Results: Mean gCBF were 44.9 +/- 5.5 during counting, 44.5 +/- 6.7 for the memory task, and 60.2 +/- 4.8 ml/min/100 g for post-ACZ (CVR of 33.9 +/- 13.2%). Task-related gCBF change was significantly related to memory score, performance on the Trail Making Test B (Trails-B), premorbid IQ, and education, and differed significantly between the learning-based groups., Conclusions: Cognitive reserve appears analogous to cardiac reserve. The ability to alter gCBF paralleled performance on general cognitive measures, was enhanced in higher levels of cognitive reserve, and was impaired in individuals who no longer appear to benefit from repeated exposure to testing.

Cerebral blood flow (CBF) was assessed during a verbal recall task using [(15)O]water positron emission tomography (PET) in older adults with mild cognitive deficits participating in a placebo-controlled donepezil trial. The placebo group demonstrated reduced CBF in the left frontal and temporal regions over the 6-month period, while those receiving donepezil did not. The placebo group's performance did not change on a list-learning task, while the donepezil group's performance improved, despite having had lower performance at intake. These findings suggest that donepezil treatment may be associated with a relative maintenance of CBF and improved list-learning.

Rather than specifying spatial relations with a closed-class set of prepositions, American Sign Language (ASL) encodes spatial relations using space itself via classifier constructions. In these constructions, handshape morphemes specify object type, and the position of the hands in signing space schematically represents the spatial relation between objects. A [15O]water PET study was conducted to investigate the neural regions engaged during the production of English prepositions and ASL locative classifier constructions in hearing subjects with deaf parents (ASL-English bilinguals). Ten subjects viewed line drawings depicting a spatial relation between two objects and were asked to produce either an ASL locative classifier construction or an English preposition that described the spatial relation. The comparison task was to name the figure object (colored red) in either ASL or in English. Describing spatial relations in either ASL or English engaged parietal cortex bilaterally. However, an interaction analysis revealed that right superior parietal cortex was engaged to a greater extent for ASL than for English. We propose that right parietal cortex is involved in the visual-motoric transformation required for ASL. The production of both English prepositions and ASL nouns engaged Broca's area to a greater extent than ASL classifier constructions. We suggest that Broca's area is not engaged because these constructions do not involve retrieval of the name of an object or the name of a spatial relation. Finally, under the same task conditions, only left parietal activation was observed for monolingual English speakers producing spatial prepositions (H. Damasio et al., 2001, NeuroImage, 13). We conclude that the right hemisphere activation observed for ASL-English bilinguals was due to their life-long experience with spatial language in ASL.

The objective of this study was to evaluate the effect of the acute administration of marijuana (MJ) on cardiovascular (CV) function and CNS pharmacokinetics (PK) of [(15)O]water in occasional (O) versus chronic (C) MJ users. Each subject received four injections of [(15)O]water (one prior and three postsmoking) on two occasions in which they received active or placebo MJ. For each injection, measures of CV function and CNS PK [(15)O]water were made. Postsmoking, MJ influenced all measured CV and [(15)O]water PK parameters. C users reported significantly lower "highness" and smaller heart rate (HR) changes, which resulted in reduced rate pressure product (RPP) changes compared to O users, even though Delta(9)-tetrahydrocannabinol levels were higher, whereas changes in blood pressure (BP), arrival time, and [(15)O]water concentration were not significantly different between the groups. Significant CV changes resulted in changes in the whole-body distribution of cardiac output rather than changes in cerebral blood flow. Chronic MJ use produces tolerance to the HR increases induced by acute MJ smoking compared to changes observed in occasional users, without changing the effects on BP and [(15)O]water PK.

Unlabelled: In this study we investigated the feasibility of using radionuclide accumulation mediated by the human sodium iodide symporter (hNIS) gene in conjunction with various imaging modalities as a reporter system to noninvasively monitor the expression of transgenes delivered for gene therapy., Methods: NIS-expressing adenovirus (Ad-hNIS) was delivered in vitro to MB-435 breast carcinoma cells. NIS-mediated accumulation of (125)I(-), (99m)TcO(4)(-), and (76)Br(-) by the cells was visualized using autoradiography, gamma-camera scintigraphy, and PET imaging, respectively., Results: For all imaging modalities, signal intensity generated by the cells correlated linearly both with the amount of Ad-hNIS and with the activity of radionuclide added to the cells., Conclusion: hNIS-mediated cellular accumulation of radionuclide was clearly visualized by all 3 imaging modalities tested. This preliminary study demonstrates the feasibility of using hNIS for monitoring the location and magnitude of expression of genes delivered during gene therapy.

The accurate determination of cerebrovascular reserve (CVR), especially in elderly subjects, entails several technical issues. From a review of the literature, the optimal technique employs quantitative 15O-water PET imaging determinations of cerebral blood flow (CBF) and acetazolamide (ACZ) (1 g iv with measurements at 10- to 20-min post-administration) as the vasodilating agent. CBF and CVR measurements were made using this methodology on 12 elderly subjects (3 males, 9 females, 66-84 years of age) meeting criteria for mild cognitive impairment (MCI) without other significant medical problems. Applying this quantitative technique, the cognitive and emotional status of the subject during the imaging procedure influenced the magnitude of the measurements. The semiquantitative measures resulted in even more pronounced subject state influences. The conditions under which CBF or CVR measurements are made should be controlled and reported. If semiquantitative techniques (e.g., single-photon emission-computed tomography [SPECT] imaging) must be employed for the determination of CVR, the validity of any measurement is dependent on the careful control of the general physiological status (e.g., heart rate, blood pressure, level of anxiety) of the patient.

This study examined regional cerebral blood flow (rCBF) changes associated with visually induced sad affect in healthy elderly persons. Subjects viewed sadness-laden, happiness-laden, and emotionally neutral image sets while rCBF was recorded using [(15)O] water PET. The sad image set included human faces and scenery/objects ("scenes"). To control for secondary sensory processing, the neutral and happy comparison sets included exclusively either human faces or scenes. During the sad condition, the ventral prefrontal and temporal cortices were more active compared with happy and neutral scenes conditions and the thalamus was more active compared with happy and neutral faces conditions. Ventral prefrontal cortex and thalamus were associated with processing of sad visual stimuli, whether compared with neutral or happy stimuli. The specific findings associated with sad affect were contingent on the comparison stimuli content (scenes or human faces), not affect (i.e., comparison with neutral or happy conditions).

Objective: Schizophrenia is currently conceptualized as a disease of functional neural connectivity, leading to symptoms that affect aspects of mental activity, including perception, attention, memory, and emotion. The neural substrates of its emotional components have not been extensively studied with functional neuroimaging. Previous neuroimaging studies have examined medicated patients with schizophrenia. The authors measured regional cerebral blood flow (rCBF) during performance of a task that required unmedicated patients to recognize the emotional valence of visual images and to determine whether they were pleasant or unpleasant., Method: The authors examined rCBF in 17 healthy volunteers and 18 schizophrenia patients who had not received antipsychotic medications for at least 3 weeks during responses to pleasant and unpleasant visual stimuli. Areas of relative increases or decreases in rCBF were measured by using the [(15)O]H(2)O method., Results: When patients consciously evaluated the unpleasant images, they did not activate the phylogenetically older fear-danger recognition circuit (e.g., the amygdala) used by the healthy volunteers, although they correctly rated them as unpleasant. Likewise, the patients showed no activation in areas of the prefrontal cortex normally used to recognize the images as pleasant and were unable to recognize them as such. Areas of decreased CBF were widely distributed and comprised subcortical regions such as the thalamus and cerebellum., Conclusions: This failure of the neural systems used to support emotional attribution is consistent with pervasive problems in experiencing emotions by schizophrenia patients. The widely distributed nature of the abnormalities suggests the importance of subcortical nodes in overall dysfunctional connectivity.