Biomedical subjects

Dinko Franceschi

Publications and source records attributed to Dinko Franceschi.

12 recordsLinked to original sources

PubMed2005

Low doses of alcohol substantially decrease glucose metabolism in the human brain.

Moderate doses of alcohol decrease glucose metabolism in the human brain, which has been interpreted to reflect alcohol-induced decreases in brain activity. Here, we measure the effects of two relatively low doses of alcohol (0.25 g/kg and 0.5 g/kg, or 5 to 10 mM in total body H2O) on glucose metabolism in the human brain. Twenty healthy control subjects were tested using positron emission tomography (PET) and FDG after placebo and after acute oral administration of either 0.25 g/kg, or 0.5 g/kg of alcohol, administered over 40 min. Both doses of alcohol significantly decreased whole-brain glucose metabolism (10% and 23% respectively). The responses differed between doses; whereas the 0.25 g/kg dose predominantly reduced metabolism in cortical regions, the 0.5 g/kg dose reduced metabolism in cortical as well as subcortical regions (i.e. cerebellum, mesencephalon, basal ganglia and thalamus). These doses of alcohol did not significantly change the scores in cognitive performance, which contrasts with our previous results showing that a 13% reduction in brain metabolism by lorazepam was associated with significant impairment in performance on the same battery of cognitive tests. This seemingly paradoxical finding raises the possibility that the large brain metabolic decrements during alcohol intoxication could reflect a shift in the substrate for energy utilization, particularly in light of new evidence that blood-borne acetate, which is markedly increased during intoxication, is a substrate for energy production by the brain.

Adult↗

PubMed2005

Abdominal muscle uptake on FDG PET secondary to multiple rib fractures and use of accessory muscles of respiration.

A 69-year-old man with a history of lung cancer was referred for FDG whole body positron emission tomography (PET) with computed tomography (CT) fusion. Three days before the study, the patient was involved in a motor vehicle accident (MVA). In addition to hypermetabolic lesions representing metastatic lung cancer, PET scan showed marked anterior and lateral abdominal muscle uptake. Multiple focal abnormalities were seen on the PET scan that corresponded to multiple rib fractures on the CT scan that were secondary to the MVA. When the patient was interviewed, he stated that he had thoracic wall pain that prevented him from breathing properly. This case illustrates an unusual pattern of increased anterior and lateral abdominal muscle uptake as a result of pain while breathing.

Abdominal Muscles↗

PubMed2005

PET findings in pulmonary dirofilariasis.

This case demonstrates hypermetabolic activity in a pulmonary round infarct secondary to dirofilariasis. This case further illustrates that pulmonary dirofilariasis, like other infectious causes of pulmonary nodules, can be PET positive.

Animals↗

PubMed2005

Increased standardized uptake value in the primary lesion predicts nodal or distant metastases at presentation in lung cancer.

Standardized uptake value (SUV) has been linked to tumor aggressiveness and long-term prognosis. Based on the hypothesis that positron emission tomography (PET) SUV serves as a surrogate for biologic aggression, we investigated whether SUV in the primary lesion, independent of size, correlates with the presence of nodal or distant metastases at the time of presentation. We retrospectively reviewed computed tomography (CT) scan, PET scan, and histologic findings of consecutive patients in our lung cancer referral population evaluated between December 15, 2000 and April 15, 2004. Only patients with primary non-small-cell lung cancer and pathologic confirmation of nodal status or conventionally accepted non-PET proof of distant metastases were included for analysis. One hundred thirty-nine patients had complete results, including CT, PET, and independent confirmation of nodal or distant disease. The stage distribution was as follows: 33 IA, 24 IB, 5 IIA, 9 IIB, 21 IIIA, 8 IIIB, and 39 IV. Simple logistic regression analysis demonstrated a highly significant correlation between SUV of the primary lesion and the presence of nodal or distant metastases at the time of presentation (P = 0.0036). When odds ratios were calculated, a 13% increase in the likelihood of nodal/distant disease was found for every unit increase in SUV. We conclude that PET SUV, independent of size, is a marker of biologic aggression. Elevated SUV in the primary lesion at presentation should prompt high suspicion and mandates meticulous search for nodal or distant disease.

Adult↗

PubMed2005

Comparison of monoamine oxidase a in peripheral organs in nonsmokers and smokers.

UNLABELLED: Smokers have reduced levels of brain monoamine oxidase A (MAO A) leading to speculation that MAO A inhibition by tobacco smoke may underlie some of the neurophysiologic effects of smoking. Because smoking exposes peripheral organs as well as the brain to MAO A-inhibitory compounds, we determined whether smokers would also have reduced MAO A in peripheral organs. METHODS: We measured MAO A in peripheral organs in a group of 9 smokers and compared it with a group of nonsmokers studied previously. MAO A was measured using PET and serial scans with the MAO A-specific radiotracers (11)C-clorgyline and deuterium-substituted (11)C-clorgyline ((11)C-clorgyline-D2) using the deuterium isotope effect to assess binding specificity. The time course of radiotracer in the arterial plasma was also measured and data from the tissue time-activity curves and the arterial input function were analyzed using a 3-compartment model to estimate k(3), which represents the rate-limiting step for the irreversible binding of labeled clorgyline to MAO A. RESULTS: Tracer uptake at plateau was reduced with deuterium substitution for the heart, lungs, and kidneys, indicating specificity for MAO. There was no difference in organ uptake at plateau between nonsmokers and smokers though, for the smokers, the efflux of tracer from peak uptake to plateau was slower for the lungs. The area under the time-activity curve for the arterial plasma was also significantly reduced for smokers versus nonsmokers and the reduction occurred in the first few minutes after radiotracer injection. Smokers had an approximately 50% reduction in k(3) when compared with nonsmokers; however, k(3) did not differ for nonsmokers and smokers for the heart and the kidneys. CONCLUSION: Because MAO A breaks down serotonin, norepinephrine, dopamine, and tyramine, and because the lung is a major metabolic organ in degrading some of these substances, reduced lung MAO A may contribute to some of the physiologic effects of smoking. This study also revealed that the concentration of the radiotracers in the arterial plasma is significantly lower for the smoker versus the nonsmoker and that this appears to be caused in part by retention of the radiotracer in lungs. If this is generally true for other substances that are administered intravenously, then this needs to be considered as a variable that may contribute to different short-term behavioral responses to intravenously administered drugs for nonsmokers versus smokers.

Adult↗

PubMed2003

Low monoamine oxidase B in peripheral organs in smokers.

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,l-[11C]deprenyl and deuterium-substituted l-[11C]deprenyl (l-[11C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke.

Humans↗

PubMed2003

Monoamine oxidase A imaging in peripheral organs in healthy human subjects.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of many biogenic and dietary amines. Though studies of MAO have focused mainly on its regulatory role in the brain, MAO in peripheral organs also represents a vast mechanism for detoxifying vasoactive compounds as well as for terminating the action of physiologically active amines, which can cross the blood brain barrier. Indeed, robust central and peripheral MAO activity is a major requirement in the safe use of many CNS drugs, particularly antidepressants, and thus an awareness of the MAO inhibitory potential of drugs is essential in therapeutics. In this study, we examined the feasibility of quantifying MAO A in peripheral organs in healthy human subjects using comparative positron emission tomography (PET) imaging with carbon-11 (t(1/2): 20.4 min) labeled clorgyline ([(11)C]clorgyline) a suicide inactivator of MAO A and its deuterium labeled counterpart ([(11)C]clorgyline-D2). Heart, lungs, kidneys, thyroid, and spleen showed a robust deuterium isotope effect characteristic of MAO and the magnitude of the effect was similar to that of trancylcypromine, an irreversible MAO inhibitor used in the treatment of depression. Liver time-activity curves were not affected by deuterium substitution precluding the estimation of liver MAO in vivo. In organs showing an isotope effect, MAO A is greatest in the lungs and kidneys followed by the thyroid and heart. This method, which has been previously applied in the human brain, opens the possibility to also directly assess the effects of different variables including smoking, dietary substances, drugs, disease, and genetics on peripheral MAO A in humans.

Adult↗

PubMed2003

Alcohol intoxication induces greater reductions in brain metabolism in male than in female subjects.

BACKGROUND: The mechanisms underlying the gender differences in alcohol drinking behavior and alcohol's effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects. METHODS: Ten female and 10 male healthy controls were scanned with positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda). RESULTS: Alcohol significantly and consistently decreased whole-brain metabolism. The magnitude of these changes was significantly larger in male (-25 +/- 6%) than in female (-14 +/- 11%; p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self-reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects. CONCLUSIONS: This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohol's modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.

Adult↗

PubMed2002

"Nonhedonic" food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect.

The drive for food is one of the most powerful of human and animal behaviors. Dopamine, a neurotransmitter involved with motivation and reward, its believed to regulate food intake in laboratory animals by modulating its rewarding effects through the nucleus accumbens (NA). Here we assess the involvement of dopamine in "nonhedonic" food motivation in humans. Changes in extracellular dopamine in striatum in response to nonhedonic food stimulation (display of food without consumption) were evaluated in 10 food-deprived subjects (16-20 h) using positron emission tomography (PET) and [11C]raclopride (a D2 receptor radioligand that competes with endogenous dopamine for binding to the receptor). To amplify the dopamine changes we pretreated subjects with methylphenidate (20 mg p.o.), a drug that blocks dopamine transporters (mechanism for removal of extracellular dopamine). Although the food stimulation when preceded by placebo did not increase dopamine or the desire for food, the food stimulation when preceded by methylphenidate (20 mg p.o.) did. The increases in extracellular dopamine were significant in dorsal (P < 0.005) but not in ventral striatum (area that included NA) and were significantly correlated with the increases in self-reports of hunger and desire for food (P < 0.01). These results provide the first evidence that dopamine in the dorsal striatum is involved in food motivation in humans that is distinct from its role in regulating reward through the NA. In addition it demonstrates the ability of methylphenidate to amplify weak dopamine signals.

Adult↗

PubMed2002

Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications.

Methylphenidate (Ritalin) is an effective drug in the treatment of attention deficit hyperactivity disorder. However, the doses required therapeutically vary significantly between subjects and it is not understood what determines these differences. Since methylphenidate's therapeutic effects are in part due to increases in extracellular DA secondary to blockade of dopamine transporters (DAT), the variability could reflect differences in levels of DAT blockade. Here we used PET to assess if for a given dose of methylphenidate the differences in DAT blockade account for the variability in methylphenidate-induced increases in extracellular DA. Ten healthy adult subjects were tested before and 60 min after oral methylphenidate (60 mg) with PET to estimate DAT occupancy (with [(11)C]cocaine as the radioligand) and levels of extracellular DA (with [(11)C]raclopride as the D2 receptor radioligand that competes with endogenous DA for binding to the receptor). Methylphenidate significantly blocked DAT (60 +/- 11%) and increased extracellular DA in brain (16 +/- 8% reduction in [(11)C]raclopride binding in striatum). However, the correlation between methylphenidate-induced DAT blockade and DA increases was not significant. These results indicate that for a given dose of methylphenidate, individual differences in DAT blockade are not the main source for the intersubject variability in MP-induced increases in DA. This finding suggests that individual differences in response to MP are due in part to individual differences in DA release, so that for an equivalent level of DAT blockade, MP would induce smaller DA changes in subjects with low than with high DA cell activity.

Administration, Oral↗

PubMed2002

Strategy for the formation of parametric images under conditions of low injected radioactivity applied to PET studies with the irreversible monoamine oxidase A tracers [11C]clorgyline and deuterium-substituted [11C]clorgyline.

The construction of parametric positron emission tomography images of enzyme or receptor concentration obtained using irreversibly binding radiotracers presents problems not usually encountered with reversibly binding radiotracers. Difficulties are most apparent in brain regions having low blood flow and/or high enzyme or receptor concentration and are exacerbated with noisy data. This is especially true when minimal doses of radiotracer are administered. A comparison was recently reported of the irreversible monoamine oxidase A (MAO A) radiotracers [11C]clorgyline (CLG) and deuterium-substituted [11C]clorgyline (CLG-D) in the human brain using region of interest (ROI) analysis in which the authors observed an unexpected loss of image contrast with CLG-D compared with CLG. In order to more fully investigate patterns of binding of these irreversibly binding radiotracers, a strategy was devised to reduce noise in the generation of parametric images of the model term related to enzyme or receptor concentration. The generalized linear least squares (GLLS) method of Feng et al. (1995), a rapid linear method that is unbiased, was used for image-wide parameter estimation. Since GLLS can fail in the presence of large amounts of noise, local voxels were grouped within the image to increase the signal, and the GLLS method was combined with the standard nonlinear estimation methods when necessary. Voxels were grouped together depending on their proximity and whether they fell within a specified range of the time-integrated image. It was assumed that voxels meeting both criteria are functionally related. Simulations reflecting varying enzyme concentrations were performed to assess precision and accuracy of parameter estimates in the presence of varying amounts of noise. Using this approach, images were generated of the combination parameter lambdak3 (lambda = K1/k2, where K1 and k2 are plasma-to-tissue and tissue-to-plasma transport constants, respectively) that is related to enzyme concentration as well as images of the transport constant K1 for individual subjects. Reasonably high-quality images of both K1 and lambdak3 were obtained for CLG and CLG-D for individual subjects even with low injected doses averaging 6 mCi. While there were no differences in the K1 images, the lambdak3 images revealed the loss of contrast previously reported for CLG-D using the ROI analysis. This method should be generalizable to other tracers and should facilitate the analysis of group differences.

Brain↗

PubMed2002

PET imaging of monoamine oxidase B in peripheral organs in humans.

UNLABELLED: Monoamine oxidase (MAO) regulates neurotransmitter concentration in the brain and is also an important detoxifying enzyme in peripheral organs. It occurs in 2 subtypes, MAO A and MAO B. Their relative ratios in different organs are variable, depending on the particular organ and species, making it difficult to extrapolate measures from animals to humans. The purpose of this study was to investigate the feasibility of imaging MAO B in peripheral organs in humans with PET. METHODS: Nine healthy subjects (7 males, 2 females; mean age +/- SD, 37 +/- 7 y) received 2 dynamic PET studies of the torso area 2 h apart with 11C-L-deprenyl and deuterium-substituted 11C-L-deprenyl (11C-L-deprenyl-D2). Time-activity curves for heart, lungs, liver, kidneys, and spleen and arterial plasma input were measured for each study. The uptake at plateau and the incorporation quotient (IQ = uptake/plasma input) as well as model terms K1 (which is a function of blood flow) and k3 and lambdak3 (which are kinetic terms proportional to MAO B) were compared to identify organs that showed reduced values with deuterium substitution (deuterium isotope effect) characteristic of MAO B. In addition, a sensitivity analysis compared the 2 tracers with respect to their ability to quantify MAO B. RESULTS: Heart, lungs, kidneys, and spleen showed a robust deuterium isotope effect on uptake, IQ, k3, and lambdak3. The arterial plasma input function was significantly larger for 11C-L-deprenyl-D2 than for 11C-L-deprenyl. Liver time-activity curves were not affected by deuterium substitution and model terms could not be estimated. In organs showing an isotope effect, lambdak3 showed the rank order: kidneys >or= heart > lungs = spleen. A sensitivity analysis showed that 11C-L-deprenyl-D2 is a better index of MAO activity than 11C-L-deprenyl. CONCLUSION: This study demonstrates that (a) the deuterium isotope effect is useful in assessing the binding specificity of labeled deprenyl to peripheral MAO B; (b) MAO B can be visualized and quantified in the heart, lungs, kidneys, and spleen but not in the liver; (c) with the exception of the liver, which cannot be measured, MAO B activity is highest in the kidneys and heart; and (d) quantitation in organs having high levels of MAO B is improved by the use of 11C-L-deprenyl-D2, similar to prior studies on the brain. This study indicates that 11C-L-deprenyl-D2 will be useful for measuring the effects of different variables, including tobacco smoke exposure on MAO B activity in peripheral organs in humans.

Adult↗