Melatonin deficiency decreases brown adipose tissue acute thermogenic capacity of in rats measured by 18F-FDG PET.

OBJECTIVE: Melatonin has been shown to increase brown adipose tissue (BAT) mass, which can lead to important metabolic effects, such as bodyweight reduction and glycemic improvement. However, BAT mass can only be measured invasively and. The gold standard for non-invasive measurement of BAT activity is positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d-glucose (18F-FDG PET). There is no study, to our knowledge, that has evaluated if melatonin influences BAT activity, measured by this imaging technique in animals. METHODS: Three experimental groups of Wistar rats (control, pinealectomy, and pinealectomy replaced with melatonin) had an 18F-FDG PET performed at room temperature and after acute cold exposure. The ratio of increased BAT activity after cold exposure/room temperature was called "acute thermogenic capacity" (ATC) We also measured UCP-1 mRNA expression to correlate with the 18F-FDG PET results. RESULTS: Pinealectomy led to reduced acute thermogenic capacity, compared with the other groups, as well as reduced UCP1 mRNA expression. CONCLUSION: Melatonin deficiency impairs BAT response when exposed to acute cold exposure. These results can lead to future studies of the influence of melatonin on BAT, in animals and humans, without needing an invasive evaluation of BAT.

Comparison of different quantification methods for 18F-fluorodeoxyglucose-positron emission tomography studies in rat brains.

OBJECTIVES: This study aimed to evaluate several methods to estimate glucose consumption in the male Wister rat brain as measured by PET. METHODS: Fourteen male Wistar normoglycemic rats were studied. The input function consisted of seventeen blood samples drawn manually from the femoral artery. Glucose uptake values were calculated using the input function resulting from the arterial blood samples and the tissue time-activity curve derived from the PET images. The estimated glucose consumption rate (Ki) based on the 2-tissue compartment model (2TCM) served as the standard for comparisons with the values calculated by the Patlak analysis and with the fractional uptake rate (FUR), standardized uptake value (SUV) and glucose corrected SUV (SUVglu). RESULTS: No significant difference between the standard Ki and the Patlak Ki was observed. The standard Ki was also found to have strong correlations and concordance with the Ki value estimated by the Patlak analysis. The FUR method presented an excellent correlation with the Ki value obtained by the 2TCM/Patlak analyses, in contrast to the SUV or SUVglu. CONCLUSIONS: From a methodological point of view, the present findings confirm the theoretical limitations of the cerebral SUV and SUVglu as a substitute for Ki in the estimation of glucose consumption in the brain. Our data suggest that the FUR is the surrogate to Ki.

Effects of ketamine/xylazine and isoflurane on rat brain glucose metabolism measured by 18 F-fluorodeoxyglucose-positron emission tomography.

The aim of the present study was to investigate changes in glucose metabolism in male Wistar rats induced by the anesthetics isoflurane and ketamine combined with xylazine via 18 F-fluorodeoxyglucose-positron emission tomography. We analyzed the differential effects of the anesthetics on 18 F-fluorodeoxyglucose uptake and pharmacokinetics in 33 rats using quantification methods: (a) the standardized uptake value, (b) voxel-based analyses, and (c) kinetic analysis. Both anesthetics reduced glucose uptake in the entire brain. The voxel-based analyses detected smaller uptake reductions in the bilateral primary somatosensory system cortex and part of the limbic system in the ketamine-xylazine (KX) group and in the vestibular nucleus in the isoflurane group. Through kinetic analysis, we found that the volume of distribution and the membrane transport rate K1 were reduced in the KX group. Through various methods of 18 F-fluorodeoxyglucose-positron emission tomography quantification, the present study found that anesthesia with the ketamine-xylazine combination induced a global reduction of glucose metabolism compared with isoflurane; this reduction of metabolism was relatively lower in the primary somatosensory cortex and part of the limbic system. The volume of distribution of 18 F-fluorodeoxyglucose and its Glut1-mediated transport across the brain membranes (K1 ) were decreased in the KX group.

Comparison of different quantification methods for 18F-fluorodeoxyglucose-positron emission tomography studies in rat brains

OBJECTIVES: This study aimed to evaluate several methods to estimate glucose consumption in the male Wister rat brain as measured by PET. METHODS: Fourteen male Wistar normoglycemic rats were studied. The input function consisted of seventeen blood samples drawn manually from the femoral artery. Glucose uptake values were calculated using the input function resulting from the arterial blood samples and the tissue time-activity curve derived from the PET images. The estimated glucose consumption rate (Ki) based on the 2-tissue compartment model (2TCM) served as the standard for comparisons with the values calculated by the Patlak analysis and with the fractional uptake rate (FUR), standardized uptake value (SUV) and glucose corrected SUV (SUVglu). RESULTS: No significant difference between the standard Ki and the Patlak Ki was observed. The standard Ki was also found to have strong correlations and concordance with the Ki value estimated by the Patlak analysis. The FUR method presented an excellent correlation with the Ki value obtained by the 2TCM/Patlak analyses, in contrast to the SUV or SUVglu. CONCLUSIONS: From a methodological point of view, the present findings confirm the theoretical limitations of the cerebral SUV and SUVglu as a substitute for Ki in the estimation of glucose consumption in the brain. Our data suggest that the FUR is the surrogate to Ki.

Methods for quantification of cerebral glycolytic metabolism using 2-deoxy-2-[18 F]fluoroglucose in small animals

Abstract Introduction The use of the same imaging and quantification techniques in small animals and clinical studies presents the opportunity for direct translational research in drug discovery and development, in neuropharmacological basis of neurological and psychiatric diseases, and in optimization of drug therapy. Thus, positron emission tomography (PET) studies in rodents can bridge the gap between pre-clinical and clinical research. The aim should be to find a method with capability to measure, without compromising accuracy, glucose distribution in the structures of the brain, which can also be used in pathological situations and with applicability for other substances than glucose analogue. Methods This is a systematic review of several assessment techniques available, including visual and quantitative methods that enable the investigation of the transport mechanisms and enzymes involved in glucose metabolism in the brain. In addition to the ex vivo methods, PET with glucose analogues allows in vivo analyses using qualitative, semiquantitative and quantitative methods. Results These techniques provide different results, and the applicability of a specific method is related to the purpose of the study and the multiple factors that may interfere in the process. Conclusion This review provides a solid background of tools and quantification methods for medical physicists and other professionals interested in cerebral glycolytic metabolism quantification in experimental animals. It also addresses the main factors related to animals, equipment and techniques that are used, as well as how these factors should be understood to better interpret the results obtained from experiments.

Brain metabolism and cerebrospinal fluid biomarkers profile of non-amnestic mild cognitive impairment in comparison to amnestic mild cognitive impairment and normal older subjects.

INTRODUCTION: Mild cognitive impairment (MCI) is classically considered a transitional stage between normal aging and dementia. Non-amnestic MCI (naMCI) patients, however, typically demonstrate cognitive deficits other than memory decline. Furthermore, as a group, naMCI have a lower rate of an eventual dementia diagnosis as compared to amnestic subtypes of MCI (aMCI). Unfortunately, studies investigating biomarker profiles of naMCI are scarce. The study objective was to investigate the regional brain glucose metabolism (rBGM) with [18F]FDG-PET and cerebrospinal fluid (CSF) biomarkers in subjects with naMCI as compared to a control group (CG) and aMCI subjects. METHODS: Ninety-five patients were included in three different groups: naMCI (N = 32), aMCI (N = 33) and CG (N = 30). Patients underwent brain MRI and [18F]FDG-PET. A subsample (naMCI = 26, aMCI = 28) also had an assessment of amyloid-ß, tau, and phosphorylated tau levels in the CSF. RESULTS: Both MCI groups had lower rBGM in relation to the CG in the precuneus. Subjects with naMCI showed decreased right prefrontal metabolism as well as higher levels of CSF amyloid-ß relative to aMCI subjects. CONCLUSION: While amnestic MCI subjects showed a biomarker profile classically related to MCI due to Alzheimer's disease, naMCI patients illustrated a decrease in both prefrontal hypometabolism and higher CSF amyloid-ß levels relative to the aMCI group. These biomarker findings indicate that naMCI is probably a heterogeneous group with similar precuneus hypometabolism compared to aMCI, but additional frontal hypometabolism and less amyloid-ß deposition in the brain. Clinical follow-up and reappraisal of biomarkers of the naMCI group is needed to determine the outcome and probable etiological diagnosis.

Effects of Aerobic Training on Cognition and Brain Glucose Metabolism in Subjects with Mild Cognitive Impairment.

BACKGROUND: Aerobic training (AT) is a promising intervention for mild cognitive impairment (MCI). OBJECTIVE: To evaluate the effects of AT on cognition and regional brain glucose metabolism (rBGM) in MCI patients. METHODS: Subjects performed a twice-a-week, moderate intensity, AT program for 24 weeks. Assessment with ADAS-cog, a comprehensive neuropsychological battery, and evaluation of rBGM with positron emission tomography with 18F-fluorodeoxyglucose ([18F]FDG-PET) were performed before and after the intervention. Aerobic capacity was compared using the maximal oxygen consumption VO2max (mL/Kg/min). [18F]FDG-PET data were analyzed on a voxel-by-voxel basis with SPM8 software. RESULTS: Forty subjects were included, with a mean (M) age of 70.3 (5.4) years and an initial Mini-Mental State Exam score of 27.4 (1.7). Comparisons using paired t-tests revealed improvements in the ADAS-cog (M difference: -2.7 (3.7), p <  0.001) and VO2max scores (M difference: 1.8 (2.0) mL/kg/min, p <  0.001). Brain metabolic analysis revealed a bilateral decrease in the rBGM of the dorsal anterior cingulate cortex, pFWE = 0.04. This rBGM decrease was negatively correlated with improvement in a visuospatial function/attentional test (rho =-0.31, p = 0.04). Several other brain areas also showed increases or decreases in rBGM. Of note, there was an increase in the retrosplenial cortex, an important node of the default mode network, that was negatively correlated with the metabolic decrease in the dorsal anterior cingulate cortex (r =-0.51, p = 0.001). CONCLUSION: AT improved cognition and changed rBGM in areas related to cognition in subjects with MCI.

Changes in neuropsychological tests and brain metabolism after bariatric surgery.

CONTEXT: The mechanisms by which obesity alters the cerebral function and the effect of weight loss on the brain have not been completely clarified. OBJECTIVE: The objective of the study was to assess the effect of bariatric surgery on the cognitive function and cerebral metabolism. DESIGN: Seventeen obese women were studied prior to and 24 weeks after bariatric surgery using neuropsychological tests and positron emission tomography. SETTING: The study was conducted in a reference center for the treatment of obesity of a Brazilian public university. PARTICIPANTS: Thirty-three women paired by age and level of education made up two groups: 17 severely obese patients and 16 lean patients. They did not have diabetes mellitus or a family history of dementia. MAIN OUTCOME MEASURES: Comparison of performance in neuropsychological tests and cerebral metabolism of the obese women before and after bariatric surgery was measured. The results found at the two moments were compared with those of the women of normal weight. RESULTS: Women with a mean age of 40.5 years and mean body mass index of 50.1 kg/m(2) when compared with women with mean body mass index of 22.3 kg/m(2) showed increased cerebral metabolism, especially in the posterior cingulate gyrus (P < .004). No difference was found between the groups for the neuropsychological tests. After 24 weeks the cerebral metabolism of the obese women was lower, similar to the lean women, and there was an improvement of executive function, accompanying changes of metabolic and inflammatory parameters. CONCLUSIONS: Obese women may have increased cerebral metabolism when compared with women of normal weight, and this appears to reverse after weight loss induced by bariatric surgery, accompanied by improved executive function.

Early postnatal rat ventricle resection leads to long-term preserved cardiac function despite tissue hypoperfusion.

One-day-old mice display a brief capacity for heart regeneration after apex resection. We sought to examine this response in a different model and to determine the impact of this early process on long-term tissue perfusion and overall cardiac function in response to stress. Apical resection of postnatal rats at day 1 (P1) and 7 (P7) rendered 18 ± 1.0% and 16 ± 1.3% loss of cardiac area estimated by magnetic resonance imaging (MRI), respectively (P > 0.05). P1 was associated with evidence of cardiac neoformation as indicated by Troponin I and Connexin 43 expression at 21 days postresection, while in the P7 group mainly scar tissue replacement ensued. Interestingly, there was an apparent lack of uniform alignment of newly formed cells in P1, and we detected cardiac tissue hypoperfusion for both groups at 21 and 60 days postresection using SPECT scanning. Direct basal cardiac function at 60 days, when the early lesion is undetectable, was preserved in all groups, whereas under hemodynamic stress the degree of change on LVDEP, Stroke Volume and Stroke Work indicated diminished overall cardiac function in P7 (P < 0.05). Furthermore, the End-Diastolic Pressure-Volume relationship and increased interstitial collagen deposition in P7 is consistent with increased chamber stiffness. Taken together, we provide evidence that early cardiac repair response to apex resection in rats also leads to cardiomyocyte neoformation and is associated to long-term preservation of cardiac function despite tissue hypoperfusion.

Long-term lithium treatment reduces glucose metabolism in the cerebellum and hippocampus of nondemented older adults: an [¹8F]FDG-PET study.

Lithium modulates several intracellular pathways related to neuroplasticity and resilience against neuronal injury. These properties have been consistently reported in experimental models, and involve the up-regulation of neurotrophic response and autophagy, and down-regulation of apoptosis, oxidative stress, and inflammation. Clinical and epidemiological studies in bipolar disorder show that acute treatment with lithium increases plasma concentrations of brain-derived neurotrophic factor, and long-term treatment lowers the risk of dementia. Neuroimaging studies indicate that lithium use is further associated with increased cortical thickness and larger hippocampal volumes. The objective of the present study was to evaluate whether these neurobiological properties of lithium reflect in increased regional brain glucose metabolism, as shown by [(18)F]FDG-PET. Participants (n = 19) were nondemented older adults recruited at the end point of a controlled trial addressing clinical and biological effects of lithium in a sample of patients with amnestic mild cognitive impairment. Twelve patients who had received low-dose lithium carbonate for 4 years were compared to seven matched controls. Chronic lithium treatment was not associated with any significant increase in brain glucose metabolism in the studied areas. Conversely, we found a significant reduction in glucose uptake in several clusters of the cerebellum and in both hippocampi. These findings were not associated with any clinical evidence of toxicity. The clinical implications of the present findings need to be clarified by future controlled studies, particularly in the light of the potential use of lithium as a disease-modifying treatment approach for certain neurodegenerative disorders, namely, Alzheimer's disease and amyotrophic lateral sclerosis.

Association between major depressive symptoms in heart failure and impaired regional cerebral blood flow in the medial temporal region: a study using 99m Tc-HMPAO single photon emission computerized tomography (SPECT).

BACKGROUND AND PURPOSE: Depressive symptoms are frequently associated with heart failure (HF), but the brain mechanisms underlying such association are unclear. We hypothesized that the presence of major depressive disorder (MDD) emerging after the onset of HF would be associated with regional cerebral blood flow (rCBF) abnormalities in medial temporal regions previously implicated in primary MDD, namely the hippocampus and parahippocampal gyrus. METHOD: Using 99mTc-SPECT, we measured rCBF in 17 elderly MDD-HF patients, 17 non-depressed HF patients, and 18 healthy controls, matched for demographic variables. Group differences were investigated with Statistical Parametric Mapping. RESULTS: Significant rCBF reductions in MDD-HF patients relative to both non-depressed HF patients and healthy controls were detected in the left anterior parahippocampal gyrus and hippocampus (ANOVA, p=0.008 corrected for multiple comparisons) and the right posterior hippocampus and parahippocampal gyrus (p=0.005 corrected). In the overall HF group, there was a negative correlation between the severity of depressive symptoms and rCBF in the right posterior hippocampal/parahippocampal region (p=0.045 corrected). CONCLUSIONS: These findings are consistent with the notion that the medial temporal region is vulnerable to brain perfusion deficits associated with HF, and provide evidence that such functional deficits may be specifically implicated in the pathophysiology of MDD associated with HF.

Localized cerebral blood flow reductions in patients with heart failure: a study using 99mTc-HMPAO SPECT.

BACKGROUND AND PURPOSE: Reduced resting global cerebral blood flow has been previously detected in association with heart failure (HF), but it is not clear whether there are brain regions that could be specifically affected by those brain perfusion deficits. The authors used a fully automated, voxel-based image analysis method to investigate, across the entire cerebral volume, the presence of resting regional cerebral blood flow (rCBF) abnormalities in HF patients compared to healthy controls. METHODS: rCBF was evaluated with 99mTc-single-photon emission computed tomography in 17 HF patients (New York Heart Association functional class II or III) and 18 elderly healthy volunteers. Voxel-based analyses of rCBF data were conducted using the statistical parametric mapping software. RESULTS: Significant rCBF reductions in HF patients relative to controls (P<.05, corrected for multiple comparisons) were detected in 2 foci, encompassing, respectively, the left and right precuneus and cuneus and the right lateral temporoparietal cortex and posterior cingulated gyrus. In the HF group, there was also a significant direct correlation between the degree of cognitive impairment as assessed using the Cambridge Mental Disorders of the Elderly Examination and rCBF on a voxel cluster involving the right posterior cingulate cortex and precuneus, located closely to the site where between-group rCBF differences had been identified. CONCLUSIONS: These preliminary findings indicate that posterior cortical areas of the brain may be particularly vulnerable to brain perfusion reductions associated with HF and suggest that functional deficits in these regions might be relevant to the pathophysiology of the cognitive impairments presented by HF patients.