Cerebral Metabolic Abnormalities Research Articles

Effect of Cannabidiol in LPS-Induced Toxicity in Astrocytes: Possible Role for Cannabinoid Type-1 Receptors.

Cerebral metabolic abnormalities are common in neurodegenerative diseases. Previous studies have shown that mitochondrial damage alters ATP production and increases reactive oxygen species (ROS) release which may contribute to neurodegeneration. In the present study, we investigated the neuroprotective effects of cannabidiol (CBD), a non-psychoactive component derived from marijuana (Cannabis sativa L.), on astrocytic bioenergetic balance in a primary cell culture model of lipopolysaccharide (LPS)-induced neurotoxicity. Astrocytic metabolic profiling using an extracellular flux analyzer demonstrated that CBD decreases mitochondrial proton leak, increased spare respiratory capacity and coupling efficiency in LPS-stimulated astrocytes. Simultaneously, CBD increased astrocytic glycolytic capacity and glycolysis reserve in a cannabinoid receptor type 1 (CB1)-dependent manner. CBD-restored metabolic changes were correlated with a significant decrease in the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) concentration and reduction of ROS production in LPS-stimulated astrocytes. These results suggest that CBD may inhibit LPS-induced metabolic impairments and inflammation by enhancing astrocytic metabolic glycolysis versus oxidative phosphorylation through its action on CB1 receptors. The present findings suggest CBD as a potential anti-inflammatory treatment in metabolic pathologies and highlight a possible role for the cannabinoidergic system in the modulation of mitochondrial oxidative stress. CBD enhances mitochondrial bioenergetic profile, attenuates proinflammatory cytokines release, and ROS overproduction of astrocytes stimulated by LPS. These effects are not mediated directly by CB1 receptors, while these receptors seem to have a key role in the anti-inflammatory response of the endocannabinoid system on astrocytes, as their specific inhibition by SR141716A led to increased pro-inflammatory cytokines release and ROS production. The graphical abstract is created with BioRender.com.

Cerebral Hemodynamic and Metabolic Abnormalities in Neonatal Hypocalcemia: Findings from Advanced MRI.

Neonatal hypocalcemia is the most common metabolic disorder, and whether asymptomatic disease should be treated with calcium supplements remains controversial. We aimed to quantify neonatal hypocalcemia's global CBF and cerebral metabolic rate of oxygen (CMRO2) using physiologic MR imaging and elucidate the pathophysiologic vulnerabilities of neonatal hypocalcemia. A total of 37 consecutive patients with neonatal hypocalcemia were enrolled. They were further divided into subgroups with and without structural MR imaging abnormalities, denoted as neonatal hypocalcemia-a (n = 24) and neonatal hypocalcemia-n (n = 13). Nineteen healthy neonates were enrolled as a control group. Brain physiologic parameters determined using phase-contrast MR imaging, T2-relaxation-under-spin-tagging MR imaging, and brain volume were compared between patients with neonatal hypocalcemia (their subgroups) and controls. Predictors for neonatal hypocalcemia-related brain injuries were identified using multivariate logistic regression analysis and expressed as ORs with 95% CIs. Patients with neonatal hypocalcemia showed significantly lower CBF and CMRO2 compared with controls. Furthermore, the neonatal hypocalcemia-a subset (versus controls or neonatal hypocalcemia-n) had significantly lower CBF and CMRO2. There was no obvious difference in CBF and CMRO2 between the neonatal hypocalcemia-n subset and controls. CBF and CMRO2 were independently associated with neonatal hypocalcemia. The ORs were 0.80 (95% CI, 0.65-0.99) and 0.97 (95% CI, 0.89-1.05) for CBF and CMRO2, respectively. Neonatal hypocalcemia with structural damage may exhibit lower hemodynamics and cerebral metabolism. CBF may be useful in assessing the need for calcium supplementation in asymptomatic neonatal hypocalcemia to prevent brain injury.

Abnormal cerebral metabolism and metabolic connectivity in individuals with heroin dependence: an integrated resting-state PET/fMRI study in large-scale networks.

Increasing evidence suggests that heroin addiction may be related to the dysfunction among the triple brain network (default mode network [DMN], salience network [SN] and executive control network [ECN]). However, the characteristics of glucose metabolism and metabolic connectivity among core regions of the triple brain network remain unknown. Therefore, we hypothesized that individuals with heroin dependence would show abnormal glucose metabolism and accompanied abnormal metabolic connectivity within the triple brain network. Individuals with heroin dependence and healthy controls matched for age and sex underwent integrated positron emission tomography/magnetic resonance imaging (PET/MRI). Differences in glucose metabolism and metabolic connectivity among the DMN, SN and ECN were analyzed based on 18F-fluorodeoxyglucose PET and resting-state fMRI data. We included 36 individuals with heroin dependence and 30 matched healthy controls in our study. The heroin dependence group showed a significant reduction of glucose metabolism in the bilateral anterior insula (AI) and inferior parietal lobule (IPL), and a significantly decreased metabolic connectivity between the right AI and the left dorsolateral prefrontal cortex (DLPFC). The daily dose of methadone was negatively correlated with glucose metabolism of the right AI and right IPL. The results revealed the glucose metabolism alterations and metabolic connectivity only within the triple brain network in individuals with heroin dependence; additional brain networks should be investigated in future studies. Although methadone is an opioid with a similar neurophysiological mechanism as heroin, the specific chronic effects of methadone on cerebral metabolism and metabolic connectivity should also be investigated in future studies. Our findings suggest that long-term opioid use might, to some extent, be associated with reduced synergistic ability between the SN and ECN, which may be associated with the dysfunction of cognitive control. In particular, the right AI, which showed hypometabolism and related reduction in SN-ECN metabolic connectivity, should receive increasing attention in future studies.

Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60years, with follow-ups occurring from 2 to 37years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.

Ferrous sulfate reverses cerebral metabolic abnormality induced by minimal hepatic encephalopathy.

Orally administered ferrous iron was previously reported to significantly improve the cognition and locomotion of patients with minimal hepatic encephalopathy (MHE). However, the metabolic mechanisms of the therapeutic effect of ferrous iron are unknown. In this study, MHE was induced in rats by partial portal vein ligation (PPVL), and was treated with ferrous sulfate. The Morris water maze was used to evaluate the cognitive condition of the rats. The metabolites observed by NMR and validated by liquid chromatography-mass spectrometry were defined as the key affected metabolites. The enzyme activities and trace element contents in the rat brains were also investigated. The Mn content was found to be increased but the ferrous iron content decreased in the cortex and striatum in MHE. Decreased oxoglutarate dehydrogenase activity and increased glutamine synthetase (GS) and pyruvate carboxylase (PC) activity were observed in the cortex of MHE rats. Decreased pyruvate dehydrogenase activity and increased GS and PC activity were observed in the striatum of MHE rats. The levels of BCAAs and taurine were significantly decreased, and the contents of GABA, lactate, arginine, aspartate, carnosine, citrulline, cysteine, glutamate, glutamine, glycine, methionine, ornithine, proline, threonine and tyrosine were significantly increased. These metabolic abnormalities described above were restored after treatment with ferrous sulfate. Pathway enrichment analysis suggested that urea cycle, aspartate metabolism, arginine and proline metabolism, glycine and serine metabolism, and glutamate metabolism were the major metabolic abnormalities in MHE rats, but these processes could be restored and cognitive impairment could be improved by ferrous sulfate administration.

Effects of Bilateral Subthalamic Nucleus Stimulation on Depressive Symptoms and Cerebral Glucose Metabolism in Parkinson's Disease: A 18F-Fluorodeoxyglucose Positron Emission Tomography/Computerized Tomography Study.

Subthalamic nucleus (STN) deep brain stimulation (DBS) can improve motor symptoms in Parkinson’s disease (PD), as well as potentially improving otherwise intractable comorbid depressive symptoms. To address the latter issue, we evaluated the severity of depressive symptoms along with the severity of motor symptoms in 18 PD patients (mean age, 58.4 ± 5.4 years; 9 males, 9 females; mean PD duration, 9.4 ± 4.4 years) with treatment-resistant depression (TRD) before and after approximately 1 year of STN-DBS treatment. Moreover, to gain more insight into the brain mechanism mediating the therapeutic action of STN-DBS, we utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess cerebral regional glucose metabolism in the patients at baseline and 1-year follow-up. Additionally, the baseline PET data from patients were compared with PET data from an age- and sex-matched control group of 16 healthy volunteers. Among them, 12 PD patients underwent post-operative follow-up PET scans. Results showed that the severity of both motor and depressive symptoms in patients with PD-TRD was reduced significantly at 1-year follow-up. Also, patients used significantly less antiparkinsonian medications and antidepressants at 1-year follow-up, as well as experiencing improved daily functioning and a better quality of life. Moreover, relative to the PET data from healthy controls, PD-TRD patients displayed widespread abnormalities in cerebral regional glucose metabolism before STN-DBS treatment, which were partially recovered at 1-year follow-up. Additionally, significant correlations were observed between the patients’ improvements in depressive symptoms following STN-DBS and post-operative changes in glucose metabolism in brain regions implicated in emotion regulation. These results support the view that STN-DBS provides a promising treatment option for managing both motor and depressive symptoms in patients who suffer from PD with TRD. However, the results should be interpreted with caution due to the observational nature of the study, small sample size, and relatively short follow-up.

In vivo magnetic resonance spectrometry imaging demonstrates comparable adaptation of brain energy metabolism to metabolic stress induced by 72 h of fasting in depressed patients and healthy volunteers

Major depressive disorder (MDD) is characterized by dysregulation of stress systems and by abnormalities in cerebral energy metabolism. Stress induction has been shown to impact neurometabolism in healthy individuals. Contrarily, neurometabolic changes in response to stress are insufficiently investigated in MDD patients. Metabolic stress was induced in MDD patients (MDD, N = 24) and in healthy individuals (CTRL, N = 22) by application of an established fasting protocol in which calorie intake was omitted for 72 h. Both study groups were comparable regarding age, gender distribution, and body mass index (BMI). Fasting-induced effects on brain high-energy phosphate levels and membrane phospholipid metabolism were assessed using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Two-way repeated measures ANOVAs did not reveal significant interaction effects (group x fasting) or group differences in adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), phosphodiesters (PDE), or pH levels between MDD and CTRL. Fasting, independent of group, significantly increased ATP and decreased Pi levels and an overall increase in PME/PDE ratio as marker for membrane turnover was observed. Overall these results indicate reactive changes in cerebral energetics and in membrane phospholipid metabolism in response to fasting. The observed effects did not significantly differ between CTRL and MDD, indicating that neurometabolic adaptation to metabolic stress is preserved in MDD patients.

Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder.

BackgroundPrevious studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients.MethodsA total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated.ResultsThe decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients.ConclusionsThe findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.

Diagnostic utility of positron emission tomography-computed tomography and indications for 18F-Fluorodeoxyglucose and amyloid-tracers

Positron emission tomography-computed tomography (PET-CT) is a nuclear medicine imaging technique widely used in oncology, cardiology and neurology where it’is becoming of great interest especially because of its role in the diagnosis and differential diagnosis between several pathological conditions involving the nervous system. In neurodegenerative diseases, the most used PET-CT radiopharmaceuticals are 18Fluoro-Fluorodeoxyglucose (18FFDG), a glucose analogue that is able to identify abnormalities of cerebral glucose metabolism, and amyloid-tracers (11C-PiB, 18F-Florbetapir, 18F-Flutemetamol, 18F-Florbetaben) that are able to detect presence of amyloid plaques. Depending on the specific characteristic of tracers and patient’s disease, the examination has dedicated appropriate indications that are illustrated in this article. PET-CT, with its several tracers, is an accurate tool in evaluating neurodegenerative diseases. 18F-FDG is considered a hallmark of the stage of the disease. Glucose hypometabolism in specific cerebral areas allows distinguishing different degenerative diseases. Amyloid tracers are considered the hallmark of the state of the disease. The uptake of PET-amyloids tracers reflects the cortical regional density of amyloid plaques.

Evolution of lobar abnormalities of cerebral glucose metabolism in 41 children with drug-resistant epilepsy.

We analyzed long-term changes of lobar glucose metabolic abnormalities in relation to clinical seizure variables and development in a large group of children with medically refractory epilepsy. Forty-one children (25 males) with drug-resistant epilepsy had a baseline positron emission tomography (PET) scan at a median age of 4.7years; the scans were repeated after a median of 4.3years. Children with progressive neurological disorders or space-occupying lesion-related epilepsy and those who had undergone epilepsy surgery were excluded. The number of affected lobes on 2-deoxy-2(18 F)-fluoro-D-glucose-PET at baseline and follow-up was correlated with epilepsy variables and developmental outcome. On the initial PET scan, 24 children had unilateral and 13 had bilateral glucose hypometabolism, whereas 4 children had normal scans. On the follow-up scan, 63% of the children showed an interval expansion of the hypometabolic region, and this progression was associated with persistent seizures. In contrast, 27% showed less extensive glucose hypometabolism at follow-up; most of these subjects manifested a major interval decrease in seizure frequency. Delayed development was observed in 21 children (51%) at baseline and 28 (68%) at follow-up. The extent of glucose hypometabolism at baseline correlated with developmental levels at the time of both baseline (r=.31, P=.05) and follow-up scans (r=.27, P=.09). In this PET study of unoperated children with focal epilepsy, the lobar pattern of glucose hypometabolism changed over time in 90% of the cases. The results support the notion of an expansion of metabolic dysfunction in children with persistent frequent seizures and its association with developmental delay, and support that optimized medical treatment to control seizures may contribute to better neurocognitive outcome if no surgery can be offered.

Associations of neurofunctional, morphometric and metabolic abnormalities with clinical symptom severity and recognition deficit in obsessive–compulsive disorder

BackgroundObsessive–compulsive disorder (OCD) causes neural dysfunction associated with cognitive deficit and emotional dysregulation. This study assessed the associations of the neurofunctional changes, gray matter (GM) and white matter (WM) volume alterations in conjunction with in vivo metabolic changes on the working memory tasks in patients with OCD. MethodsEighteen patients with OCD and 18 healthy controls matched for age, sex, and educational levels underwent high-resolution T1-weighted magnetic resonance imaging (MRI), event-related functional MRI (fMRI), and proton magnetic resonance spectroscopy (1H-MRS) at 3T. ResultsIn fMRI, patients with OCD showed lower activities in the cerebellum, inferior temporal gyrus, orbitofrontal gyrus, dorsolateral prefrontal cortex and calcarine gyrus compared to the controls. In VBM, the patients showed significantly reduced GM volumes, especially in the cerebellum, hippocampus, and superior temporal gyrus, together with significantly reduced WM volumes in the retrolenticular part of the internal capsule, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal gyrus. In 1H-MRS, the ratios of N-acetylaspartate/creatine and choline/creatine were significantly lower in the DLPFC of the patients than in the controls, whereas the ratio of β∙γ-glutamine-glutamate/creatine was significantly higher in the patients than in the controls. LimitationsThis study examined small numbers of subjects in each one of the groups. ConclusionsThe findings will be helpful to aid us in understanding of neurocognitive impairment in OCD, and thus, enhancing the diagnostic accuracy for OCD by additional information on the associated brain functional deficit, cerebral volume change and metabolic abnormality.

Mitochondrial dysfunction and cerebral metabolic abnormalities in patients with mitochondrial encephalomyopathy subtypes: Evidence from proton MR spectroscopy and muscle biopsy.

Accumulated evidence indicates that cerebral metabolic features, evaluated by proton magnetic resonance spectroscopy (1 H-MRS), are sensitive to early mitochondrion dysfunction associated with mitochondrial encephalomyopathy (ME). The metabolite ratios of lactate (lac)/Cr, N-acetyl aspartate (NAA)/creatine (Cr), total choline (tCho)/Cr, and myoinositol (mI)/Cr are measured in the infarct-like lesions by 1 H-MRS and may reveal metabolic changes associated with ME. However, the application of this molecular imaging technique in the investigation of the pathology of ME subtypes is unknown. In this study, cerebral metabolic features of pathologically diagnosed ME cases, that is, 19 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); nine chronic progressive external ophthalmoplegia (CPEO); and 23 healthy controls, were investigated using 1 H-MRS. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic power of the cerebral metabolites. Histochemical evaluation was carried out on muscle tissues derived from biopsy to assess the abnormal mitochondrial proliferation. The association between cerebral metabolic and mitochondrial cytopathy was examined by correlation analysis. Patients with MELAS or CPEO exhibited a significantly higher Lac/Cr ratio and a lower NAA/Cr ratio compared with controls. The ROC curve of Lac/Cr ratio indicated prominent discrimination between MELAS or CPEO and healthy control subjects, whereas the NAA/Cr ratio may present diagnostic power in the distinction of MELAS from CPEO. Lower NAA/Cr ratio was associated with higher Lac/Cr in MELAS, but not in CPEO. Furthermore, higher ragged-red fibers (RRFs) percentages were associated with elevated Lac/Cr and reduced NAA/Cr ratios, notably in MELAS. This association was not noted in the case of mI/Cr ratio. Mitochondrial cytopathy (lactic acidosis and RRFs on muscle biopsy) was associated with neuronal viability but not glial proliferation, notably in MELAS. Mitochondrial neuronopathy and neuronal vulnerability are considered significant causes in the pathogenesis of MELAS, particularly with regard to stroke-like episodes.

Objective 3D surface evaluation of intracranial electrophysiologic correlates of cerebral glucose metabolic abnormalities in children with focal epilepsy.

To determine the spatial relationship between 2-deoxy-2[18 F]fluoro-D-glucose (FDG) metabolic and intracranial electrophysiological abnormalities in children undergoing two-stage epilepsy surgery, statistical parametric mapping (SPM) was used to correlate hypo- and hypermetabolic cortical regions with ictal and interictal electrocorticography (ECoG) changes mapped onto the brain surface. Preoperative FDG-PET scans of 37 children with intractable epilepsy (31 with non-localizing MRI) were compared with age-matched pseudo-normal pediatric control PET data. Hypo-/hypermetabolic maps were transformed to 3D-MRI brain surface to compare the locations of metabolic changes with electrode coordinates of the ECoG-defined seizure onset zone (SOZ) and interictal spiking. While hypometabolic clusters showed a good agreement with the SOZ on the lobar level (sensitivity/specificity = 0.74/0.64), detailed surface-distance analysis demonstrated that large portions of ECoG-defined SOZ and interictal spiking area were located at least 3 cm beyond hypometabolic regions with the same statistical threshold (sensitivity/specificity = 0.18-0.25/0.94-0.90 for overlap 3-cm distance); for a lower threshold, sensitivity for SOZ at 3 cm increased to 0.39 with a modest compromise of specificity. Performance of FDG-PET SPM was slightly better in children with smaller as compared with widespread SOZ. The results demonstrate that SPM utilizing age-matched pseudocontrols can reliably detect the lobe of seizure onset. However, the spatial mismatch between metabolic and EEG epileptiform abnormalities indicates that a more complete SOZ detection could be achieved by extending intracranial electrode coverage at least 3 cm beyond the metabolic abnormality. Considering that the extent of feasible electrode coverage is limited, localization information from other modalities is particularly important to optimize grid coverage in cases of large hypometabolic cortex. Hum Brain Mapp 38:3098-3112, 2017. © 2017 Wiley Periodicals, Inc.

Region-specific cerebral metabolic alterations in streptozotocin-induced type 1 diabetic rats: an in vivo proton magnetic resonance spectroscopy study.

Clinical and experimental in vivo (1)H-magnetic resonance spectroscopy ((1)H-MRS) studies have demonstrated that type 1 diabetes mellitus (T1DM) is associated with cerebral metabolic abnormalities. However, less is known whether T1DM induces different metabolic disturbances in different brain regions. In this study, in vivo (1)H-MRS was used to measure metabolic alterations in the visual cortex, striatum, and hippocampus of streptozotocin (STZ)-induced uncontrolled T1DM rats at 4 days and 4 weeks after induction. It was observed that altered neuronal metabolism occurred in STZ-treated rats as early as 4 days after induction. At 4 weeks, T1DM-related metabolic disturbances were clearly region specific. The diabetic visual cortex had more or less normal-appearing metabolic profile; while the striatum and hippocampus showed similar abnormalities in neuronal metabolism involving N-acetyl aspartate and glutamate; but only the hippocampus exhibited significant changes in glial markers such as taurine and myo-inositol. It is concluded that cerebral metabolic perturbations in STZ-induced T1DM rats are region specific at 4 weeks after induction, perhaps as a manifestation of varied vulnerability among the brain regions to sustained hyperglycemia.

Consistency of FDG uptake on 18F-FDG PET/CT and regional homogeneity on functional MRI in major depression disorder patients

Objective To investigate the changes of cerebral regional glucose metabolism and regional homogeneity (ReHo) and their relation in patients with major depression disorder (MDD) using 18F-FDG PET/CT and functional MRI (fMRI). Methods A total of 18 MDD patients (6 males, 12 females, age: (33.00±7.59) years) and 17 healthy controls (6 males, 11 females, age: (34.59±8.96) years) underwent 18F-FDG PET/CT and fMRI. The changes of glucose metabolism on PET and ReHo on fMRI were analyzed individually by SPM and ReHo fMRI 1.0 software. Pearson correlation analysis was used. Results Compared with the glucose metabolism of control subjects, those of MDD patients decreased in the bilateral superior, middle and inferior frontal gyri, bilateral superior and middle temporal gyri, bilateral anterior cingulate cortices, bilateral putamina and caudate nuclei and the left pallidum. Meanwhile the glucose metabolism increased in the bilateral hippocampi and the left thalamus. The ReHo in MDD patients decreased in bilateral superior and middle frontal gyri, left pallidum, bilateral putamina, left anterior cingulate cortex, whereas increased ReHo was found in right hippocampus and right thalamus. The SUV of bilateral superior, middle and inferior frontal gyri, bilateral superior and middle temporal gyri, bilateral putamina, left caudate, left pallidum, left anterior cingulate cortex, bilateral hippocampi and bilateral thalami were correlated with ReHo (r=0.51-0.83, all P 0.05). Conclusion There may be relative characteristic models of abnormal cerebral metabolism and cerebral dysfunction impairment in MDD patients, and the changes of cerebral regional glucose metabolism may be correlated with the changes of ReHo. Key words: Depressive disorder; Brain; Tomography, emission-computed; Tomography, X-ray computed; Magnetic resonance imaging; Deoxyglucose

Preliminary Study of Brain Glucose Metabolism Changes in Patients with Lung Cancer of Different Histological Types

Background:Cerebral glucose metabolism changes are always observed in patients suffering from malignant tumors. This preliminary study aimed to investigate the brain glucose metabolism changes in patients with lung cancer of different histological types.Methods:One hundred and twenty patients with primary untreated lung cancer, who visited People's Hospital of Zhengzhou University from February 2012 to July 2013, were divided into three groups based on histological types confirmed by biopsy or surgical pathology, which included adenocarcinoma (52 cases), squamous cell carcinoma (43 cases), and small-cell carcinoma (25 cases). The whole body 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) of these cases was retrospectively studied. The brain PET data of three groups were analyzed individually using statistical parametric maps (SPM) software, with 50 age-matched and gender-matched healthy controls for comparison.Results:The brain resting glucose metabolism in all three lung cancer groups showed regional cerebral metabolic reduction. The hypo-metabolic cerebral regions were mainly distributed at the left superior and middle frontal, bilateral superior and middle temporal and inferior and middle temporal gyrus. Besides, the hypo-metabolic regions were also found in the right inferior parietal lobule and hippocampus in the small-cell carcinoma group. The area of the total hypo-metabolic cerebral regions in the small-cell carcinoma group (total voxel value 3255) was larger than those in the adenocarcinoma group (total voxel value 1217) and squamous cell carcinoma group (total voxel value 1292).Conclusions:The brain resting glucose metabolism in patients with lung cancer shows regional cerebral metabolic reduction and the brain hypo-metabolic changes are related to the histological types of lung cancer.

Age-dependent decreases of high energy phosphates in cerebral gray matter of patients with bipolar I disorder: A preliminary phosphorus-31 magnetic resonance spectroscopic imaging study

ObjectivesTo identify abnormalities in high energy phosphate cerebral metabolism in euthymic bipolar disorder. MethodsPhosphorus-31 magnetic resonance spectroscopic imaging (31P MRSI) data were acquired from the entire brain of 9 euthymic adults with bipolar disorder and 13 healthy adults. Estimates of phosphocreatine (PCr) and adenosine triphosphate (ATP) in homogeneous gray and white matter were obtained by tissue regression analysis. ResultsAnalyses of covariance revealed the effect of age to be significantly different between bipolar and healthy groups for concentrations of PCr (p=0.0018) and ATP (p=0.013) in gray matter. These metabolites were negatively correlated with age in gray matter in bipolar subjects while PCr was positively correlated with age in gray matter of healthy subjects. Additionally, age-corrected concentrations of PCr in gray matter were significantly elevated in bipolar subjects (p=0.0048). LimitationsGiven that this cross-sectional study possessed a small sample and potentially confounding effects of medication status, we recommend a larger, longitudinal study to more robustly study relationships between bioenergetic impairment and duration of disease. ConclusionsOur results suggest bioenergetic impairment related to mitochondrial function may be progressive in multi-episode bipolar subjects as they age.

Investigation of (11)C-PiB equivocal PET findings.

We have encountered occasional equivocal findings when assessing cerebral cortical amyloid retention with (11)C-Pittsburgh compound B (PiB) PET. We investigated the diagnostic significance of equivocal PiB PET findings. This retrospective study included 101 consecutive patients complaining of cognitive disorders (30 Alzheimer's disease, 25 mild cognitive impairment, 8 Lewy body disease, 7 frontotemporal lobar degeneration, 31 others) who underwent both (11)C-PiB PET and (18)F-fluorodeoxy-D-glucose (FDG) PET. We visually classified PiB-positive, PiB-equivocal or PiB-negative ratings according to cortical uptake. For quantitative assessments of PiB PET, standard uptake values referred to cerebellar cortex (SUVR) were calculated in regional template volume of interests (frontal, temporoparietal, precuneus/posterior cingulate cortex, cerebral white matter and cerebellar cortex). The results of visual assessment were compared with the regional and mean cortical SUVRs and cortical-to-white matter ratio of PiB uptake, as well as clinical and FDG PET findings. Among the 101 scans, 41 were PiB negative, 11 were PiB equivocal, and 49 were rated PiB positive in the visual assessments. The mean cortical SUVR and cortical-to-white matter ratio were 0.97 ± 0.07 and 0.57 ± 0.21 in PiB-negative, 1.51 ± 0.17 and 0.75 ± 0.06 in PiB equivocal and 2.10 ± 0.33 and 0.97 ± 0.11 in PiB-positive group, respectively. Nine of 11 subjects with PiB-equivocal findings had cognitive impairments and FDG distribution compatible with Alzheimer's disease or dementia with Lewy bodies. We considered equivocal visual findings on PiB PET equivalent to PiB-positive with slight cortical uptake. In addition, slight cortical amyloid deposits were considered to cause cerebral metabolic abnormality and cognitive impairment. Although mean cortical SUVR was more sensitive than visual assessment because of low cortical-to-white matter contrast due to non-specific accumulation in white matter, it is important not to overlook small amounts of cortical uptake of PiB in visual inspection for exact diagnosis.

Integrating transcriptomics with metabolic modeling predicts biomarkers and drug targets for Alzheimer's disease.

Accumulating evidence links numerous abnormalities in cerebral metabolism with the progression of Alzheimer's disease (AD), beginning in its early stages. Here, we integrate transcriptomic data from AD patients with a genome-scale computational human metabolic model to characterize the altered metabolism in AD, and employ state-of-the-art metabolic modelling methods to predict metabolic biomarkers and drug targets in AD. The metabolic descriptions derived are first tested and validated on a large scale versus existing AD proteomics and metabolomics data. Our analysis shows a significant decrease in the activity of several key metabolic pathways, including the carnitine shuttle, folate metabolism and mitochondrial transport. We predict several metabolic biomarkers of AD progression in the blood and the CSF, including succinate and prostaglandin D2. Vitamin D and steroid metabolism pathways are enriched with predicted drug targets that could mitigate the metabolic alterations observed. Taken together, this study provides the first network wide view of the metabolic alterations associated with AD progression. Most importantly, it offers a cohort of new metabolic leads for the diagnosis of AD and its treatment.

Value of proton magnetic resonance spectroscopy of brain to study the cerebral metabolic abnormalities in COPD: Initial experience

BackgroundChronic obstructive pulmonary disease (COPD) patients were found to have cerebral metabolic abnormalities. Proton magnetic resonance spectroscopy (1H MRS) is a sensitive technique that detects metabolic changes of the brain. ObjectiveTo study the cerebral metabolic changes in COPD patients using 1H MRS. MethodsThis study was carried-out on twenty symptomatic COPD patients (16 male and 4 female) and age matched group of 20 healthy controls (11 male and 19 female). Pulmonary function tests, respiratory muscle strength, resting arterial blood gases, and 1H MRS of the brain were carried out on all subjects. The parieto-temporal and occipital regions were localized for 1H MRS. The metabolic ratios of N-acetyl aspartate to creatine (NAA/Cr) and choline to creatine (Cho/Cr) were calculated by the single voxel technique. ResultsIn comparison with healthy control subjects, the mean values of Cho/Cr in COPD patients were lower in parieto-temporal and occipital areas (0.99±0.21 vs. 1.10±0.31; P=0.22) (0.81±0.26 vs. 0.88±0.21; P=0.37), respectively while, the mean values of NAA/Cr in COPD patients were higher in both parieto-temporal and occipital areas of the brain (1.82±0.35 vs. 1.68±0.22; P=0.14) (1.59±0.31 vs. 1.39±0.39; P=0.08), respectively. In COPD patients, significant positive correlations were observed between maximal expiratory pressure (MEP) and NAA/Cr in parieto-temporal area of the brain. ConclusionsThe cerebral metabolites, arterial blood gases, respiratory muscle strength, and pulmonary function tests are altered in symptomatic COPD patients. 1H MRS is a non invasive technique that detects cerebral metabolic changes in COPD patients.