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Rationale: After alcohol ingestion, the brain partly switches from consumption of glucose to consumption of the alcohol metabolite acetate. In heavy drinkers, the switch persists after abrupt abstinence, leading to the hypothesis that the resting brain may be “starved” when acetate levels suddenly drop during abstinence, despite normal blood glucose, contributing to withdrawal symptoms. We hypothesized that ketone bodies, like acetate, could act as alternative fuels in the brain and alleviate withdrawal symptoms. Objectives: We previously reported that a ketogenic diet during alcohol exposure reduced acute withdrawal symptoms in rats. Here, our goals were to test whether (1) we could reproduce our findings, in mice and with longer alcohol exposure; (2) ketone bodies alone are sufficient to reduce withdrawal symptoms (clarifying mechanism); (3) introduction of ketogenic diets at abstinence (a clinically more practical implementation) would also be effective. Methods: Male C57BL/6NTac mice had intermittent alcohol exposure for 3 weeks using liquid diet. Somatic alcohol withdrawal symptoms were measured as handling-induced convulsions; anxiety-like behavior was measured using the light-dark transition test. We tested a ketogenic diet, and a ketone monoester supplement with a regular carbohydrate-containing diet. Results: The regular diet with ketone monoester was sufficient to reduce handling-induced convulsions and anxiety-like behaviors in early withdrawal. Only the ketone monoester reduced handling-induced convulsions when given during abstinence, consistent with faster elevation of blood ketones, relative to ketogenic diet. Conclusions: These findings support the potential utility of therapeutic ketosis as an adjunctive treatment in early detoxification in alcohol-dependent patients seeking to become abstinent. Trial registration: clinicaltrials.gov NCT03878225, NCT03255031

Exposure to moderate hypoxia in humans leads to cerebral lactate production, which occurs even when the cerebral metabolic rate of oxygen (CMRO2) is unaffected. We searched for the mechanism of this lactate production by testing the hypothesis of upregulation of cerebral glycolysis mediated by hypoxic sensing. Describing the pathways counteracting brain hypoxia could help us understand brain diseases associated with hypoxia. A total of 65 subjects participated in this study: 30 subjects were exposed to poikilocapnic hypoxia, 14 were exposed to isocapnic hypoxia, and 21 were exposed to carbon monoxide (CO). Using this setup, we examined whether lactate production reacts to an overall reduction in arterial oxygen concentration or solely to reduced arterial oxygen partial pressure. We measured cerebral blood flow (CBF), CMRO2, and lactate concentrations by magnetic resonance imaging and spectroscopy. CBF increased (P 0.076) in all groups, as expected. Lactate increased in groups inhaling hypoxic air (poikilocapnic hypoxia: $0.0136\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P Lactate production was not associated with reduced CMRO2. These results point toward a mechanism of lactate production by upregulation of glycolysis mediated by sensing a reduced arterial oxygen pressure. The released lactate may act as a signaling molecule engaged in vasodilation.

Background: Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of 18F-DOPA to 18F-dopamine (k3) and the effect of treatment on psychotic symptoms in antipsychotic-naïve patients with first-episode psychosis. We further explored the effect of treatment with a partial dopamine D2 receptor agonist (aripiprazole) on k3 and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method. Methods: Sixty-two individuals (31 patients and 31 control subjects) underwent 18F-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale. Results: High baseline decarboxylation rates (k3) were associated with more positive symptoms at baseline (p < .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k3 for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k3 or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment. Conclusions: Striatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k3 and treatment effect potentially implicate on new treatment strategies.

We asked if sensation-seeking is linked to premorbid personality characteristics in patients with addictive disorders, or the characteristics follow the sensation-seeking activity. We interpreted the former as a state associated with normal rates of dopamine synthesis, and the latter as a trait of individuals with abnormally high rates of synthesis. We previously determined dopaminergic receptor density in striatum, and we now tested the hypothesis that an elevated dopaminergic condition with increased extracellular dopamine and receptor density follows increased dopamine synthesis capacity in highly sensation-seeking individuals, as measured by positron emission tomography of 18 men with tracer fluorodopa (FDOPA). We detected a site in left caudate nucleus where the volume of distribution of FDOPA-derived metabolites correlated negatively with FDOPA metabolite turnover, consistent with decreased metabolite breakdown in highly sensation-seeking subjects. High rates of sensation-seeking attenuated the dopamine turnover in association with a low rate of dopamine recycling, low dopamine oxidation, and elevated extracellular dopamine and receptors in caudate nucleus. In contrast, low rates of sensation-seeking were associated with rapid dopamine recycling, rapid dopamine oxidation, low extracellular dopamine, and low receptor density. We conclude that the modulation of dopaminergic neurotransmission associated with sensation-seeking is a state of sensation-seeking, rather than a trait of personality following abnormal regulation of dopaminergic neurotransmission.

Excessive sucrose consumption elicits addiction-like craving that may underpin the obesity epidemic. Opioids and dopamine mediate the rewarding effects of drugs of abuse, and of natural rewards from stimuli such as palatable food. We investigated the effects of sucrose using PET imaging with [11C]carfentanil (μ-opioid receptor agonist) and [11C]raclopride (dopamine D2/3 receptor antagonist) in seven female anesthetized Göttingen minipigs. We then gave minipigs access to sucrose solution for one hour on 12 consecutive days and performed imaging again 24 hours after the final sucrose access. In a smaller sample of five minipigs, we performed an additional [11C]carfentanil PET session after the first sucrose exposure. We calculated voxel-wise binding potentials (BPND) using the cerebellum as a region of non-displaceable binding, analyzed differences with statistical non-parametric mapping, and performed a regional analysis. After 12 days of sucrose access, BPND of both tracers had declined significantly in striatum, nucleus accumbens, thalamus, amygdala, cingulate cortex and prefrontal cortex, consistent with down-regulation of receptor densities. After a single exposure to sucrose, we found decreased binding of [11C]carfentanil in nucleus accumbens and cingulate cortex, consistent with opioid release. The lower availability of opioid and dopamine receptors may explain the addictive potential associated with intake of sucrose.

BackgroundAutonomic nervous system dysfunction (ANSD) is known to affect glucose metabolism in the mammalian body. Tradition holds that glucose homeostasis is regulated by the peripheral nervous system, and contemporary therapeutic intervention reflects this convention.ObjectivesThe present study tested the role of cerebral regulation of ANSD as consequence of novel understanding of glucose metabolism and treatment target in type 2 diabetes (T2D), suggested by the claim that the pressure pain sensitivity (PPS) of the chest bone periosteum may be a measure of cerebral ANSD.DesignIn a randomized controlled trial of 144 patients with T2D, we tested the claim that 6 months of this treatment would reduce PPS and improve peripheral glucose metabolism.ResultsIn the active treatment group, mean glycated hemoglobin A1c (HbA1c) declined from 53.8 to 50.5 mmol/mol (intragroup p = 0.001), compared with the change from 53.8 to 53.4 mmol/mol in the control group, with the same level of diabetes treatment but not receiving the active treatment (between group p = 0.036). Mean PPS declined from 76.6 to 56.1 units (p < 0.001) in the active treatment group and from 77.5 to 72.8 units (p = 0.02; between group p < 0.001) in the control group. Changes of PPS and HbA1c were correlated (r = 0.37; p < 0.001).ConclusionWe conclude that the proposed approach to treatment of T2D is a potential supplement to conventional therapy.Clinical Trial Registration:www.clinicaltrials.gov (NCT 03576430).

Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) show large between-subject and regional variability, but the relationships between CBF and CMRO2 measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO2 measures with independent and quantitative PET techniques. We included resting CBF and CMRO2 measurements from 50 healthy volunteers (aged 22–81yr), and calculated the regional and global values of oxygen delivery (DO2) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO2 measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial PCO2 and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between DO2 and CMRO2, resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO2 in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by PCO2 and hemoglobin concentration. NEW & NOTEWORTHY Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO2, but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual measures of oxygen metabolism. The analysis further showed smaller, but significant regional differences of oxygen extraction fraction at rest.

Evidence suggests that synapses are affected first in Parkinson’s disease (PD). Here, we tested the claim that pathological accumulation of α-synuclein, and subsequent synaptic disruption, occur in absence of dopaminergic neuron loss in PD. We determined early synaptic changes in rats that overexpress human α-synuclein by local injection of viral-vectors in midbrain. We aimed to achieve α-synuclein levels sufficient to induce terminal pathology without significant loss of nigral neurons. We tested synaptic disruption in vivo by analyzing motor defects and binding of a positron emission tomography (PET) radioligand to the vesicular monoamine transporter 2, (VMAT2), [11C]dihydrotetrabenazine (DTBZ). Animals overexpressing α-synuclein had progressive motor impairment and, 12 weeks post-surgery, showed asymmetric in vivo striatal DTBZ binding. The PET images matched ligand binding in post-mortem tissue, and histological markers of dopaminergic integrity. Histology confirmed the absence of nigral cell death with concomitant significant loss of striatal terminals. Progressive aggregation of proteinase-K resistant and Ser129-phosphorylated α-synuclein was observed in dopaminergic terminals, in dystrophic swellings that resembled axonal spheroids and contained mitochondria and vesicular proteins. In conclusion, pathological α-synuclein in nigro-striatal axonal terminals leads to early axonal pathology, synaptic disruption, dysfunction of dopaminergic neurotransmission, motor impairment, and measurable change of VMAT2 in the absence of cell loss.

According to the World Health Organization (WHO), dementia is a disorder that occurs as result of a neurodegenerative process in brain, and usually is chronic or progressive by nature. Most descriptions of senile dementia date back to Alois Alzheimer. In 1906, Alzheimer described the first patient, Auguste Deter, who suffered from the disorder that later became known as Alzheimer's disease. Although, the history of the disease before 1906 is quite rich, little has been said about the contributions of ancient and medieval physicians to the understanding of dementia. Over the centuries, the concept of senile dementia changed from an inevitable mental decline with aging, to different sets of clinical features with narrow limits of diagnosis of a disease in its own right. Documentation of the historical origins of prevention, diagnosis, and therapies of dementia would make an important contribution to a more complete understanding of this pathological degeneration of dementia. The present review focuses on the contributions of Avicenna (AD 980-1037) to the development of diagnosis and the discovery of etiology of different forms of dementia, with the goal of revealing the extent to which dementia was understood in the golden age of Islam in Persia.

Background: Electroconvulsive therapy is an effective therapy of depression. We hypothesized that the beneficial effects are mediated partly by decreased serotonin receptor availability in the cortex. Aims: We used positron emission tomography with the serotonin 5HT2A receptor radioligand [11C]MDL100,907 to determine serotonin receptor availability in response to electroconvulsive stimulation (ECS). Methods: Seven Göttingen minipigs were deeply anaesthetized and imaged at baseline before the onset of ECS, and at 1–2 and 8–10 days after the end of a clinical course of ECS, consisting of 10 sessions over 3.5 weeks, and post-ECS values were compared to baseline. One additional minipig was anaesthetized over 10 sessions without ECS, as a control. We analysed images with the Ichise model for binding in cortex and hippocampus, followed by whole-brain analysis by statistical non-parametric mapping. Results: We found significantly increased binding potential of [11C]MDL100,907 in the cortex and hippocampus 1–2 days after ECS, consistent with increased serotonin receptor availability compared to baseline. By 8–10 days after the final ECS, the average tracer binding had returned towards baseline. However, we also found significantly decreased tracer binding in the subcortical regions of olfactory bulb, pons, thalamus and striatum. Conclusions: With ECS, minipigs, unlike primates but like rodents, have higher availability at cortical and hippocampal 5HT2A receptors. Decreased tracer binding is consistent with reduced serotonin receptor availability as a differential effect of ECS on 5HT2A receptors in subcortical regions of minipig brain.

Purpose: We tested the hypothesis that lateralized hemispheric glucose metabolism may have diagnostic implications in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Methods: We performed FDG-PET/CT in 23 patients (mean age 63.7 years, range 50–78, 17 females) diagnosed with AD (n = 15) or MCI (n = 8) during a six-month period in 2014. Ten neurologically healthy individuals (HIs) (mean age 62.5 years, range 43–75, 5 females) served as controls. A neuroimaging expert provided visual assessment of diaschisis. The total hemispheric glucose metabolism ratio (THGr) was calculated, and with area-under the curve of receiver operating characteristics (AUC-ROC) we generated a “Network Diaschisis Test (NDT)”. Results: The qualitative detection of cerebral (Ce) and cerebellar (Cb) diaschisis was 7/15 (47%), 0/8 (0%), and 0/10 (0%) in AD, MCI, and HI groups, respectively. Median cerebral THGr was 0.68 (range 0.43–0.99), 0.86 (range 0.64–0.98), and 0.95 (range 0.65–1.00) for AD, MCI, and HI groups, respectively (p = 0.04). Median cerebellar THGr was, respectively, 0.70 (range 0.18–0.98), 0.70 (range 0.48–0.81), and 0.84 (range 0.75–0.96) (p = 0.0138). A positive NDT yielded a positive predictive value of 100% for the presence of AD or MCI and a 86% negative predictive value for healthy brain. Moreover, the diagnostic manifestation of THGr between MCI and AD led to a positive predictive value of 100% for AD, but a negative predictive value of 42.9% for MCI. Conclusion: Patients with AD or MCI had more pronounced diaschisis, lateralized hemispheric glucose metabolism and lower THGr compared to healthy controls. The NDT distinguished AD and MCI patients from HIs, and AD from MCI patients with a high positive predictive value and moderate and low negative predictive values. THGr can be a straightforward source of investigating neuronal network diaschisis in AD and MCI and in other cerebral diseases, across institutions.

The glymphatic system is a brain-wide cerebrospinal fluid (CSF) transport system that utilizes the perivascular space for fast inflow of CSF. Arterial pulsations are a major driver of glymphatic CSF inflow, and hypertension that causes vascular pathologies, such as arterial stiffening and perivascular alterations, may impede the inflow. We used dynamic contrast-enhanced MRI (DCE-MRI) to assess the effect of hypertension on glymphatic transport kinetics in male young and adult spontaneously hypertensive (SHR) rats compared with age-matched normotensive Wistar-Kyoto rats (WKY). We anesthetized the rats with dexmedetomidine/isoflurane and infused paramagnetic contrast (Gd-DOTA) into the cisterna magna (CM) during DCE-MRI to quantify glymphatic transport kinetics. Structural MRI analysis showed that cerebroventricular volumes are larger and brain volumes significantly smaller in SHR compared to WKY rats, irrespective of age. We observed ventricular reflux of Gd-DOTA in SHR rats only, indicating abnormal CSF flow dynamics secondary to innate hydrocephalus. One-tissue compartment analysis revealed impeded glymphatic transport of Gd-DOTA in SHR compared with WKY rats in both age groups, implying that glymphatic transport, including solute clearance from brain parenchyma, is impaired during evolving hypertension in young SHR, an effect that worsens in states of chronic hypertension. The study demonstrates the suppression of glymphatic clearance in SHR rats and thus offers new insight into the co-existence of hypertension and concomitant vascular pathologies in Alzheimer's disease. The study further highlights the importance of considering the distribution of tracers in the CSF compartment in the analysis of the glymphatic system.Significance statement: The glymphatic system contributes to the removal of amyloid beta from the brain and is disrupted in Alzheimer's disease and aging. Using a rat model of hypertension, we measured gross CSF flow and tracked glymphatic influx and efflux rates with dynamic contrast-enhanced MRI, showing that glymphatic transport is compromised in both early and advanced stages of hypertension. The study provides a new perspective on the importance for brain metabolite and fluid homeostasis of maintaining healthy blood vessels, an increasingly pertinent issue in an aging population that in part may explain the link between vascular pathology and Alzheimer's disease.

Objective The aim of this study was to examine if combined pain (pain in the upper and lower body), high occupational mechanical exposures, and job strain predict sickness absence and permanent work disability, particularly if co-occurring. Methods This longitudinal study was based on the musculoskeletal research database at the Danish Ramazzini Centre. We linked baseline information from 2001–2004 on musculoskeletal pain, job titles, and covariates with register information on sickness absence and permanent work disability. Mechanical and psychosocial exposure estimates were obtained from job exposure matrices. We used multivariable Cox regression. Results The study included 25 292 persons. Compared to low occupational mechanical exposures and no pain, low mechanical exposures and combined pain showed an adjusted hazard ratio (HR adj ) of 1.81 [95% confidence interval (95% CI) 1.58–2.08], while high mechanical exposures and combined pain showed HR adj 3.71 (95% CI 3.24–4.25) for sickness absence. The corresponding values for permanent work disability were 3.35 (95% CI 1.74–6.45) and 4.59 (95% CI 2.36–8.94). Job strain showed an association with sickness absence [HR adj 1.24 (95% CI 1.10–1.39)], while low social support was associated with both sickness absence and permanent work disability [HR adj 1.30 (95% CI 1.19–1.41) and 2.19 (95% CI 1.41–3.41), respectively]. Conclusions Combined pain in the upper and lower body was associated with sickness absence and permanent work disability, and high occupational mechanical exposures further increased the risk. Job strain showed a modest association with sickness absence, while low social support at work was associated with both outcomes, especially permanent work disability.

Schizophrenia patients are often obese or overweight and poor dietary choices appear to be a factor in this phenomenon. Poor diet has been found to have complex consequences for the mental state of patients. Thus, this study investigated whether an unhealthy diet [i.e. high fat diet (HFD)] impacts on the behaviour of a genetic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. transmembrane domain Nrg1 mutant mice: Nrg1 HET). Female Nrg1 HET and wild-type-like littermates (WT) were fed with either HFD or a control chow diet. The mice were tested for baseline (e.g. anxiety) and schizophrenia-relevant behaviours after 7 weeks of diet exposure. HFD increased body weight and impaired glucose tolerance in all mice. Only Nrg1 females on HFD displayed a hyper-locomotive phenotype as locomotion-suppressive effects of HFD were only evident in WT mice. HFD also induced an anxiety-like response and increased freezing in the context and the cued version of the fear conditioning task. Importantly, CHOW-fed Nrg1 females displayed impaired social recognition memory, which was absent in HFD-fed mutants. Sensorimotor gating deficits of Nrg1 females were not affected by diet. In summary, HFD had complex effects on the behavioural phenotype of test mice and attenuated particular cognitive deficits of Nrg1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex.

Brain growth across childhood is a dynamic process associated with specific energy requirements. A disproportionately higher rate of glucose utilization (CMRglucose) compared with oxygen consumption (CMRO2) was documented in children's brain and suggestive of non-oxidative metabolism of glucose. Several candidate metabolic pathways may explain the CMRglucose-CMRO2 mismatch, and lactate production is considered a major contender. The ~33% excess CMRglucose equals 0.18 μmol glucose/g/min and predicts lactate release of 0.36 μmol/g/min. To validate such scenario, we measured the brain lactate concentration ([Lac]) in 65 children to determine if indeed lactate accumulates and is high enough to (1) account for the glucose consumed in excess of oxygen and (2) support a high rate of lactate efflux from the young brain. Across childhood, brain [Lac] was lower than predicted, and below the range for adult brain. In addition, we re-calculated the CMRglucose-CMRO2 mismatch itself by using updated lumped constant values. The calculated cerebral metabolic rate of lactate indicated a net influx of 0.04 μmol/g/min, or in terms of CMRglucose, of 0.02 μmol glucose/g/min. Accumulation of [Lac] and calculated efflux of lactate from brain are not consistent with the increase in non-oxidative metabolism of glucose. In addition, the value for the lumped constant for [18F]fluorodeoxyglucose has a high impact on calculated CMRglucose and use of updated values alters or eliminates the CMRglucose-CMRO2 mismatch in developing brain. We conclude that the presently-accepted notion of non-oxidative metabolism of glucose during childhood must be revisited and deserves further investigations.

Here, we tested the claim that nicotine attenuates the signs of brain dysfunction in the model of brain aging induced by D-galactose (DGal) in mice. We administered nicotine at doses of 0.1, 0.5 and 1 mg/kg by the subcutaneous (s.c.) or at 0.1 mg/kg by the intranasal (i.n.) routes in mice that had received DGal at the dose of 500 mg/kg subcutaneous (s.c.) for 6 weeks. We assessed animal withdrawal signs as the number of presented somatic signs, thermal hyperalgesia, elevated plus maze (EPM) and open field tests. We evaluated spatial memory and recognition with Barnes maze and novel object recognition (NOR) tests. We tested brain tissue for reactive oxygen species (ROS), mitochondrial membrane potential, caspase-3, Bax, Bcl-2, cytochrome C, brain-derived neurotrophic factor and nerve growth factor levels. Nicotine administration in model groups (0.5 mg/kg s.c. and 0.1 mg/kg i.n. doses) significantly attenuated impairment of spatial and episodic memories in comparison to normal saline-received model group. These doses also reduced mito-oxidative damage as well as apoptosis and raised neurotrophic factors level in model groups in comparison to normal saline-received model group. The 1 mg/kg s.c. dose nicotine revealed withdrawal signs compared with the other nicotine-received groups. Nicotine at specific doses and routes has the potential to attenuate age-related cognitive impairment, mito-oxidative damage, and apoptosis. The doses raise neurotrophic factors without producing withdrawal signs.

Purpose: Malignant cells exhibit increased rates of aerobic glycolysis. Here, we tested whether the accumulation of fluoro-deoxyglucose-6-phosphate (FDG6P) in ovarian cancers of differential malignancy reflects inversely correlated elevations of hexokinase (HK) and glucose-6-phosphatase (G6Pase) activities. Procedures: Twenty-nine women with suspected ovarian cancer had positron emission tomography (PET) prior to surgery. From fresh-frozen tissue, we determined the activities of HK and G6Pase, and from the PET images, we determined the tumor maximum standardized uptake value (SUVmax) of 2-deoxy-2-[18F]fluoro-D-glucose. Results: The SUVmax of malignant lesions significantly exceeded the SUVmax of benign (p < 0.005) and borderline lesions (p < 0.0005) that did not differ significantly. We found no significant correlation between measured HK or G6Pase activities and histological tumor type or SUVmax except that G6Pase activities were higher in malignant than borderline lesions (p < 0.05). Measured HK and G6Pase activities correlated inversely (p < 0.05). The slopes from the regression lines of the three correlations yielded positively correlated abscissa and ordinate intercepts, designated HKmax and G6Pasemax, respectively (r = 0.67, p < 0.0001). The positive correlations between the abscissa and ordinate intercepts with SUVmax had regression coefficients of r = 0.44, p < 0.05; and r = 0.39, p < 0.05, respectively. Conclusions: The results distinguished two ovarian cancer phenotypes, one with elevated HK activity and low G6Pase activity, and another with the opposite characteristics.

Incretin hormones, notably glucagon-like peptide-1 (GLP-1), are gluco-regulatory hormones with pleiotropic effects also in the central nervous system. Apart from a local production of GLP-1, systemic administration of the hormone has been shown to influence a number of cerebral pathologies, including neuroinflammation. Given the brains massive dependence on glucose as its major fuel, we here review the mechanistics of cerebral glucose transport and metabolism, focusing on the deleterious effects of both hypo- and hyperglycaemia. GLP-1, when administered as long-acting analogues or intravenously, appears to decrease transport of glucose in normoglycaemic conditions, without affecting the total cerebral glucose content. During hypoglycaemia this effect seems abated, whereas during hyperglycaemia GLP-1 regulates cerebral glucose metabolism towards stable levels resembling normoglycaemia. In Alzheimer's disease, a 6-month intervention with GLP-1 maintained cerebral glucose levels at baseline levels, contrasting the decline otherwise seen in Alzheimer's. Kinetic studies suggest blood-brain barrier (BBB) glucose transport as the key player in GLP-1 mediated effects on cerebral glucose metabolism. This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’

The α7 nicotinic acetylcholine receptor (nAChR) increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The a7-nAChR primarily is located in cerebral cortex and sub-cortical regions, compared to the α4β2 nAChR subtype that has a more subcortical distribution. The highly cortical distribution suggests a role of a7-nAChR in cognition. We expanded the first-in-human PET imaging of α7-nAChR with [18F]ASEM from five to 21 healthy non-smoking volunteers and added preliminary evidence of binding in six male patients with schizophrenia. Study aims included 1) confirmation of test-retest reproducibility of [18F]ASEM binding in normal volunteers, 2) demonstration of specificity of [18F]ASEM binding by competition with DMXB-A, an α7-nAChR partial agonist previously tested in clinical trials of patients with schizophrenia, 3) estimation of [18F]ASEM binding potentials and α7-nAChR density in vivo in humans, and 4) α7-nAChR binding in patients with schizophrenia compared to healthy volunteers.Test-retest PET confirmed reproducibility (>90%) (variability ≤ 7%) of [18F]ASEM volume of distribution (Vt) estimates in healthy volunteers. Repeated sessions of PET in five healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7-nAChR by DMXB-A at 17-49% for plasma concentrations at 60-200 nM DMXB-A. In agreement with evidence post-mortem, α7-nAChR density (Bmax) averaged 0.67-0.82 nM and inhibitor affinity constant (Ki) averaged 170-385 nM. Median Vt in a feasibility study of six patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus. Mann-Whitney test identified cingulate cortex and hippocampus as regions with significantly lower median Vt in patients than in healthy volunteers when a single outlier patient was excluded from analysis (P = 0.02, corrected for multiple comparisons).

Because the human brain consumes a disproportionate fraction of the resting body’s energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease.

There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer’s disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (Tmax) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, Tmax estimates correlated inversely with the duration of AD, as did the estimates of CMRglc that in turn were positively correlated with cognition. The GLP-1 analog treatment, compared to placebo, highly significantly raised the Tmax estimates of cerebral cortex from 0.72 to 1.1 umol/g/min, equal to Tmax estimates in healthy volunteers. The result is consistent with the claim that GLP-1 analog treatment restores glucose transport at the BBB.

BACKGROUND: Vagal nerve stimulation (VNS) emerged as an anti-epileptic therapy, and more recently as a potential antidepressant intervention.OBJECTIVE/HYPOTHESIS: We hypothesized that salutary effects of VNS are mediated, at least in part, by augmentation of the inhibitory effects of cortical monoaminergic neurotransmission at appropriate receptors, specifically adrenoceptors. Our objective was to measure the effect of acute VNS on α2 adrenoceptor binding.METHODS: Using positron emission tomography (PET), we measured changes in noradrenaline receptor binding associated with acute VNS stimulation in six anesthetized Göttingen minipigs. We used the selective α2 adrenoceptor antagonist [11C]yohimbine, previously shown to be sensitive to competition from the receptor's endogenous ligands, as a surrogate marker of monoamine release. PET records were acquired 4-6 weeks after the implant of a VNS electrode in minipigs before and within 30 min of the initiation of 1 mA stimulation. Kinetic analysis with the Logan graphical linearization generated tracer volumes of distribution for each condition. We used an averaged value of the distribution volume of non-displaceable ligand (VND), to calculate binding potentials for selected brain regions of each animal.RESULTS: VNS treatment markedly reduced the binding potential of yohimbine in limbic, thalamic and cortical brain regions, in inverse correlation with the baseline binding potential.CONCLUSION: The result is consistent with release of noradrenaline by antidepressant therapy, implying a possible explanation for the antidepressant effect of VNS.

We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippocampus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce cAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the blood-brain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucose- and glycogen-saving response. HCAR1 may contribute to optimizing the cAMP concentration. For instance, in the prefrontal cortex, excessively high cAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than cAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells.

We describe a novel method of kinetic analysis of radioligand binding to neuroreceptors in brain in vivo, here applied to noradrenaline receptors in rat brain. The method uses positron emission tomography (PET) of [11C]yohimbine binding in brain to quantify the density and affinity of α2 adrenoceptors under condition of changing radioligand binding to plasma proteins. We obtained dynamic PET recordings from brain of Spraque Dawley rats at baseline, followed by pharmacological challenge with unlabeled yohimbine (0.3 mg/kg). The challenge with unlabeled ligand failed to diminish radioligand accumulation in brain tissue, due to the blocking of radioligand binding to plasma proteins that elevated the free fractions of the radioligand in plasma. We devised a method that graphically resolved the masking of unlabeled ligand binding by the increase of radioligand free fractions in plasma. The Extended Inhibition Plot introduced here yielded an estimate of the volume of distribution of non-displaceable ligand in brain tissue that increased with the increase of the free fraction of the radioligand in plasma. The resulting binding potentials of the radioligand declined by 50–60% in the presence of unlabeled ligand. The kinetic unmasking of inhibited binding reflected in the increase of the reference volume of distribution yielded estimates of receptor saturation consistent with the binding of unlabeled ligand.

Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [11C]Pittsburgh Compound B ([11C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer's disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute cerebral blood flow indices (sCBF) from the early accumulation of the tracer in brain tissue. Objective: We tested the hypothesis that a change of cerebral blood flow is correlated with the degree of tracer [11C]PiB retention, reflecting dendritic spine pathology and consequent inhibition of brain energy metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer's disease. Methods: Previously reported images of [11C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer's Disease (AD), eight subjects with dementia with Lewy bodies (DLB), five patients with frontotemporal lobar degeneration (FTLD), five patients with mild cognitive impairment, and 29 age-matched healthy control subjects (HC)], underwent analysis of PiB delivery and retention by means of WARM for quantitation of [11C]PiB's binding potentials (BPND) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [11C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [11C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among estimates. Results: For AD, the discriminatory power of [11C]PiB binding potential (BPND) by WARM exceeded the power of SUVR that in turn exceeded the power of sCBF estimates. Differences of [11C]PiB binding and sCBF measures between AD and HC both were highly significant (p < 0.001). For all the dementia groups as a whole, sCBF estimates revealed the greatest discrimination between the patient and HC groups. WARM resolves a major issue of amyloid load quantification with [11C]PiB in human brain by determining absolute sCBF and amyloid load measures from the same images. The two parameter approach provides key discriminary information in AD for which [11C]PiB traditionally is used, as well as for the distinct flow deficits in FTLD, and the marked parietal and occipital lobe flow deficits in DLB. Conclusion: We conclude that WARM yields estimates of two important variables that together discriminate among patients with dementia, including AD, and healthy volunteers, with ROC that are superior to conventional methods of analysis. The distinction between estimates of flow and amyloid load from the same dynamic emission tomograms provides valuable pathogenetic information.

Leber's Hereditary Optic Neuropathy (LHON) shares features with Multiple Sclerosis (MS). Both diseases develop optic lesions. Frequent secondary LHON mutations in MS patients may explain the optic damage. Here, we tested the hypothesis that secondary LHON mutations are associated with optic neuritis (ON) in MS patients. We recruited 56 MS subjects with ON and 47 MS subjects without ON. DNA was extracted by salting out, after sampling of peripheral blood from each participant. We completed Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis with appropriate primers and restriction endonucleases for seven secondary LHON mutations. Products were visualized using 3% agarose gel electrophoresis with the aid of DNA safe stain in a UV transilluminator. Accuracy of the genotyping procedure was confirmed by sequencing. Data was analyzed using chi square and Fisher exact tests and logistic regression analysis. There was no significant difference between the numbers of MS subjects with ON and without ON that carried secondary LHON mutations (T4216C [P = 0.1], A4917G [P = 0.2], G13708A [P = 0.6], G15257A [P = 1], G15812A [P = 0.8], G15927A [P = 1], G15928A [P = 0.4]). The evidence from the present study are not consistent with the hypothesis that secondary LHON mutations are associated with ON in MS subjects.

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS ( n=14), MCS ( n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers ( n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.

People attempt to change their lifestyle when obesity impairs their quality of life. The attempts often fail when multiple habits must be changed in unison. Here we explore relations among food addiction, the neurobiology of habits, and caloric restriction, when people seek to return to normal eating behaviour, with particular emphasis on the role of dopaminergic neurotransmission. Severely obese individuals have specific neurobiological characteristics in common with drug abusers, including low availability of dopamine receptors in the striatum, impaired neuronal responses to dopamine, and reduced activity in prefrontal regions of the cerebral cortex. The neurobiological characteristics suggest that obese people also have a pathological dependence in common with addicts, in the form of food addiction. Malnutrition and dieting both relate to binge eating, possibly as a compensation for a reduced cognitive reward condition. The combination of caloric restriction and food addiction imparts a high risk of relapse as a result of further reduction of dopaminergic neurotransmission and the subsequent loss of reward. As with drugs of abuse, ingestion of large quantities of sugar in circumstances of uncontrolled eating increases dopamine release in the nucleus accumbens. This and other evidence suggests that abuse of food is a habit learned by means of mechanisms centred in the basal ganglia, with an increased risk of relapse in the presence of associative amplifiers. This risk is predicted by the relationship between dopamine receptor availability in the striatum and sensation-seeking in the form of an inverted U, suggested by recent findings, consistent with two opposite states of hypodopaminergic and hyperdopaminergic neuromodulation. Summations > With neurobiological similarities among the brain functions of individuals with behaviour suggestive of addiction, obese individuals with reduced reward sensitivity suffer from pathological addiction to food. > Both undernutrition and dieting are positively correlated with strong craving for food and accompanying overeating, evidently as a compensation for reduced activity of neurobiological reward mechanisms. > The combination of caloric restriction and food addiction alone has a high risk of continued bouts of overeating as results of the reduced gain from dopaminergic neurotransmission maintained by repeated relapses. The risk can be diminished by lifestyle modifications that at the very least include exercise and counselling or group therapy. The inverted U-shaped model is a measure of the efficiency of a given individual’s reward system.

The most dramatic progress in the restoration of hearing takes place in the first months after cochlear implantation. To map the brain activity underlying this process, we used positron emission tomography at three time points: within 14 days, three months, and six months after switch-on. Fifteen recently implanted adult implant recipients listened to running speech or speech-like noise in four sequential PET sessions at each milestone. CI listeners with postlingual hearing loss showed differential activation of left superior temporal gyrus during speech and speech-like stimuli, unlike CI listeners with prelingual hearing loss. Furthermore, Broca’s area was activated as an effect of time, but only in CI listeners with postlingual hearing loss. The study demonstrates that adaptation to the cochlear implant is highly related to the history of hearing loss. Speech processing in patients whose hearing loss occurred after the acquisition of language involves brain areas associated with speech comprehension, which is not the case for patients whose hearing loss occurred before the acquisition of language. Finally, the findings confirm the key role of Broca’s area in restoration of speech perception, but only in individuals in whom Broca’s area has been active prior to the loss of hearing.

Rates of cerebral blood flow (CBF) and glucose consumption (CMRglc) rise in cerebral cortex during continuous stimulation, while the oxygen-glucose index (OGI) declines as an index of mismatched coupling of oxygen consumption (cerebral metabolic rate of oxygen—CMRO2) to CBF and CMRglc. To test whether the mismatch reflects a specific role of aerobic glycolysis during functional brain activation, we determined CBF and CMRO2 with positron emission tomography (PET) when 12 healthy volunteers executed finger-to-thumb apposition of the right hand. Movements began 1, 10, or 20 minutes before administration of the radiotracers. In primary and supplementary motor cortices and cerebellum, CBF had increased at 1 minute of exercise and remained elevated for the duration of the 20-minute session. In contrast, the CMRO2 numerically had increased insignificantly in left M1 and supplementary motor area at 1 minute, but had declined significantly at 10 minutes, returning to baseline at 20 minutes. As measures of CMRglc are impossible during short-term activations, we used measurements of CBF as indices of CMRglc. The decline of CMRO2 at 10 minutes paralleled a calculated decrease of OGI at this time. The implied generation of lactate in the tissue suggested an important hypothetical role of the metabolite as regulator of CBF during activation.

Context: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists provide beneficial cardiovascular effects by protecting against ischemia and reperfusion injury. Type 2 diabetes mellitus patients have reduced glycolysis in the heart. Objective: We hypothesized that cardioprotection by GLP-1 is achieved through increased glucose availability and utilization and aimed to assess the effect of exenatide, a synthetic GLP-1 receptor agonist, on myocardial glucose uptake (MGU), myocardial glucose transport, and myocardial blood flow (MBF). Design and Methods: We conducted a randomized, double-blinded, placebo-controlled crossover study in eight male, insulin-naive, type 2 diabetes mellitus patients without coronary artery disease. Positron emission tomography was used to determine the effect of exenatide on MGU and MBF during a pituitary-pancreatic hyperglycemic clamp with (18)F-fluorodeoxyglucose and (13)N-ammonia as tracers. Results: Overall, exenatide did not alter MGU. However, regression analysis revealed that exenatide altered initial clearance of glucose over the membrane of cardiomyocytes and MGU, depending on the level of insulin resistance (P = 0.017 and 0.010, respectively). Exenatide increased MBF from 0.73 ± 0.094 to 0.85 ± 0.091 ml/g · min (P = 0.0056). Except for an increase in C-peptide levels, no differences in circulating hormones or metabolites were found. Conclusions: The action of exenatide as an activator or inhibitor of the glucose transport and glucose uptake in cardiomyocytes is dependent on baseline activity of glucose transport and insulin resistance. Exenatide increases MBF without changing MGU.

J. Neurochem (2012) 120, 806–817. Abstract Recent studies suggest that l-3,4 dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a severe complication of conventional l-DOPA therapy of Parkinson’s disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT1A agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the l-DOPA-induced increase in extracellular DA and decrease in [11C]raclopride binding in an animal model of advanced Parkinson’s disease and LID, we measured extracellular DA in response to l-DOPA or a combination of l-DOPA and the 5-HT1A agonist, 8-OHDPAT, with microdialysis, and determined [11C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [11C]raclopride at baseline and after two pharmacological challenges with l-DOPA + benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomitant with ratings of LID severity. The baseline increase of [11C]raclopride-binding potential (BPND) in lesioned striatum was eliminated by the l-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this l-DOPA-induced displacement of [11C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the l-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the l-DOPA-induced decrease of [11C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of l-DOPA on [11C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons.

Objectives – Evidence from experimental animal models of Parkinson’s disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei. Materials and methods – Using the HRRT, we performed [18F]-fluorodeoxyglucose (FDG) scans on 21 patients with PD and 11 age-matched controls. We employed three types of normalization: white matter, global mean, and data-driven normalization. We performed volume-of-interest analyses of small subcortical gray matter structures. Voxel-based comparisons were performed to investigate the extent of cortical hypometabolism. Results – The most significant level of relative subcortical hypermetabolism was detected in the external pallidum (GPe), irrespective of normalization strategy. Hypermetabolism was suggested also in the internal pallidum, thalamic subnuclei, and the putamen. Widespread cortical hypometabolism was seen in a pattern very similar to previously reported patterns in patients with PD. Conclusion – The presence and extent of subcortical hypermetabolism in PD is dependent on type of normalization. However, the present findings suggest that PD, in addition to widespread cortical hypometabolism, is probably characterized by true hypermetabolism in the GPe. This finding was predicted by the animal 2-deoxyglucose autoradiography literature, in which high-magnitude hypermetabolism was also most robustly detected in the GPe.

The dopamine system is believed to affect gambling behavior in pathological gambling. Particularly, dopamine release in the ventral striatum appears to affect decision-making in the disorder. This study investigated dopamine release in the ventral striatum in relation to gambling performance on the Iowa Gambling Task (IGT) in 16 Pathological Gamblers (PG) and 14 Healthy Controls (HC). We used Positron Emission Tomography (PET) to measure the binding potential of [(11)C] raclopride to dopamine D2/3 receptors during a baseline and gambling condition. We hypothesized that decreased raclopride binding potentials in the ventral striatum during gambling (indicating dopamine release) would be associated with higher IGT performance in Healthy Controls, but lower IGT performance in Pathological Gamblers. The results showed that Pathological Gamblers with dopamine release in the ventral striatum had significantly lower IGT performance than Healthy Controls. Furthermore, dopamine release was associated with significantly higher IGT performance in Healthy Controls and significantly lower IGT performance in Pathological Gamblers. The results suggest that dopamine release is involved both in adaptive and maladaptive decision-making. These findings may contribute to a better understanding of dopaminergic dysfunctions in pathological gambling and substance related addictions.

Aims Gambling excitement is believed to be associated with biological measures of pathological gambling. Here, we tested the hypothesis that dopamine release would be associated with increased excitement levels in Pathological Gamblers compared with Healthy Controls. Design Pathological Gamblers and Healthy Controls were experimentally compared in a non-gambling (baseline) and gambling condition. Measurements We used Positron Emission Tomography (PET) with the tracer raclopride to measure dopamine D 2/3 receptor availability in the ventral striatum during a non-gambling and gambling condition of the Iowa Gambling Task (IGT). After each condition participants rated their excitement level. Setting Laboratory experiment. Participants 18 Pathological Gamblers and 16 Healthy Controls. Findings Pathological Gamblers with dopamine release in the ventral striatum had significantly higher excitement levels than Healthy Controls despite lower IGT performance. No differences in excitement levels and IGT performance were found between Pathological Gamblers and Healthy Controls without dopamine release. Pathological Gamblers showed a significant correlation between dopamine release and excitement level, while no such interaction was found in Healthy Controls. Conclusions In pathological gamblers dopamine release in the ventral striatum appears to be associated with increased excitement levels despite lower IGT performance. The results might suggest a ‘double deficit’ function of dopamine in pathological gambling, where dopamine release reinforces maladaptive gambling through increasing excitement levels, reducing inhibition of risky decisions, or a combination of both. These findings may have implications for the understanding of dopamine in pathological gambling and other forms of addiction.

Maximal exercise may be limited by central fatigue defined as an inability of the central nervous system to fully recruit the involved muscles. This study evaluated whether a reduction in the cerebral oxygen-to-carbohydrate index (OCI) and in the cerebral mitochondrial oxygen tension relate to the ability to generate a maximal voluntary contraction and to the transcranial magnetic stimulated force generation. To determine the role of a reduced OCI and in central fatigue, 16 males performed low intensity, maximal intensity and hypoxic cycling exercise. Exercise fatigue was evaluated by ratings of perceived exertion (RPE), arm maximal voluntary force (MVC), and voluntary activation of elbow flexor muscles assessed with transcranial magnetic stimulation. Low intensity exercise did not produce any indication of central fatigue or marked cerebral metabolic deviations. Exercise in hypoxia ( 0.10) reduced cerebral oxygen delivery ∼25% and decreased 11 ± 4 mmHg (P < 0.001) together with OCI (6.2 ± 0.7 to 4.8 ± 0.5, P < 0.001). RPE increased while MVC and voluntary activation were reduced (P < 0.05). During maximal exercise declined 8 ± 4 mmHg (P < 0.05) and OCI to 3.8 ± 0.5 (P < 0.001). RPE was 18.5, and MVC and voluntary activation were reduced (P < 0.05). We observed no signs of muscular fatigue in the elbow flexors and all control MVCs were similar to resting values. Exhaustive exercise provoked cerebral deoxygenation, metabolic changes and indices of fatigue similar to those observed during exercise in hypoxia indicating that reduced cerebral oxygenation may play a role in the development of central fatigue and may be an exercise capacity limiting factor.

Udgivelsesdato: 2010-Feb-15 PET studies with the DOPA decarboxylase substrate 6-[(18)F]fluoro-l-DOPA (FDOPA) reveal the storage of [(18)F]-fluorodopamine within synaptic vesicles, mainly of dopamine fibres. As such, FDOPA PET is a sensitive indicator of the integrity of the nigrostriatal dopamine innervation. Nonetheless, there have been several reports of focal elevations of FDOPA utilization in brain of patients with Parkinson's disease (PD), all based on reference tissue methods. To investigate this phenomenon further, we used voxel-wise steady-state kinetic analysis to search for regions of elevated FDOPA utilization (K; ml g(-1) min(-1)) and steady-state trapping (V(d); ml g(-1)) in a group of well-characterized patients with early, asymmetric PD, who were contrasted with an age-matched control group. Subtraction of the population mean parametric maps revealed foci of increased FDOPA utilization K (+25%) in the bilateral medial nucleus accumbens, whereas the expected declines in the trapping of FDOPA were seen in the caudate and putamen. This observation suggests hyperfunction of catecholamine fibres innervating specifically the limbic striatum, which could guide the design of future prospective FDOPA-PET studies of the impulse control disorders occurring in some PD patients under treatment with dopamine agonists. A focus of increased FDOPA influx and also V(d) was detected in the periaqueductal grey, consistent with some earlier reports based on reference tissue analysis. Increased FDOPA trapping in the periaqueductal grey of PD patients seems consistent with recent reports of increased activity of serotonin neurons in a rat model of parkinsonism.

The radioligand [carbonyl-(11)C]WAY-100635 ((11)C-WAY) is a PET tracer of the serotonin 5HT(1A) receptors in the human brain. It is metabolized so rapidly in the circulation that it behaves more as a chemical microsphere than as a tracer subject to continuous exchange between the circulation and brain tissue. Although reference tissue methods are useful as analyses of uptake of some radioligands with indeterminate arterial input functions, their use to analyze (11)C-WAY uptake and binding is challenged by the rapid plasma metabolism, which violates the assumption that regions of interest and reference regions continue to exchange radioligand with the circulation during the entire uptake period. Here, we proposed a method of calculation (Hypotime) that specifically uses the washout rather than the accumulation of (11)C-WAY to determine binding potentials (BP(ND)), without the use of regression analysis.A total of 19 healthy volunteers (age range, 23-73 y) underwent PET to test the Hypotime application of the chemical microsphere properties of (11)C-WAY to identify regions of binding and nonbinding on the exclusive basis of the rate of washout of (11)C-WAY.The results of the Hypotime method were compared with the simplified but multilinearized reference tissue method (MLSRTM). The distribution of receptor BP(ND) obtained with Hypotime was consistent with previous autoradiography of postmortem brain tissue, with the highest values of BP(ND) recorded in the medial temporal lobe and decline of receptor availability with age. The values in the basal ganglia and cerebellum were negligible. The MLSRTM, in contrast, yielded lower BP(ND) in all regions and only weakly revealed the decline with age.The simple and computationally efficient Hypotime method gave reliable values of BP(ND) without the use of regression. The MLSRTM, on the other hand, appeared to be affected by the early disappearance of the radioligand from the circulation and the associated uncertain late presence of (11)C-WAY in the circulation.

Udgivelsesdato: 1985-Oct The x-ray contrast material metrizamide is structurally related to 2-deoxyglucose and inhibits brain glucose phosphorylation both in vitro and in vivo. in vivo. In vivo, however, the present autoradiographic study with labeled 2-deoxyglucose revealed a local increase of glucose metabolic rate in an area of direct metrizamide application to the cerebral cortex. The local increase was 137% above the metabolic rate calculated for the contralateral region. Regions outside the application site showed no difference between the glucose metabolic rates of the ipsi- and contralateral hemispheres. Evidence from the literature suggests that metrizamide may stimulate cortical activity by inhibiting acetylcholinesterase.

Udgivelsesdato: 1990-Mar Cerebral metabolic rate for glucose (CMRglc) was studied in rats using [6-14C]glucose. After intravenous injection, the radioactivity of the parietal cortex was corrected for loss of labeled CO2 and divided by the integral of the arterial plasma glucose concentration, determined during tracer circulation. Treatment with insulin, resulting in plasma glucose concentrations less than 2.6 mmol/l, reduced CMRglc to 64% of the values found in control animals. CMRglc did not change in animals with acute hyperglycemia produced by intraperitoneal injection of a glucose solution or in diabetes-prone rats with or without insulin treatment.

Context: An interaction between ghrelin, which is implicated in the regulation of short- and long-term energy balance, and thyroid function has been reported in hyperthyroidism in which ghrelin levels are reversibly suppressed. We measured serum ghrelin levels and metabolic indices in hypothyroid patients before and after l-thyroxine replacement. Patients and Methods: Eleven patients were examined twice: 1) in the hypothyroid state and 2) after at least 2 months of euthyroidism. Ten healthy subjects served as a control group. Ghrelin was measured in conjunction with indirect calorimetry and a hyperinsulinemic euglycemic clamp. Results: Serum ghrelin levels were increased by 32% under basal conditions in the hypothyroid state (PRE) as compared with posttreatment (POST) (picograms per milliliter): 976.4 ± 80.8 vs. 736.8 ± 67.1 (P < 0.001). This difference prevailed during the clamp, but a decline was observed in both states: 641.4 ± 82.2 vs. 444.3 ± 66.8 μg/ml (P = 0.005). The hypothyroid state was associated with decreased resting energy expenditure, increased respiratory quotient, and insulin resistance. Serum ghrelin levels as well as the metabolic aberrations became normalized after l-thyroxine replacement as compared with the control subjects. Conclusion: Serum ghrelin levels are reversibly increased in hypothyroid patients. It remains to be investigated whether this represents a direct effect of iodothyronines on ghrelin secretion or clearance or a compensatory response to the abnormal energy metabolism in hypothyroid patients.

Schizophrenia is a severe mental disorder striking mainly young adults and leading to life-long disability in a substantial portion of the sufferers. On the other hand, substantial knowledge about its etiology and pathogenesis is still lacking. Therefore the European Science Foundation (ESF) sponsored a meeting of a panel of European experts on schizophrenia research to discuss the state of art and future perspectives of key topics in this area. The fields covered genetics, epidemiology, animal models, molecular neuropathology and imaging. This was a first step to establish a network of European groups dedicated to Schizophrenia research. The coming calls of the frame work program will be used to strengthen this network in order to achieve substantial progress in understanding and treating this devastating illness.

Objectives – Post-stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (pB) of the 5-HT1A receptor antagonist [carbonyl–11C]WAY-100635, which is reversible by selective serotonin re-uptake inhibitor (SSRI) treatment. Materials and Methods – We PET scanned patients with acute stroke and PC and age-matched control subjects. Maps of receptor availability were generated from the images of eight cortical regions and raphe nuclei. Results – The maps showed highest binding in limbic areas and raphe nuclei, while binding in basal ganglia and cerebellum was negligible. Baseline binding potentials of patients were lower than that of control subjects (3.7 ± 0.6 vs 4.2 ± 0.2). Treatment with SSRI markedly reduced free receptor sites, whereas placebo administration led to a global increase. Discussion – The study is the first suggestion of changes of serotonergic neurotransmission in the early phase of stroke and the modulation of these changes with SSRI treatment.

Summary Background Circulating ghrelin levels are reported to be suppressed by insulin, GH and free fatty acids (FFAs). However, insulin, GH and FFA levels are all interdependent, and it is therefore difficult to delineate their independent effects on ghrelin secretion. Objective To isolate and define the impact of GH, GH receptor (GHR) blockade and intravenous FFA infusion on total circulating ghrelin levels during a hyperinsulinaemic glucose clamp with identical insulin levels. Design In a randomized design, eight healthy males each underwent an 8-h hyperinsulinaemic glucose clamp on four occasions together with either: (1) control (saline), (2) intravenous FFA infusion (intralipid/heparin infusion 4 h), (3) a GH bolus (0·5 mg i.v.) or (4) GHR blockade (pegvisomant, 30 mg s.c.). Results Hyperinsulinaemia per se resulted in a decrease in ghrelin concentrations of about 15%. During FFA exposure, ghrelin levels were suppressed by about 22% when compared with saline [area under the curve (AUC)ghrelin0−240 122·7 ± 10·9 vs. 97·6 ± 13·4 pg/ml/min, P = 0·001], followed by a rebound increase upon discontinuation of the infusion. Furthermore, average ghrelin concentration (AUCghrelin) was significantly inversely correlated to average FFA levels (AUCFFA) (r = −0·33, P

Musical expertise is associated with structural and functional changes in the brain that underlie facilitated auditory perception. We investigated whether the phase locking (PL) and amplitude modulations (AM) of neuronal oscillations in response to musical chords are correlated with musical expertise and whether they reflect the prototypicality of chords in Western tonal music. To this aim, we recorded magnetoencephalography (MEG) while musicians and non-musicians were presented with common prototypical major and minor chords, and with uncommon, non-prototypical dissonant and mistuned chords, while watching a silenced movie. We then analyzed the PL and AM of ongoing oscillations in the theta (4-8 Hz) alpha (8-14 Hz), beta- (14-30 Hz) and gamma- (30-80 Hz) bands to these chords. We found that musical expertise was associated with strengthened PL of ongoing oscillations to chords over a wide frequency range during the first 300 ms from stimulus onset, as opposed to increased alpha-band AM to chords over temporal MEG channels. In musicians, the gamma- band PL was strongest to non-prototypical compared to other chords, while in non-musicians PL was strongest to minor chords. In both musicians and non-musicians the long-latency (> 200 ms) gamma-band PL was also sensitive to chord identity, and particularly to the amplitude modulations (beats) of the dissonant chord. These findings suggest that musical expertise modulates oscillation PL to musical chords and that the strength of these modulations is dependent on chord prototypicality.

In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Muller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.

We quantified the binding potentials ( BPND) of [11C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [11C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [11C]yohimbine dynamic positron emission tomography (PET) recordings were applied to five Sprague Dawley rats at baseline, followed by acute amphetamine administration (2 mg/kg) to induce elevation of the endogenous level of noradrenaline. The volume of distribution ( VT) of [11C]yohimbine was obtained using Logan plot with arterial plasma input. Because alpha-2 adrenoceptors are distributed throughout the brain, the estimation of the BPND is complicated by the absence of an anatomic region of no displaceable binding. We used the Inhibition plot to acquire the reference volume, VND, from which we calculated the BPND. Acute pharmacological challenge with amphetamine induced a significant decline of [11C]yohimbine BPND of ∼38% in all volumes of interest. The BPND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [11C]yohimbine binding is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission.

Improvements in neurosurgical and neurological intensive care have led to increased numbers of survivors from severe traumatic brain injury (TBI). Following coma, some patients undergo transition into prolonged disorders of consciousness, including minimally conscious state (MCS) and the unresponsive wakefulness syndrome (UWS) [1]. The clinical hallmarks of consciousness are arousal and awareness. In chronic disorders of consciousness, patients commonly reestablish subcortical functions of arousal, but with decline or absence of cortical functions, leading to loss of awareness. Whereas UWS patients show no responsiveness at the bedside, MCS patients elicit fluctuating but reproducible signs of awareness of their surroundings. By convention, emergence from MCS occurs when the patient regains a capacity for functional communication or object use. Long-term recovery of consciousness from UWS remains uncertain, but progression into MCS is an important indicator of better prognosis.

Udgivelsesdato: 2006-Jun The left inferior prefrontal cortex (LIPC) is involved in speech comprehension by people who hear normally. In contrast, functional brain mapping has not revealed incremental activity in this region when users of cochlear implants comprehend speech without silent repetition. Functional brain maps identify significant changes of activity by comparing an active brain state with a presumed baseline condition. It is possible that cochlear implant users recruited alternative neuronal resources to the task in previous studies, but, in principle, it is also possible that an aberrant baseline condition masked the functional increase. To distinguish between the two possibilities, we tested the hypothesis that activity in the LIPC characterizes high speech comprehension in postlingually deaf CI users. We measured cerebral blood flow changes with positron emission tomography (PET) in CI users who listened passively to a range of speech and non-speech stimuli. The pattern of activation varied with the stimulus in users with high speech comprehension, unlike users with low speech comprehension. The high-comprehension group increased the activity in prefrontal and temporal regions of the cerebral cortex and in the right cerebellum. In these subjects, single words and speech raised activity in the LIPC, as well as in left and right temporal regions, both anterior and posterior, known to be activated in speech recognition and complex phoneme analysis in normal hearing. In subjects with low speech comprehension, sites of increased activity were observed only in the temporal lobes. We conclude that increased activity in areas of the LIPC and right temporal lobe is involved in speech comprehension after cochlear implantation.