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Objective Cocaine is a highly addictive psychostimulant that affects synaptic activity with structural and functional adaptations of neurons. The transmembrane synaptic vesicle glycoprotein 2A (SV2A) of pre-synaptic vesicles is commonly used to measure synaptic density, as a novel approach to the detection of synaptic changes. We do not know if a single dose of cocaine suffices to affect pre-synaptic SV2A density, especially during adolescence when synapses undergo intense maturation. Here, we explored potential changes of pre-synaptic SV2A density in target brain areas associated with the cocaine-induced boost of dopaminergic neurotransmission, specifically testing if the effects would last after the return of dopamine levels to baseline. Methods: We administered cocaine (20 mg/kg i.p.) or saline to rats in early adolescence, tested their activity levels and removed the brains 1 hour and 7 days after injection. To evaluate immediate and lasting effects, we did autoradiography with [3H]UCB-J, a specific tracer for SV2A, in medial prefrontal cortex, striatum, nucleus accumbens, amygdala, and dorsal and ventral areas of hippocampus. We also measured the striatal binding of [3H]GBR-12935 to test cocaine’s occupancy of the dopamine transporter at both times of study. Results: We found a significant increase of [3H]UCB-J binding in the dorsal and ventral sections of hippocampus 7 days after the cocaine administration compared to saline-injected rats, but no differences 1 hour after the injection. The [3H]GBR-12935 binding remained unchanged at both times. Conclusion: Cocaine provoked lasting changes of hippocampal synaptic SV2A density after a single exposure during adolescence

Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BPND declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications.

Introduction: Autonomic nervous system dysfunction (ANSD) is associated with negative prognosis of ischemic heart disease (IHD) and has been found also to be related to elevated measures of sensitivity to pain from pressure (PPS) at the sternum. Previously, we found that non-pharmacological intervention by peripheral sensory nerve stimulation, monitored by repeated home-based PPS measurements, consistently was associated with lowered PPS measures. Compared to the general Danish population, the intervention reduced the all-cause mortality in two prospective observations, one of 103 patients with IHD followed for 3 years, and one of 73 patients with stroke followed for 4.5 years. Here, we test if we can reproduce lower all-cause mortality associated with lowered PPS measures in a randomized controlled trial (RCT). Methods: Of 361 consecutively followed patients with stable IHD, 65% had elevated PPS, suggestive of ANSD. Of these, 213 participated in a randomized controlled trial (RCT) with active (n=106) or passive intervention (n=107). We compared the 5-year all-cause mortality of both groups with two corresponding subsections of approximately 35.000 members of the general population of Denmark, matching patients for gender, age, and observation period with data from Statistics Denmark, and we compared the 5-year mortality of the two RCT groups. In separate analyses, we pooled mortality data from the active group of the RCT with data from two observational studies. We registered the pooled active intervention mortality of 1.168 person-years, compared to approximately 40 million person-years of the pooled general population. Results: We observed fewer than three deaths in the active RCT group (exact number and 95% CI not available according to GDRP rules), compared to eight deaths of passive RCT group members (P=0.035). Based on the predicted mortality from the general population of eight deaths in both groups, the result is consistent with significantly reduced mortality of recipients of active intervention (P=0.011). The separate analyses of pooled data from three consecutive studies demonstrated a mean reduction of the 4.2-year all-cause mortality of 50% (P Conclusions: The predicted attenuation of ANSD associated with lowering of elevated PPS matched the lower all-cause mortality of patients with IHD.

Hypothesis and predictions: Here, we claim that amyloid beta (Aβ) accumulation is a protective mechanism that ultimately fails. We predict that more Aβ accumulates in regions with higher rates of glucose metabolism, reaching a maximum followed by progression of pathology. Background: Aβ accumulation is characteristic of Alzheimer's disease (AD) but the accumulation does not correlate with cognitive decline, unlike the rates of glucose metabolism. Strategy: We compared averaged and individual estimates of regional binding potentials of [11C]Pittsburgh compound B to regionally averaged and individual values of metabolism of [18F]fluorodeoxyglucose in brain regions of volunteers with AD. Significance: The claim explains the cognitive decline in some patients at a significantly lower level of Aβ deposition than in other patients, as well as the presence of cognitively healthy individuals with high Aβ accumulation. With further support of the hypothesis, the significance of Aβ accumulation in brains of patients with AD may require revision.

We derived three widely used linearizations from the definition of receptor availability in molecular imaging with positron emission tomography (PET). The purpose of the present research was to determine the convergence of the results of the 3 methods in terms of 3 parameters—occupancy (s), distribution volume of the nondisplaceable reference binding compartment (V(ND)), and nondisplaceable reference binding potential (BP(ND)) of the radioligand—in the absence of a gold standard. We tested 104 cases culled from the literature and calculated the goodness of fit of the least-squares and Deming II methods of linear regression when applied to the determination of s, V(ND), and BP(ND) using the goodness-of-fit parameters R(2), coefficient of variation (root-mean-square error [RMSE]), and the infinity norm (‖X‖(∞)) with both regression methods. We observed superior convergence among the values of s, V(ND), and BP(ND) for the inhibition and occupancy plots. The inhibition plot emerged as the plot with a slightly higher degree of convergence (based on R(2), RMSE, and ‖X‖(∞) value). With two regression methods (the least-squares method [LSM] and the Deming II [DM] method), the estimated values of s, V(ND), and BP(ND) generally converged. The inhibition and occupancy plots yielded the best fits to the data, according to the goodness-of-fit parameters, due primarily to absence of commingling of the dependent and independent variables tested with the saturation (original Lassen) plot. In the presence of noise, the inhibition and occupancy plots yielded higher convergences.

Background: Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. Method: We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. Results: We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Conclusions: The estimates of BPND declined significantly with age in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade).

Values of binding potentials (BP

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

The corticofugal tracts (CFT) are key agents of upper limb motor function. Although the tracts form high-intensity regions relative to surrounding tissue in T2-weighted magnetic resonance images (T2WI), the precise relations of signal intensities of the left and right CFT regions to hand function are unknown. Here, we tested the hypothesis that the different signal intensities between the left and right CFT signify clinically important differences of hand motor function. Six right-handed and six left-handed healthy volunteers participated in the study. Based on horizontal T2WI estimates, we confirmed the relationship between the signal intensity ratios of the peak values of each CFT in the posterior limbs of the internal capsules (right CFT vs. left CFT). The ratios included the asymmetry indices of the hand motor functions, including grip and pinch strength, as well as the target test (TT) that expressed the speed and accuracy of hitting a target ([right-hand score – left-hand score]/[right-hand score + left-hand score]), using simple linear regression. The signal intensity ratios of each CFT structure maintained significant linear relations with the asymmetry index of the speed (R2 = 0.542, P = 0.006) and accuracy (R2 = 0.408, P = 0.025) of the TT. We found no significant association between left and right CFT structures for grip or pinch strengths. The findings are consistent with the hypothesis that the different signal intensities of the left and right CFT images captured by T2WI serve as biological markers that reflect the dominance of manual dexterity.

BackgroundDisturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects.MethodsWe included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18F-fluorodopa (18F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion.ResultsIndividual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (Ki4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term Ki4p × GABA (p = .016).ConclusionsOur multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between Ki4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.

In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

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.

This chapter examines the interaction between tracer glucose uptake and phosphor-ylation in brain. It derives the equations for the use of labeled deoxyglucose, fluorodeoxyglucose, or glucose itself to calculate brain glucose phosphorylation. The chapter estimates the value of the “lumped constant” as a function of the glucose phosphorylation rate, the plasma glucose concentration, the maximal transport capacity of the cerebral capillary endothelium, and the plasma flow of the brain. The driving force of the loss of tracer from a compartment is the aqueous concentration of the tracer in the compartment, if the tracer is in aqueous solution. Compartmental analysis of tracer uptake in vivo serves to measure the size of the different compartments of the tracer, that is, the relative abundance of its different states, and the magnitude of the transfer coefficient or relaxation constant of each compartment. The brain has two kinetic compartments, the vascular space and an extra-vascular space, separated by a blood-brain barrier.

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.

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 ofSixty-two individuals (31 patients and 31 control subjects) underwentHigh baseline decarboxylation rates (kStriatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k

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.

Purpose: Anaesthesia routinely is used in animal neuroimaging in order to reduce head motion artefacts and minimize the influence of stress. However, anaesthetics can modify radioligand binding profiles at receptor targets studied by positron emission tomography (PET). Here, we determined the effects of two routine anaesthetics on the binding of a tracer of the serotonin 5HT2A receptors. Procedures: Isoflurane- and propofol-anesthetised Göttingen minipigs were imaged with [11C]MDL100,907 PET and analysed using regions of interest and statistical non-parametric mapping. Results: The binding potentials of the tracer in striatum under isoflurane anaesthesia significantly exceeded those obtained under propofol anaesthesia, an effect we attribute to the higher blood flow in brain induced by the former. Conclusions: Interactions between radioligands and anaesthesia must be carefully evaluated in the design of in vivo neuroimaging and interpretation of data.

Background: Muscarinic acetylcholine receptor 4 (M4) modulates dopaminergic neurotransmission and is a target for novel treatments of schizophrenia, cognitive deficits, and addiction. Impulsive and compulsive behaviors are key traits of addiction, yet the importance of M4 receptor signaling to these traits is poorly understood. We investigated impulsive action and compulsivity by measuring premature and perseverative responses in the five choice serial reaction time task (5CSRTT). Furthermore, we hypothesized that inter-trial interval (ITI) initiation settings affected training durations and test performances in these experiments. Methods: M4 -/- and wildtype mice were trained and tested on two versions of the 5CSRTT with different ITI initiation settings. One setting, the head-in condition, allowed the ITI to start while the mouse's head remained in the reward receptacle (magazine). The other setting, the head-out condition, required the mouse to remove its head from the magazine to initiate the ITI. Results and discussion: We did not observe differences in premature or perseverative responses in M4 -/- mice in either condition, but found evidence of reward-related compulsive behavior in M4 -/- mice. In the head-in condition, M4 -/- mice were slower to acquire the 5CSRTT, had more omissions, and had longer correct response latencies than wildtype mice. In the head-out condition, genotypes did not differ in training, but M4 -/- mice showed small decreases in accuracy. Our findings demonstrate that ITI initiation settings contribute to different training durations and tested behaviors in M4 -/- mice, suggesting ITI initiation settings are an important consideration for the general use of the 5CSRTT.

Anaesthesia routinely is used in animal neuroimaging in order to reduce head motion artefacts and minimize the influence of stress. However, anaesthetics can modify radioligand binding profiles at receptor targets studied by positron emission tomography (PET). Here, we determined the effects of two routine anaesthetics on the binding of a tracer of the serotonin 5HTIsoflurane- and propofol-anesthetised Göttingen minipigs were imaged with [The binding potentials of the tracer in striatum under isoflurane anaesthesia significantly exceeded those obtained under propofol anaesthesia, an effect we attribute to the higher blood flow in brain induced by the former.Interactions between radioligands and anaesthesia must be carefully evaluated in the design of in vivo neuroimaging and interpretation of data.

Muscarinic acetylcholine receptor 4 (MMWe did not observe differences in premature or perseverative responses in M

Referring to recent international articles stating that amyloid imaging or detection has a high additive value in making a diagnosis of Alzheimer's disease (AD) when previous investigations are inconclusive, the authors of this editorial argue that this statement is based on circular reasoning and, hence, misleading. Since autopsy findings and other potential indicators fit poorly with amyloid PET, they conclude that this examination has no role in the diagnosis of AD.

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.