Objective Several interventions promote axonal growth and functional recovery when initiated shortly after CNS injury, including blockade of myelin-derived inhibitors with soluble Nogo Receptor (NgR1, RTN4R) ‘decoy’ protein. We examined the efficacy of this intervention in the much more prevalent and refractory condition of chronic spinal cord injury. Methods We eliminated the NgR1 pathway genetically in mice by conditional gene targeting starting 8 weeks after spinal hemisection injury and monitored locomotion in the open field and by video kinematics over the ensuing 4 months. In a separate pharmacological experiment, intrathecal NgR1 decoy protein administration was initiated 3 months after spinal cord contusion injury. Locomotion and raphespinal axon growth were assessed during 3 months of treatment between 4 and 6 months after contusion injury. Results Conditional deletion of NgR1 in the chronic state results in gradual improvement of motor function accompanied by increased density of raphespinal axons in the caudal spinal cord. In chronic rat spinal contusion, NgR1 decoy treatment from 4–6 months after injury results in 29% (10 of 35) of rats recovering weight-bearing status compared to 0% (0 of 29) of control rats (P<0.05). Open field BBB locomotor scores showed a significant improvement in the NgR-treated group relative to the control group (P<0.005, repeated measures ANOVA). An increase in raphespinal axon density caudal to the injury is detected in NgR1-decoy-treated animals by immunohistology and by positron emission tomography using a serotonin reuptake ligand. Interpretation Antagonizing myelin-derived inhibitors signaling with NgR1 decoy augments recovery from chronic spinal cord injury.

Depression is associated with systemic inflammation, and endotoxin administration, which causes systemic inflammation, elicits mild depressive symptoms, such as fatigue and reduced interest. The neural correlates of depressive symptoms that result from systemic inflammation are poorly defined. The aim of this study was to use FDG-PET to identify brain regions involved in the response to endotoxin administration in humans. Methods Nine healthy subjects received double-blind endotoxin (0.8 ng/kg) and placebo on different days. FDG-PET was used to measure differences in the cerebral metabolic rate of glucose in regions of interest: insula, cingulate, and amygdala. Serum levels of tumor necrosis factor-alpha and interleukin-6 were used to gauge the systemic inflammatory response, and depressive symptoms were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) and other scales. Results Endotoxin administration was associated with an increase in MADRS score, increased fatigue, reduced social interest, increased levels of inflammatory cytokines, higher normalized glucose metabolism (NGM) in the insula and, at a trend level, lower NGM in the cingulate. Secondary analyses of insula and cingulate subregions indicated that these changes were driven by the right anterior insula and the right anterior cingulate. There was a negative correlation between peak cytokine levels and change in social interest, and between peak cytokine levels and change in insula NGM. There was a positive correlation between the change in NGM in the insula and change in social interest. Conclusion Systemic inflammation in humans causes an increase in depressive symptoms and concurrent changes in glucose metabolism in the insula and cingulate, brain regions that are involved in interoception, positive emotionality, and motivation.

Arterial transit time (ATT), a key parameter required to calculate absolute cerebral blood flow in arterial spin labeling (ASL), is subject to much uncertainty. In this study, ASL ATTs were estimated on a per-voxel basis using data measured by both ASL and positron emission tomography in the same subjects. The mean ATT increased by 260 6 20 (standard error of the mean) ms when the imaging slab shifted downwards by 54 mm, and increased from 630 6 30 to 1220 6 30 ms for the first slice, with an increase of 610 6 20 ms over a four-slice slab when the gap between the imaging and labeling slab increased from 20 to 74 mm. When the per-slice ATTs were employed in ASL cerebral blood flow quantification and the in-slice ATT variations ignored, regional cerebral blood flow could be significantly different from the positron emission tomography measures. ATT also decreased with focal activation by the same amount for both visual and motor tasks (~80 ms). These results provide a quantitative relationship between ATT and the ASL imaging geometry and yield an assessment of the assumptions commonly used in ASL imaging. These findings should be considered in the interpretation of, and comparisons between, different ASL-based cerebral blood flow studies. The results also provide spatially specific ATT data that may aid in optimizing the ASL imaging parameters. Key words: arterial transit time; cerebral blood flow; positron emission tomography; pulsed arterial spin labeling; brain vasculature Significant efforts have been made to improve the accuracy of absolute cerebral blood flow (CBF) measurements estimated by pulsed arterial spin labeling (ASL) MRI. To improve the inversion profile and the labeling efficiency, adiabatic or hypersecant pulses and other variants have been proposed (1-4). To overcome the signal dampening due to the off-resonance effect of the inversion radiofrequency (RF) pulse, separate coils for labeling and detection have been employed (5-9). Measurement of the arterial blood proton density was suggested to minimize the nonuniformity of the brain tissue-blood partition coefficient (k) (10), and methods have been presented to reduce the sensitivity of CBF quantification to arterial transit time (ATT) effects (contamination from intravascular arterial blood water) in CBF quantification (11-13).In ASL, water in the arteries is magnetically labeled, and when it reaches the capillary bed and exchanges with the extravascular water, the labeled water induces changes in local magnetization relative to the case in which the arterial water is undisturbed. These changes are detectable by MRI and such images of the intensity changes are perfusion weighted. Absolute CBF values can be calculated based on these perfusion-weighted intensity changes. ATTs, however, are one of the key phenomena that affect the calculation of the absolute CBF from the image intensity differences. In ASL, ATT refers to the time it takes the arterial blood to travel from the labeling site to the capillaries in the tissue being imaged. By definitio...

Introduction Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human Positron Emission Tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [11C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (VND) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated. Methods For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [11C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n = 1 and 30 mg, n = 5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (VT). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and VND. The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [11C]GR103545 in vivo KD was also estimated. Results Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that VT was reduced in all regions; thus no suitable reference region is available for the radiotracer. VND was estimated reliably from the occupancy plot of naltrexone blocking (VND = 3.4 ± 0.9 mL/cm3). The IC50 of PF-04455242 was calculated as 55 ng/mL. [11C]GR103545 in vivo KD value was estimated as 0.069 nmol/L. Conclusions [11C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy.

Although [¹¹C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [¹¹C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [¹¹C]-(+)-PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 μg kg⁻¹). The regional binding potential (BP(ND) ) and the corresponding doses of injected (+)-PHNO were used as inputs in a model that quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [¹¹C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R (K(d)/f(ND) ~0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R (K(d)/f(ND) ~11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy ~10%) were estimated at ~0.02-0.04 μg kg⁻¹ injected mass for anesthetized primate and at 0.01-0.02 μg kg⁻¹ for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [¹¹C]-(+)-PHNO.

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[11C]MRB is one of the most promising radioligands used to measure brain norepinephrine transporters (NET) with positron emission tomography (PET). The objective of this study was to evaluate the suitability of [11C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [11C]MRB arterial input functions and ATX plasma levels were also measured. A dose-dependent reduction of [11C]MRB volume of distribution was observed after correction for [11C]MRB plasma free fraction. ATX IC50 was estimated to be 31±10 ng/mL plasma. This corresponds to an effective dose (ED50) of 0.13 mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0–1.5 mg/kg). [11C]MRB binding potential BPND in the thalamus was estimated to be 1.8±0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC50 estimate obtained using MRTM2 BPND without arterial blood sampling was 21±3 ng/mL (using caudate as the reference region). This study demonstrated that [11C]MRB is suitable for drug occupancy studies of NET.