James Brasic

Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

VMAT2 and dopamine neuron loss in a primate model of Parkinson’s disease

We used positron emission tomography (PET) to measure the earliest change in dopaminergic synapses and glial cell markers in a chronic, low‐dose MPTP non‐human primate model of Parkinson’s disease (PD). In vivo levels of dopamine transporters (DAT), vesicular monoamine transporter‐type 2 (VMAT2), amphetamine‐induced dopamine release (AMPH‐DAR), D2‐dopamine receptors (D2R) and translocator protein 18 kDa (TSPO) were measured longitudinally in the striatum of MPTP‐treated animals. We report an early (2 months) decrease (46%) of striatal VMAT2 in asymptomatic MPTP animals that preceded changes in DAT, D2R, and AMPH‐DAR and was associated with increased TSPO levels indicative of a glial response. Subsequent PET studies showed progressive loss of all pre‐synaptic dopamine markers in the striatum with expression of parkinsonism. However, glial cell activation did not track disease progression. These findings indicate that decreased VMAT2 is a key pathogenic event that precedes nigrostriatal dopamine neuron degeneration. The loss of VMAT2 may result from an association with α‐synuclein aggregation induced by oxidative stress. Disruption of dopamine sequestration by reducing VMAT2 is an early pathogenic event in the dopamine neuron degeneration that occurs in the MPTP non‐human primate model of PD. Genetic or environmental factors that decrease VMAT2 function may be important determinants of PD.

A consistent and efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies

The widely used Logan plot in radioligand receptor dynamic PET studies produces marked noise-induced negative biases in the estimates of total distribution volume (DV(T)) and binding potential (BP). To avoid the inconsistencies in the estimates from the Logan plot, a new graphical analysis method was proposed and characterized in this study. The new plot with plasma input and with reference tissue input was first derived to estimate DV(T) and BP. A condition was provided to ensure that the estimate from the new plot equals DV(T) or BP. It was demonstrated theoretically that 1) the statistical expectations of the estimates from the new plot with given input are independent of the noise of the target tissue concentration measured by PET; and 2) the estimates from the time activity curves of regions of interest are identical to those from the parametric images for the new plot. The theoretical results of the new plot were also confirmed by computer simulations and fifty-five human [(11)C]raclopride dynamic PET studies. By contrast, the marked noise-induced underestimation in the DV(T) and BP images and noise-induced negative bias in the estimates from the Logan plot were demonstrated by the same data sets used for the new plot. The computational time for generating DV(T) or BP images in the human studies was reduced by 80% on average by the new plot in contrast to the Logan plot. In conclusion, the new plot is a consistent and computationally efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies.

Human Brain Imaging of α7 nAChR with [18F]ASEM: a New PET Radiotracer for Neuropsychiatry and Determination of Drug Occupancy

PurposeUsing the α7-nAChR radiotracer, [18F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer.ProceduresFive healthy male subjects were imaged for 90 min following IV [18F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [18F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding.Results[18F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [18F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (>20 ml/ml) and binding potentials >1 with TRV averaged 10.8 ± 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two α7-nAChR drugs.ConclusionsThe characteristics of [18F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [18F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.

Cognition and Amyloid Load in Alzheimer Disease Imaged With Florbetapir F 18(AV-45) Positron Emission Tomography

OBJECTIVE To examine the association between regional brain uptake of a novel amyloid positron emission tomography (PET) tracer florbetapir F 18 ([(18)F]-AV-45) and cognitive performance in a pilot study. DESIGN Cross-sectional comparison of [(18)F]-AV-45 in AD patients versus controls. SETTING Three specialty memory clinics. PARTICIPANTS Eleven participants with probable Alzheimer disease (AD) by NINDS/ADRDA criteria and 15 healthy comparison (HC) participants. MEASUREMENTS Participants underwent PET imaging following a 370 MBq (10 mCi) intravenous administration of [(18)F]-AV-45. Regional/cerebellar standardized uptake value ratios (SUVRs) were calculated. Cognition was assessed using Mini-Mental State Examination, Alzheimers Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Wechsler Logical Memory IA (immediate recall) test (LMIA), and verbal category fluency. RESULTS Greater [(18)F]-AV-45 SUVR was associated with poorer performance on all cognitive tests. In the HC group, occipital, parietal, precuneus, temporal, and cortical average SUVR was associated with greater ADAS-Cog, and greater anterior cingulate SUVR was associated with lower LMIA. Two HC participants had [(18)F]-AV-45 cortical/cerebellar SUVR greater than 1.5, one of whom had deficits in episodic recall and on follow-up met criteria for amnestic mild cognitive impairment. CONCLUSION [(18)F]-AV-45 SUVR in several brain regions was associated with worse global cognitive performance particularly in HC, suggesting its potential as a marker of preclinical AD.

PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with 18F-AZAN, a Radioligand with Optimal Brain Kinetics

We evaluated (−)-2-(6-[18F]fluoro-2,3′-bipyridin-5′-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane (18F-AZAN), a novel radiotracer that binds to α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. Methods: We tested safety tolerability and test–retest reliability (n = 5) and proposed initial quantification of 18F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the α4β2-nAChR–selective partial agonist varenicline. Results: Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for 18F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (test–retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BPND values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of 18F-AZAN brain uptake in smokers and varenicline-treated subjects. Conclusion: 18F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity α4β2-nAChR in the living human brain.

Objectively measured sleep and β-amyloid burden in older adults: A pilot study

Background/aims: Although disturbed sleep is associated with cognitive deficits, the association between sleep disturbance and Alzheimer’s disease pathology is unclear. In this pilot study, we examined the extent to which sleep duration, sleep quality, and sleep-disordered breathing are associated with β-amyloid (Aβ) deposition in the brains of living humans. Methods: We studied 13 older adults (8 with normal cognition and 5 with mild cognitive impairment). Participants completed neuropsychological testing, polysomnography, and Aβ imaging with [11C]-Pittsburgh compound B. Results: Among participants with mild cognitive impairment, higher apnea–hypopnea index and oxygen desaturation index were associated with greater Aβ deposition, globally and regionally in the precuneus. There were no significant associations between sleep-disordered breathing and Aβ deposition among cognitively normal participants. There were no significant associations between sleep duration or sleep fragmentation and Aβ deposition. Conclusion: These preliminary results suggest that among older adults with mild cognitive impairment, greater sleep-disordered breathing severity is associated with greater Aβ deposition.

Mu Opioid Receptor Binding Correlates with Nicotine Dependence and Reward in Smokers.

The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotines rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward.

GM1 ganglioside in Parkinson's disease: Pilot study of effects on dopamine transporter binding

OBJECTIVE GM1 ganglioside has been suggested as a treatment for Parkinsons disease (PD), potentially having symptomatic and disease modifying effects. The current pilot imaging study was performed to examine effects of GM1 on dopamine transporter binding, as a surrogate measure of disease progression, studied longitudinally. METHODS Positron emission tomography (PET) imaging data were obtained from a subset of subjects enrolled in a delayed start clinical trial of GM1 in PD [1]: 15 Early-start (ES) subjects, 14 Delayed-start (DS) subjects, and 11 Comparison (standard-of-care) subjects. Treatment subjects were studied over a 2.5 year period while Comparison subjects were studied over 2 years. Dynamic PET scans were performed over 90 min following injection of [(11)C]methylphenidate. Regional values of binding potential (BPND) were analyzed for several striatal volumes of interest. RESULTS Clinical results for this subset of subjects were similar to those previously reported for the larger study group. ES subjects showed early symptomatic improvement and slow symptom progression over the study period. DS and Comparison subjects were initially on the same symptom progression trajectory but diverged once DS subjects received GM1 treatment. Imaging results showed significant slowing of BPND loss in several striatal regions in GM1-treated subjects and in some cases, an increased BPND in some striatal regions was detected after GM1 use. INTERPRETATION Results of this pilot imaging study provide additional data to suggest a potential disease modifying effect of GM1 on PD. These results need to be confirmed in a larger number of subjects.

Advances in CNS Imaging Agents: Focus on PET and SPECT Tracers in Experimental and Clinical Use

AbstractThe physiological functioning of the brain is not well-known in current day medicine and the pathologies of many neuropsychiatric disorders are still not yet fully understood. With our aging population and better life expectancies, it has become imperative to find better biomarkers for disease progression as well as receptor target engagements. In the last decade, these major advances in the field of molecular CNS imaging have been made available with tools such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and neuroreceptor-targeted positron emission tomography (PET). These tools have given researchers, pharmaceutical companies, and clinical physicians a better method of understanding CNS dysfunctions, and the ability to employ improved therapeutic agents. This review is intended to provide an update on brain imaging agents that are currently used in clinical and translational research toward treatment of CNS disorders. The review begins with amyloid and tau imaging, the former of which has at least three [18F] agents that have been recently approved and will soon be available for clinical use for specific indications in the USA and elsewhere. Other prevalent PET and SPECT neurotransmitter system agents, including those newly US FDA-approved imaging agents related to the dopaminergic system, are included. A review of both mature and potentially growing PET imaging agents, including those targeting serotonin and opiate receptor systems, is also provided.