Noradrenergic control of neurobehavior in human binge-eating disorder and obesity (NOBEAD): A smartphone-supported behavioral emotion regulation intervention study protocol integrating molecular brain imaging.

OBJECTIVE: The neurobehavioral underpinnings of binge-eating disorder (BED), co-occurring with obesity (OB), are largely unknown. This research project conceptualizes BED as a disorder with dysfunctional emotion regulation (ER) linked with changes in central noradrenaline (NA) transmission and NA-modulated neuronal networks. METHODS: We expect abnormalities in NA activity in both BED and OB, but most pronounced in BED. We expect these abnormalities to be modifiable through state-of-the-art ER intervention, specifically in BED. To assess the role of NA transmission, we will quantify changes in NA transporter (NAT) availability using the highly NAT-specific [11 C]methylreboxetin (MRB) and positron emission tomography-magnetic resonance imaging (PET-MRI) that allows measuring molecular and neuronal changes before and after an ER intervention. Individual 12-session smartphone-supported acceptance-based behavioral therapy will be conducted to improve ER. Thirty individuals with OB and BED (OB + BED), 30 individuals with OB without BED (OB - BED), and 20 individuals with normal weight will undergo assessments of NAT availability and neuronal network activity under rest and stimulated conditions, clinical interviews, self-report questionnaires on eating behavior, ER, mental and physical health, and quality of life, and neuropsychological tests on executive function. Afterwards, in an experimental randomized-controlled design, individuals with OB + BED and OB - BED will be allocated to smartphone-supported ER intervention versus a waitlist and re-assessed after 10 weeks. DISCUSSION: By obtaining biological and behavioral markers, the proposed study will disentangle the involvement of NAT and the central NA system in the modulation of emotion-supporting neuronal networks that influence eating behavior. Neurobehavioral mechanisms of change during an ER intervention will be determined. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00029367. PUBLIC SIGNIFICANCE: This study investigates the central noradrenaline system by using hybrid brain imaging in conjunction with emotion regulation as a putative core biological mechanism in individuals with obesity with or without binge-eating disorder that is targeted by emotion regulation intervention. The results will provide a molecular signature beyond functional imaging biomarkers as a predictive biomarker toward precision medicine for tailoring treatments for individuals with binge-eating disorders and obesity.

(+)-[18F]Flubatine as a novel α4ß2 nicotinic acetylcholine receptor PET ligand-results of the first-in-human brain imaging application in patients with ß-amyloid PET-confirmed Alzheimer's disease and healthy controls.

PURPOSES: We present the first in-human brain PET imaging data of the new α4ß2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[18F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[18F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer's disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[18F]Flubatine binding; and whether (+)-[18F]Flubatine binding and cognitive test data respective ß-amyloid radiotracer accumulation were correlated. METHODS: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [11C]PiB PET/MRI examination. (+)-[18F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses. RESULTS: With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[18F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[18F]Flubatine binding of approximately 15% but also standard deviation of 0.4-70%. Cognitive test data and (+)-[18F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p < 0.05 each). In AD patients, (+)-[18F]Flubatine binding and [11C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[18F]Flubatine binding and [11C]PiB accumulation in the white matter was found. No adverse event related to (+)-[18F]Flubatine occurred. CONCLUSION: (+)-[18F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[18F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter ß-amyloid PET uptake and (+)-[18F]Flubatine binding indicated an association between white matter integrity and availability of α4ß2 nAChRs. Overall, (+)-[18F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4ß2 nAChR-targeting PET ligand in further clinical trials.

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study.

PURPOSE: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. METHODS: Using [18F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. RESULTS: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). CONCLUSIONS: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

The central noradrenaline (NA) stress-response network co-mediates hypothalamic-pituitary-adrenal (HPA) axis activation and arginine-vasopressin (AVP) release. Dysregulation of these systems contributes to stress-related diseases such as human obesity, but their interrelation remains unclear. The study was aimed to test for the first time in vivo whether central noradrenergic activity quantitatively indexed by the availability of the presynaptic NA transporter (NAT) is associated with HPA axis responsiveness as measured with the combined dexamethasone suppression/corticotropin releasing hormone stimulation (dex/CRH) test and copeptin as a surrogate marker of the serum AVP tone in highly obese, otherwise, healthy individuals compared to age- and sex-matched non-obese, healthy controls. In order to assess central NAT availability, positron emission tomography (PET) was applied using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and correlated with curve indicators derived from the dex/CRH test (maximum, MAX, and area under the curve, AUC, for cortisol and adrenocorticotropic hormone, ACTH) as well as with copeptin. In non-obese controls, positive correlations were found between the NAT distribution volume ratios (DVR) of the orbitofrontal cortex (OFC) and the amygdala with the HPA response (OFC: ACTHMAX r = 0.87, p = .001; cortisolMAX r = 0.86, p = .002; amygdala: ACTHMAX r = 0.86, p = .002; cortisolMAX r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisolMAX, r = -0.66, p = .04) and with copeptin (r = -0.71, p = .02). This association of central NAT availability with HPA axis responsiveness and copeptin suggests a mechanistic interaction between noradrenergic transmission with HPA axis activity and the serum AVP system that differs between non-obese individuals with prefrontal-limbic involvement and obesity with a hypothalamic-centered relationship. Whether the latter finding contributes to obesogenic behavior needs to be further explored.

Cognitive correlates of α4ß2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.

In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4ß2 nicotinic acetylcholine receptors (α4ß2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4ß2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4ß2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4ß2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4ß2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (-)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4ß2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (-)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4ß2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4ß2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (-)-18F-flubatine as PET biomarker of cholinergic α4ß2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (-)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.

Noradrenaline transporter availability on [11C]MRB PET predicts weight loss success in highly obese adults.

PURPOSE: Although the mechanisms by which the central noradrenaline (NA) system influences appetite and controls energy balance are quite well understood, its relationship to changes in body weight remains largely unknown. The main goal of this study was to further clarify whether the brain NA system is a stable trait or whether it can be altered by dietary intervention. METHODS: We aimed to compare central NA transporter (NAT) availability in ten obese, otherwise healthy individuals with a body mass index (BMI) of 42.4 ± 3.7 kg/m2 (age 34 ± 9 years, four women) and ten matched non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m2, age 33 ± 10 years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[11C]O-methylreboxetine (MRB) before and 6 months after dietary intervention. RESULTS: MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BPND) in the insula and the hippocampus of obese individuals, which correlated well with changes in BMI (-3.3 ± 5.3%; p = 0.03) following completion of the dietary intervention. Furthermore, voxel-wise regression analyses showed that lower BPND in these regions, but also in the midbrain and the prefrontal cortex, at baseline was associated with higher achieved weight loss (e.g., hippocampal area R2 = 0.80; p < 0.0001). No changes were observed in non-obese controls. CONCLUSION: These first longitudinal interventional data on NAT availability in highly obese individuals indicate that the central NA system is modifiable. Our findings suggest that NAT availability before intervention could help predict the amount and success of weight loss in obese individuals and help adjust treatment options individually by allowing prediction of the benefit of a dietary intervention.

Test-retest measurements of dopamine D1-type receptors using simultaneous PET/MRI imaging.

PURPOSE: The role of dopamine D1-type receptor (D1R)-expressing neurons in the regulation of motivated behavior and reward prediction has not yet been fully established. As a prerequisite for future research assessing D1-mediated neuronal network regulation using simultaneous PET/MRI and D1R-selective [11C]SCH23390, this study investigated the stability of central D1R measurements between two independent PET/MRI sessions under baseline conditions. METHODS: Thirteen healthy volunteers (7 female, age 33 ± 13 yrs) underwent 90-min emission scans, each after 90-s bolus injection of 486 ± 16 MBq [11C]SCH23390, on two separate days within 2-4 weeks using a PET/MRI system. Parametric images of D1R distribution volume ratio (DVR) and binding potential (BPND) were generated by a multi-linear reference tissue model with two parameters and the cerebellar cortex as receptor-free reference region. Volume-of-interest (VOI) analysis was performed with manual VOIs drawn on consecutive transverse MRI slices for brain regions with high and low D1R density. RESULTS: The DVR varied from 2.5 ± 0.3 to 2.9 ± 0.5 in regions with high D1R density (e.g. the head of the caudate) and from 1.2 ± 0.1 to 1.6 ± 0.2 in regions with low D1R density (e.g. the prefrontal cortex). The absolute variability of the DVR ranged from 2.4% ± 1.3% to 5.1% ± 5.3%, while Bland-Altman analyses revealed very low differences in mean DVR (e.g. 0.013 ± 0.17 for the nucleus accumbens). Intraclass correlation (one-way, random) indicated very high agreement (0.93 in average) for both DVR and BPND values. Accordingly, the absolute variability of BPND ranged from 7.0% ± 4.7% to 12.5% ± 10.6%; however, there were regions with very low D1R content, such as the occipital cortex, with higher mean variability. CONCLUSION: The test-retest reliability of D1R measurements in this study was very high. This was the case not only for D1R-rich brain areas, but also for regions with low D1R density. These results will provide a solid base for future joint PET/MRI data analyses in stimulation-dependent mapping of D1R-containing neurons and their effects on projections in neuronal circuits that determine behavior.

Central noradrenaline transporter availability in highly obese, non-depressed individuals.

PURPOSE: The brain noradrenaline (NA) system plays an important role in the central nervous control of energy balance and is thus implicated in the pathogenesis of obesity. The specific processes modulated by this neurotransmitter which lead to obesity and overeating are still a matter of debate. METHODS: We tested the hypothesis that in vivo NA transporter (NAT) availability is changed in obesity by using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m2), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m2) healthy controls. RESULTS: Overall, we found no significant differences in binding potential (BPND) values between obese and non-obese individuals in the investigated brain regions, including the NAT-rich thalamus (0.40 ± 0.14 vs. 0.41 ± 0.18; p = 0.84) though additional discriminant analysis correctly identified individual group affiliation based on regional BPND in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BPND patterns between both groups but this did not survive testing for multiple comparions. CONCLUSIONS: Our data do not find an overall involvement of NAT changes in human obesity. However, preliminary secondary findings of distinct regional and associative patterns warrant further investigation.

Central serotonin transporter availability in highly obese individuals compared with non-obese controls: A [(11)C] DASB positron emission tomography study.

PURPOSE: The role of the central serotonin (5-hydroxytryptamine, 5-HT) system in feeding has been extensively studied in animals with the 5-HT family of transporters (5-HTT) being identified as key molecules in the regulation of satiety and body weight. Aberrant 5-HT transmission has been implicated in the pathogenesis of human obesity by in vivo positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging techniques. However, results obtained thus far from studies of central 5-HTT availability have been inconsistent, which is thought to be brought about mainly by the low number of individuals with a high body mass index (BMI) previously used. The aim of this study was therefore to assess 5-HTT availability in the brains of highly obese otherwise healthy individuals compared with non-obese healthy controls. METHODS: We performed PET using the 5-HTT selective radiotracer [(11)C] DASB on 30 highly obese (BMI range between 35 and 55 kg/m(2)) and 15 age- and sex-matched non-obese volunteers (BMI range between 19 and 27 kg/m(2)) in a cross-sectional study design. The 5-HTT binding potential (BPND) was used as the outcome parameter. RESULTS: On a group level, there was no significant difference in 5-HTT BPND in various cortical and subcortical regions in individuals with the highest BMI compared with non-obese controls, while statistical models showed minor effects of age, sex, and the degree of depression on 5-HTT BPND. CONCLUSION: The overall finding of a lack of significantly altered 5-HTT availability together with its high variance in obese individuals justifies the investigation of individual behavioral responses to external and internal cues which may further define distinct phenotypes and subgroups in human obesity.

Evaluation of the Enantiomer Specific Biokinetics and Radiation Doses of [(18)F]Fluspidine-A New Tracer in Clinical Translation for Imaging of σ1 Receptors.

The enantiomers of [(18)F]fluspidine, recently developed for imaging of σ1 receptors, possess distinct pharmacokinetics facilitating their use in different clinical settings. To support their translational potential, we estimated the human radiation dose of (S)-(-)-[(18)F]fluspidine and (R)-(+)-[(18)F]fluspidine from ex vivo biodistribution and PET/MRI data in mice after extrapolation to the human scale. In addition, we validated the preclinical results by performing a first-in-human PET/CT study using (S)-(-)-[(18)F]fluspidine. Based on the respective time-activity curves, we calculated using OLINDA the particular organ doses (ODs) and effective doses (EDs). The ED values of (S)-(-)-[(18)F]fluspidine and (R)-(+)-[(18)F]fluspidine differed significantly with image-derived values obtained in mice with 12.9 µSv/MBq and 14.0 µSv/MBq (p < 0.025), respectively. A comparable ratio was estimated from the biodistribution data. In the human study, the ED of (S)-(-)-[(18)F]fluspidine was calculated as 21.0 µSv/MBq. Altogether, the ED values for both [(18)F]fluspidine enantiomers determined from the preclinical studies are comparable with other (18)F-labeled PET imaging agents. In addition, the first-in-human study confirmed that the radiation risk of (S)-(-)-[(18)F]fluspidine imaging is within acceptable limits. However, as already shown for other PET tracers, the actual ED of (S)-(-)-[(18)F]fluspidine in humans was underestimated by preclinical imaging which needs to be considered in other first-in-human studies.

First-in-human PET quantification study of cerebral α4ß2* nicotinic acetylcholine receptors using the novel specific radioligand (-)-[(18)F]Flubatine.

α4ß2* nicotinic receptors (α4ß2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g., Alzheimer's and Parkinson's diseases, depressive disorders, and nicotine addiction). However, there is a lack of α4ß2* nAChR specific PET radioligands with kinetics fast enough to enable quantification of nAChR within a reasonable time frame. Following on from promising preclinical results, the aim of the present study was to evaluate for the first time in humans the novel PET radioligand (-)-[(18)F]Flubatine, formerly known as (-)-[(18)F]NCFHEB, as a tool for α4ß2* nAChR imaging and in vivo quantification. Dynamic PET emission recordings lasting 270min were acquired on an ECAT EXACT HR+ scanner in 12 healthy male non-smoking subjects (71.0±5.0years) following the intravenous injection of 353.7±9.4MBq of (-)-[(18)F]Flubatine. Individual magnetic resonance imaging (MRI) was performed for co-registration. PET frames were motion-corrected, before the kinetics in 29 brain regions were characterized using 1- and 2-tissue compartment models (1TCM, 2TCM). Given the low amounts of metabolite present in plasma, we tested arterial input functions with and without metabolite corrections. In addition, pixel-based graphical analysis (Logan plot) was used. The model's goodness of fit, with and without metabolite correction was assessed by Akaike's information criterion. Model parameters of interest were the total distribution volume VT (mL/cm(3)), and the binding potential BPND relative to the corpus callosum, which served as a reference region. The tracer proved to have high stability in vivo, with 90% of the plasma radioactivity remaining as untransformed parent compound at 90min, fast brain kinetics with rapid uptake and equilibration between free and receptor-bound tracer. Adequate fits of brain TACs were obtained with the 1TCM. VT could be reliably estimated within 90min for all regions investigated, and within 30min for low-binding regions such as the cerebral cortex. The rank order of VT by region corresponded well with the known distribution of α4ß2* receptors (VT [thalamus] 27.4±3.8, VT [putamen] 12.7±0.9, VT [frontal cortex] 10.0±0.8, and VT [corpus callosum] 6.3±0.8). The BPND, which is a parameter of α4ß2* nAChR availability, was 3.41±0.79 for the thalamus, 1.04±0.25 for the putamen and 0.61±0.23 for the frontal cortex, indicating high specific tracer binding. Use of the arterial input function without metabolite correction resulted in a 10% underestimation in VT, and was without important biasing effects on BPND. Altogether, kinetics and imaging properties of (-)-[(18)F]Flubatine appear favorable and suggest that (-)-[(18)F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of α4ß2* nAChRs in neuropsychiatric disorders.

Altered serotonin transporter availability in patients with multiple sclerosis.

PURPOSE: Modulation of the immune system by the CNS may involve serotonergic regulation via the brain serotonin transporters (SERT). This regulation may be disturbed in patients with CNS disorders including multiple sclerosis (MS). Central serotonergic mechanisms have not been investigated in MS by in vivo imaging. The objective of the study was to assess the availability of SERT in antidepressant-naive patients with MS by means of PET. METHODS: Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [(11)C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and the Beck Depression Inventory (BDI). The PET data were analysed with both volume-of-interest and voxel-based analyses to determine regional SERT availability. RESULTS: Patients had lower SERT availability in the cingulate cortex, the thalamus and the insula, and increased availability in the orbitofrontal cortex. Patients with relapsing/remitting MS tended to have lower SERT in the hippocampus, whereas patients with primary progressive disease showed increased SERT availability in prefrontal regions. There was a positive correlation between SERT availability in the insula and both depression and fatigue scores (r = 0.56 vs. BDI, p = 0.02; r = 0.49 vs. WEIMuS, p = 0.05). CONCLUSION: Serotonergic neurotransmission in MS patients is altered in limbic and paralimbic regions as well as in the frontal cortex that this appears to contribute to psychiatric symptoms of MS.

Imaging of the brain serotonin transporters (SERT) with 18F-labelled fluoromethyl-McN5652 and PET in humans.

PURPOSE: [(11)C]DASB is currently the most frequently used highly selective radiotracer for visualization and quantification of central SERT. Its use, however, is hampered by the short half-life of (11)C, the moderate cortical test-retest reliability, and the lack of quantifying endogenous serotonin. Labelling with (18)F allows in principle longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly use the new highly SERT-selective (18)F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[(18)F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification. METHODS: The PET data from five healthy volunteers (three men, two women, age 39 ± 10 years) coregistered with individual MRI scans were semiquantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and total distribution volumes (V (T)) were calculated using a two-tissue compartment model and arterial input function measurements were corrected for metabolite/plasma data. Standardized uptake region-to-cerebellum ratios as a measure of specific radiotracer accumulation were compared with those of a [(11)C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38 ± 8 years). RESULTS: The two-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume (V (T)) demonstrated good identifiability based on the coefficients of variation (COV) for the volumes of interest in SERT-rich and cortical areas (COV V (T) <10%). Compared with [(11)C]DASB PET, there was a tendency to lower mean uptake values in (+)-[(18)F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[(18)F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans. CONCLUSION: The results showed that (+)-[(18)F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of the long half-life of (18)F, the widespread use within a satellite concept seems feasible.

PET Imaging of Cholinergic Neurotransmission in Neurodegenerative Disorders.

As a neuromodulator, the neurotransmitter acetylcholine plays an important role in cognitive, mood, locomotor, sleep/wake, and olfactory functions. In the pathophysiology of most neurodegenerative diseases, such as Alzheimer disease (AD) or Lewy body disorder (LBD), cholinergic receptors, transporters, or enzymes are involved and relevant as imaging targets. The aim of this review is to summarize current knowledge on PET imaging of cholinergic neurotransmission in neurodegenerative diseases. For PET imaging of presynaptic vesicular acetylcholine transporters (VAChT), (-)-18F-fluoroethoxybenzovesamicol (18F-FEOBV) was the first PET ligand that could be successfully translated to clinical application. Since then, the number of 18F-FEOBV PET investigations on patients with AD or LBD has grown rapidly and provided novel, important findings concerning the pathophysiology of AD and LBD. Regarding the α4ß2 nicotinic acetylcholine receptors (nAChRs), various second-generation PET ligands, such as 18F-nifene, 18F-AZAN, 18F-XTRA, (-)-18F-flubatine, and (+)-18F-flubatine, were developed and successfully translated to human application. In neurodegenerative diseases such as AD and LBD, PET imaging of α4ß2 nAChRs is of special value for monitoring disease progression and drugs directed to α4ß2 nAChRs. For PET of α7 nAChR, 18F-ASEM and 11C-MeQAA were successfully applied in mild cognitive impairment and AD, respectively. The highest potential for α7 nAChR PET is seen in staging, in evaluating disease progression, and in therapy monitoring. PET of selective muscarinic acetylcholine receptors (mAChRs) is still in an early stage, as the development of subtype-selective radioligands is complicated. Promising radioligands to image mAChR subtypes M1 (11C-LSN3172176), M2 (18F-FP-TZTP), and M4 (11C-MK-6884) were developed and successfully translated to humans. PET imaging of mAChRs is relevant for the assessment and monitoring of therapies in AD and LBD. PET of acetylcholine esterase activity has been investigated since the 1990s. Many PET studies with 11C-PMP and 11C-MP4A demonstrated cortical cholinergic dysfunction in dementia associated with AD and LBD. Recent studies indicated a solid relationship between subcortical and cortical cholinergic dysfunction and noncognitive dysfunctions such as balance and gait in LBD. Taken together, PET of distinct components of cholinergic neurotransmission is of great interest for diagnosis, disease monitoring, and therapy monitoring and to gain insight into the pathophysiology of different neurodegenerative disorders.

Availability of Central α4ß2* Nicotinic Acetylcholine Receptors in Human Obesity.

PURPOSE: Obesity is thought to arise, in part, from deficits in the inhibitory control over appetitive behavior. Such motivational processes are regulated by neuromodulators, specifically acetylcholine (ACh), via α4ß2* nicotinic ACh receptors (nAChR). These nAChR are highly enriched in the thalamus and contribute to the thalamic gating of cortico-striatal signaling, but also act on the mesoaccumbal reward system. The changes in α4ß2* nAChR availability, however, have not been demonstrated in human obesity thus far. The aim of our study was, thus, to investigate whether there is altered brain α4ß2* nAChR availability in individuals with obesity compared to normal-weight healthy controls. METHODS: We studied 15 non-smoking individuals with obesity (body mass index, BMI: 37.8 ± 3.1 kg/m2; age: 39 ± 14 years, 9 females) and 16 normal-weight controls (non-smokers, BMI: 21.9 ± 1.7 kg/m2; age: 28 ± 7 years, 13 females) by using PET and the α4ß2* nAChR selective (-)-[18F]flubatine, which was applied within a bolus-infusion protocol (294 ± 16 MBq). Volume-of-interest (VOI) analysis was performed in order to calculate the regional total distribution volume (VT). RESULTS: No overall significant difference in VT between the individuals with obesity and the normal-weight volunteers was found, while the VT in the nucleus basalis of Meynert tended to be lower in the individuals with obesity (10.1 ± 2.1 versus 11.9 ± 2.2; p = 0.10), and the VT in the thalamus showed a tendency towards higher values in the individuals with obesity (26.5 ± 2.5 versus 25.9 ± 4.2; p = 0.09). CONCLUSION: While these first data do not show greater brain α4ß2* nAChR availability in human obesity overall, the findings of potentially aberrant α4ß2* nAChR availability in the key brain regions that regulate feeding behavior merit further exploration.

Central Serotonin/Noradrenaline Transporter Availability and Treatment Success in Patients with Obesity.

Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [11C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [11C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m2) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.

Impact of EEG-vigilance on brain glucose uptake measured with [(18)F]FDG and PET in patients with depressive episode or mild cognitive impairment.

INTRODUCTION: [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a well-established method for the examination of the cerebral glucose metabolism of patients with affective disorder or memory impairment. An understudied question is how far results are influenced by interindividual differences in central nervous arousal as assessed with electroencephalogram (EEG-vigilance) during the PET recording. Building upon previous neuroimaging studies, we supposed an association between EEG-vigilance and normalized brain [(18)F]FDG-uptake (nFDGu) as measured by [(18)F]FDG-PET. For the first time, the present study exploratively investigated this association in a routine diagnostic work-up. MATERIALS AND METHODS: Simultaneous 31-channel EEG and [(18)F]FDG-PET under resting conditions were acquired from 14 patients with depressive episode or mild cognitive impairment (MCI). EEG-vigilance was automatically classified by using the VIGALL algorithm (Vigilance Algorithm Leipzig). A nonparametric voxelwise simple linear regression with vigilance measure as predictor and nFDGu as criterion was performed using the Statistical nonParametric Mapping toolbox. RESULTS: The main finding was a significant negative correlation between vigilance measure and nFDGu in bilateral frontal and temporal regions, bilateral cingulate gyrus and right thalamus with vigilance-related changes of nFDGu between 17.1 and 44.4%. DISCUSSION: Simultaneous EEG and [(18)F]FDG-PET under resting conditions revealed that brain regions associated with EEG-vigilance partly overlapped with regions of impaired nFDGu in depression and MCI, as reported by previous studies. Vigilance-related changes of nFDGu were about the same magnitude as disease-related metabolic changes in patients with affective disorder or memory impairment as reported in previous studies. Therefore, our data suggest that differences in EEG-vigilance might influence alterations of nFDGu in disorders such as depression or MCI. Whether this possible impact of vigilance on nFDGu should be taken into account during the routine diagnostic application of [(18)F]FDG-PET has to be explored in future studies with larger patient groups.

The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder.

The pathogenetic role of central serotonin transporters (SERT) in obsessive-compulsive disorder (OCD) has been investigated in vivo by positron emission tomography (PET) or single-photon emission computed tomography (SPECT) studies with inconsistent results. This might reflect methodological differences but possibly also the pathophysiological heterogeneity of the disorder, i.e. the age at onset of OCD. The aim of our study was to compare SERT availability in patients with OCD to healthy controls (HC) taking into account the onset type, other factors and covariates (e.g. SERT genotype, age, depression level, gender). We studied 19 drug-naive OCD patients (36±13 yr, eight females) with early onset (EO-OCD, n=6) or with late onset (LO-OCD, n=13), and 21 HC (38±8 yr, nine females) with PET and the SERT-selective radiotracer [11C]DASB. Statistical models indicated that a variety of covariates and their interaction influenced SERT availability measured by distribution volume ratios (DVR). These models revealed significant effects of onset type on DVR with lower values in LO-OCD (starting at age 18 yr) compared to EO-OCD and HC in limbic (e.g. the amygdala), paralimbic brain areas (the anterior cingulate cortex), the nucleus accumbens and striatal regions, as well as borderline significance in the thalamus and the hypothalamus. The putamen, nucleus accumbens and hypothalamus were found with significant interaction between two SERT gene polymorphisms (SERT-LPR and VNTR). These findings suggest that late but not early onset of OCD is associated with abnormally low SERT availability. In part, functional polymorphisms of the SERT gene might determine the differences.

Individualized quantification of brain ß-amyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer's disease and healthy controls.

PURPOSE: Complementing clinical findings with those generated by biomarkers--such as ß-amyloid-targeted positron emission tomography (PET) imaging--has been proposed as a means of increasing overall accuracy in the diagnosis of Alzheimer's disease (AD). Florbetaben ([(18)F]BAY 94-9172) is a novel ß-amyloid PET tracer currently in global clinical development. We present the results of a proof of mechanism study in which the diagnostic efficacy, pharmacokinetics, safety and tolerability of florbetaben were assessed. The value of various quantitative parameters derived from the PET scans as potential surrogate markers of cognitive decline was also investigated. METHODS: Ten patients with mild-moderate probable AD (DSM-IV and NINCDS-ADRDA criteria) and ten age-matched (≥ 55 years) healthy controls (HCs) were administered a single dose of 300 MBq florbetaben, which contained a tracer mass dose of < 5 µg. The 70-90 min post-injection brain PET data were visually analysed by three blinded experts. Quantitative assessment was also performed via MRI-based, anatomical sampling of predefined volumes of interest (VOI) and subsequent calculation of standardized uptake value (SUV) ratios (SUVRs, cerebellar cortex as reference region). Furthermore, single-case, voxelwise analysis was used to calculate individual "whole brain ß-amyloid load". RESULTS: Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be ß-amyloid positive (p = 0.001), with high inter-reader agreement (weighted kappa ≥ 0.88). When compared to HCs, the neocortical SUVRs were significantly higher in the ADs (with descending order of effect size) in frontal cortex, lateral temporal cortex, occipital cortex, anterior and posterior cingulate cortices, and parietal cortex (p = 0.003-0.010). Voxel-based group comparison confirmed these differences. Amongst the PET-derived parameters, the Statistical Parametric Mapping-based whole brain ß-amyloid load yielded the closest correlation with the Mini-Mental State Examination scores (r = -0.736, p < 0.001), following a nonlinear regression curve. No serious adverse events or other safety concerns were seen. CONCLUSION: These results indicate florbetaben to be a safe and efficacious ß-amyloid-targeted tracer with favourable brain kinetics. Subjects with AD could be easily differentiated from HCs by both visual and quantitative assessment of the PET data. The operator-independent, voxel-based analysis yielded whole brain ß-amyloid load which appeared valuable as a surrogate marker of disease severity.

Central Noradrenergic Neurotransmission and Weight Loss 6 Months After Gastric Bypass Surgery in Patients with Severe Obesity.

PURPOSE: Roux-en-Y gastric bypass (RYGB) surgery is currently the most efficient treatment to achieve long-term weight loss in individuals with severe obesity. This is largely attributed to marked reductions in food intake mediated in part by changes in gut-brain communication. Here, we investigated for the first time whether weight loss after RYGB is associated with alterations in central noradrenaline (NA) neurotransmission. MATERIALS AND METHODS: We longitudinally studied 10 individuals with severe obesity (8 females; age 43.9 ± 13.1 years; body mass index (BMI) 46.5 ± 4.8 kg/m2) using (S,S)-[11C]O-methylreboxetine and positron emission tomography to estimate NA transporter (NAT) availability before and 6 months after surgery. NAT distribution volume ratios (DVR) were calculated by volume-of-interest analysis and the two-parameter multilinear reference tissue model (reference region: occipital cortex). RESULTS: The participants responded to RYGB surgery with a reduction in BMI of 12.0 ± 3.5 kg/m2 (p < 0.001) from baseline. This was paralleled by a significant reduction in DVR in the dorsolateral prefrontal cortex (pre-surgery 1.12 ± 0.04 vs. post-surgery 1.07 ± 0.04; p = 0.019) and a general tendency towards reduced DVR throughout the brain. Furthermore, we found a strong positive correlation between pre-surgery DVR in hypothalamus and the change in BMI (r = 0.78; p = 0.01). CONCLUSION: Reductions in BMI after RYGB surgery are associated with NAT availability in brain regions responsible for decision-making and homeostasis. However, these results need further validation in larger cohorts, to assess whether brain NAT availability could prognosticate the outcome of RYGB on BMI.