Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle. METHODS: In this longitudinal case-control study, we acquired 118 [11C]DASB positron emission tomography scans measuring 5-HTT nondisplaceable binding potential (BPND) in 30 patients with PMDD and 29 controls during 2 menstrual cycle phases (periovulatory, premenstrual). The primary outcome was midbrain and prefrontal cortex 5-HTT BPND. We tested whether BPND changes correlated with depressed mood. RESULTS: Linear mixed effects modeling (significant group × time × region interaction) showed a mean increase of 18% in midbrain 5-HTT BPND (mean [SD] periovulatory = 1.64 [0.40], premenstrual = 1.93 [0.40], delta = 0.29 [0.47]: t29 = -3.43, p = .0002) in patients with PMDD, whereas controls displayed a mean 10% decrease in midbrain 5-HTT BPND (periovulatory = 1.65 [0.24] > premenstrual = 1.49 [0.41], delta = -0.17 [0.33]: t28 = -2.73, p = .01). In patients, increased midbrain 5-HTT BPND correlated with depressive symptom severity (R2 = 0.41, p < .0015) across the menstrual cycle. CONCLUSIONS: These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients with PMDD. These neurochemical findings argue for systematic testing of pre-symptom-onset dosing of selective serotonin reuptake inhibitors or nonpharmacological strategies to augment extracellular serotonin in people with PMDD.

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.

HPA Axis Responsiveness Associates with Central Serotonin Transporter Availability in Human Obesity and Non-Obesity Controls.

BACKGROUND: Alterations of hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. OBJECTIVE: To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). STUDY PARTICIPANTS: Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. METHODS: HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. RESULTS: OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = -0.49, p = 0.009). CONCLUSION: The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.

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.

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.

Striatal dopamine transporter availability and individual clinical course within the 1-year follow-up of deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease.

OBJECTIVE: Degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum is responsible for the motor symptoms in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established procedure to alleviate these symptoms in advanced PD. Yet the mechanism of action, especially the effects of STN-DBS on the availability of striatal dopamine transporter (DAT) as a marker of nigrostriatal nerve cell function, remains largely unknown. The aim of this study was therefore to evaluate whether 1) DAT availability changes within 1 year of STN-DBS and 2) the clinical outcome can be predicted based on preoperative DAT availability. METHODS: Twenty-seven PD patients (mean age 62.7 ± 8.9 years; mean duration of illness 13.0 ± 4.9 years; PD subtypes: akinetic-rigid, n = 11; equivalence, n = 13; and tremor-dominant, n = 3) underwent [123I]FP-CIT SPECT preoperatively and after 1 year of STN-DBS. DAT availability as determined by the specific binding ratio (SBR) was assessed by volume of interest (VOI) analysis of the caudate nucleus and the putamen ipsilateral and contralateral to the clinically more affected side. RESULTS: Unified Parkinson's Disease Rating Scale (UPDRS) III scores improved significantly (mean preoperative on medication 25.6 ± 12.3, preoperative off medication 42.3 ± 15.2, postoperative on medication/off stimulation 41.4 ± 13.2, and postoperative on medication/on stimulation 16.1 ± 9.4; preoperative on medication vs postoperative on medication/on stimulation, p = 0.006), while the levodopa-equivalent daily dose was reduced (mean preoperative 957 ± 440 mg vs postoperative 313 ± 189 mg, p < 0.001). The SBR did not differ significantly before and 1 year after DBS, regardless of PD subtype. Preoperative DAT availability was not related to the change in UPDRS III score, but the change in DAT availability was significantly correlated with the change in UPDRS III score (contralateral head of the caudate VOI, p = 0.014; contralateral putamen VOI, p = 0.018). CONCLUSIONS: Overall, DAT availability did not change significantly after 1 year of STN-DBS. However, on an individual basis, the improvement in UPDRS III score was associated with an increase in DAT availability, whereas DAT availability before STN-DBS surgery did not predict the clinical outcome. Whether a subtype-specific pattern of preoperative DAT availability can become a reliable predictor of successful STN-DBS must be evaluated in larger study cohorts.

(+)-[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.

Increased pulmonary serotonin transporter in patients with chronic obstructive pulmonary disease who developed pulmonary hypertension.

PURPOSE: Pulmonary hypertension (PH) is characterized by a progressive remodelling of the pulmonary vasculature resulting in right heart failure and eventually death. The serotonin transporter (SERT) may be involved in the pathogenesis of PH in patients with chronic-obstructive pulmonary disease (COPD). This study investigated for the first time the SERT in vivo availability in the lungs of patients with COPD and PH (COPD+PH). METHODS: SERT availability was assessed using SERT-selective [11C]DASB and positron emission tomography/computed tomography (PET/CT) with dynamic acquisition over 30 min in 4 groups of 5 participants each: COPD, COPD+PH, pulmonary arterial hypertension, and a healthy control (HC). Time activity curves were generated based on a volume of interest within the middle lobe. Tissue-to-blood concentration ratios after 25 to 30 min (TTBR25-30) served as receptor parameter for group comparison and were corrected for lung tissue attenuation. Participants underwent comprehensive pulmonary workup. Statistical analysis included group comparisons and correlation analysis. RESULTS: [11C]DASB uptake peak values did not differ among the cohorts after adjusting for lung tissue attenuation, suggesting equal radiotracer delivery. Both the COPD and COPD+PH cohort showed significantly lower TTBR25-30 values after correction for lung attenuation than HC. Attenuation corrected TTBR25-30 values were significantly higher in the COPD+PH cohort than those in the COPD cohort and higher in non-smokers than in smokers. They positively correlated with invasively measured severity of PH and inversely with airflow limitation and emphysema. Considering all COPD patients ± PH, they positively correlated with right heart strain (NT-proBNP). CONCLUSION: By applying [11C]DASB and PET/CT, semiquantitative measures of SERT availability are demonstrated in the lung vasculature of patients with COPD and/or PH. COPD patients who developed PH show increased pulmonary [11C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.

Higher HbA1c levels associate with lower hippocampal serotonin transporter availability in non-diabetic adults with obesity.

The current study aimed to investigate whether the in vivo availability of central serotonin reuptake transporters (5-HTT) is associated with plasma levels of glycosylated hemoglobin (HbA1c) in non-diabetic humans with obesity. 5-HTT availability was measured by using positron emission tomography (PET) imaging with the 5-HTT selective radiotracer [11C]DASB in 23 non-diabetic individuals with obesity and 14 healthy, non-obesity controls. Parametric images of binding potential BPND were generated from the PET data and analyzed together with HbA1c levels by using volume of interest analysis for brain areas relevant to appetite control. Voxel-based morphometry (VBM) of individual magnetic resonance imaging data was further performed to correlate grey matter density (GMD) maps with HbA1c. We found significant negative correlations between HbA1c levels and BPND in right and left hippocampus in obesity (r = - 0.717, p < 0.001, and r = - 0.557, p = 0.006, respectively). VBM analyses revealed that higher HbA1c levels were associated with GMD in the right para-hippocampal area. Our results indicate that chronically high blood glucose levels may evoke changes in hippocampal 5-HTT levels that are in part tied to local microstructure.

Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients.

The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood, and exerts anti-inflammatory and neuroprotective effects. Alterations of monoamine signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. We assessed central noradrenaline transporter (NAT) availability using positron emission tomography (PET) and the NAT selective radiotracer S,S-[11C]O-methylreboxetine in immunotherapy-naïve patients with relapsing-remitting MS (RRMS; n = 11) compared to healthy controls (HC; n = 12), and its association to lesion load, time since manifestation, the expanded disability status scale (EDSS), the fatigue scale Würzburger Erschöpfungsinventar bei MS (WEIMuS) and Beck Depression Inventory (BDI). We found NAT availability to be increased in the thalamus, amygdala, putamen and pons/midbrain of MS patients. No relation to clinical or psychometric variables was found. These first data indicate higher NAT availability in subcortical brain regions of immunotherapy-naïve RRMS patients. If these changes of noradrenergic neurotransmission predispose to psychiatric symptoms or associate with disease activity needs to be investigated in longitudinal studies or a larger sample which allows subgroup analyses.

Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S,S)-O-[11C]methylreboxetine positron emission tomography study.

The norepinephrine transporter (NET) has been suggested to play a critical role in attention-deficit/hyperactivity disorder (ADHD). In this prospective controlled study we tested the a-priori-hypothesis that central NET availability is altered in adult ADHD patients compared to healthy controls. Study participants underwent single positron emission tomography-magnetic resonance imaging (PET-MRI). MRI sequences included high resolution T1-MPRAGE data for regions of interest (ROI) delineation and voxel-based morphometry (VBM) and T2-weighted fluid-attenuated inversion-recovery for detection and exclusion of pathological abnormalities. NET availability was assessed by NET-selective (S,S)-O-[11C]methylreboxetine; regional distribution volume ratios (DVR) were calculated based on individual PET-MRI data co-registration and a multi-linear reference tissue model with two constraints (MRTM2; reference region: occipital cortex). VBM analysis revealed no difference in local distribution of gray matter between the 20 ADHD patients (9 females, age 31.8 ± 7.9 years, 488 ± 8 MBq injected activity) and the 20 age-matched and sex-matched control participants (9 females, age 32.3 ± 7.9 years, 472 ± 72 MBq). In mixed-model repeated-measures analysis with NET availability as dependent and ROI as repeated measure we found a significant main effect group in fronto-parietal-thalamic-cerebellar regions (regions on the right: F1,25 = 12.30, p = .002; regions on the left: F1,41 = 6.80, p = .013) indicating a reduced NET availability in ADHD patients. None of the other investigated brain regions yielded significant differences in NET availability between groups after applying a Benjamini-Hochberg correction at a significance level of 0.05. Overall our findings demonstrate the pathophysiological involvement of NET availability in adult ADHD.

Early after Administration [11C]PiB PET Images Correlate with Cognitive Dysfunction Measured by the CERAD Test Battery.

BACKGROUND: Amyloid-ß (Aß) and [18F]FDG PET are established as amyloid pathology and neuronal injury biomarkers. Early after administration Aß PET images have the potential to replace [18F]FDG PET images allowing dual biomarker delivery by the administration of a single tracer. For [18F]FDG PET data, a correlation with cognitive performance is known. OBJECTIVE: The aim of this study was to investigate whether early after administration [11C]PiB PET data also correlate with cognitive performance. METHODS: The early after administration [11C]PiB PET data of 31 patients with cognitive impairment were evaluated. CERAD subtests were summarized to five cognitive domains. The resulting z scores were correlated with the PET data on a voxel- and VOI-based approach. Additional subgroup analyses (MCI versus dementia, Aß-positive versus Aß-negative subjects) were performed. RESULTS: Significant correlations between cognitive performance and early after administration [11C]PiB PET data were found between left temporo-parietal SUVR and language domain, bilateral occipital as well as left temporal SUVR and executive function, left pre- and postcentral SUVRs, and visuospatial abilities. For the episodic and immediate memory domains, the analysis at the high significance level did not show any correlated cluster, however, the exploratory analysis did. CONCLUSION: Our study revealed correlations between deficits in different cognitive domains and regional early after administration [11C]PiB PET data similar to those known from [18F]FDG PET studies. Thus, our data support the assumption that early [11C]PiB PET data have a potential as neuronal injury biomarker. Head-to-head double-tracer studies of larger cohorts are needed to confirm this assumption.

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.

Dual Time-Point [18F]Florbetaben PET Delivers Dual Biomarker Information in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: Current research diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18F]FBB PET is able to deliver both blood flow and amyloid-ß (Aß) load surrogates. OBJECTIVE: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers. METHODS: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs for the late PET data) analyzed. RESULTS: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aß-positive. 17% of the MCIs were categorized as "MCI due to AD-high likelihood", 44% of the probable ADs as "probable AD with high evidence of AD pathophysiological process" and 28% of the possible ADs as "possible AD with evidence of AD pathophysiological process". 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p < 0.005) in Aß-positive versus Aß-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p = 0.006). CONCLUSION: Dual time-point [18F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18F]FBB PET has great potential to supplement diagnostic dementia workups.

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.

The association between in vivo central noradrenaline transporter availability and trait impulsivity.

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8±9.3, 21-52 years of age) with a body mass index (BMI) ranging from 21.7kg/m2 to 47.8kg/m2. Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior.

Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity.

CONTEXT: Increased activities of the arginine-vasopressin (AVP) system and the hypothalamic-pituitary-adrenal (HPA) axis were shown to be associated with human obesity, but relationships between these systems in obesity remain unclear. OBJECTIVES: To assess HPA axis responsiveness and its relation to serum concentrations of the AVP-surrogate copeptin in subjects with obesity (OB) in comparison to non-obesity controls (NOC). METHODS: In a cross-sectional monocentric study, thirty-nine OB (f/m 25/14; age 36.5±10.0years; body mass index, BMI, 41.5±4.7kg/m2) were compared to twenty-two NOC (f/m 12/10; age 35.3±8.5years; BMI 23.1±2.4kg/m2), matched for age and sex. All individuals underwent the combined dexamethasone/CRH test. MAIN OUTCOME MEASURES: Plasma ACTH and cortisol curve indicators derived from the dex/CRH test (post-CRH concentrations 30min after 100µg CRH; maximum concentration, MAX; area-under-the-curve, AUC; ACTH/cortisol ratios). Copeptin was assessed in 1500h samples of the dex/CRH test (after 1.5mg of oral dexamethasone, prior to CRH administration). RESULTS: Copeptin serum concentrations were higher in OB (median [IQR]: OB 4.62 [2.60-5.88] vs. NOC 3.04 [2.52-4.29] pmol/l, P=0.04). Correspondingly, OB showed higher post-CRH cortisol concentrations (OB: 51.5 [25.9-159.3] vs. NOC: 28.6 [20.0-41.6] nmol/l, P=0.01) and a lower post-CRH ACTH/cortisol ratio (OB: 0.028 [0.016-0.053] vs. NOC: 0.048 [0.034-0.070] pmol/nmol, P<0.01). Serum copeptin was significantly associated with HPA responsiveness in OB (post-CRH ACTH: R=0.42, P<0.01), driven by OB men (post-CRH ACTH: R=0.76, P<0.01, post-CRH cortisol: R=0.64, P=0.02). All associations withstand adjustments for BMI and age. CONCLUSIONS: The association between increased copeptin with ACTH and cortisol release suggests a potential mechanistic interaction of the AVP system with HPA activation in human obesity. The relation of copeptin and HPA responsiveness should be further validated in situations with pronounced HPA activation, such as depression or multiple sclerosis.

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.