[en] Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer's disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4β2* nicotinic acetylcholine receptor (α4β2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD. Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹⁸F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP_ND) of 2-[¹⁸F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis. Both patients with AD and MCI showed a significant reduction in 2-[¹⁸F]FA-85380 BP_ND in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[¹⁸F]FA-85380 BP_ND correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[¹⁸F]FA-85380 BP_ND. 2-[¹⁸F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4β2* nAChRs which seems to be an early event in AD. In addition, 2-[¹⁸F]FA-85380 PET might give prognostic information about a conversion from MCI to AD. (orig.)

[en] For regional quantification of nuclear brain imaging data, defining volumes of interest (VOIs) by hand is still the gold standard. As this procedure is time-consuming and operator-dependent, a variety of software tools for automated identification of neuroanatomical structures were developed. As the quality and performance of those tools are poorly investigated so far in analyzing amyloid PET data, we compared in this project four algorithms for automated VOI definition (HERMES Brass, two PMOD approaches, and FreeSurfer) against the conventional method. We systematically analyzed florbetaben brain PET and MRI data of ten patients with probable Alzheimer's dementia (AD) and ten age-matched healthy controls (HCs) collected in a previous clinical study. VOIs were manually defined on the data as well as through the four automated workflows. Standardized uptake value ratios (SUVRs) with the cerebellar cortex as a reference region were obtained for each VOI. SUVR comparisons between ADs and HCs were carried out using Mann-Whitney-U tests, and effect sizes (Cohen's d) were calculated. SUVRs of automatically generated VOIs were correlated with SUVRs of conventionally derived VOIs (Pearson's tests). The composite neocortex SUVRs obtained by manually defined VOIs were significantly higher for ADs vs. HCs (p=0.010, d=1.53). This was also the case for the four tested automated approaches which achieved effect sizes of d=1.38 to d=1.62. SUVRs of automatically generated VOIs correlated significantly with those of the hand-drawn VOIs in a number of brain regions, with regional differences in the degree of these correlations. Best overall correlation was observed in the lateral temporal VOI for all tested software tools (r=0.82 to r=0.95, p<0.001). Automated VOI definition by the software tools tested has a great potential to substitute for the current standard procedure to manually define VOIs in β-amyloid PET data analysis. (orig.)

[en] Complementing clinical findings with those generated by biomarkers - such as β-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 ([¹⁸F]BAY 94-9172) is a novel β-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. 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 β-amyloid load''. Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be β-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 β-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. These results indicate florbetaben to be a safe and efficacious β-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 β-amyloid load which appeared valuable as a surrogate marker of disease severity. (orig.)

[en] 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). SERT availability was assessed using SERT-selective [${}^{11}$C]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 (TTBR${}_{25\text{â<!-- ?? -->}\text{€<!-- ??? -->}\text{“<!-- ??? -->}30}$) 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. [${}^{11}$C]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 TTBR${}_{25\text{â<!-- ?? -->}\text{€<!-- ??? -->}\text{“<!-- ??? -->}30}$ values after correction for lung attenuation than HC. Attenuation corrected TTBR${}_{25\text{â<!-- ?? -->}\text{€<!-- ??? -->}\text{“<!-- ??? -->}30}$ 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). By applying [${}^{11}$C]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 [${}^{11}$C]DASB uptake compared to COPD patients without PH indicating an implication of pulmonary SERT in the development of PH in COPD patients.

[en] ["1"8F]FDG is a commonly used neuronal injury biomarker for early and differential diagnosis of dementia. Typically, the blood supply to the brain is closely coupled to glucose consumption. Early uptake of the Aβ tracer ["1"1C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with ["1"8F]FDG uptake. Uptake data for "1"8F-labelled Aβ PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aβ tracer ["1"8F]FBB in the diagnosis of Alzhimers disease (AD). This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either ["1"1C]PiB (11 patients) or ["1"8F]FBB (11 patients) in routine clinical practice. Images were acquired 1 - 9 min after administration of both tracers and 40 - 70 min and 90 - 110 min after administration of ["1"1C]PiB and ["1"8F]FBB, respectively. The patients also underwent ["1"8F]FDG brain PET imaging. PET data were analysed visually and semiquantitatively. Associations between early Aβ tracer uptake and dementia as well as brain atrophy were investigated. Regional visual scores of early Aβ tracer and ["1"8F]FDG PET images were significantly correlated (Spearman's ρ = 0.780, P < 0.001). Global brain visual analysis revealed identical results between early Aβ tracer and ["1"8F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the ["1"8F]FDG data (r = 0.779, P < 0.001), but there were no differences between ["1"8F]FBB and ["1"1C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and ["1"8F]FDG PET images were correlated with MMSE scores (ρ = 0.458, P = 0.032, and ρ = 0.456, P = 0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aβ tracer PET images compared with ["1"8F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison. Early ["1"8F]FBB and ["1"1C]PiB PET brain images are similar to ["1"8F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of ["1"8F]FDG. Thus, Aβ tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. The potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts. (orig.)

[en] 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. Included in this study were 23 patients with MS and 22 matched healthy volunteers who were investigated with PET and the SERT-selective marker [¹¹C]DASB, and distribution volume ratios were determined. Clinical assessment of the patients included the expanded disability status scale, the MS fatigue scale Wuerzburger Erschoepfungsinventar 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. 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). 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. (orig.)

[en] The role of dopamine D_1-type receptor (D_1R)-expressing neurons in the regulation of motivated behavior and reward prediction has not yet been fully established. As a prerequisite for future research assessing D_1-mediated neuronal network regulation using simultaneous PET/MRI and D_1R-selective ["1"1C]SCH23390, this study investigated the stability of central D_1R measurements between two independent PET/MRI sessions under baseline conditions. Thirteen healthy volunteers (7 female, age 33 ± 13 yrs) underwent 90-min emission scans, each after 90-s bolus injection of 486 ± 16 MBq ["1"1C]SCH23390, on two separate days within 2-4 weeks using a PET/MRI system. Parametric images of D_1R distribution volume ratio (DVR) and binding potential (BP_N_D) 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 D_1R density. The DVR varied from 2.5 ± 0.3 to 2.9 ± 0.5 in regions with high D_1R density (e.g. the head of the caudate) and from 1.2 ± 0.1 to 1.6 ± 0.2 in regions with low D_1R 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 BP_N_D values. Accordingly, the absolute variability of BP_N_D ranged from 7.0% ± 4.7% to 12.5% ± 10.6%; however, there were regions with very low D_1R content, such as the occipital cortex, with higher mean variability. The test-retest reliability of D_1R measurements in this study was very high. This was the case not only for D_1R-rich brain areas, but also for regions with low D_1R density. These results will provide a solid base for future joint PET/MRI data analyses in stimulation-dependent mapping of D_1R-containing neurons and their effects on projections in neuronal circuits that determine behavior. (orig.)

[en] [¹¹C]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 ¹¹C, the moderate cortical test-retest reliability, and the lack of quantifying endogenous serotonin. Labelling with ¹⁸F 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 ¹⁸F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[¹⁸F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification. 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 [¹¹C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38 ± 8 years). 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 [¹¹C]DASB PET, there was a tendency to lower mean uptake values in (+)-[¹⁸F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[¹⁸F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans. The results showed that (+)-[¹⁸F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of the long half-life of ¹⁸F, the widespread use within a satellite concept seems feasible. (orig.)

[en] 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. 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. MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BP_ND) 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 BP_ND 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 R ² = 0.80; p < 0.0001). No changes were observed in non-obese controls. 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. (orig.)

[en] 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. We performed PET using the 5-HTT selective radiotracer ["1"1C] 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 (BP_N_D) was used as the outcome parameter. On a group level, there was no significant difference in 5-HTT BP_N_D 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 BP_N_D. 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. (orig.)