[Show abstract][Hide abstract] ABSTRACT: Introduction:
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.
Full-text · Article · Jan 2016 · European journal of nuclear medicine and molecular imaging
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Full-text · Article · Nov 2015 · European Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Goal:
Neocortical atrophy reduces the positron emission tomography (PET) signal potentially impacting the diagnostic efficacy of β-amyloid (Aβ) brain PET imaging. This study investigated whether partial volume effect correction (PVEC), adjusting for this atrophy bias, improves the accuracy of florbetaben Aβ PET.
We analyzed florbetaben PET and magnetic resonance imaging (MRI) data obtained (1) from 10 patients with probable Alzheimer's disease (AD) and 10 age-matched healthy controls (HCs), (2) from 31 subjects who underwent in vivo imaging and post mortem histopathology for Aβ plaques, and (3) from five subjects with repeated PET and MR imaging after one year. The imaging data were co-registered and segmented. PVEC was performed using the voxel-based modified Müller-Gärtner method (PVELab, SPM8). From the PET data, regional as well as composite standardized uptake ratios (SUVRs) with/without PVEC were obtained. In the MRI data, mesial temporal lobe atrophy was determined by the Scheltens scale, and grey matter (GM) volumes by voxel-based morphometry.
In cohort (1), effect sizes for AD vs. HC separation increased by PVEC from 1.68 to 2.0 for composite, and from 0.04 to 1.04 for mesial temporal cortex SUVRs. Mesial temporal cortex SUVR increase by PVEC was correlated with the Scheltens atrophy score (r=0.84, p<0.001), and that of the composite SUVR with the composite GM volume (r=-0.75, p<0.001). In cohort (2), PVEC increased the correlation between mesial temporal cortex SUVR and histopathology score of Aβ plaque load from r=0.28 (P = 0.09) to r=0.37 (P = 0.03). In cohort (3), PVEC did not affect the missing serial composite SUVR change over time for the Aβ-negative subject. This was in contrast to the Aβ-positive subjects in which PVEC changed estimation of composite SUVR dynamics in two of the four patients investigated.
The influence of PVEC on florbetaben Aβ PET data is associated with the degree of brain atrophy. Thus, PVEC increases the ability of florbetaben PET to discriminate between AD patients and HCs, to detect Aβ plaques in the atrophic mesial temporal cortex, and potentially to evaluate changes of brain Aβ load over time. As such, PVEC should be considered especially in cases with brain atrophy in future use of quantitative florbetaben PET scan assessment.
Full-text · Article · Nov 2015 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered.
In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [(11)C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL-Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL-Lite).
In a small group of lean-to-morbidly obese individuals (n=20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain's homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n=19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL-Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual's emotional well-being was.
This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network.International Journal of Obesity advance online publication, 1 December 2015; doi:10.1038/ijo.2015.216.
No preview · Article · Oct 2015 · International Journal of Obesity
[Show abstract][Hide abstract] ABSTRACT: α4β2* nicotinic receptors (α4β2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g. Alzheimer´s and Parkinson’s disease, depressive disorders, and nicotine addiction). However, there is a lack of α4β2* 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 α4β2* nAChR imaging and in vivo quantification.
[Show abstract][Hide abstract] ABSTRACT: 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 [(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.
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.
Full-text · Article · Feb 2014 · European Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Over the last years, β-amyloid brain PET imaging has emerged as an important tool supporting the clinical diagnosis of Alzheimer's disease (AD). Florbetaben is a 18F-labeled β-amyloid-targeted PET tracer [Lancet Neurol 2011] currently in Phase 3 clinical development. In principle, in β-amyloid PET imaging, concomitant neocortical atrophy restrains the PET signal and therewith the capability of this “hot spot” imaging technique to diagnose AD. Thus, the question arises whether atrophy/partial volume effect correction (PVEC) enhances the accuracy of florbetaben PET.
No preview · Article · Jul 2013 · Alzheimer's and Dementia
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
(18)F-florbetaben is a novel (18)F-labeled tracer for PET imaging of β-amyloid deposits in the human brain. We evaluated the kinetic model-based approaches to the quantification of β-amyloid binding in the brain from dynamic PET data. The validity of the practically useful tissue ratio was also evaluated against the model-based parameters.
(18)F-florbetaben PET imaging was performed with concurrent multiple arterial sampling after tracer injection (300 MBq) in 10 Alzheimer disease (AD) patients and 10 age-matched healthy controls. Regional brain-tissue time-activity curves for 90 min were analyzed by a 1-tissue-compartment model and a 2-tissue-compartment model (2TCM) with metabolite-corrected plasma data estimating the specific distribution volume (VS) and distribution volume ratio (DVR [2TCM]) and a multilinear reference tissue model estimating DVR (DVR [MRTM]) using the cerebellar cortex as the reference tissue. Target-to-reference tissue standardized uptake value ratios (SUVRs) at 70-90 min were also calculated.
All brain regions required 2TCM to describe the time-activity curves. All β-amyloid binding parameters in the cerebral cortex (VS, DVR [2TCM], DVR [MRTM], and SUVR) were significantly increased in AD patients (P < 0.05), and there were significant linear correlations among these parameters (r(2) > 0.83). Effect sizes in group discrimination between 8 β-amyloid-positive AD scans and 9 β-amyloid-negative healthy control scans for all binding parameters were excellent, being largest for DVR (2TCM) (4.22) and smallest for VS (3.25) and intermediate and the same for DVR (MRTM) and SUVR (4.03).
These results suggest that compartment kinetic model-based quantification of β-amyloid binding from (18)F-florbetaben PET data is feasible and that all β-amyloid binding parameters including SUVR are excellent in discriminating between β-amyloid-positive and -negative scans.
Full-text · Article · Mar 2013 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: [(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.
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).
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.
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.
Full-text · Article · Feb 2012 · European Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Jun 2011 · The International Journal of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: 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 ([(18)F]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.
Full-text · Article · May 2011 · European Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: [(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.
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.
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%.
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.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: 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 alpha4beta2* nicotinic acetylcholine receptor (alpha4beta2* 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. METHODS: Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP(ND)) of 2-[(18)F]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. RESULTS: Both patients with AD and MCI showed a significant reduction in 2-[(18)F]FA-85380 BP(ND) in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[(18)F]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-[(18)F]FA-85380 BP(ND). CONCLUSION: 2-[(18)F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in alpha4beta2* nAChRs which seems to be an early event in AD. In addition, 2-[(18)F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.
[Show abstract][Hide abstract] ABSTRACT: 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-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(18)F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP(ND)) of 2-[(18)F]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-[(18)F]FA-85380 BP(ND) in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[(18)F]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-[(18)F]FA-85380 BP(ND).
2-[(18)F]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-[(18)F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.
Full-text · Article · Nov 2010 · European Journal of Nuclear Medicine