Showing papers by "Swen Hesse published in 2016"

Early [(18)F]florbetaben and [(11)C]PiB PET images are a surrogate biomarker of neuronal injury in Alzheimer's disease.

Abstract: [18F]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 [11C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with [18F]FDG uptake. Uptake data for 18F-labelled Aβ PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aβ tracer [18F]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 [11C]PiB (11 patients) or [18F]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 [11C]PiB and [18F]FBB, respectively. The patients also underwent [18F]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 [18F]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 [18F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the [18F]FDG data (r = 0.779, P < 0.001), but there were no differences between [18F]FBB and [11C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and [18F]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 [18F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison. Early [18F]FBB and [11C]PiB PET brain images are similar to [18F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [18F]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.

Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice

Abstract: The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal 18F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. 18F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively.

Role of 18F-FDG-PET imaging in the diagnosis of autoimmune encephalitis

Abstract: Establishing the clinical diagnosis of autoimmune encephalitis can be challenging as patients present with various unspecific symptoms. In a Position Paper in The Lancet Neurology, Francesc Graus and colleagues proposed an initial diagnostic work-up relying on conventional neurological evaluation and standard diagnostic tests such as MRI, CSF sampling, and EEG. This approach would enable clinicians to make a timely diagnosis of “possible autoimmune encephalitis”, allowing initiation of immunotherapy. In a second step, the authors proposed comprehensive antibody testing to help to establish a diagnosis of “probable autoimmune encephalitis” or “defi nite autoimmune encephalitis”, potentially enabling refinement of treatment. With regards to brain imaging, the proposed diagnostic framework solely relies on MRI. However, as acknowledged by Graus and colleagues, limbic encephalitis is known to occur in a relevant fraction of patients with normal or non-specifi c MRI fi ndings. In limbic encephalitis, 18fluorodeoxyglucose (18F-FDG) PET imaging has been reported to typically reveal medial temporal lobe hypermetabolism even in MRI-negative or inconclusive cases, suggesting that it could be more sensitive than MRI (figure). In the Position Paper by Graus and colleauges, this important evidence is mentioned only as a footnote in panel 2. Although we commend the Position Paper, we suggest a stronger consideration of 18F-FDG-PET imaging in supporting the diagnosis of autoimmune encephalitis. This proposal is also supported by results of one of the largest multimodal neuroimaging case series in limbic encephalitis, which demonstrated that 18F-FDG-PET imaging might even have a diagnostic role in patients with autoantibody-negative limbic encephalitis. Furthermore, the differences in PET-based glucose metabolism patterns in such patients support the existence of limbic encephalitis subtypes associated with antibodies that are yet to be identifi ed. Apart from the stated potential of 18F-FDG-PET imaging for improved early diagnosis of limbic encephalitis, we propose the following scenarios in which diagnoses of autoimmune encephalitis could be supported in the future by this molecular imaging approach. First, in limbic encephalitis and in other autoimmune encephalitis subtypes 18F-FDG-PET imaging also shows, in a relevant number of patients, extra-limbic metabolic abnormalities (mainly in the brainstem, cerebellum, or cerebral cortex). These PET findings were associated with clinical symptoms and active disease status more strongly than the MRI fi ndings. Thus, 18F-FDG-PET imaging has the potential to improve estimation of disease severity in patients with autoimmune encephalitis, with implications for follow-up evaluation and therapy monitoring. Second, in the future, 18F-FDG-PET imaging might have a role in the diagnosis of anti-NMDA receptor encephalitis, an entity for which MRI has poor sensitivity. Several 18F-FDGPET imaging studies in these patients have shown metabolic abnormalities in diff erent brain areas, including the frontal, temporal, and occipital lobes, and the basal ganglia, cerebellum, and brainstem. Again, the PET fi ndings were more clearly associated with the clinical picture (ie, basal ganglia involvement and presence of movement disorders), disease severity, and recovery after therapy than the MRI fi ndings. Finally, on a practical note, 18F-FDGPET imaging is an attractive future addition to the proposed work-up for two reasons. First, whole-body 18F-FDGPET imaging is often done in patients with paraneoplastic syndromes to screen for malignancy. Such wholebody imaging can easily be extended to cover the brain without increases in radiation burden. Second, in the past few years, with the introduction of combined PET and MRI systems, many groups have already started to replace MRI with PET–MRI in the diagnostic algorithm for other brain disorders. We encourage feasibility studies for the use of this method in autoimmune encephalitis. We agree that, as a next step, the proposed diagnostic framework for autoimmune encephalitis needs to be tested in clinical practice. Further testing can also provide an opportunity to assess the contribution of 18F-FDGPET imaging in the scenarios discussed here. In parallel, the imaging community needs to refi ne standard procedures for acquisition and reading of PET imaging data in autoimmune encephalitis, and to confi rm the results in large prospective studies.

A novel thermoregulatory role for PDE10A in mouse and human adipocytes

Abstract: Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear. By utilizing small‐animal PET/MRI and the novel radioligand [18F]‐AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP‐10 recruited BAT and potentiated thermogenesis in vivo . In diet‐induced obese mice, chronic administration of MP‐10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity. Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP‐10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes. ![][1] PDE inhibitors hold promise for the treatment of obesity due to their ability to induce a thermogenic program in adipocytes. This study reveals that the PDE10A inhibitor MP‐10 has thermoregulatory effects on mouse and human white and brown adipocytes. EMBO Mol Med (2016) 8: 796–812 [1]: /embed/graphic-1.gif

Evaluation of software tools for automated identification of neuroanatomical structures in quantitative β-amyloid PET imaging to diagnose Alzheimer’s disease

Abstract: 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.

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

Abstract: The enantiomers of [18F]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)-(−)-[18F]fluspidine and (R)-(+)-[18F]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)-(−)-[18F]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)-(−)-[18F]fluspidine and (R)-(+)-[18F]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)-(−)-[18F]fluspidine was calculated as 21.0 μSv/MBq. Altogether, the ED values for both [18F]fluspidine enantiomers determined from the preclinical studies are comparable with other 18F-labeled PET imaging agents. In addition, the first-in-human study confirmed that the radiation risk of (S)-(−)-[18F]fluspidine imaging is within acceptable limits. However, as already shown for other PET tracers, the actual ED of (S)-(−)-[18F]fluspidine in humans was underestimated by preclinical imaging which needs to be considered in other first-in-human studies.

Implementation of the European multicentre database of healthy controls for [(123)I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes.

Abstract: Even though [123I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS with previously inconclusive findings can be improved by the use of iterative reconstruction algorithms and an improved semiquantitative evaluation which additionally implemented a correction algorithm for patient age and gamma camera dependency (EARL-BRASS; Hermes Medical Solutions, Sweden). We identified 101 patients with inconclusive findings who underwent an [123I]FP-CIT SPECT between 2003 and 2010 as part of the diagnostic process of suspected PS at the University of Munich, and re-evaluated these scans using iterative reconstruction algorithms and the new corrected EARL-BRASS. Clinical follow-up was obtained in 62 out of the 101 patients and constituted the gold standard for the re-evaluation to assess the possible improvement in diagnostic accuracy. Clinical follow-up confirmed the diagnosis of PS in 11 of the 62 patients. In patients in whom both visual and semiquantitative analysis showed concordant findings (48 patients), a high negative predictive value (93 %), positive predictive value (100 %) and accuracy (94 %) were found, and thus a correct diagnosis was obtained in 45 of the 48 patients. Among the 14 patients with discordant findings, the additional semiquantitative analysis correctly identified all five of nine patients patients without PS by nonpathological semiquantitative findings in visually pathological or inconclusive scans. In contrast, four of the remaining five patients with decreased semiquantitative values but visually normal scans did not show a PS during follow-up. The age-corrected and camera-corrected mode of evaluation using EARL-BRASS provided a notable improvement in the diagnostic accuracy of [123I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [123I]FP-CIT binding due to age-related loss of the dopamine transporter or pathological loss of binding.

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

Abstract: 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 [11C] DASB on 30 highly obese (BMI range between 35 and 55 kg/m2) and 15 age- and sex-matched non-obese volunteers (BMI range between 19 and 27 kg/m2) 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.

Feasibility and acceptance of simultaneous amyloid PET/MRI.

Abstract: Purpose Established Alzheimer’s disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time.

The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight.

Abstract: The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight

Effortful control as a dimension of temperament is negatively associated with prefrontal serotonin transporter availability in obese and non-obese individuals

Abstract: There is evidence that temperamental factors are associated with obesity; however, the biological mechanism of such association remains elusive. We aimed to investigate a possible association between serotonin transmission and regulative temperament in obese and non-obese individuals by using positron emission tomography (PET) imaging of serotonin transporters (SERT) and the Adult Temperament Questionnaire. Twenty-nine obese individuals with body mass index (BMI) ≥ 35 kg/m2 and 13 non-obese controls (BMI < 30 kg/m2) underwent PET with [11C]-labeled DASB (highly selective for SERT) and self-completed the Effortful Control (EC) scale of the Adult Temperament Questionnaire-Short Form (ATQ). With the help of this questionnaire, we aimed to assess the capacity of self-regulation. Overall, for obese and non-obese individuals together, VOI-based (volume of interest) analysis showed significant negative correlations between SERT BPND and ATQ-EC AC (Activation Control) subscale in several brain regions (all r ≤ −0.47). Obese and non-obese individuals separated showed equally strong positive, but non-significant correlations. The analysis did not reveal any significant correlations of SERT availability and ATQ-EC IC (Inhibitory Control) or ATQ-EC AtC (Attentional Control) subscale within and between the two groups. The results indicate that regulative temperament – particularly the capacity to mitigate negatively toned impulses and to resist inappropriate avoidance behavior – might be associated with the prefrontal serotonergic system.

Sex differences in serotonin–hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight

Abstract: Sex differences in serotonin–hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight

Measurements of dopamine D1-type receptors using simultaneous PET-MRI scanner: Study on test-retest reliability

Abstract: 1795 Objectives The role of dopamine D1-type receptor (D1R)-expressing neurons in the regulation of motivated behavior and future reward prediction remains elusive. In order to assess D1-mediated neuronal network regulation using truly simultaneous PET-MRI and D1R-selective [11C]SCH23390, the aim of this study was to calculate the stability of D1R-binding potential (BPnd) intra-individually in the brain between two independent PET-MRI measurements under neutral conditions. Methods Fifteen healthy volunteers (7 females, aged 33 ± 13yrs) underwent two 90-min emission scans each after 90-sec bolus infusion of 486 ± 16MBq [11C]SCH23390 on two separate days within 2 weeks (scan1 and scan2) using mMR biograph (SIEMENS). For attenuation correction (AC), a two-point MRI Dixon VIBE sequence was obtained in parallel to the PET acquisition, resulting in segmented AC maps. After performing motion correction with SPM8, the parametric images of D1R BPnd were generated in PMOD3.2 (PMOD Technologies, Zurich, Switzerland) by multi-linear reference tissue model with two parameters with the cerebellar cortex as receptor free reference region. For VOI-analysis, BPnd data were then co-registered with the individual spatially reoriented T1 MRI data (PMOD3.2) and target VOIs were manually drawn on consecutive transversal MRI slices. SPM8 was used for voxel-wise comparison with spatially normalized BPnd images. For group comparison scan1 vs scan2 a paired t-test was applied, which was considered significant at p Results Neither voxel-wise nor VOI-based analyses revealed significant differences in BPnd between the two measurements with calculated BPnd of 1.47 ± 0.30 (scan1) and 1.45 ± 0.31 (scan2) for the nucleus accumbens; 1.90 ± 0.39 (scan1) and 1.91 ± 0.56 (scan2) for the head of the caudate; 1.57 ± 0.44 (scan1) and 1.58 ± 0.53 (scan2) for the putamen; 0.36 ± 0.13 (scan1) and 0.36 ± 0.13 (scan2) for the dorsolateral prefrontal cortex; and 0.29 ± 0.09 (scan1) and 0.28 ± 0.09 (scan2) for the substantia nigra/ventral tegmental area. This resulted in absolute variabilities (%) of 8.1 ± 6.7; 8.1 ± 7.2; 8.5 ± 8.0; 13.5 ± 13.3; and 14.8 ± 14.3. Mean differences according to Bland-Altman analyses were very low (0.013 ± 0.17; -0.011 ± 0.24; -0.013 ± 0.23; 0.003 ± 0.05; and 0.011 ± 0.05, respectively) and intraclass correlation (one-way, random) indicated very high agreement (0.93; 0.92; 0.95; 0.97; and 0.93). Conclusions Test-retest reliability of D1R measurements using [11C]SCH3390 and simultaneous PET-MRI is high not only in D1R-rich brain areas but also in areas with lower D1R content. These measurements will provide the base for future multimodal joint PET-MRI data analyses in stimulation-dependent mapping of D1R-containing neurons and their effects on neuronal circuits determining behavior.