Matthias Reimold

Impact of Age on the Relationships of Brown Adipose Tissue with Sex and Adiposity in Humans

OBJECTIVE Brown adipose tissue (BAT) regulates energy homeostasis and fat mass in mammals and newborns and, most likely, in adult humans. Because BAT activity and BAT mass decline with age in humans, the impact of BAT on adiposity may decrease with aging. In the present study we addressed this hypothesis and further investigated the effect of age on the sex differences in BAT activity and BAT mass. RESEARCH DESIGN AND METHODS Data from 260 subjects (98 with BAT and 162 study date–matched control subjects) who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) under thermoneutral conditions were analyzed. BAT activity and BAT mass were determined in the upper body. RESULTS BAT activity and BAT mass were higher in female (1.59 ± 0.10 and 32 ± 5 g vs. 1.02 ± 0.10 and 18 ± 4 g, both P ≤ 0.0006) than in male subjects. In multivariate analyses, sex (P < 0.0001), age (P < 0.0001), and BMI (P = 0.0018) were associated independently with BAT activity. Interestingly, only in male subjects was there an interaction between BMI and age in determining BAT activity (P = 0.008) and BAT mass (P = 0.0002); BMI decreased with increasing BAT activity and BAT mass in the lowest age tertile (Spearman rank correlation coefficient rs = −0.38, P = 0.015 and rs = −0.37, P = 0.017, respectively), not in the higher age tertiles. Furthermore, BAT activity and mass differed between female and male subjects only in the upper two age tertiles (all P ≤ 0.09). CONCLUSIONS Our data corroborate that, in general, BAT activity and BAT mass are elevated in female subjects and in younger people. Importantly, we provide novel evidence that the impact of BAT activity and BAT mass on adiposity appears to decline with aging only in male subjects. Furthermore, while BAT activity and BAT mass only moderately decline with increasing age in female subjects, a much stronger effect is found in male subjects.

Hybrid PET/MRI of Intracranial Masses: Initial Experiences and Comparison to PET/CT

Simultaneous PET and MRI using new hybrid PET/MRI systems promises optimal spatial and temporal coregistration of structural, functional, and molecular image data. In a pilot study of 10 patients with intracranial masses, the feasibility of tumor assessment using a PET/MRI system comprising lutetium oxyorthosilicate scintillators coupled to avalanche photodiodes was evaluated, and quantification accuracy was compared with conventional PET/CT datasets. Methods: All measurements were performed with a hybrid PET/MRI scanner consisting of a conventional 3-T MRI scanner in combination with an inserted MRI-compatible PET system. Attenuation correction of PET/MR images was computed from MRI datasets. Diagnoses at the time of referral were low-grade astrocytoma (n = 2), suspicion of low-grade astrocytoma (n = 1), anaplastic astrocytoma (World Health Organization grade III; n = 1), glioblastoma (n = 2), atypical neurocytoma (n = 1), and meningioma (n = 3). In the glial tumors, 11C-methionine was used for PET; in the meningiomas, 68Ga-DOTATOC was administered. Tumor–to–gray matter and tumor–to–white matter ratios were calculated for gliomas, and tracer uptake of meningiomas was referenced to nasal mucosa. PET/MRI was performed directly after clinically indicated PET/CT examination. Results: In all patients, the PET datasets showed similar diagnostic image quality on the hybrid PET/MRI and the PET/CT studies; however, slight streak artifacts were visible in coronal and sagittal sections when using the higher intrinsic resolution of the PET/MRI insert. Prefiltering of images with a 4-mm gaussian filter at a resolution comparable to that of the PET/CT system virtually eliminated these artifacts. Although acquisition of the PET/MR images started at 30–60 min after PET/CT (20.4-min half-life of 11C) acquisition, the signal-to-noise ratio was good enough, thus underlining the high sensitivity of the PET insert, compared with whole-body PET systems. The computed tumor–to–reference tissue ratios exhibited an excellent accordance between the PET/MRI and PET/CT systems, with a Pearson correlation coefficient of 0.98. Mean paired relative error was 7.9% ± 12.2%. No significant artifacts or distortions were detected in the simultaneously acquired MR images using the PET/MRI scanner. Conclusion: Structural, functional, and molecular imaging in patients with brain tumors is feasible with diagnostic imaging quality using simultaneous hybrid PET/MR image acquisition.

Correlation of Stable Elevations in Striatal μ-Opioid Receptor Availability in Detoxified Alcoholic Patients With Alcohol Craving: A Positron Emission Tomography Study Using Carbon 11–Labeled Carfentanil

Main Outcome Measures: After 1 to 3 weeks of abstinence, the availability of μ-opiate receptors in the ventral striatum, including the nucleus accumbens, was significantly elevated in alcoholic patients compared with healthy controls and remained elevated when 12 alcoholic patients had these levels measured 5 weeks later (P .05 corrected for multiple testing). Higher availability of μ-opiate receptors in this brain area correlated significantly with the intensity of alcohol craving as assessed by the OCDS.

The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study

BACKGROUND Increased echogenicity of the substantia nigra (SN), as determined by transcranial sonography (TCS), is characteristic of idiopathic Parkinsons disease (iPD). The results of initial retrospective studies indicate that this ultrasound sign is specific for iPD and can help to differentiate it from atypical parkinsonian syndromes (aPS); however, these early studies were done in patients with later disease stages and known clinical diagnosis. We aimed to determine the diagnostic value of TCS in the early stages of parkinsonian syndromes, when the clinical symptoms often do not enable a definite diagnosis to be made. METHODS 60 patients who presented with the first, but still unclear, clinical symptoms of parkinsonism had TCS in this prospective blinded study. Investigators were blinded to the results of the clinical investigations, the ultrasound findings, and the diagnosis at time of investigation. The patients were followed-up every 3 months for 1 year to assess and re-evaluate the clinical symptoms. The patients in whom a clinical diagnosis could not be made with certainty were investigated with raclopride PET or dopamine transporter single-photon emission computed tomography (SPECT), or both. FINDINGS A clinical diagnosis of parkinsonism could not be established at baseline in 38 patients. At 12 months, 39 patients were clinically categorised as having iPD. Compared with endpoint diagnosis, the sensitivity of TCS at baseline was 90%7% and the specificity was 82.4%; the positive predictive value of TCS for iPD was 92.9% and the classification accuracy was 88.3%. INTERPRETATION TCS is an easy to implement, non-invasive, and inexpensive technique that could help in the early differential diagnosis of parkinsonian syndromes. The routine use of TCS in the clinic could enable disease-specific therapy to be started earlier. FUNDING Michael J Fox Foundation for Parkinsons Research.

Dose-Dependent Attenuation of Auditory Phantom Perception (Tinnitus) by PET-Guided Repetitive Transcranial Magnetic Stimulation

Recent data suggest that chronic tinnitus is a “phantom auditory perception” caused by maladaptive neuroplasticity and subsequent hyperactivity in an extended neuronal network including the primary auditory cortex, higher‐order association areas, and parts of the limbic system. It was suggested that attenuation of this tinnitus‐associated hyperactivity may offer a rational option for lasting tinnitus reduction. Here, we tested the hypothesis that tinnitus loudness can be attenuated by low‐frequency repetitive transcranial magnetic stimulation (rTMS) individually navigated to cortical areas with excessive tinnitus‐related activity as assessed by [15O]H2O positron‐emission tomography (PET). Nine patients with chronic tinnitus underwent this combined functional imaging and rTMS‐study. Group analysis of the PET data showed tinnitus‐related increases of regional cerebral blood flow in the left middle and inferior temporal as well as right temporoparietal cortex and posterior cingulum. Repetitive TMS was performed at 1 Hz and 120% of the motor threshold for 5, 15, and 30 min, navigated to the individual maximum of tinnitus‐related cortical hyperactivity. A noncortical stimulation site with the same distance to the ear served as sham control. Tinnitus loudness was reduced after temporoparietal, PET‐guided low‐frequency rTMS. This reduction, lasting up to 30 min, was dependent on the number of stimuli applied, differed from sham stimulation, and was negatively correlated with the length of the medical history of tinnitus in our patients. These data show the feasibility and effectiveness of rTMS guided by individual functional imaging to induce a lasting, dose‐dependent attenuation of tinnitus. Of note, these effects were related to stimulation of cortical association areas, not primary auditory cortex, emphasizing the crucial role of higher‐order sensory processing in the pathophysiology of chronic tinnitus. Hum Brain Mapp, 2007.

Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics

About one fourth of Lewy body disease (LBD) patients show cortical beta-amyloid load, basically a hallmark of Alzheimer disease (AD). Using [11C]PIB-PET, we tested whether LBD patients with beta-amyloid burden differ from those without with respect to demographic, clinical, biochemical and genetic parameters. Thirty-five LBD subjects (9 patients with Lewy body dementia, DLB; 12 demented Parkinson patients, PDD; 14 non-demented PD, PDND) underwent [11C]PIB-PET, and were classified as either PIB(+) or PIB(-) according to cortical PIB uptake. PIB+ and PIB(-) patients were then compared according to demographic, clinical, biochemical and genetic parameters. None of the PDND, but four PDD and four DLB subjects were PIB+. In PIB+ subjects, ApoE4 prevalence was higher, CSF Abeta42 levels were lower and, among demented patients, PIB-binding was associated with a lower MMSE score. Motor symptoms were not associated with PIB binding. Thus, LBD patients with cortical beta-amyloid show characteristics usually observed in AD.

18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer

PurposeThe aim of this study was to evaluate FDG-PET for assessment of therapy response and for prediction of patient outcome after neo-adjuvant radio-chemotherapy (NARCT) of advanced non-small cell lung cancer (NSCLC).MethodsSeventy patients with histologically proven stage III NSCLC underwent FDG-PET investigations before and after NARCT. Changes in FDG uptake and PET findings after completion of NARCT were compared with (1) the histology of tumour samples obtained at surgery or repeat mediastinoscopy, and (2) treatment results in terms of achieved operability and long-term survival.ResultsThe mean average FDG uptake of the primary tumours in the patient group decreased significantly during NARCT (p = 0.004). Sensitivity, specificity and overall accuracy of FDG-PET were 94.5%, 80% and 91%, respectively, for the detection of residual viable primary tumour, and 77%, 68% and 73%, respectively, for the presence of lymph node metastases. A negative PET scan or a reduction in the standardised uptake value (SUV) of more than 80% was the best predictive factor for a favourable outcome of further treatment. Progressive disease according to PET (new tumour manifestations or increasing SUV) was significantly correlated with an unfavourable outcome (p = 0.005). In this subgroup, survival of patients who underwent surgery was not significantly different from survival among those who did not undergo surgery, whereas for the whole patient group, complete tumour resection had a significant influence on outcome.ConclusionFDG-PET is suitable to assess response to NARCT in patients with stage III NSCLC accurately. It was highly predictive for treatment outcome and patient survival. PET may be helpful in improving restaging after NARCT by allowing reliable assessment of residual tumour viability.

Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype.

SummaryBackground. Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [11C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. Method. We assessed 5-HTT binding potential (BP2) in the midbrain of 19 healthy subjects with positron emission tomography and [11C]DASB. Accounting for the hypothesized functional similarity of LG and S in driving 5-HTT transcription, we assessed whether LALA homozygotes display increased midbrain BP2 compared with carriers of at least one S allele. Results. BP2 in the midbrain was significantly increased in LALA homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. Conclusions. This in vivo study provides further evidence that subjects homozygous for the LA allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections.

Simultaneous Whole-Body PET/MR Imaging in Comparison to PET/CT in Pediatric Oncology: Initial Results

PURPOSE To compare positron emission tomography (PET)/magnetic resonance (MR) imaging and PET/computed tomography (CT) for lesion detection and interpretation, quantification of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) uptake, and accuracy of MR-based PET attenuation correction in pediatric patients with solid tumors. Materials and Methods This prospective study had local ethics committee and German Federal Institute for Drugs and Medical Devices approval. Written informed consent was obtained from all patients and legal guardians. Twenty whole-body (18)F-FDG PET/CT and (18)F-FDG PET/MR examinations were performed in 18 pediatric patients (median age, 14 years; range, 11-17 years). (18)F-FDG PET/CT and (18)F-FDG PET/MR data were acquired sequentially on the same day for all patients. PET standardized uptake values (SUVs) were quantified with volume of interest measurements in lesions and healthy tissues. MR-based PET attenuation correction was compared with CT-derived attenuation maps (µ-maps). Lesion detection was assessed with separate reading of PET/CT and PET/MR data. Estimates of radiation dose were derived from the applied doses of (18)F-FDG and CT protocol parameters. Descriptive statistical analyses were performed to report correlation coefficients and relative deviations for comparison of SUVs, rates of lesion detection, and percentage reductions in radiation dose. RESULTS PET SUVs showed strong correlations between PET of PET/CT (PETCT) and PET of PET/MR (PETMR) (r > 0.85 for most tissues). Apart from drawbacks of MR-based PET attenuation correction in osseous structures and lungs, similar SUVs were found on PET images corrected with CT-based µ-maps (13.1% deviation of SUVs for bone marrow and <5% deviation for other tissues). Lesion detection rate with PET/MR imaging was equivalent to that with PET/CT (61 areas of focal uptake on PETMR images vs 62 areas on PETCT images). Advantages of PET/MR were observed especially in soft-tissue regions. Furthermore, PET/MR offered significant dose reduction (73%) compared with PET/CT. CONCLUSION Pediatric oncologic PET/MR is technically feasible, showing satisfactory performance for PET quantification with SUVs similar to those of PET/CT. Compared with PET/CT, PET/MR demonstrates equivalent lesion detection rates while offering markedly reduced radiation exposure. Thus, PET/MR is a promising modality for the clinical work-up of pediatric malignancies. Online supplemental material is available for this article.

Is standardised 18F-FDG uptake value an outcome predictor in patients with stage III non-small cell lung cancer?

PurposeRecent studies have demonstrated the relevance of 18F-FDG uptake as an independent prognostic factor for recurrence of operable non-small cell lung cancer (NSCLC). This corresponds with the experimental finding that FDG uptake correlates with the proliferative activity of tumour cells (Higashi et al., J Nucl Med 2000;41:85-92). On the basis of these observations, we studied the influence of FDG uptake on prognosis and occurrence of distant metastases in patients with advanced NSCLC.MethodsOne hundred and fifty-nine patients with NSCLC of UICC stage IIIA or IIIB were included in the study. In all patients, neoadjuvant treatment was planned to achieve operability. FDG PET was performed as an additional staging procedure prior to the initiation of therapy. Clinical outcome data in terms of overall survival, disease-free survival and incidence of distant metastases could be obtained for 137 patients and were correlated with the average standardised uptake value of the tumour (SUVavg). Furthermore, other factors influencing SUVavg and patient outcome (histological tumour type, grading, UICC stage, tumour size) were analysed.ResultsSUVavg was significantly influenced by tumour histology, UICC stage and tumour size. No significant difference could be shown for grading. In 38 out of the 159 patients (24%), FDG PET revealed previously unsuspected distant metastases. The incidence of distant metastases significantly correlated with SUVavg. Overall survival tended to decrease with increasing SUVavg; however, significance was only reached when a cut-off of 12.0 was applied (p=0.05).ConclusionFDG uptake is an independent prognostic factor in patients with UICC stage III NSCLC, although less distinctively so than has been reported for stage I/II tumours.