Publications by authors named "Philipp M Meyer"

23 Publications

  • Page 1 of 1

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [F] fluspidine and [F] fallypride PET study.

Eur J Nucl Med Mol Imaging 2021 Apr 29;48(4):1103-1115. Epub 2020 Sep 29.

Department of Nuclear Medicine, University of Leipzig Medical Center, Leipzig, Germany.

Purpose: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [F] fluspidine and [F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD.

Methods: Using [F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot.

Results: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%).

Conclusions: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
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http://dx.doi.org/10.1007/s00259-020-05030-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041674PMC
April 2021

(+)-[F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand-results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer's disease and healthy controls.

Eur J Nucl Med Mol Imaging 2021 Mar 16;48(3):731-746. Epub 2020 Sep 16.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

Purposes: We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[F]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 (+)-[F]Flubatine binding; and whether (+)-[F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated.

Methods: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [C]PiB PET/MRI examination. (+)-[F]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). (+)-[F]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 (+)-[F]Flubatine binding of approximately 15% but also standard deviation of 0.4-70%. Cognitive test data and (+)-[F]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, (+)-[F]Flubatine binding and [C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[F]Flubatine binding and [C]PiB accumulation in the white matter was found. No adverse event related to (+)-[F]Flubatine occurred.

Conclusion: (+)-[F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR-targeting PET ligand in further clinical trials.
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http://dx.doi.org/10.1007/s00259-020-05029-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036219PMC
March 2021

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

Transl Psychiatry 2019 11 15;9(1):301. Epub 2019 Nov 15.

Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, 04103, Leipzig, Germany.

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-[C]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: F = 12.30, p = .002; regions on the left: F = 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.
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http://dx.doi.org/10.1038/s41398-019-0619-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858438PMC
November 2019

Current radiotracers to image neurodegenerative diseases.

EJNMMI Radiopharm Chem 2019 Jul 26;4(1):17. Epub 2019 Jul 26.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

The term of neurodegenerative diseases covers a heterogeneous group of disorders that are distinguished by progressive degeneration of the structure and function of the nervous system such as dementias, movement disorders, motor neuron disorders, as well as some prion disorders. In recent years, a paradigm shift started for the diagnosis of neurodegenerative diseases, for which successively clinical testing is supplemented by biomarker information. In research scenarios, it was even proposed recently to substitute the current syndromic by a biological definition of Alzheimer's diseases. PET examinations with various radiotracers play an important role in providing non-invasive biomarkers and co-morbidity information in neurodegeneration. Information on co-morbidity, e.g. Aβ plaques and Lewy-bodies or Aβ plaques in patients with aphasia or the absence of Aβ plaques in clinical AD patients are of interest to expand our knowledge about the pathogenesis of different phenotypically defined neurodegenerative diseases. Moreover, this information is also important in therapeutic trials targeting histopathological abnormalities.The aim of this review is to present an overview of the currently available radiotracers for imaging neurodegenerative diseases in research and in routine clinical settings. In this context, we also provide a short summary of the most frequent neurodegenerative diseases from a nuclear medicine point of view, their clinical and pathophysiological as well as nuclear imaging characteristics, and the resulting need for new radiotracers.
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http://dx.doi.org/10.1186/s41181-019-0070-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660543PMC
July 2019

and Human Metabolism of ()-[F]Fluspidine - A Radioligand for Imaging σ Receptors With Positron Emission Tomography (PET).

Front Pharmacol 2019 13;10:534. Epub 2019 Jun 13.

Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.

()-[F]fluspidine (()-[F]) has recently been explored for positron emission tomography (PET) imaging of sigma-1 receptors in humans. In the current report, we have used plasma samples of healthy volunteers to investigate the radiometabolites of ()-[F] and elucidate their structures with LC-MS/MS. For the latter purpose additional studies were conducted by incubation of ()-[F] and ()- with human liver microsomes (HLM). metabolites were characterized by interpretation of MS/MS fragmentation patterns from collision-induced dissociation or by use of reference compounds. Thereby, structures of corresponding radio-HPLC-detected radiometabolites, both and (human), could be identified. By incubation with HLM, mainly debenzylation and hydroxylation occurred, beside further mono- and di-oxygenations. The product hydroxylated at the fluoroethyl side chain was glucuronidated. Plasma samples (10, 20, 30 min p.i., = 5-6), obtained from human subjects receiving 250-300 MBq ()-[F] showed 97.2, 95.4, and 91.0% of unchanged radioligand, respectively. In urine samples (90 min p.i.) the fraction of unchanged radioligand was only 2.6% and three major radiometabolites were detected. The one with the highest percentage, also found in plasma, matched the glucuronide formed . Only a small amount of debenzylated metabolite was detected. In conclusion, our metabolic study, in particular the high fractions of unchanged radioligand in plasma, confirms the suitability of ()-[F] as PET radioligand for sigma-1 receptor imaging.
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http://dx.doi.org/10.3389/fphar.2019.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585474PMC
June 2019

Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls.

Stress 2019 01 29;22(1):93-102. Epub 2018 Oct 29.

a Integrated Research and Treatment Center (IFB) Adiposity Diseases , Leipzig University Medical Center , Leipzig , Germany.

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-[C]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: ACTH r = 0.87, p = .001; cortisol r = 0.86, p = .002; amygdala: ACTH r = 0.86, p = .002; cortisol r = 0.79, p = .006), while in obesity, the hypothalamic DVR correlated inversely with the HPA axis response (cortisol, 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.
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http://dx.doi.org/10.1080/10253890.2018.1511698DOI Listing
January 2019

Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.

Brain 2018 06;141(6):1840-1854

Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Leipzig, Germany.

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 α4β2 nicotinic acetylcholine receptors (α4β2-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 α4β2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4β2-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 α4β2-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 α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-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 α4β2-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.
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http://dx.doi.org/10.1093/brain/awy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972585PMC
June 2018

Noradrenaline transporter availability on [C]MRB PET predicts weight loss success in highly obese adults.

Eur J Nucl Med Mol Imaging 2018 07 7;45(9):1618-1625. Epub 2018 Apr 7.

Integrated Research and Treatment Center (IFB) AdiposityDiseases, University Medical Center, Leipzig, Germany.

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/m (age 34 ± 9 years, four women) and ten matched non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m, age 33 ± 10 years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[C]O-methylreboxetine (MRB) before and 6 months after dietary intervention.

Results: MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BP) 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 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 = 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.
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http://dx.doi.org/10.1007/s00259-018-4002-7DOI Listing
July 2018

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

Psychiatry Res Neuroimaging 2017 Sep 23;267:9-14. Epub 2017 Jun 23.

Integrated Treatment and Research Centre (IFB) AdiposityDiseases, Leipzig University Medical Centre, Liebigstraße 20, 04103 Leipzig, Germany; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.

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-[C]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/m to 47.8kg/m. 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.
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http://dx.doi.org/10.1016/j.pscychresns.2017.06.013DOI Listing
September 2017

Test-retest measurements of dopamine D-type receptors using simultaneous PET/MRI imaging.

Eur J Nucl Med Mol Imaging 2017 Jun 14;44(6):1025-1032. Epub 2017 Feb 14.

Department of Nuclear Medicine, University of Leipzig, Liebigstrasse 18, D-04103, Leipzig, Germany.

Purpose: The role of dopamine D-type receptor (DR)-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-mediated neuronal network regulation using simultaneous PET/MRI and DR-selective [C]SCH23390, this study investigated the stability of central DR 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 [C]SCH23390, on two separate days within 2-4 weeks using a PET/MRI system. Parametric images of DR distribution volume ratio (DVR) and binding potential (BP) 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 DR density.

Results: The DVR varied from 2.5 ± 0.3 to 2.9 ± 0.5 in regions with high DR density (e.g. the head of the caudate) and from 1.2 ± 0.1 to 1.6 ± 0.2 in regions with low DR 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 values. Accordingly, the absolute variability of BP ranged from 7.0% ± 4.7% to 12.5% ± 10.6%; however, there were regions with very low DR content, such as the occipital cortex, with higher mean variability.

Conclusion: The test-retest reliability of DR measurements in this study was very high. This was the case not only for DR-rich brain areas, but also for regions with low DR density. These results will provide a solid base for future joint PET/MRI data analyses in stimulation-dependent mapping of DR-containing neurons and their effects on projections in neuronal circuits that determine behavior.
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http://dx.doi.org/10.1007/s00259-017-3645-0DOI Listing
June 2017

Central noradrenaline transporter availability in highly obese, non-depressed individuals.

Eur J Nucl Med Mol Imaging 2017 Jun 9;44(6):1056-1064. Epub 2017 Jan 9.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

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-[C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m) healthy controls.

Results: Overall, we found no significant differences in binding potential (BP) 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 BP in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BP 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.
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http://dx.doi.org/10.1007/s00259-016-3590-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538358PMC
June 2017

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

Molecules 2016 Sep 1;21(9). Epub 2016 Sep 1.

Department of Nuclear Medicine, University Hospital Leipzig, Leipzig 04103, Germany.

The enantiomers of [(18)F]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)-(-)-[(18)F]fluspidine and (R)-(+)-[(18)F]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)-(-)-[(18)F]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)-(-)-[(18)F]fluspidine and (R)-(+)-[(18)F]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)-(-)-[(18)F]fluspidine was calculated as 21.0 μSv/MBq. Altogether, the ED values for both [(18)F]fluspidine enantiomers determined from the preclinical studies are comparable with other (18)F-labeled PET imaging agents. In addition, the first-in-human study confirmed that the radiation risk of (S)-(-)-[(18)F]fluspidine imaging is within acceptable limits. However, as already shown for other PET tracers, the actual ED of (S)-(-)-[(18)F]fluspidine in humans was underestimated by preclinical imaging which needs to be considered in other first-in-human studies.
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http://dx.doi.org/10.3390/molecules21091164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273209PMC
September 2016

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

Eur J Nucl Med Mol Imaging 2016 Jun 18;43(6):1096-104. Epub 2015 Nov 18.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00259-015-3243-yDOI Listing
June 2016

Simultaneous PET/MRI in stroke: a case series.

J Cereb Blood Flow Metab 2015 Sep 15;35(9):1421-5. Epub 2015 Jul 15.

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Prospective studies on magnetic resonance imaging (MRI)-guided systemic thrombolysis >4.5 hours after stroke onset did not reach their primary end points. It was discussed and observed in post hoc data re-assessment that this was partly because of limited MRI accuracy to measure critical hypoperfusion. We report the first cases of simultaneous [(15)O]H2O-positron emission tomography (PET)/MRI in stroke patients and an ovine model. Discrepancies between simultaneously obtained PET and MRI readouts were observed that might explain the above current limitations of stroke MRI. By offering highly complementary information, [(15)O]H2O-PET/MRI might help to identify critically hypoperfused tissue resulting in an improved patient stratification in thrombolysis trials.
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http://dx.doi.org/10.1038/jcbfm.2015.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640332PMC
September 2015

First-in-human PET quantification study of cerebral α4β2* nicotinic acetylcholine receptors using the novel specific radioligand (-)-[(18)F]Flubatine.

Neuroimage 2015 Sep 30;118:199-208. Epub 2015 May 30.

Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.

α4β2* nicotinic receptors (α4β2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g., Alzheimer's and Parkinson's diseases, 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. Dynamic PET emission recordings lasting 270min were acquired on an ECAT EXACT HR+ scanner in 12 healthy male non-smoking subjects (71.0±5.0years) following the intravenous injection of 353.7±9.4MBq of (-)-[(18)F]Flubatine. Individual magnetic resonance imaging (MRI) was performed for co-registration. PET frames were motion-corrected, before the kinetics in 29 brain regions were characterized using 1- and 2-tissue compartment models (1TCM, 2TCM). Given the low amounts of metabolite present in plasma, we tested arterial input functions with and without metabolite corrections. In addition, pixel-based graphical analysis (Logan plot) was used. The model's goodness of fit, with and without metabolite correction was assessed by Akaike's information criterion. Model parameters of interest were the total distribution volume VT (mL/cm(3)), and the binding potential BPND relative to the corpus callosum, which served as a reference region. The tracer proved to have high stability in vivo, with 90% of the plasma radioactivity remaining as untransformed parent compound at 90min, fast brain kinetics with rapid uptake and equilibration between free and receptor-bound tracer. Adequate fits of brain TACs were obtained with the 1TCM. VT could be reliably estimated within 90min for all regions investigated, and within 30min for low-binding regions such as the cerebral cortex. The rank order of VT by region corresponded well with the known distribution of α4β2* receptors (VT [thalamus] 27.4±3.8, VT [putamen] 12.7±0.9, VT [frontal cortex] 10.0±0.8, and VT [corpus callosum] 6.3±0.8). The BPND, which is a parameter of α4β2* nAChR availability, was 3.41±0.79 for the thalamus, 1.04±0.25 for the putamen and 0.61±0.23 for the frontal cortex, indicating high specific tracer binding. Use of the arterial input function without metabolite correction resulted in a 10% underestimation in VT, and was without important biasing effects on BPND. Altogether, kinetics and imaging properties of (-)-[(18)F]Flubatine appear favorable and suggest that (-)-[(18)F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of α4β2* nAChRs in neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.neuroimage.2015.05.065DOI Listing
September 2015

Altered serotonin transporter availability in patients with multiple sclerosis.

Eur J Nucl Med Mol Imaging 2014 May 22;41(5):827-35. Epub 2014 Feb 22.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany,

Purpose: 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.

Methods: 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.

Results: 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).

Conclusion: 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.
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http://dx.doi.org/10.1007/s00259-013-2636-zDOI Listing
May 2014

Imaging of the brain serotonin transporters (SERT) with 18F-labelled fluoromethyl-McN5652 and PET in humans.

Eur J Nucl Med Mol Imaging 2012 Jun 17;39(6):1001-11. Epub 2012 Feb 17.

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Purpose: [(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.

Methods: 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).

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00259-012-2078-zDOI Listing
June 2012

Individualized quantification of brain β-amyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer's disease and healthy controls.

Eur J Nucl Med Mol Imaging 2011 Sep 6;38(9):1702-14. Epub 2011 May 6.

Department of Nuclear Medicine, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany.

Purpose: 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.

Methods: 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".

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00259-011-1821-1DOI Listing
September 2011

Impact of EEG-vigilance on brain glucose uptake measured with [(18)F]FDG and PET in patients with depressive episode or mild cognitive impairment.

Neuroimage 2011 May 26;56(1):93-101. Epub 2011 Jan 26.

Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Semmelweisstr. 10, 04103 Leipzig, Germany.

Introduction: [(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.

Materials And Methods: 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.

Results: 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%.

Discussion: 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.
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http://dx.doi.org/10.1016/j.neuroimage.2011.01.059DOI Listing
May 2011

The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder.

Int J Neuropsychopharmacol 2011 Jun 14;14(5):606-17. Epub 2011 Jan 14.

Department of Nuclear Medicine, University of Leipzig, Germany.

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.
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http://dx.doi.org/10.1017/S1461145710001604DOI Listing
June 2011

Preserved serotonin transporter binding in de novo Parkinson's disease: negative correlation with the dopamine transporter.

J Neurol 2011 Jan 21;258(1):19-26. Epub 2010 Jul 21.

Department of Neurology, University of Leipzig, Liebigstrasse 20, 04103, Leipzig, Germany.

Recent imaging and neuropathological studies indicate reduced serotonin transporter (SERT) in advanced Parkinson's disease (PD). However, data on SERT in early PD patients are sparse. Following the hypothesis that the serotonergic system is damaged early in PD, the aim of our study was to investigate SERT availability by means of PET imaging. Since the loss of dopaminergic neurons is the pathologic hallmark of PD and SERT might be associated with psychiatric co-morbidity, we further sought to correlate SERT availability with the availability of dopamine transporter (DAT) and depressive or motor symptoms in early PD. We prospectively recruited nine early PD patients (4 female, 5 male; 42-76 years) and nine age matched healthy volunteers (5 female, 4 male; 42-72 years). Diagnosis of PD was confirmed by the UK brain bank criteria and DAT imaging. SERT availability was measured by means of [11C]DASB PET. For neuropsychiatric assessment done on the day of PET we applied UPDRS parts I, II and III, Beck's Depression Inventory, Hamilton Rating Scale for Depression, Mini-Mental State Examination and Demtect. SERT was not reduced in any of 14 investigated regions of interest in the nine PD patients compared to healthy controls (p>0.13). SERT was negatively associated with DAT in the striatum (r=-0.69; p=0.04) but not within the midbrain. There was no correlation of SERT availability with depressive symptoms. No alteration of SERT binding in our patients suggests that the serotonergic system is remarkably preserved in early PD. Correlation with DAT might point to a compensatory regulation of the serotonergic system in early stages of PD.
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http://dx.doi.org/10.1007/s00415-010-5666-5DOI Listing
January 2011

Reduced alpha4beta2*-nicotinic acetylcholine receptor binding and its relationship to mild cognitive and depressive symptoms in Parkinson disease.

Arch Gen Psychiatry 2009 Aug;66(8):866-77

Department of Nuclear Medicine, University of Leipzig, Liebigstr 18, 04103 Leipzig, Germany.

Context: Cognitive or depressive disorders are frequently noted in patients with Parkinson disease (PD) and may be related to altered signaling through alpha4beta2*-nicotinic acetylcholine receptors (alpha4beta2*-nAChRs).

Objective: To assess the availability of alpha4beta2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD.

Design: Crossover comparison between patients with PD and healthy volunteers (control group) using the alpha4beta2*-nAChR-specific radioligand 2-[(18)F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[(18)F]FA-85380) and positron emission tomography.

Setting: Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Participants: Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers.

Main Outcome Measures: Level of 2-[(18)F]FA-85380 binding potential (2-FA BP), a measure of alpha4beta2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed.

Results: In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum.

Conclusions: There is a broad reduction of alpha4beta2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.
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http://dx.doi.org/10.1001/archgenpsychiatry.2009.106DOI Listing
August 2009

Monoamine transporter availability in Parkinson's disease patients with or without depression.

Eur J Nucl Med Mol Imaging 2009 Mar 27;36(3):428-35. Epub 2008 Nov 27.

Department of Nuclear Medicine, University of Leipzig, Stephanstrasse 11, 04103 Leipzig, Germany.

Purpose: Depression is a common symptom in patients suffering from Parkinson's disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD-D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [(123)I]FP-CIT.

Methods: A magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [(123)I]FP-CIT binding coefficient V(3)'' in the striatum, thalamus and midbrain/brainstem regions.

Results: PD+D patients had significantly lower V(3)'' compared with PD-D patients in the striatum (p<0.001), thalamus (p=0.002), and midbrain/brainstem (p=0.025). Only PD+D patients without selective serotonin reuptake inhibitor (SSRI) treatment showed lower thalamic and midbrain V(3)'' than controls (p<0.001, p=0.029). In a small sub-group of SSRI-treated PD+D patients neither thalamic V(3)'' nor midbrain/brainstem V(3)'' differed from those in PD-D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318).

Conclusion: Our data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor symptoms in this common movement disorder.
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http://dx.doi.org/10.1007/s00259-008-0979-7DOI Listing
March 2009