Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Konkret geht es um den Diabetes-Patienten mit kardiovaskulären Erkrankungen oder Risiken, die Herzinsuffizienz sowie die kardiovaskuläre Primär- und Sekundärprävention. Sind Sie hier schon auf dem neuesten Stand? Unsere Experten beleuchten, wo und warum das bisherige Procedere geändert werden soll und was in der Praxis sinnvoll ist. Holen Sie sich Ihr Update und 2 CME-Punkte beim MMW-Webinar am 24. April von 17.30 bis 19 Uhr. 
Erweiterte Suche
Anmelden
nach oben
Molecular Imaging and Biology
Erschienen in: Molecular Imaging and Biology 2/2020

17.05.2019 | Research Article

GABAA Receptors in the Mongolian Gerbil: a PET Study Using [18F]Flumazenil to Determine Receptor Binding in Young and Old Animals

verfasst von: M. Kessler, M. Mamach, R. Beutelmann, M. Lukacevic, S. Eilert, P. Bascuñana, A. Fasel, F. M. Bengel, J. P. Bankstahl, T. L. Ross, G. M. Klump, G. Berding

Erschienen in: Molecular Imaging and Biology | Ausgabe 2/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Plastic changes in the central auditory system involving the GABAergic system accompany age-related hearing loss. Such processes can be investigated with positron emission tomography (PET) imaging using [18F]flumazenil ([18F]FMZ). Here, [18F]FMZ PET-based modeling approaches allow a simple and reliable quantification of GABAA receptor binding capacity revealing regional differences and age-related changes.

Procedures

Sixty-minute list-mode PET acquisitions were performed in 9 young (range 5–6 months) and 11 old (range 39–42 months) gerbils, starting simultaneously with the injection of [18F]FMZ via femoral vein. Non-displaceable binding potentials (BPnd) with pons as reference region were calculated for auditory cortex (AC), inferior colliculus (IC), medial geniculate body (MGB), somatosensory cortex (SC), and cerebellum (CB) using (i) a two-tissue compartment model (2TCM), (ii) the Logan plot with image-derived blood-input (Logan (BI)), (iii) a simplified reference tissue model (SRTM), and (iv) the Logan reference model (Logan (RT)). Statistical parametric mapping analysis (SPM) comparing young and old gerbils was performed using 3D parametric images for BPnd based on SRTM. Results were verified with in vitro autoradiography from five additional young gerbils. Model assessment included the Akaike information criterion (AIC). Hearing was evaluated using auditory brainstem responses.

Results

BPnd differed significantly between models (p < 0.0005), showing the smallest mean difference between 2TCM as reference and SRTM as simplified procedure. SRTM revealed the lowest AIC values. Both volume of distribution (r2 = 0.8793, p = 0.018) and BPnd (r2 = 0.8216, p = 0.034) correlated with in vitro autoradiography data. A significant age-related decrease of receptor binding was observed in auditory (AC, IC, MGB) and other brain regions (SC and CB) (p < 0.0001, unpaired t test) being confirmed by SPM using pons as reference (p < 0.0001, uncorrected).

Conclusion

Imaging of GABAA receptor binding capacity in gerbils using [18F]FMZ PET revealed SRTM as a simple and robust quantification method of GABAA receptors. Comparison of BPnd in young and old gerbils demonstrated an age-related decrease of GABAA receptor binding.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
2.
Cherry SR, Gambhir SS (2001) Use of positron emission tomography in animal research. ILAR J 42:219–232PubMedCrossRef
3.
Ametamey SM, Honer M, Schubiger PA (2008) Molecular imaging with PET. Chem Rev 108:1501–1516PubMedCrossRef
4.
Marriott CJ, Cadorette JE, Lecomte R, Scasnar V, Rousseau J, van Lier J (1994) High-resolution PET imaging and quantitation of pharmaceutical biodistributions in a small animal using avalanche photodiode detectors. J Nucl Med 35:1390–1396PubMed
5.
Farde L (1996) The advantage of using positron emission tomography in drug research. Trends Neurosci 19:211–214PubMedCrossRef
6.
Fujita M (2001) In vivo receptor imaging with PET and SPET-pitfalls in quantification. Int Rev Psychiatry 13:34–39CrossRef
7.
Dupont P, Warwick J (2009) Kinetic modelling in small animal imaging with PET. Methods 48:98–103PubMedCrossRef
8.
Ingvar M, Eriksson L, Rogers GA, Stone-Elander S, Widén L (1991) Rapid feasibility studies of tracers for positron emission tomography: high-resolution PET in small animals with kinetic analysis. J Cereb Blood Flow Metab 11:926–931PubMedCrossRef
9.
Maggi A, Schmidt MJ, Ghetti B, Enna SJ (1979) Effect of aging on neurotransmitter receptor binding in rat and human brain. Life Sci 24:367–373PubMedCrossRef
10.
McQuail JA, Frazier CJ, Bizon JL (2015) Molecular aspects of age-related cognitive decline: the role of GABA signaling. Trends Mol Med 21:450–460PubMedPubMedCentralCrossRef
11.
Owens DF, Kriegstein AR (2002) Is there more to gaba than synaptic inhibition? Nat Rev Neurosci 3:715–727PubMedCrossRef
12.
13.
Nutt D (2006) GABAA receptors: subtypes, regional distribution, and function. J Clin Sleep Med 2:S7–S11
14.
Young AB, Chu D (1990) Distribution of GABAA and GABAB receptors in mammalian brain: potential targets for drug development. Drug Dev Res 21:161–167CrossRef
15.
Bowery NG, Hudson AL, Price GW (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20:365–383PubMedCrossRef
16.
Nutt DJ, Malizia AL (2001) New insights into the role of the GABAA;—benzodiazepine receptor in psychiatric disorder. Br J Psychiatry 179:390–396PubMedCrossRef
17.
Schultz LM (1997) REVIEW: GABAergic inhibitory processes and hippocampal long-term potentiation. Neuroscientist 3:226–236CrossRef
18.
Rodnick ME, Hockley BG, Sherman P, Quesada C, Battle MR, Jackson A, Linder KE, Macholl S, Trigg WJ, Kilbourn MR, Scott PJH (2013) Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain. Nucl Med Biol 40:901–905PubMedPubMedCentralCrossRef
19.
20.
Caspary DM, Holder TM, Hughes LF, Milbrandt JC, McKernan RM, Naritoku DK (1999) Age-related changes in GABAA receptor subunit composition and function in rat auditory system. Neuroscience 93:307–312PubMedCrossRef
21.
Mandema JW, Gubbens-Stibbe JM, Danhof M (1991) Stability and pharmacokinetics of flumazenil in the rat. Psychopharmacology 103:384–387PubMedCrossRef
22.
Odano I, Halldin C, Karlsson P, Varrone A, Airaksinen AJ, Krasikova RN, Farde L (2009) [18F]flumazenil binding to central benzodiazepine receptor studies by PET--quantitative analysis and comparisons with [11C]flumazenil. NeuroImage 45:891–902PubMedCrossRef
23.
Caspary DM, Ling L, Turner JG, Hughes LF (2008) Inhibitory neurotransmission, plasticity and aging in the mammalian central auditory system. J Exp Biol 211:1781–1791PubMedCrossRef
24.
Caspary DM, Milbrandt JC, Helfert RH (1995) Central auditory aging: GABA changes in the inferior colliculus. Exp Gerontol 30:349–360PubMedCrossRef
25.
Milbrandt JC, Albin RL, Caspary DM (1994) Age-related decrease in GABAB receptor binding in the Fischer 344 rat i inferior colliculus. Neurobiol Aging 15:699–703PubMedCrossRef
26.
Milbrandt JC, Albin RL, Turgeon SM, Caspary DM (1996) GABAA receptor binding in the aging rat inferior colliculus. Neuroscience 73:449–458PubMedCrossRef
27.
Ryan A (1976) Hearing sensitivity of the mongolian gerbil, Meriones unguiculatis. J Acoust Soc Am 59:1222–1226PubMedCrossRef
28.
Mills JH, Schmiedt RA, Kulish LF (1990) Age-related changes in auditory potentials of mongolian gerbil. Hear Res 46:201–210PubMedCrossRef
29.
Akaike H (1974) A new look at the statistical model identification. IEEE Trans Autom Control 19:716–723CrossRef
30.
31.
Preshlock S, Calderwood S, Verhoog S, Tredwell M, Huiban M, Hienzsch A, Gruber S, Wilson TC, Taylor NJ, Cailly T, Schedler M, Collier TL, Passchier J, Smits R, Mollitor J, Hoepping A, Mueller M, Genicot C, Mercier J, Gouverneur V (2016) Enhanced copper-mediated 18F-fluorination of aryl boronic esters provides eight radiotracers for PET applications. Chem Commun (Camb) 52:8361–8364CrossRef
32.
33.
Beutelmann R, Laumen G, Tollin D, Klump GM (2015) Amplitude and phase equalization of stimuli for click evoked auditory brainstem responses. J Acoust Soc Am 137:EL71–EL77PubMedCrossRef
34.
Laumen G, Tollin DJ, Beutelmann R, Klump GM (2016) Aging effects on the binaural interaction component of the auditory brainstem response in the Mongolian gerbil: effects of interaural time and level differences. Hear Res 337:46–58PubMedPubMedCentralCrossRef
35.
Kessler M, Mamach M, Beutelmann R, Bankstahl JP, Bengel FM, Klump GM, Berding G (2018) Activation in the auditory pathway of the gerbil studied with 18F-FDG PET: effects of anesthesia. Brain Struct Funct 223:4293–4305PubMedCrossRef
36.
Radtke-Schuller S, Schuller G, Angenstein F, Grosser OS, Goldschmidt J, Budinger E (2016) Brain atlas of the Mongolian gerbil (Meriones unguiculatus) in CT/MRI-aided stereotaxic coordinates. Brain Struct Funct 221(Suppl 1):1–272PubMedPubMedCentralCrossRef
37.
Thackeray JT, Bankstahl JP, Bengel FM (2015) Impact of image-derived input function and fit time intervals on Patlak quantification of myocardial glucose uptake in mice. J Nucl Med 56:1615–1621PubMedCrossRef
38.
Kuntner C (2014) Kinetic modeling in pre-clinical positron emission tomography. Z Med Phys 24:274–285PubMedCrossRef
39.
Koeppe RA, Holthoff VA, Frey KA, Kilbourn MR, Kuhl DE (1991) Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 11:735–744PubMedCrossRef
40.
Dedeurwaerdere S, Gregoire M-C, Vivash L, Roselt P, Binns D, Fookes C, Greguric I, Pham T, Loc’h C, Katsifis A, Hicks RJ, O’Brien TJ, Myers DE (2009) In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat. Eur J Nucl Med Mol Imaging 36:958–965PubMedCrossRef
41.
Vivash L, Gregoire MC, Lau EW, Ware RE, Binns D, Roselt P, Bouilleret V, Myers DE, Cook MJ, Hicks RJ, O'Brien TJ (2013) 18F-flumazenil: a gamma-aminobutyric acid A-specific PET radiotracer for the localization of drug-resistant temporal lobe epilepsy. J Nucl Med 54:1270–1277PubMedCrossRef
42.
Morris JS, Friston KJ, Dolan RJ (1998) Experience-dependent modulation of tonotopic neural responses in human auditory cortex. Proc R Soc B Biol Sci 265:649–657CrossRef
43.
Gunn RN, Gunn SR, Turkheimer FE, Aston JAD, Cunningham VJ (2002) Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. J Cereb Blood Flow Metab 22:1425–1439PubMedCrossRef
44.
Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4:153–158PubMedCrossRef
45.
Klumpers U, H M, Veltman DJ, Boellaard R et al (2007) Comparison of plasma input and reference tissue models for analysing [11C]flumazenil studies. J Cereb Blood Flow Metab 28:579–587PubMedCrossRef
46.
Geeraerts T, P Coles J, I Aigbirhio F et al (2011) Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury. Ann Nucl Med 25:396–405PubMedCrossRef
47.
Miederer I, Ziegler SI, Liedtke C, Spilker ME, Miederer M, Sprenger T, Wagner KJ, Drzezga A, Boecker H (2009) Kinetic modelling of [11C]flumazenil using data-driven methods. Eur J Nucl Med Mol Imaging 36:659–670PubMedCrossRef
48.
Lopes Alves I, Vállez García DV, Parente A, Doorduin J, da Silva AMM, Koole M, Dierckx R, Willemsen A, Boellaard R (2018) Parametric imaging of [11C]flumazenil binding in the rat brain. Mol Imaging Biol 20:114–123PubMedCrossRef
49.
Zanotti-Fregonara P, Chen K, Liow J-S, Fujita M, Innis RB (2011) Image-derived input function for brain PET studies: many challenges and few opportunities. J Cereb Blood Flow Metab 31:1986–1998PubMedPubMedCentralCrossRef
50.
Hammers A, Panagoda P, Heckemann RA et al (2007) [11C]flumazenil PET in temporal lobe epilepsy: do we need an arterial input function or kinetic modeling? J Cereb Blood Flow Metab 28:207–216PubMedCrossRef
51.
Lanz B, Poitry-Yamate C, Gruetter R (2014) Image-derived input function from the vena cava for 18F-FDG PET studies in rats and mice. J Nucl Med 55:1380–1388PubMedCrossRef
52.
Tsartsalis S, Tournier BB, Graf CE, Ginovart N, Ibáñez V, Millet P (2018) Dynamic image denoising for voxel-wise quantification with statistical parametric mapping in molecular neuroimaging. PLoS One 13:e0203589–e0203589PubMedPubMedCentralCrossRef
53.
Golla SSV, Adriaanse SM, Yaqub M, Windhorst AD, Lammertsma AA, van Berckel BNM, Boellaard R (2017) Model selection criteria for dynamic brain PET studies. EJNMMI Physics 4:30PubMedPubMedCentralCrossRef
54.
Parente A, Vállez García D, Shoji A, Lopes Alves I, Maas B, Zijlma R, Dierckx RAJO, Buchpiguel CA, de Vries EFJ, Doorduin J (2017) Contribution of neuroinflammation to changes in [11C]flumazenil binding in the rat brain: evaluation of the inflamed pons as reference tissue. Nucl Med Biol 49:50–56PubMedCrossRef
55.
Barnard EA, Skolnick P, Olsen RW et al (1998) International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev 50:291–313PubMed
56.
Palner M, Beinat C, Banister S, Zanderigo F, Park JH, Shen B, Hjoernevik T, Jung JH, Lee BC, Kim SE, Fung L, Chin FT (2016) Effects of common anesthetic agents on [18F]flumazenil binding to the GABAA receptor. EJNMMI Res 6:80PubMedPubMedCentralCrossRef
57.
Gyulai MD, Ferenc E, Mintun MD et al (2001) Dose-dependent enhancement of in vivo GABAA–benzodiazepine receptor binding by isoflurane. Anesthesiology 95:585–593PubMedCrossRef
58.
Rissman RA, De Blas AL, Armstrong DM (2007) GABAA receptors in aging and Alzheimer’s disease. J Neurochem 103:1285–1292PubMedCrossRef
59.
Rissman RA, Mobley WC (2011) Implications for treatment: GABAA receptors in aging, down syndrome and Alzheimer’s disease. J Neurochem 117:613–622PubMedPubMedCentral
60.
Prieto E, Collantes M, Delgado M, Juri C, García-García L, Molinet F, Fernández-Valle ME, Pozo MA, Gago B, Martí-Climent JM, Obeso JA, Peñuelas I (2011) Statistical parametric maps of 18F-FDG PET and 3-D autoradiography in the rat brain: a cross-validation study. Eur J Nucl Med Mol Imaging 38:2228–2237PubMedCrossRef
61.
Benfenati F, Cimino M, Agnati LF, Fuxe K (1986) Quantitative autoradiography of central neurotransmitter receptors: methodological and statistical aspects with special reference to computer-assisted image analysis. Acta Physiol Scand 128:129–146PubMedCrossRef
62.
Pike VW, Halldin C, Crouzel C, Barré L, Nutt DJ, Osman S, Shah F, Turton DR, Waters SL (1993) Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites--current status. Nucl Med Biol 20:503–525PubMedCrossRef
63.
Andersson JD, Halldin C (2013) PET radioligands targeting the brain GABAA /benzodiazepine receptor complex. J Label Compd Radiopharm 56:196–206CrossRef
64.
Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G (2000) GABA(a) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815–850PubMedCrossRef
65.
66.
Banay-Schwartz M, Palkovits M, Lajtha A (1993) Heterogeneous distribution of functionally important amino acids in brain areas of adult and aging humans. Neurochem Res 18:417–423PubMedCrossRef
67.
Caspary DM, Raza A, Lawhorn Armour BA, Pippin J, Arneric SP (1990) Immunocytochemical and neurochemical evidence for age-related loss of GABA in the inferior colliculus: implications for neural presbycusis. J Neurosci 10:2363–2372PubMedPubMedCentralCrossRef
68.
Gutierrez A, Khan ZU, Morris SJ, De Blas AL (1994) Age-related decrease of GABAA receptor subunits and glutamic acid decarboxylase in the rat inferior colliculus. J Neurosci 14:7469–7477PubMedPubMedCentralCrossRef
69.
Milbrandt JC, Hunter C, Caspary DM (1997) Alterations of GABAA receptor subunit mRNA levels in the aging Fischer 344 rat inferior colliculus. J Comp Neurol 379:455–465PubMedCrossRef
70.
Godfrey DA, Chen K, O'Toole TR, Mustapha A (2017) Amino acid and acetylcholine chemistry in the central auditory system of young, middle-aged and old rats. Hear Res 350:173–188PubMedCrossRef
71.
Burianova J, Ouda L, Profant O, Syka J (2009) Age-related changes in GAD levels in the central auditory system of the rat. Exp Gerontol 44:161–169PubMedCrossRef
72.
Ymer S, Draguhn A, Wisden W, Werner P, Keinänen K, Schofield PR, Sprengel R, Pritchett DB, Seeburg PH (1990) Structural and functional characterization of the gamma 1 subunit of GABAA/benzodiazepine receptors. EMBO J 9:3261–3267PubMedPubMedCentralCrossRef
73.
Hoekzema E, Rojas S, Herance R, Pareto D, Abad S, Jiménez X, Figueiras FP, Popota F, Ruiz A, Flotats N, Fernández FJ, Rocha M, Rovira M, Víctor VM, Gispert JD (2012) In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain. Neurobiol Aging 33:1457–1465PubMedCrossRef
74.
Hamezah HS, Durani LW, Ibrahim NF, Yanagisawa D, Kato T, Shiino A, Tanaka S, Damanhuri HA, Ngah WZW, Tooyama I (2017) Volumetric changes in the aging rat brain and its impact on cognitive and locomotor functions. Exp Gerontol 99:69–79PubMedCrossRef
Metadaten
Titel
GABAA Receptors in the Mongolian Gerbil: a PET Study Using [18F]Flumazenil to Determine Receptor Binding in Young and Old Animals
verfasst von
M. Kessler
M. Mamach
R. Beutelmann
M. Lukacevic
S. Eilert
P. Bascuñana
A. Fasel
F. M. Bengel
J. P. Bankstahl
T. L. Ross
G. M. Klump
G. Berding
Publikationsdatum
17.05.2019
Verlag
Springer International Publishing
Erschienen in
Molecular Imaging and Biology / Ausgabe 2/2020
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-019-01371-0

Weitere Artikel der Ausgabe 2/2020

Molecular Imaging and Biology 2/2020 Zur Ausgabe

Research Article

Evaluation of a Neurokinin-1 Receptor–Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging

Research Article

Simultaneous PET/MRI in the Evaluation of Breast and Prostate Cancer Using Combined Na[18F] F and [18F]FDG: a Focus on Skeletal Lesions

Letter to the Editor

Simultaneous PET/MRI in the Evaluation of Breast and Prostate Cancer Using Combined Na[18F]F and [18F]FDG: a Focus on Skeletal Lesions

Research Article

Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403

Research Article

Distribution of Brown Adipose Tissue Radiodensity in Young Adults: Implications for Cold [18F]FDG-PET/CT Analyses

Letter to the Editor

Response to: Letter to the Editors: Re: Simultaneous PET/MRI in the Evaluation of Breast and Prostate Cancer Using Combined Na[18F]F and [18F]FDG: A Focus on Skeletal Lesions

Neu im Fachgebiet Radiologie

18.04.2024 | Pädiatrische Notfallmedizin | Nachrichten

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

08.04.2024 | Andrologie | Nachrichten

Wie toxische Männlichkeit der Gesundheit von Männern schadet

29.03.2024 | Diagnostische Radiologie | Nachrichten

Studie bestätigt Potenzial von KI in der Radiologie

26.03.2024 | Koronare Herzerkrankung | Nachrichten

Quantitative Angiografie könnte IVUS-Alternative darstellen
weitere anzeigen

Update Radiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen