Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 3/2011

01-03-2011 | Original Article

Decreased cerebral α4β2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer’s disease assessed with positron emission tomography

Authors: Kai Kendziorra, Henrike Wolf, Philipp Mael Meyer, Henryk Barthel, Swen Hesse, Georg Alexander Becker, Julia Luthardt, Andreas Schildan, Marianne Patt, Dietlind Sorger, Anita Seese, Herman-Josef Gertz, Osama Sabri

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2011

Login to get access

Abstract

Purpose

Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer’s disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4β2* nicotinic acetylcholine receptor (α4β2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD.

Methods

Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BPND) of 2-[18F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis.

Results

Both patients with AD and MCI showed a significant reduction in 2-[18F]FA-85380 BPND in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[18F]FA-85380 BPND correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[18F]FA-85380 BPND.

Conclusion

2-[18F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4β2* nAChRs which seems to be an early event in AD. In addition, 2-[18F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.
Literature
1.
Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982;217:408–17.CrossRefPubMed
2.
Davis KL, Mohs RC, Marin D, Purohit DP, Perl DP, Lantz M, et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA 1999;281:1401–6.CrossRefPubMed
3.
DeKosky ST, Ikonomovic MD, Styren SD, Beckett L, Wisniewski S, Bennett DA, et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 2002;51:145–55.CrossRefPubMed
4.
Bowen DM, Benton JS, Spillane JA, Smith CC, Allen SJ. Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci 1982;57:191–202.CrossRefPubMed
5.
Whitehouse PJ, Martino AM, Antuono PG, Lowenstein PR, Coyle JT, Price DL, et al. Nicotinic acetylcholine binding sites in Alzheimer’s disease. Brain Res 1986;371:146–51.CrossRefPubMed
6.
Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 1991;7:695–702.CrossRefPubMed
7.
Dai J, Buijs RM, Kamphorst W, Swaab DR. Impaired axonal transport of cortical neurons in Alzheimer’s disease is associated with neuropathological changes. Brain Res 2002;948:138–44.CrossRefPubMed
8.
Lindstrom J, Anand R, Peng X, Gerzanich V, Wang F, Li Y. Neuronal nicotinic receptor subtypes. Ann N Y Acad Sci 1995;757:100–16.CrossRefPubMed
9.
Martin-Ruiz CM, Court JA, Molnar E, Lee M, Gotti C, Mamalaki A, et al. Alpha4 but not alpha3 and alpha7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer’s disease. J Neurochem 1999;73:1635–40.CrossRefPubMed
10.
Horti AG, Scheffel U, Koren AO, Ravert HT, Mathews WB, Musachio JL, et al. 2-[18F]Fluoro-A-85380, an in vivo tracer for the nicotinic acetylcholine receptors. Nucl Med Biol 1998;25:599–603.CrossRefPubMed
11.
Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al. Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240–6.CrossRefPubMed
12.
Kessler J, Calabrese P, Kalbe E, Berger F. DemTect: a new dementia screening instrument. Psycho 2000;26:343–7.
13.
Schildan A, Patt M, Sabri O. Synthesis procedure for routine production of 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380). Appl Radiat Isot 2007;65:1244–8.CrossRefPubMed
14.
Sabri O, Erkwoh R, Schreckenberger M, Owega A, Sass H, Buell U. Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics. Lancet 1997;349:1735–9.CrossRefPubMed
15.
Sabri O, Ringelstein EB, Hellwig D, Schneider R, Schreckenberger M, Kaiser HJ, et al. Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy. Stroke 1999;30:556–66.PubMed
16.
Sabri O, Owega A, Schreckenberger M, Sturz L, Fimm B, Kunert P, et al. A truly simultaneous combination of functional transcranial Doppler sonography and H(2)(15)O PET adds fundamental new information on differences in cognitive activation between schizophrenics and healthy control subjects. J Nucl Med 2003;44:671–81.PubMed
17.
Sorger D, Becker GA, Hauber K, Schildan A, Patt M, Birkenmeier G, et al. Binding properties of the cerebral alpha4beta2 nicotinic acetylcholine receptor ligand 2-[18F]fluoro-A-85380 to plasma proteins. Nucl Med Biol 2006;33:899–906.CrossRefPubMed
18.
Sorger D, Becker GA, Patt M, Schildan A, Grossmann U, Schliebs R, et al. Measurement of the alpha4beta2* nicotinic acetylcholine receptor ligand 2-[(18)F]fluoro-A-85380 and its metabolites in human blood during PET investigation: a methodological study. Nucl Med Biol 2007;34:331–42.CrossRefPubMed
19.
Chefer SI, London ED, Koren AO, Pavlova OA, Kurian V, Kimes AS, et al. Graphical analysis of 2-[18F]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain. Synapse 2003;48:25–34.CrossRefPubMed
20.
Gallezot JD, Bottlaender MA, Delforge J, Valette H, Saba W, Dollé F, et al. Quantification of cerebral nicotinic acetylcholine receptors by PET using 2-[18F]fluoro-A-85380 and the multiinjection approach. J Cereb Blood Flow Metab 2008;28:172–89.CrossRefPubMed
21.
Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007;27:1533–39.CrossRefPubMed
22.
Meyer PM, Strecker K, Kendziorra K, Becker G, Hesse S, Woelpl D, et al. Reduced alpha4beta2*-nicotinic acetylcholine receptor binding and its relationship to mild cognitive and depressive symptoms in Parkinson disease. Arch Gen Psychiatry 2009;66:866–77.CrossRefPubMed
23.
Brody AL, Mandelkern MA, London ED, Olmstead RE, Farahi J, Scheibal D, et al. Cigarette smoking saturates brain alpha(4)beta(2) nicotinic acetylcholine receptors. Arch Gen Psychiatry 2006;63:907–15.CrossRefPubMed
24.
Terrière E, Sharman M, Donaghey C, Herrmann L, Lonie J, Strachan M, et al. alpha4 beta2-nicotinic receptor binding with 5-IA in Alzheimer’s disease: methods of scan analysis. Neurochem Res 2008;33:643–51.CrossRefPubMed
25.
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15:273–89.CrossRefPubMed
26.
Arendt T, Bigl V. Alzheimer’s disease as a presumptive threshold phenomenon. Neurobiol Aging 1987;8:552–54.CrossRefPubMed
27.
Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott M, et al. Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases. Eur J Pharmacol 2000;393:215–22.CrossRefPubMed
28.
Nordberg A, Alafuzoff I, Winblad B. Nicotinic and muscarinic subtypes in the human brain: changes with aging and dementia. J Neurosci Res 1992;31:103–11.CrossRefPubMed
29.
Pimlott SL, Piggott M, Owens J, Greally E, Court JA, Jaros E, et al. Nicotinic acetylcholine receptor distribution in Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease, and vascular dementia: in vitro binding study using 5-[(125)I]-A-85380. Neuropsychopharmacology 2004;29:108–16.CrossRefPubMed
30.
Rinne JO, Myllykylä T, Lönnberg P, Marjamäki P. A postmortem study of brain nicotinic receptors in Parkinson’s and Alzheimer’s disease. Brain Res 1991;547:167–70.CrossRefPubMed
31.
Nordberg A, Lundqvist H, Hartvig P, Lilja A, Långström B. Kinetic analysis of regional (S)(-)11C-nicotine binding in normal and Alzheimer brains—in vivo assessment using positron emission tomography. Alzheimer Dis Assoc Disord 1995;9:21–7.CrossRefPubMed
32.
O’Brien JT, Colloby SJ, Pakrasi S, Perry EK, Pimlott SL, Wyper DJ, et al. alpha4beta2 nicotinic receptor status in Alzheimer’s disease using 123I-5IA-85380 single-photon-emission computed tomography. J Neurol Neurosurg Psychiatry 2007;78:356–62.CrossRefPubMed
33.
Nordberg A, Hartvig P, Lilja A, Vitanen M, Amberla K, Lundqvist H, et al. Decreased uptake and binding of 11C-nicotine in brain of Alzheimer patients as visualized by positron emission tomography. J Neural Transm Park Dis Dement Sect 1990;2:215–24.CrossRefPubMed
34.
Ellis JR, Villemagne VL, Nathan PJ, Mulligan RS, Gong SJ, Chan JG, et al. Relationship between nicotinic receptors and cognitive function in early Alzheimer’s disease: a 2-[18F]fluoro-A-85380 PET study. Neurobiol Learn Mem 2008;90:404–12.CrossRefPubMed
35.
Mitsis EM, Reech KM, Bois F, Tamagnan GD, Macavoy MG, Seibyl JP, et al. 123I-5-IA-85380 SPECT imaging of nicotinic receptors in Alzheimer disease and mild cognitive impairment. J Nucl Med 2009;50:1455–63.CrossRefPubMed
36.
Yakushev I, Hammers A, Fellgiebel A, Schmidtmann I, Scheurich A, Buchholz HG, et al. SPM-based count normalization provides excellent discrimination of mild Alzheimer’s disease and amnestic mild cognitive impairment from healthy aging. Neuroimage 2009;44:43–50.CrossRefPubMed
37.
Giovacchini G, Conant S, Herscovitch P, Theodore WH. Using cerebral white matter for estimation of nondisplaceable binding of 5-HT1A receptors in temporal lobe epilepsy. J Nucl Med 2009;50:1794–800.CrossRefPubMed
38.
39.
Soonawala D, Amin T, Ebmeier KP, Steele JD, Dougall NJ, Best J, et al. Statistical parametric mapping of (99m)Tc-HMPAO-SPECT images for the diagnosis of Alzheimer’s disease: normalizing to cerebellar tracer uptake. Neuroimage 2002;17:1193–202.CrossRefPubMed
40.
Staley JK, van Dyck CH, Weinzimmer D, Brenner E, Baldwin RM, Tamagnan GD, et al. 123I-5-IA-85380 SPECT measurement of nicotinic acetylcholine receptors in human brain by the constant infusion paradigm: feasibility and reproducibility. J Nucl Med 2005;46:1466–72.PubMed
Metadata
Title
Decreased cerebral α4β2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer’s disease assessed with positron emission tomography
Authors
Kai Kendziorra
Henrike Wolf
Philipp Mael Meyer
Henryk Barthel
Swen Hesse
Georg Alexander Becker
Julia Luthardt
Andreas Schildan
Marianne Patt
Dietlind Sorger
Anita Seese
Herman-Josef Gertz
Osama Sabri
Publication date
01-03-2011
Publisher
Springer-Verlag
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2011
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-010-1644-5

Other articles of this Issue 3/2011

European Journal of Nuclear Medicine and Molecular Imaging 3/2011 Go to the issue

Original Article

Molecular imaging of σ receptors: synthesis and evaluation of the potent σ1 selective radioligand [18F]fluspidine

Focus On...

Čerenkov radioactive optical imaging: a promising new strategy

Short Communication

In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa)

Book Review

Dominique Delbeke, Ora Israel (eds): Hybrid PET/CT and SPECT/CT Imaging: A Teaching File

Image of the Month

A case of thymoma detected by 18F-choline positron emission tomography/computed tomography

Original Article

Prognostic implications of post-stress ejection fraction decrease detected by gated SPECT in the absence of stress-induced perfusion abnormalities