Skip to main content

Advertisement

SpringerLink
Log in

Acetylcholine receptors in dementia and mild cognitive impairment

  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

To clarify whether changes in the cholinergic transmission occur early in the course of Alzheimer’s disease (AD), we carried out positron emission tomography (PET) with the radioligand 2-[18F]F-A-85380, which is supposed to be specific for α4β2 nicotinic acetylcholine receptors (nAChRs).

Method

We included patients with moderate to severe AD and patients with amnestic mild cognitive impairment (MCI), presumed to present preclinical AD.

Results

Both patients with AD and MCI showed significant reductions in α4β2 nAChRs in brain regions typically affected by AD pathology. These findings indicate that a reduction in α4β2 nAChRs occurs during early symptomatic stages of AD. The α4β2 nAChR availability in these regions correlated with the severity of cognitive impairment, indicating a stage sensitivity of the α4β2 nAChR status.

Conclusion

Together, our results provide evidence for the potential of 2-[18]F-A-85380 nAChR PET in the diagnosis of patients at risk for AD. Because of the extraordinary long acquisition time with 2-[18F]F-A-85380, we developed the new α4β2 nAChR-specific radioligands (+)- and (−)-[18F]norchloro-fluoro-homoepibatidine (NCFHEB) and evaluated them preclinically. (−)-[18F]NCFHEB shows twofold higher brain uptake and significantly shorter acquisition times. Therefore, (−)-[18F]NCFHEB should be a suitable radioligand for larger clinical investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

References

  1. Lobo A, Launer LJ, Fratiglioni L, Andersen K, Di Carlo A, Breteler MMB, et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology 2000;54:S4–9.

    PubMed  CAS  Google Scholar 

  2. Dugue M, Neugroschl J, Sewell M, Marin D. Review of dementia. Mount Sinai J Med 2003;70:45–53.

    Google Scholar 

  3. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–6.

    Article  PubMed  CAS  Google Scholar 

  4. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006;368:387–403.

    Article  PubMed  CAS  Google Scholar 

  5. Walsh DM, Selkoe DJ. Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 2004;44:181–93.

    Article  PubMed  CAS  Google Scholar 

  6. Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. A specific amyloid-[beta] protein assembly in the brain impairs memory. Nature 2006;440:352–7.

    Article  PubMed  CAS  Google Scholar 

  7. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741–66.

    PubMed  CAS  Google Scholar 

  8. Perl DP. Neuropathology of Alzheimer’s disease and related disorders. Neurol Clin 2000;18:847–64.

    Article  PubMed  CAS  Google Scholar 

  9. Lovestone S, Reynolds CH. The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 1997;78:309–24.

    Article  PubMed  CAS  Google Scholar 

  10. Perry E, Walker M, Grace J, Perry R. Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 1999;22:273–80.

    Article  PubMed  CAS  Google Scholar 

  11. Bowen DM, Smith CB, White P, Davison AN. Neurotransmitter-related enzymes and indexes of hypoxia in senile dementia and other abiotrophies. Brain 1976;99:459–96.

    Article  PubMed  CAS  Google Scholar 

  12. Davies P, Maloney AJF. Selective loss of central cholinergic neurons in Alzheimers-Disease. Lancet 1976;2:1403.

    Article  PubMed  CAS  Google Scholar 

  13. Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE. Neurotransmitter enzyme abnormalities in senile dementia—choline-acetyltransferase and glutamic-acid decarboxylase activities in necropsy brain-tissue. J Neurol Sci 1977;34:247–65.

    Article  PubMed  CAS  Google Scholar 

  14. Nilsson L, Nordberg A, Hardy J, Wester P, Winblad B. Physostigmine restores H-3 acetylcholine efflux from Alzheimer brain-slices to normal level. J Neural Transm 1986;67:275–85.

    Article  PubMed  CAS  Google Scholar 

  15. Rylett RJ, Ball MJ, Colhoun EH. Evidence for high-affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimers-Disease. Brain Res 1983;289:169–75.

    Article  PubMed  CAS  Google Scholar 

  16. Sivaprakasam K. Towards a unifying hypothesis of Alzheimer’s disease: cholinergic system linked to plaques, tangles and neuroinflammation. Curr Med Chem 2006;13:2179–88.

    Article  PubMed  CAS  Google Scholar 

  17. Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982;217:408–17.

    Article  PubMed  CAS  Google Scholar 

  18. Pirttila T, Wilcock G, Truyen L, Damaraju CV. Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicenter trial. Eur J Neurol 2004;11:734–41.

    Article  PubMed  CAS  Google Scholar 

  19. Whitehead A, Perdomo C, Pratt RD, Birks J, Wilcock GK, Evans JG. Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer’s disease: a meta-analysis of individual patient data from randomised controlled trials. Int J Geriatr Psychiatry 2004;19:624–33.

    Article  PubMed  Google Scholar 

  20. Bowen DM, Benton JS, Spillane JA, Smith CCT, Allen SJ. Choline acetyltransferase activity and histopathology of frontal neocortex from biopsies of demented patients. J Neurol Sci 1982;57:191–202.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. Dai J, Buijs RM, Kamphorst W, Swaab DF. Impaired axonal transport of cortical neurons in Alzheimer’s disease is associated with neuropathological changes. Brain Res 2002;948:138–44.

    Article  PubMed  CAS  Google Scholar 

  24. Lindström J, Anand R, Peng X, Gerzanich V, Wang F, Li YB. Neuronal nicotinic receptor subtypes. Ann NY Acad Sci 1995;757:100–16.

    Article  PubMed  Google Scholar 

  25. Martin-Ruiz CM, Court JA, Molnar E, Lee M, Gotti C, Mamalaki A, et al. α4 but not α3 and α7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer’s disease. J Neurochem 1999;73:1635–40.

    Article  PubMed  CAS  Google Scholar 

  26. Warpman U, Nordberg A. Epibatidine and ABT 418 reveal selective losses of α4β2 nicotinic receptors in Alzheimer brains. Neuroreport 1995;6:2419–23.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  29. Maelicke A, Schrattenholz A, Storch A, Schröder B, Gutbrod O, Methfessel C, et al. Noncompetitive agonism at nicotinic acetylcholine-receptors—functional-significance for cns signal-transduction. J Recept Signal Transduct Res 1995;15:333–53.

    Article  PubMed  CAS  Google Scholar 

  30. Maelicke A, Schrattenholz A, Samochocki M, Radina M, Albuquerque EX. Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Behav Brain Res 2000;113:199–206.

    Article  PubMed  CAS  Google Scholar 

  31. Fujii S, Ji ZX, Morita N, Sumikawa K. Acute and chronic nicotine exposure differentially facilitate the induction of LTP. Brain Res 1999;846:137–43.

    Article  PubMed  CAS  Google Scholar 

  32. Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA. Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 1996;383:713–6.

    Article  PubMed  CAS  Google Scholar 

  33. Levin ED, Simon BB. Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology (Berl) 1998;138:217–30.

    Article  CAS  Google Scholar 

  34. Maelicke A. Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Dement Geriatr Cogn Disord 2000;11:11–8.

    Article  PubMed  CAS  Google Scholar 

  35. Picciotto MR, Zoli M. Nicotinic receptors in aging and dementia. J Neurobiol 2002;53:641–55.

    Article  PubMed  CAS  Google Scholar 

  36. Nordberg A. PET studies and cholinergic therapy in Alzheimer’s disease. Rev Neurol 1999;155:S53–63.

    PubMed  Google Scholar 

  37. Nordberg A. Nicotinic receptor abnormalities of Alzheimer’s disease: therapeutic implications. Biol Psychiatry 2001;49:200–10.

    Article  PubMed  CAS  Google Scholar 

  38. Schliebs R. Basal forebrain cholinergic dysfunction in Alzheimer’s disease—interrelationship with beta-amyloid, inflammation and neurotrophin signaling. Neurochem Res 2005;30:895–908.

    Article  PubMed  CAS  Google Scholar 

  39. Moran MA, Mufson EJ, Gomezramos P. Colocalization of cholinesterases with beta-amyloid protein in aged and Alzheimers brains. Acta Neuropathol 1993;85:362–9.

    Article  PubMed  CAS  Google Scholar 

  40. Mesulam MM. Alzheimer plaques and cortical cholinergic innervation. Neuroscience 1986;17:275–6.

    Article  PubMed  CAS  Google Scholar 

  41. Racchi M, Sironi M, Caprera A, Konig G, Govoni S. Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein. Mol Psychiatry 2001;6:520–8.

    Article  PubMed  CAS  Google Scholar 

  42. Mori F, Lai CC, Fusi F, Giacobini E. Cholinesterase-inhibitors increase secretion of apps in rat-brain cortex. Neuroreport 1995;6:633–6.

    Article  PubMed  CAS  Google Scholar 

  43. Lahiri DK, Farlow MR, Nürnberger JI, Greig NH. Effects of cholinesterase inhibitors on the secretion of beta-amyloid precursor protein in cell cultures. Ann NY Acad Sci 1997;826:416–21.

    Article  PubMed  CAS  Google Scholar 

  44. Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C, et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 1996;16:881–91.

    Article  PubMed  CAS  Google Scholar 

  45. Racchi M, Govoni S. The pharmacology of amyloid precursor protein processing. Exp Gerontol 2003;38:145–57.

    Article  PubMed  CAS  Google Scholar 

  46. Zhang X. Cholinergic activity and amyloid precursor protein processing in aging and Alzheimer’s disease. Curr Drug Targets 2004;3:137–52.

    Article  CAS  Google Scholar 

  47. Mufson EJ, Chen EY, Cochran EJ, Beckett LA, Bennett DA, Kordower JH. Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment. Exp Neurol 1999;158:469–90.

    Article  PubMed  CAS  Google Scholar 

  48. Harkany T, O’Mahony S, Kelly JP, Soos K, Toro I, Penke B, et al. Beta-Amyloid(Phe(SO3H)(24))25–35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation. Behav Brain Res 1998;90:133–45.

    Article  PubMed  CAS  Google Scholar 

  49. Bartolini M, Bertucci C, Cavrini V, Andrisano V. Beta-amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 2003;65:407–16.

    Article  PubMed  CAS  Google Scholar 

  50. Alvarez A, Opazo C, Alarcon R, Garrido J, Inestrosa NC. Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils. J Mol Biol 1997;272:348–61.

    Article  PubMed  CAS  Google Scholar 

  51. Reyes AE, Chacon MA, Dinamarca MC, Cerpa W, Morgan C, Inestrosa NC. Acetylcholinesterase-A beta complexes are more toxic than A beta fibrils in rat hippocampus—effect on rat beta-amyloid aggregation, laminin expression, reactive astrocytosis, and neuronal cell loss. Am J Pathol 2004;164:2163–74.

    PubMed  CAS  Google Scholar 

  52. Alvarez A, Alarcon R, Opazo C, Campos EO, Munoz FJ, Calderon FH, et al. Stable complexes involving acetylcholinesterase and amyloid-beta peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer’s fibrils. J Neurosci 1998;18:3213–23.

    PubMed  CAS  Google Scholar 

  53. Rees T, Hammond PI, Soreq H, Younkin S, Brimijoin S. Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex. Neurobiol Aging 2003;24:777–87.

    Article  PubMed  CAS  Google Scholar 

  54. Lahiri DK, Utsuki T, Chen D, Farlow MR, Shoaib M, Ingram DK, et al. Nicotine reduces the secretion of Alzheimer’s beta-amyloid precursor protein containing beta-amyloid peptide in the rat without altering synaptic proteins. Ann NY Acad Sci 2002;965:364–72.

    Article  PubMed  CAS  Google Scholar 

  55. Seo JH, Kim SH, Kim HS, Park CH, Jeong SJ, Lee JH, et al. Effects of nicotine on APP secretion and Aβ- or CT105-induced toxicity. Biol Psychiatry 2001;49:240–7.

    Article  PubMed  CAS  Google Scholar 

  56. Efthimiopoulos S, Vassilacopoulou D, Ripellino JA, Tezapsidis N, Robakis NK. Cholinergic agonists stimulate secretion of soluble full-length amyloid precursor protein in neuroendocrine cells. Proc Natl Acad Sci USA 1996;93:8046–50.

    Article  PubMed  CAS  Google Scholar 

  57. de Leon MJ, Mosconi L, Blennow K, DeSanti S, Zinkowsky R, Metha PD, et al. Imaging and CSF studies in the preclinical diagnosis of Alzheimer’s disease. Ann NY Acad Sci 2007;1097:114–45.

    Article  PubMed  CAS  Google Scholar 

  58. Klunk WE, Engler H, Nordberg A, Wang YM, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306–19.

    Article  PubMed  CAS  Google Scholar 

  59. Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006;355:2652–63.

    Article  PubMed  CAS  Google Scholar 

  60. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol of Aging 2007 (in press) (Corrected proof, DOI 10.1016/j.neurobiolaging 2007.03.029)

  61. Kemppainen NM, Aalto S, Wilson IA, Nagren K, Helin S, Bruck A, et al. PET amyloid ligand [C-11]PIB uptake is increased in mild cognitive impairment. Neurology 2007;68:1603–6.

    Article  PubMed  CAS  Google Scholar 

  62. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007;68:1718–25.

    Article  PubMed  CAS  Google Scholar 

  63. Klingner M, Apelt J, Kumar A, Sorger D, Sabri O, Steinbach J, et al. Alterations in cholinergic and non-cholinergic neurotransmitter receptor densities in transgenic Tg2576 mouse brain with [beta]-amyloid plaque pathology. Int J Dev Neurosci 2003;21:357–69.

    Article  PubMed  CAS  Google Scholar 

  64. 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.

    Article  PubMed  CAS  Google Scholar 

  65. Gilmor ML, Erickson JD, Varoqui H, Hersh LB, Bennett DA, Cochran EJ, et al. Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 1999;411:693–704.

    Article  PubMed  CAS  Google Scholar 

  66. Rinne JO, Kaasinen V, Jarvenpaa T, Nagren K, Roivainen A, Yu M, et al. Brain acetylcholinesterase activity impairment and early Alzheimer’s in mild cognitive disease. J Neurol Neurosurg Psychiatry 2003;74:113–5.

    Article  PubMed  CAS  Google Scholar 

  67. 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.

    Article  PubMed  CAS  Google Scholar 

  68. Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 2007;47:699–729.

    Article  PubMed  CAS  Google Scholar 

  69. Gotti C, Riganti L, Vailanti S, Clementi F. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr Pharm Des 2006;12:407–28.

    Article  PubMed  CAS  Google Scholar 

  70. Gotti C, Zoli M, Clementi F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci 2006;27:482–91.

    Article  PubMed  CAS  Google Scholar 

  71. Connolly CN, Wafford KA. The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function. Biochem Soc Trans 2004;32:529–34.

    Article  PubMed  CAS  Google Scholar 

  72. Cordero-Erausquin M, Marubio LM, Klink R, Changeux JP. Nicotinic receptor function: new perspectives from knockout mice. Trends Pharmacol Sci 2000;21:211–7.

    Article  PubMed  CAS  Google Scholar 

  73. Graham AJ, Martin-Ruiz CM, Teaktong T, Ray MA, Court JA. Human brain nicotinic receptors, their distribution and participation in neuropsychiatric disorders. Curr Drug Targets CNS Neurol Disord 2002;1:387.

    Article  PubMed  CAS  Google Scholar 

  74. Sullivan JP, DonnellyRoberts D, Briggs CA, Anderson DJ, Gopalakrishnan M, PiattoniKaplan M, et al. A-85380 [3-(2(S)-azetidinylmethoxy)pyridine]: in vitro pharmacological properties of a novel, high affinity α4β2 nicotinic acetylcholine receptor ligand. Neuropharmacology 1996;35:725–34.

    Article  PubMed  CAS  Google Scholar 

  75. Ding YS, Fowler J. New-generation radiotracers for nAChR and NET. Nucl Med Biol 2005;32:707–18.

    Article  PubMed  CAS  Google Scholar 

  76. Fukuyama H. Functional brain imaging in Parkinson’s disease—overview. J Neurol 2004;251:vii1–3.

    Article  PubMed  Google Scholar 

  77. Hirose S, Mitsudome A, Okada M, Kaneko S. Genetics of idiopathic epilepsies. Epilepsia 2005;46:38–43.

    Article  PubMed  CAS  Google Scholar 

  78. Mihailescu S, Drucker-Colin R. Nicotine, brain nicotinic receptors, and neuropsychiatric disorders. Arch Med Res 2000;31:131–44.

    Article  PubMed  CAS  Google Scholar 

  79. Quik M, McIntosh JM. Striatal α6* nicotinic acetylcholine receptors: potential targets for Parkinson’s disease therapy. J Pharmacol Exp Ther 2006;316:481–9.

    Article  PubMed  CAS  Google Scholar 

  80. Williams M. Genome-based drug discovery: prioritizing disease-susceptibility/disease-associated genes as novel drug targets for schizophrenia. Curr Opin Investig Drugs 2003;4:31–6.

    PubMed  CAS  Google Scholar 

  81. Youdim MBH, Buccafusco JJ. CNS targets for multi-functional drugs in the treatment of Alzheimer’s and Parkinson’s diseases. J Neural Transm 2005;112:519–37.

    Article  PubMed  CAS  Google Scholar 

  82. Horti AG, Villemagne VL. The quest for Eldorado: Development of radioligands for in vivo imaging of nicotinic acetylcholine receptors in human brain. Curr Pharm Des 2006;12:3877–900.

    Article  PubMed  CAS  Google Scholar 

  83. Nordberg A, Hartvig P, Lilja A, Viitanen 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 Parkinson’s Dis Dement Sect 1990;2:215–24.

    Article  CAS  Google Scholar 

  84. Nordberg A, Hartvig P, Lilja A, Viitanen M, Amberla K, Lundqvist H, et al. Nicotine receptors in the brain of patients with Alzheimer’s disease. Studies with 11C-nicotine and positron emission tomography. Acta Radiol Suppl 1991;376:165–6.

    PubMed  CAS  Google Scholar 

  85. Nyback H, Halldin C, Ahlin A, Curvall M, Eriksson L. Pet studies of the uptake of (s)-[C-11]nicotine and (r)-[C-11]nicotine in the human brain—difficulties in visualizing specific receptor-binding in-vivo. Psychopharmacology 1994;115:31–6.

    Article  PubMed  CAS  Google Scholar 

  86. 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.

    Article  PubMed  CAS  Google Scholar 

  87. Gallezot JD, Bottlaender M, Gregoire MC, Roumenov D, Deverre JR, Coulon C, et al. In vivo Imaging of human cerebral nicotinic acetylcholine receptors with 2-F-18-fluoro-A-85380 and PET. J Nucl Med 2005;46:240–7.

    PubMed  CAS  Google Scholar 

  88. Kimes AS, Horti AG, London ED, Chefer SI, Contoreggi C, Ernst M, et al. 2-[F-18]F-A85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans. Faseb J 2003;10:1331–3.

    Google Scholar 

  89. Shumway DA, Pavlova OA, Mukhin AG. A simplified method for the measurement of nonmetabolized 2-[F-18]F-A-85380 in blood plasma using solid-phase extraction. Nucl Med Biol 2007;34:221–8.

    Article  PubMed  CAS  Google Scholar 

  90. Staley JK, van Dyck CH, Weirizimmer D, Brenner E, Baldwin RA, Tamagnan GD, et al. I-123-5-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  CAS  Google Scholar 

  91. Staley JK, Krishnan-Sarin S, Cosgrove KP, Krantzler E, Frohlich E, Perry E, et al. Human tobacco smokers in early abstinence have higher levels of β2* nicotinic acetylcholine receptors than nonsmokers. J Neurosci 2006;26:8707–14.

    Article  PubMed  CAS  Google Scholar 

  92. Picard F, Bruel D, Servent D, Saba W, Fruchart-Gaillard C, Schollhorn-Peyronneau MA, et al. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. Brain 2006;129:2047–60.

    Article  PubMed  CAS  Google Scholar 

  93. O’Brien JT, Colloby SJ, Pakrasi S, Perry EK, Pimlott SL, Wyper DJ, et al. α4β2 nicotinic receptor status in Alzheimer’s disease using 123I-5IA-85380 SPECT. J Neurol Neurosurg Psychiatry 2007;78:356–62.

    Article  PubMed  CAS  Google Scholar 

  94. Gündisch D, Koren AO, Horti AG, Pavlova OA, Kimes AS, Mukhin AG, et al. In vitro characterization of 6-[F-18]fluoro-A85380, a high-affinity ligand for alpha 4 beta 2*nicotinic acetylcholine receptors. Synapse 2005;55:89–97.

    Article  PubMed  CAS  Google Scholar 

  95. Mukhin AG, Gündisch D, Horti AG, Koren AO, Tamagnan G, Kimes AS, et al. 5-Iodo-A-85380, an alpha 4 beta 2 subtype-selective ligand for nicotinic acetylcholine receptors. Mol Pharmacol 2000;57:642–9.

    PubMed  CAS  Google Scholar 

  96. Horti AG, Scheffel U, Koren AO, Ravert HT, Mathews WB, Musachio JL, et al. 2-[F-18]fluoro-A-85380, an in vivo tracer for the nicotinic acetylcholine receptors. Nucl Med Biol 1998;25:599–603.

    Article  PubMed  CAS  Google Scholar 

  97. Chefer SI, London ED, Koren AO, Pavlova OA, Kurian V, Kimes AS, et al. Graphical analysis of 2-[F-18]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain. Synapse 2003;48:25–34.

    Article  PubMed  CAS  Google Scholar 

  98. 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.

    Article  PubMed  CAS  Google Scholar 

  99. Sabri O, Hellwig D, Schreckenberger M, Cremerius U, Schneider R, Kaiser HJ, et al. Correlation of neuropsychological, morphological and functional (regional cerebral blood flow and glucose utilization) findings in cerebral microangiopathy. J Nucl Med 1998;39:147–54.

    PubMed  CAS  Google Scholar 

  100. 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  CAS  Google Scholar 

  101. Sorger D, Becker GA, Hauber K, Schildan A, Patt M, Birkenmeier G, et al. Binding properties of the cerebral α4β2 nicotinic acetylcholine receptor ligand 2-[18F]fluoro-A-85380 to plasma proteins. Nucl Med Biol 2006;33:899–906.

    Article  PubMed  CAS  Google Scholar 

  102. Sorger D, Becker GA, Patt M, Schildan A, Grossmann U, Schliebs R, et al. Measurement of the α4β2* nicotinic acetylcholine receptor ligand 2-[18F]Fluoro-A-85380 and its metabolites in human blood during PET investigation: a methodological study. Nucl Med Biol 2007;34:331–42.

    Article  PubMed  CAS  Google Scholar 

  103. Ding YS, Fowler JS, Logan J, Wang GJ, Telang F, Garza V, et al. 6-[F-18]fluoro-A-85380, a new PET tracer for the nicotinic acetylcholine receptor: Studies in the human brain and in vivo demonstration of specific binding in white matter. Synapse 2004;53:184–9.

    Article  PubMed  CAS  Google Scholar 

  104. 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.

    Article  PubMed  CAS  Google Scholar 

  105. Aubert I, Araujo DM, Cecyre D, Robitaille Y, Gauthier S, Quirion R. Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer’s and Parkinson’s diseases. J Neurochem 1992;58:529–41.

    Article  PubMed  CAS  Google Scholar 

  106. 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.

    Article  PubMed  CAS  Google Scholar 

  107. Anchisi D, Borroni B, Franceschi M, Kerrouche N, Kalbe E, Beuthien-Beumann B, et al. Heterogeneity of brain glucose metabolism in mild cognitive impairment and clinical progression to Alzheimer disease. Arch Neurol 2005;62:1728–33.

    Article  PubMed  Google Scholar 

  108. Friedland RP, Brun A, Budinger TF. Pathological and positron emission tomographic correlations in Alzheimers-disease. Lancet 1985;1:228.

    Article  PubMed  CAS  Google Scholar 

  109. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997;42:85–94.

    Article  PubMed  CAS  Google Scholar 

  110. Boxer AL, Rankin KP, Miller BL, Schuff N, Weiner M, Gorno-Tempini ML, et al. Cinguloparietal atrophy distinguishes Alzheimer disease from semantic dementia. Arch Neurol 2003;60:949–56.

    Article  PubMed  Google Scholar 

  111. Fox NC, Crum WR, Scahill RI, Stevens JM, Janssen JC, Rossor MN. Imaging of onset and progression of Alzheimer’s disease with voxel-compression mapping of serial magnetic resonance images. Lancet 2001;358:201–5.

    Article  PubMed  CAS  Google Scholar 

  112. Fischer P, Jungwirth S, Zehetmayer S, Weissgram S, Hoenigschnabl S, Gelpi E, et al. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology 2007;68:288–91.

    Article  PubMed  CAS  Google Scholar 

  113. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE. A diagnostic-approach in Alzheimers-disease using 3-dimensional stereotaxic surface projections of fluorine-18-FDG PET. J Nucl Med 1995;36:1238–48.

    PubMed  CAS  Google Scholar 

  114. Frölich L. Cholinergic pathology in Alzheimer’s disease—discrepancies between clinical experience and pathophysiological findings. J Neural Transm 2002;109:1003–14.

    Article  PubMed  Google Scholar 

  115. Arendt T, Bigl V. Alzheimers-Disease as a presumptive threshold phenomenon. Neurobiol Aging 1987;8:552–4.

    Article  PubMed  CAS  Google Scholar 

  116. Meyer P, Kendziorra K, Barthel H, Hesse S, Becker G, Sorger D, et al. Quantitative assessment of the cerebral α4β2 nicotinic acetylcholine receptors in Parkinsons disease: a PET study using 2-[18F]F-A-85380. J Nucl Med 2005;46:65.

    Google Scholar 

  117. Meyer P, Kendziorra K, Hesse S, Becker G, Strecker K, Patt M, et al. Nicotinic acetylcholine receptors (α4β2) and their relationship to cognitive and mood symptoms in Parkinson’s disease (PD): a 2-F18-F-A-85380-PET (2FA-PET) study. J Nucl Med 2006;47:209.

    Google Scholar 

  118. Meyer P, Kendziorra K, Hesse S, Becker G, Strecker K, Hensel A, et al. Nicotinic acetylcholine receptors (α4β2) and their relationship to cognitive and mood symptoms in Parkinson disease: a 2-[18F]-F-A-85380 PET study. Neuroimage 2006;31:T151.

    Article  Google Scholar 

  119. Mckhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical-diagnosis of Alzheimers-disease—report of the NINCDS-ADRDA work group under the auspices of department-of-health-and-human-services task-force on Alzheimers-disease. Neurology 1984;34:939–44.

    PubMed  CAS  Google Scholar 

  120. Nagy Z, Esiri MM, Hindley NJ, Joachim C, Morris JH, King EMF, et al. Accuracy of clinical operational diagnostic criteria for Alzheimer’s disease in relation to different pathological diagnostic protocols. Dement Geriatr Cogn Disord 1998;9:219–26.

    Article  PubMed  CAS  Google Scholar 

  121. Dolci L, Dolle F, Valette H, Vaufrey F, Fuseau C, Bottlaender M, et al. Synthesis of a fluorine-18 labeled derivative of epibatidine for in vivo nicotinic acetylcholine receptor PET imaging. Bioorg Med Chem 1999;7:467–79.

    Article  PubMed  CAS  Google Scholar 

  122. Patt JT, Spang JE, Buck A, Cristina H, Arras M, Schubiger PA, et al. Synthesis and in vivo studies of the stereoisomers of N-[11C]methyl-homoepibatidine. Nucl Med Biol 2001;28:645–55.

    Article  PubMed  CAS  Google Scholar 

  123. Avalos M, Parker MJ, Maddox FN, Carroll FI, Luetje CW. Effects of pyridine ring substitutions on affinity, efficacy, and subtype selectivity of neuronal nicotinic receptor agonist epibatidine. J Pharmacol Exp Ther 2002;302:1246–52.

    Article  PubMed  CAS  Google Scholar 

  124. Horti AG, Scheffel U, Kimes AS, Musachio JL, Ravert HT, Mathews WB, et al. Synthesis and evaluation of N-[C-11]methylated analogues of epibatidine as tracers for positron emission tomographic studies of nicotinic acetylcholine receptors. J Med Chem 1998;41:4199–206.

    Article  PubMed  CAS  Google Scholar 

  125. Smith DF, Jakobsen S. Stereoselective neuroimaging in vivo. Eur Neuropsychopharmacol 2007;17:507–22.

    Article  PubMed  CAS  Google Scholar 

  126. Nordberg A, Lilja A, Lundqvist H, Hartvig P, Amberla K, Viitanen M, et al. Tacrine restores cholinergic nicotinic receptors and glucose-metabolism in Alzheimer patients as visualized by positron emission tomography. Neurobiol Aging 1992;13:747–58.

    Article  PubMed  CAS  Google Scholar 

  127. Bohnen N, Frey K. Imaging of cholinergic and monoaminergic neurochemical changes in neurodegenerative disorders. Mol Imaging Biol 2007;9:243–57.

    Article  PubMed  Google Scholar 

  128. Tomizawa M, Cowan A, Casida JE. Analgesic and toxic effects of neonicotinoid insecticides in mice. Toxicol Appl Pharmacol 2001;177:77–83.

    Article  PubMed  CAS  Google Scholar 

  129. Deuther-Conrad W, Patt JT, Feuerbach D, Wegner F, Brust P, Steinbach J. Norchloro-fluoro-homoepibatidine: specificity to neuronal nicotinic acetylcholine receptor subtypes in vitro. Farmaco 2004;59:785–92.

    Article  PubMed  CAS  Google Scholar 

  130. Abreo MA, Lin NH, Garvey DS, Gunn DE, Hettinger AM, Wasicak JT, et al. Novel 3-pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors. J Med Chem 1996;39:817–25.

    Article  PubMed  CAS  Google Scholar 

  131. Xiao Y, Kellar KJ. The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor subtype binding sites stably expressed in transfected mammalian cells. J Pharmacol Exp Ther 2004;310:98–107.

    Article  PubMed  CAS  Google Scholar 

  132. Kulak JM, Sum J, Musachio JL, McIntosh JM, Quik M. 5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha 4 beta 2*subtypes. J Neurochem 2002;81:403–6.

    Article  PubMed  CAS  Google Scholar 

  133. Jensen AA, Frolund B, Liljefors T, Krogsgaard-Larsen P. Neuronal nicotinic acetylcholine receptors: Structural revelations, target identifications, and therapeutic inspirations. J Med Chem 2005;48:4705–45.

    Article  PubMed  CAS  Google Scholar 

  134. Lai A, Parameswaran N, Khwaja M, Whiteaker P, Lindström JM, Fan H, et al. Long-term nicotine treatment decreases striatal α6* nicotinic acetylcholine receptor sites and function in mice. Mol Pharmacol 2005;67:1639–47.

    Article  PubMed  CAS  Google Scholar 

  135. Deuther-Conrad W, Patt JT, Lockman PR, Allen DD, Patt M, Schildan A, et al. Norchloro-fluoro-homoepibatidine (NCFHEB)—a promising radioligand for neuroimaging nicotinic acetylcholine receptors with PET. Eur Neuropsychopharmacol 2008;18:222–29.

    Article  PubMed  CAS  Google Scholar 

  136. Vaupel DB, Tella SR, Huso DL, Wagner VO, Mukhin AG, Chefer SI, et al. Pharmacological and toxicological evaluation of 2-fluoro-3(2(S)-azetidinylmethoxy)pyridine (2-F-A-85380), a ligand for imaging cerebral nicotinic acetylcholine receptors with positron emission tomography. J Pharmacol Exp Ther 2005;312:355–65.

    Article  PubMed  CAS  Google Scholar 

  137. Deuther-Conrad W, Wevers A, Becker G, Schildan A, Patt M, Sabri O, et al. Autoradiography of 2[F-18]F-A-85380 on nicotinic acetylcholine receptors in the porcine brain in vitro. Synapse 2006;59:201–10.

    Article  PubMed  CAS  Google Scholar 

  138. London ED, Scheffel U, Kimes AS, Kellar KJ. In-Vivo Labeling of Nicotinic Acetylcholine-Receptors in Brain with [H-3] Epibatidine. Eur J Pharmacol 1995;278:R1–2.

    Article  PubMed  CAS  Google Scholar 

  139. Musachio JL, Villemagne VL, Scheffel U, Stathis M, Finley P, Horti A, et al. [I-125/123]IPH: A radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors. Synapse 1997;26:392–9.

    Article  PubMed  CAS  Google Scholar 

  140. Iida Y, Ogawa M, Ueda M, Tominaga A, Kawashima H, Magata Y, et al. Evaluation of 5-C-11-methyl-A-85380 as an imaging agent for PET invesvigations of brain nicotinic acetylcholine receptors. J Nucl Med 2004;45:878–84.

    PubMed  CAS  Google Scholar 

  141. Zhang Y, Pavlova OA, Chefer SI, Hall AW, Kurian V, Brown LL, et al. 5-substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with low picomolar affinity for α4β2 nicotinic acetylcholine receptor and wide range of lipophilicity: Potential probes for imaging with positron emission tomography. J Med Chem 2004;47:2453–65.

    Article  PubMed  CAS  Google Scholar 

  142. Waterhouse RN. Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents. Mol Imaging Biol 2003;5:376–89.

    Article  PubMed  Google Scholar 

  143. Allen DD, Lockman PR, Roder KE, Dwoskin LP, Crooks PA. Active transport of high-affinity choline and nicotine analogs into the central nervous system by the blood-brain barrier choline transporter. J Pharmacol Exp Ther 2003;304:1268–74.

    Article  PubMed  CAS  Google Scholar 

  144. Allen DD, Lockman PR. The blood–brain barrier choline transporter as a brain drug delivery vector. Life Sci 2003;73:1609–15.

    Article  PubMed  CAS  Google Scholar 

  145. Friedrich A, George RL, Bridges CC, Prasad PD, Ganapathy V. Transport of choline and its relationship to the expression of the organic cation transporters in a rat brain microvessel endothelial cell line (RBE4). Biochim Biophys Acta Biomembr 2001;1512:299–307.

    Article  CAS  Google Scholar 

  146. Brust P, Jordan K. Effects of the nootropic AWD 52-39 on the blood–brain transfer of leucine, choline and glucose in rats after 14-D exposure to ethanol. Pharmazie 1992;47:616–20.

    PubMed  CAS  Google Scholar 

  147. Cornford EM, Cornford ME. Nutrient transport and the blood–brain-barrier in developing animals. Fed Proc 1986;45:2065–72.

    PubMed  CAS  Google Scholar 

  148. Kassiou M, Bottlaender M, Loc, h C, Dolle F, Musachio JL, Coulon C, et al. Pharmacological evaluation of a Br-76 analog of epibatidine: a potent ligand for studying brain nicotinic acetylcholine receptors. Synapse 2002;45:95–104.

    Article  PubMed  CAS  Google Scholar 

  149. Ding YS, Kil KE, Lin KS, Ma W, Yokota Y, Carroll IF. A novel nicotinic acetylcholine receptor antagonist radioligand for PET studies. Bioorg Med Chem Lett 2006;16:1049–53.

    Article  PubMed  CAS  Google Scholar 

  150. Paterson D, Nordberg A. Neuronal nicotinic receptors in the human brain. Prog Neurobiol 2000;61:75–111.

    Article  PubMed  CAS  Google Scholar 

  151. Brust P, Patt JT, Deuther-Conrad W, Becker G, Patt M, Schildan A, et al. In vivo measurement of nicotinic acetylcholine receptors with [18F]norchloro-fluoro-homoepibatidine (NCFHEB). Synapse 2008;62:205–18.

    Article  PubMed  CAS  Google Scholar 

  152. Mitkovski S, Villemagne VL, Novakovic KE, O, Keefe G, Tochon-Danguy H, Mulligan RS, et al. Simplified quantification of nicotinic receptors with 2[F-18]F-A-85380 PET. Nucl Med Biol 2005;32:585–91.

    Article  PubMed  CAS  Google Scholar 

  153. Dart MJ, Wasicak JT, Ryther KB, Schrimpf MR, Kim KH, Anderson DJ, et al. Structural aspects of high affinity ligands for the α4β2 neuronal nicotinic receptor. Pharm Acta Helv 2000;74:115–23.

    Article  PubMed  CAS  Google Scholar 

  154. Grinevich VP, Letchworth SR, Lindenberger KA, Menager J, Mary V, Sadieva KA, et al. Heterologous expression of human α6β4β3α5 nicotinic acetylcholine receptors: binding properties consistent with their natural expression require quaternary subunit assembly including the alpha 5 subunit. J Pharmacol Exp Ther 2005;312:619–26.

    Article  PubMed  CAS  Google Scholar 

  155. Sorger D, Becker GA, Patt M, Schildan A, Grossmann U, Schliebs R, et al. Measurement of the α4β2*nicotinic acetylcholine receptor ligand 2-[F-18]Fluoro-A-85380 and its metabolites in human blood during PET investigation: a methodological study. Nucl Med Biol 2007;34:331–42.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank all colleagues from the Departments of Nuclear Medicine and Psychiatry of the Leipzig University and of the Institute of Interdisciplinary Isotope Research, who contributed to the presented data.

Conflict of interest statement

There are no conflicts of interest for any of the authors.

Author information

Authors and Affiliations

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

    Osama Sabri & Kai Kendziorra

  2. Department of Psychiatry, University of Leipzig, Johannisallee 20, 04103, Leipzig, Germany

    Henrike Wolf & Hermann-Josef Gertz

  3. Institute of Interdisciplinary Isotope Research, Permoserstrasse 15, 04318, Leipzig, Germany

    Peter Brust

Authors
  1. Osama Sabri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai Kendziorra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henrike Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hermann-Josef Gertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Brust
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Osama Sabri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabri, O., Kendziorra, K., Wolf, H. et al. Acetylcholine receptors in dementia and mild cognitive impairment. Eur J Nucl Med Mol Imaging 35 (Suppl 1), 30–45 (2008). https://doi.org/10.1007/s00259-007-0701-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-007-0701-1

Keywords

Search

Navigation