, Volume 188, Issue 4, pp 509–520 | Cite as

PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer’s disease

  • Ahmadul Kadir
  • Ove Almkvist
  • Anders Wall
  • Bengt Långström
  • Agneta Nordberg
Original Investigation



Patients suffering from Alzheimer’s disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the α4β2 nAChR subtype was observed in postmortem AD brain tissue. The α4 and α7 nAChR subunits were suggested to play an important role in cognitive function. Positron emission tomography (PET) has so far been used to visualize neuronal nAChRs in vivo by 11C-nicotine binding.


To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET.

Materials and methods

Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 15O-water for regional cerebral blood flow and (S)(−)11C-nicotine was used to assess nicotine binding sites in the brain by PET. Cognitive function was assessed using neuropsychological tests of global cognition, episodic memory, attention, and visuospatial ability.


Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests [Digit Symbol test (r=−0.44 and p=0.02) and Trail Making Test A (TMT-A) (r=0.42 and p=0.03)]. No significant correlation was observed between 11C-nicotine binding and the results of tests of episodic memory or visuospatial ability. Regional analysis showed that 11C-nicotine binding in the frontal and parietal cortex, which are the main areas for attention, correlated significantly with the Digit Symbol test and TMT-A results.


Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention.


Alzheimer’s disease (AD) Nicotinic acetylcholine receptors (nAChRs) Positron emission tomography (PET) 11C-nicotine binding Cognition Attention 



This research was supported by the Swedish Research Council (project no. 05817), Stiftelsen for Gamla Tjänarinnor, Stohne’s Foundation, and Swedish Brain Power.


  1. Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM (2002) Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer’s disease treatment studies. Am J Psychiatry 159:738–745PubMedCrossRefGoogle Scholar
  2. Alhainen K, Helkala EL, Riekkinen P (1993) Psychometric discrimination of tetrahydroaminoacridine responders in Alzheimer patients. Dementia 4:54–58PubMedGoogle Scholar
  3. Almkvist O, Jelic V, Amberla K, Hellstrom-Lindahl E, Meurling L, Nordberg A (2001) Responder characteristics to a single oral dose of cholinesterase inhibitor: a double-blind placebo-controlled study with tacrine in Alzheimer patients. Dement Geriatr Cogn Disord 12:22–32PubMedCrossRefGoogle Scholar
  4. Anderson J (1995) A rapid and accurate method to realign PET-scans utilizing image edge information. J Nucl Med 36:657–669PubMedGoogle Scholar
  5. Aubert I, Araujo DM, Cecyre D, Robitaille Y, Gauthier S, Quirion R (1992) Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer’s and Parkinson’s diseases. J Neurochem 58:529–541PubMedCrossRefGoogle Scholar
  6. Backman L, Forsell Y (1994) Episodic memory functioning in a community-based sample of old adults with major depression: utilization of cognitive support. J Abnorm Psychol 103:361–370PubMedCrossRefGoogle Scholar
  7. Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti B, Davis JG, Constantine G, Mathis CA, Moore RY, DeKosky ST (2005) Cognitive correlates of alterations in acetylcholinesterase in Alzheimer’s disease. Neurosci Lett 380:127–132PubMedCrossRefGoogle Scholar
  8. Cabeza R, Nyberg L (2000) Imaging cognition II: an empirical review of 275 PET and fMRI studies. J Cogn Neurosci 12:1–47PubMedCrossRefGoogle Scholar
  9. Cahn-Weiner DA, Sullivan EV, Shear PK, Fama R, Lim KO, Yesavage JA, Tinklenberg JR, Pfefferbaum A (1999) Brain structural and cognitive correlates of clock drawing performance in Alzheimer’s disease. J Int Neuropsychol Soc 5:502–509PubMedCrossRefGoogle Scholar
  10. Calhoun ME, Mao Y, Roberts JA, Rapp PR (2004) Reduction in hippocampal cholinergic innervation is unrelated to recognition memory impairment in aged rhesus monkeys. J Comp Neurol 475:238–246PubMedCrossRefGoogle Scholar
  11. Chefer SI, London ED, Koren AO, Pavlova OA, Kurian V, Kimes AS, Horti AG, Mukhin AG (2003) Graphical analysis of 2-[18F]FA binding to nicotinic acetylcholine receptors in rhesus monkey brain. Synapse 48:25–34PubMedCrossRefGoogle Scholar
  12. Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190PubMedCrossRefGoogle Scholar
  13. Ding YS, Fowler JS, Logan J, Wang GJ, Telang F, Garza V, Biegon A, Pareto D, Rooney W, Shea C, Alexoff D, Volkow ND, Vocci F (2004) 6-[18F]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 53:184–189PubMedCrossRefGoogle Scholar
  14. Duchek JM, Hunt L, Ball K, Buckles V, Morris JC (1997) The role of selective attention in driving and dementia of the Alzheimer type. Alzheimer Dis Assoc Disord 1(Suppl 11):48–56CrossRefGoogle Scholar
  15. Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ (1992) A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol 41:31–37PubMedGoogle Scholar
  16. Foldi NS, Lobosco JJ, Schaefer LA (2002) The effect of attentional dysfunction in Alzheimer’s disease: theoretical and practical implications. Semin Speech Lang 23:139–150PubMedCrossRefGoogle Scholar
  17. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198PubMedCrossRefGoogle Scholar
  18. Foster NL, Chase TN, Fedio P, Patronas NJ, Brooks RA, Di Chiro G (1983) Alzheimer’s disease: focal cortical changes shown by positron emission tomography. Neurology 33:961–965PubMedGoogle Scholar
  19. Gallezot JD, Bottlaender M, Gregoire MC, Roumenov D, Deverre JR, Coulon C, Ottaviani M, Dolle F, Syrota A, Valette H (2005) In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET. J Nucl Med 46:240–247PubMedGoogle Scholar
  20. Guan ZZ, Zhang X, Ravid R, Nordberg A (2000) Decreased protein levels of nicotinic receptor subunits in the hippocampus and temporal cortex of patients with Alzheimer’s disease. J Neurochem 74:237–243PubMedCrossRefGoogle Scholar
  21. Guillozet AL, Weintraub S, Mash DC, Mesulam MM (2003) Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 60:729–736PubMedCrossRefGoogle Scholar
  22. Gundisch D, Koren AO, Horti AG, Pavlova OA, Kimes AS, Mukhin AG, London ED (2005) In vitro characterization of 6-[18F]fluoro-A-85380, a high-affinity ligand for alpha4beta2* nicotinic acetylcholine receptors. Synapse 55:89–97PubMedCrossRefGoogle Scholar
  23. Haxby JV, Duara R, Grady CL, Cutler NR, Rapoport SI (1985) Relations between neuropsychological and cerebral metabolic asymmetries in early Alzheimer’s disease. J Cereb Blood Flow Metab 5:193–200PubMedGoogle Scholar
  24. Herholz K, Adams R, Kessler J, Szelies B, Grond M, Heiss W (1990) Criteria for the diagnosis of Alzheimer’s disease with positron emission tomography. Dementia 1:156–164Google Scholar
  25. Herholz K, Nordberg A, Salmon E, Perani D, Kessler J, Mielke R, Halber M, Jelic V, Almkvist O, Collette F, Alberoni M, Kennedy A, Hasselbalch S, Fazio F, Heiss WD (1999) Impairment of neocortical metabolism predicts progression in Alzheimer’s disease. Dement Geriatr Cogn Disord 10:494–504PubMedCrossRefGoogle Scholar
  26. Herscovitch P, Markham J, Raichle ME (1983) Brain blood flow measured with intravenous H2(15)O. I. Theory and error analysis. J Nucl Med 24:782–789PubMedGoogle Scholar
  27. Ikonomovic MD, Mufson EJ, Wuu J, Cochran EJ, Bennett DA, DeKosky ST (2003) Cholinergic plasticity in hippocampus of individuals with mild cognitive impairment: correlation with Alzheimer’s neuropathology. J Alzheimers Dis 5:39–48PubMedGoogle Scholar
  28. Jones GM, Sahakian BJ, Levy R, Warburton DM, Gray JA (1992) Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer’s disease. Psychopharmacology (Berl) 108:485–494CrossRefGoogle Scholar
  29. Kadir A, Almkvist O, Wall A, Darreh-Shori T, Grut M, Strandberg B, Ringheim A, Erikson B, Blomquist G, Långström B, Nordberg A (2006a) PET imaging of acetylcholinesterase activity and nicotinebinding in galantamine treated AD patients. In preparationGoogle Scholar
  30. Kadir A, Darreh-Shori T, Almkvist O, Wall A, Långström B, Nordberg A (2006b) Changes in the brain 11C-nicotine bindingsites in mild AD patients following rivastigmine treatment assessed by PET. In preparationGoogle Scholar
  31. Lawrence AD, Sahakian BJ (1995) Alzheimer disease, attention, and the cholinergic system. Alzheimer Dis Assoc Disord 2(Suppl 9):43–49Google Scholar
  32. Lezak M (1995) Neuropsychological assessment, 3rd edn. Oxford University Press, London, UKGoogle Scholar
  33. Lundqvist H, Nordberg A, Hartvig P, Langstrom B (1998) (S)-(−)-[11C]nicotine binding assessed by PET: a dual tracer model evaluated in the rhesus monkey brain. Alzheimer Dis Assoc Disord 12:238–246PubMedGoogle Scholar
  34. Luria A (1966) Higher cortical functions in man. Basic Books, New YorkGoogle Scholar
  35. Maziere M, Delforge J (1995) PET imaging [11C]nicotine: historical aspects. In: Domino E (ed) Brain imaging of nicotine and tobacco smoking. NPP Books, Ann Arbor, pp 13–28Google Scholar
  36. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMedGoogle Scholar
  37. Mega MS, Dinov ID, Porter V, Chow G, Reback E, Davoodi P, O’Connor SM, Carter MF, Amezcua H, Cummings JL (2005) Metabolic patterns associated with the clinical response to galantamine therapy: a fludeoxyglucose f 18 positron emission tomographic study. Arch Neurol 62:721–728PubMedCrossRefGoogle Scholar
  38. Mogg AJ, Jones FA, Pullar IA, Sharples CG, Wonnacott S (2004) Functional responses and subunit composition of presynaptic nicotinic receptor subtypes explored using the novel agonist 5-iodo-A-85380. Neuropharmacology 47:848–859PubMedCrossRefGoogle Scholar
  39. Nagahama Y, Okina T, Suzuki N, Nabatame H, Matsuda M (2005) Neural correlates of impaired performance on the clock drawing test in Alzheimer’s disease. Dement Geriatr Cogn Disord 19:390–396PubMedCrossRefGoogle Scholar
  40. Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL (1988) Intravenous nicotine in Alzheimer’s disease: a pilot study. Psychopharmacology (Berl) 95:171–175Google Scholar
  41. Nobili F, Brugnolo A, Calvini P, Copello F, De Leo C, Girtler N, Morbelli S, Piccardo A, Vitali P, Rodriguez G (2005) Resting SPECT–neuropsychology correlation in very mild Alzheimer’s disease. Clin Neurophysiol 116:364–375PubMedCrossRefGoogle Scholar
  42. Nordberg A (1999) PET studies and cholinergic therapy in Alzheimer’s disease. Rev Neurol (Paris) 4(Suppl 155):S53–S63Google Scholar
  43. Nordberg A (2001) Nicotinic receptor abnormalities of Alzheimer’s disease: therapeutic implications. Biol Psychiatry 49:200–210PubMedCrossRefGoogle Scholar
  44. Nordberg A (2006) Visualization of nicotinic and muscarinic receptors in brain by positron emission tomography. In: Ezio G, Pepeu G (eds) The brain cholinergic system. Martin Dunitz, LondonGoogle Scholar
  45. Nordberg A, Winblad B (1986) Reduced number of [3H]nicotine and [3H]acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci Lett 72:115–119PubMedCrossRefGoogle Scholar
  46. Nordberg A, Hartvig P, Lilja A, Viitanen M, Amberla K, Lundqvist H, Andersson Y, Ulin J, Winblad B, Langstrom B (1990) 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 2:215–224PubMedCrossRefGoogle Scholar
  47. Nordberg A, Alafuzoff I, Winblad B (1992) Nicotinic and muscarinic subtypes in the human brain: changes with aging and dementia. J Neurosci Res 31:103–111PubMedCrossRefGoogle Scholar
  48. Nordberg A, Lundqvist H, Hartvig P, Lilja A, Langstrom B (1995) Kinetic analysis of regional (S)(−)11C-nicotine binding in normal and Alzheimer brains—in vivo assessment using positron emission tomography. Alzheimer Dis Assoc Disord 9:21–27PubMedCrossRefGoogle Scholar
  49. Nordberg A, Lundqvist H, Hartvig P, Andersson J, Johansson M, Hellstrom-Lindahi E, Langstrom B (1997) Imaging of nicotinic and muscarinic receptors in Alzheimer’s disease: effect of tacrine treatment. Dement Geriatr Cogn Disord 8:78–84PubMedGoogle Scholar
  50. Nordberg A, Amberla K, Shigeta M, Lundqvist H, Viitanen M, Hellstrom-Lindahl E, Johansson M, Andersson J, Hartvig P, Lilja A, Langstrom B, Winblad B (1998) Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities. Alzheimer Dis Assoc Disord 12:228–237PubMedGoogle Scholar
  51. Ober BA, Jagust WJ, Koss E, Delis DC, Friedland RP (1991) Visuoconstructive performance and regional cerebral glucose metabolism in Alzheimer’s disease. J Clin Exp Neuropsychol 13:752–772PubMedGoogle Scholar
  52. Pabreza LA, Dhawan S, Kellar KJ (1991) [3H]Cytisine binding to nicotinic cholinergic receptors in brain. Mol Pharmacol 39:9–12PubMedGoogle Scholar
  53. Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75–111PubMedCrossRefGoogle Scholar
  54. Perry RJ, Hodges JR (2000) Fate of patients with questionable (very mild) Alzheimer’s disease: longitudinal profiles of individual subjects’ decline. Dement Geriatr Cogn Disord 11:342–349PubMedCrossRefGoogle Scholar
  55. Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott M, Haroutunian V, Buxbaum JD, Nasland J, Davis K, Gotti C, Clementi F, Tzartos S, Cohen O, Soreq H, Jaros E, Perry R, Ballard C, McKeith I, Court J (2000) Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases. Eur J Pharmacol 393:215–222PubMedCrossRefGoogle Scholar
  56. Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse PA (1999) Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease. Psychopharmacology (Berl) 142:334–342CrossRefGoogle Scholar
  57. Raichle ME, Martin WR, Herscovitch P, Mintun MA, Markham J (1983) Brain blood flow measured with intravenous H2(15)O. II. Implementation and validation. J Nucl Med 24:790–798PubMedGoogle Scholar
  58. Robbins TW, McAlonan G, Muir JL, Everitt BJ (1997) Cognitive enhancers in theory and practice: studies of the cholinergic hypothesis of cognitive deficits in Alzheimer’s disease. Behav Brain Res 83:15–23PubMedCrossRefGoogle Scholar
  59. Robertson LC, Lamb MR, Knight RT (1988) Effects of lesions of temporal-parietal junction on perceptual and attentional processing in humans. J Neurosci 8:3757–3769PubMedGoogle Scholar
  60. Rusted JM, Graupner L, Tennant A, Warburton DM (1998) Effortful processing is a requirement for nicotine-induced improvements in memory. Psychopharmacology (Berl) 138:362–368CrossRefGoogle Scholar
  61. Rusted JM, Newhouse PA, Levin ED (2000) Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer’s disease and Parkinson’s disease. Behav Brain Res 113:121–129PubMedCrossRefGoogle Scholar
  62. Sahakian BJ, Jones GM (1991) The effects of nicotine on attention, information processing, and working memory in patients with dementia of the Alzheimer type. In: Adlkofer F, Thruau K (eds) Effects of nicotine on biological system. Birkhauser Verlag, BaselGoogle Scholar
  63. Sahakian BJ, Owen AM, Morant NJ, Eagger SA, Boddington S, Crayton L, Crockford HA, Crooks M, Hill K, Levy R (1993) Further analysis of the cognitive effects of tetrahydroaminoacridine (THA) in Alzheimer’s disease: assessment of attentional and mnemonic function using CANTAB. Psychopharmacology (Berl) 110:395–401CrossRefGoogle Scholar
  64. Sihver W, Fasth KJ, Horti AG, Koren AO, Bergstrom M, Lu L, Hagberg G, Lundqvist H, Dannals RF, London ED, Nordberg A, Langstrom B (1999) Synthesis and characterization of binding of 5-[76Br]bromo-3-[[2(S)-azetidinyl]methoxy]pyridine, a novel nicotinic acetylcholine receptor ligand, in rat brain. J Neurochem 73:1264–1272PubMedCrossRefGoogle Scholar
  65. Snaedal J, Johannesson T, Jonsson JE, Gylfadottir G (1996) The effects of nicotine in dermal plaster on cognitive functions in patients with Alzheimer’s disease. Dementia 7:47–52PubMedGoogle Scholar
  66. Teipel SJ, Willoch F, Ishii K, Burger K, Drzezga A, Engel R, Bartenstein P, Moller HJ, Schwaiger M, Hampel H (2005) Resting state glucose utilization and the CERAD cognitive battery in patients with Alzheimer’s disease. Neurobiol Aging 27(5):681–690CrossRefGoogle Scholar
  67. Vellas B, Cunha L, Gertz HJ, De Deyn PP, Wesnes K, Hammond G, Schwalen S (2005) Early onset effects of galantamine treatment on attention in patients with Alzheimer’s disease. Curr Med Res Opin 21:1423–1429PubMedCrossRefGoogle Scholar
  68. Vitaliano PP, Breen AR, Albert MS, Russo J, Prinz PN (1984) Memory, attention, and functional status in community-residing Alzheimer type dementia patients and optimally healthy aged individuals. J Gerontol 39:58–64PubMedGoogle Scholar
  69. Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL (1994) Basal forebrain lesions in monkeys disrupt attention but not learning and memory. J Neurosci 14:167–186PubMedGoogle Scholar
  70. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44:181–193PubMedCrossRefGoogle Scholar
  71. Warpman U, Nordberg A (1995) Epibatidine and ABT 418 reveal selective losses of alpha 4 beta 2 nicotinic receptors in Alzheimer brains. Neuroreport 6:2419–2423PubMedGoogle Scholar
  72. Watson CCND, Casey ME et al (1997) Evaluation of simulation based scatter correction for 3D PET cardiac imaging. IEEE Trans Nucl Sci 21:136–144Google Scholar
  73. Wechsler D (1981) Wechsler Adult Intelligence Scale—revised manual. Psychological Corporation, New YorkGoogle Scholar
  74. Wevers A, Monteggia L, Nowacki S, Bloch W, Schutz U, Lindstrom J, Pereira EF, Eisenberg H, Giacobini E, de Vos RA, Steur EN, Maelicke A, Albuquerque EX, Schroder H (1999) Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer’s disease: histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein. Eur J Neurosci 11:2551–2565PubMedCrossRefGoogle Scholar
  75. White HK, Levin ED (1999) Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology (Berl) 143:158–165CrossRefGoogle Scholar
  76. White HK, Levin ED (2004) Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology (Berl) 171:465–471CrossRefGoogle Scholar
  77. Wilson AL, Langley LK, Monley J, Bauer T, Rottunda S, McFalls E, Kovera C, McCarten JR (1995) Nicotine patches in Alzheimer’s disease: pilot study on learning, memory, and safety. Pharmacol Biochem Behav 51:509–514PubMedCrossRefGoogle Scholar
  78. Yu WF, Guan ZZ, Bogdanovic N, Nordberg A (2005) High selective expression of alpha7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer’s disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques. Exp Neurol 192:215–225PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ahmadul Kadir
    • 1
  • Ove Almkvist
    • 2
    • 3
    • 4
  • Anders Wall
    • 5
  • Bengt Långström
    • 5
  • Agneta Nordberg
    • 1
    • 3
  1. 1.Department of Neurobiology, Care Sciences and Society, Division of Molecular NeuropharmacologyKarolinska Institutet, Karolinska University Hospital HuddingeStockholmSweden
  2. 2.Department of Neurobiology, Care Sciences and SocietyKarolinska Institutet, Karolinska University Hospital HuddingeStockholmSweden
  3. 3.Department of Geriatric MedicineKarolinska University Hospital HuddingeStockholmSweden
  4. 4.Department of PsychologyStockholm UniversityStockholmSweden
  5. 5.Uppsala ImanetUppsalaSweden

Personalised recommendations