Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Quantification of brain cholinergic denervation in Alzheimer’s disease using PET imaging with [18F]-FEOBV

Abstract

18F-fluoroethoxybenzovesamicol (FEOBV) is a new PET radiotracer that binds to the vesicular acetylcholine transporter. In both animals and healthy humans, FEOBV was found sensitive and reliable to characterize presynaptic cholinergic nerve terminals in the brain. It has been used here for we believe the first time in patients with Alzheimer’s disease (AD) to quantify brain cholinergic losses. The sample included 12 participants evenly divided in healthy subjects and patients with AD, all assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) cognitive scales. Every participant underwent three consecutive PET imaging sessions with (1) the FEOBV as a tracer of the cholinergic terminals, (2) the 18F-NAV4694 (NAV) as an amyloid-beta tracer, and (3) the 18F-Fluorodeoxyglucose (FDG) as a brain metabolism agent. Standardized uptake value ratios (SUVRs) were computed for each tracer, and compared between the two groups using voxel wise t-tests. Correlations were also computed between each tracer and the cognitive scales, as well as between FEOBV and the two other radiotracers. Results showed major reductions of FEOBV uptake in multiple cortical areas that were evident in each AD subject, and in the AD group as a whole when compared to the control group. FDG and NAV were also able to distinguish the two groups, but with lower sensitivity than FEOBV. FEOBV uptake values were positively correlated with FDG in numerous cortical areas, and negatively correlated with NAV in some restricted areas. The MMSE and MoCA cognitive scales were found to correlate significantly with FEOBV and with FDG, but not with NAV. We concluded that PET imaging with FEOBV is more sensitive than either FDG or NAV to distinguish AD patients from control subjects, and may be useful to quantify disease severity. FEOBV can be used to assess cholinergic degeneration in human, and may represent an excellent biomarker for AD.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Dournaud P, Delaere P, Hauw JJ, Epelbaum J . Differential correlation between neurochemical deficits, neuropathology, and cognitive status in Alzheimer's disease. Neurobiol Aging 1995; 16: 817–823.

    Article  CAS  PubMed  Google Scholar 

  2. Grothe MJ, Schuster C, Bauer F, Heinsen H, Prudlo J, Teipel SJ . Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia. J Neurol 2014; 261: 1939–1948.

    Article  PubMed  Google Scholar 

  3. Mufson EJ, Ikonomovic MD, Counts SE, Perez SE, Malek-Ahmadi M, Scheff SW et al. Molecular and cellular pathophysiology of preclinical Alzheimer’s disease. Behav Brain Res 2016; 311: 54–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schmitz TW, Spreng RN, Alzheimer's Disease Neuroimaging Initiative. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology. Nat Commun 2016; 7: 13249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Landry E, Rosa-Neto P, Massarweh G, Aliaga A, Mzengeza S, Bedard MA . Distribution of [18F]-FEOBV in rat: a promising tracer for imaging cholinergic innervation densities. Can J Neurol Sci 2008; 35: S46.

    Article  Google Scholar 

  6. Landry St-Pierre EV, Rosa Neto P, Massarweh GA, Aliaga AN, Mzengeza SH, Bedard MA . Plasma chromatographic profile of [18F]-FEOBV in rat: results and implications for clinical applications. Can J Neurol Sci 2008; 35: S46–S47.

    Article  Google Scholar 

  7. Mzengeza S, Massarweh G, Rosa Neto P, Soucy JP, Bedard MA . Radiosynthesis of [18F] FEOV and in vivo PET imaging of acetylcholine vesicular transporter in the rat. J Cereb Blood Flow Metab 2007; 27: 10–7U.

    Google Scholar 

  8. Cyr M, Parent MJ, Mechawar N, Rosa-Neto P, Soucy JP, Aliaga A et al. PET imaging with [18 F] fluoroethoxybenzovesamicol ([18 F] FEOBV) following selective lesion of cholinergic pedunculopontine tegmental neurons in rat. Nucl Med Biol 2014; 41: 96–101.

    Article  CAS  PubMed  Google Scholar 

  9. Parent M, Bedard MA, Aliaga A, Soucy JP, St-Pierre EL, Cyr M et al. PET imaging of cholinergic deficits in rats using [18 F] fluoroethoxybenzovesamicol ([18 F] FEOBV). Neuroimage 2012; 62: 555–561.

    Article  CAS  PubMed  Google Scholar 

  10. Parent MJ, Bedard MA, Aliaga A, Minuzzi L, Mechawar N, Soucy JP et al. Cholinergic depletion in Alzheimer’s disease shown by [18F] FEOBV autoradiography. Int J Mol Imaging 2013; 2013: 205045.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rosa-Neto P, Alliaga A, Mzengeza S, Massarweh G, Landry E, Bédard MA et al. Imaging vesicular acetylcholine transporter in rodents using [18F] Fluoroethoxybenzovesamicol and micro-PET. J Cer Blood Flow Metab 2007; 27 (Suppl 1): PP03–PP07.

    Google Scholar 

  12. Soucy JP, Rosa P, Massarweh G, Aliaga A, Schirrmacher E, Bédard MA et al. Imaging of cholinergic terminals in the non-human primate brain using FEOBVFEOBV PET: development of a tool to assess cholinergic losses in Alzheimer's disease. Alzheimers Dement 2010; 6: S286.

    Article  Google Scholar 

  13. Mulholland GK, Wieland DM, Kilbourn MR, Frey KA, Sherman PS, Carey JE et al. [18F] fluoroethoxybenzovesamicol, a PET radiotracer for the vesicular acetylcholine transporter and cholinergic synapses. Synapse 1998; 30: 263–274.

    Article  CAS  PubMed  Google Scholar 

  14. Mazère J, Meissner WG, Mayo W, Sibon I, Lamare F, Guilloteau D et al. Progressive supranuclear palsy: in vivo SPECT imaging of presynaptic vesicular acetylcholine transporter with [123I]-iodobenzovesamicol. Radiology 2012; 265: 537–543.

    Article  PubMed  Google Scholar 

  15. Warren NM, Piggott MA, Perry EK, Burn DJ . Cholinergic systems in progressive supranuclear palsy. Brain 2005; 128: 239–249.

    Article  CAS  PubMed  Google Scholar 

  16. Schmeichel AM, Buchhalter LC, Low PA, Parisi JE, Boeve BW, Sandroni P et al. Mesopontine cholinergic neuron involvement in Lewy body dementia and multiple system atrophy. Neurology 2008; 70: 368–373.

    Article  CAS  PubMed  Google Scholar 

  17. Petrou M, Frey KA, Kilbourn MR, Scott PJ, Raffel DM, Bohnen NI et al. In vivo imaging of human cholinergic nerve terminals with (–)-5-18F-fluoroethoxybenzovesamicol: biodistribution, dosimetry, and tracer kinetic analyses. J Nucl Med 2014; 55: 396–404.

    Article  CAS  PubMed  Google Scholar 

  18. Jagust W, Reed B, Mungas D, Ellis W, Decarli C . What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia? Neurology 2007; 69: 871–877.

    Article  CAS  PubMed  Google Scholar 

  19. Rowe CC, Pejoska S, Mulligan RS, Jones G, Chan JG, Svensson S et al. Head-to-head comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for beta-amyloid imaging in aging and dementia. J Nucl Med 2013; 54: 880–886.

    Article  CAS  PubMed  Google Scholar 

  20. Cselényi Z, Jönhagen ME, Forsberg A, Halldin C, Julin P, Schou M et al. Clinical validation of 18F-AZD4694, an amyloid-β–specific PET radioligand. J Nucl Med 2012; 53: 415–424.

    Article  PubMed  Google Scholar 

  21. Dubois B, Feldman HH, Jacova C, DeKosky ST, Barberger-Gateau P, Cummings J et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria. Lancet Neurol 2007; 6: 734–746.

    Article  PubMed  Google Scholar 

  22. Mathotaarachchi S, Wang S, Shin M, Pascoal TA, Benedet AL, Kang MS et al. VoxelStats: a MATLAB package for multi-modal voxel-wise brain image analysis. Front Neuroinformatics 2016; 10: 20.

    Article  Google Scholar 

  23. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR . Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 1982; 215: 1237–1239.

    Article  CAS  PubMed  Google Scholar 

  24. Mesulam M, Geula C . Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol 1988; 275: 216–240.

    Article  CAS  PubMed  Google Scholar 

  25. Liu AK, Chang RC, Pearce RK, Gentleman SM . Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease. Acta Neuropathol 2015; 129: 527–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lehéricy S, Hirsch ÉC, Cervera‐Piérot P, Hersh LB, Bakchine S, Piette F et al. Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease. J Comp Neurol 1993; 330: 15–31.

    Article  PubMed  Google Scholar 

  27. Mufson EJ, Cochran E, Benzing W, Kordower JH . Galaninergic innervation of the cholinergic vertical limb of the diagonal band (Ch2) and bed nucleus of the Stria terminalis in aging, Alzheimer's disease and down's syndrome (Part 1 of 2). Dement Geriatr Cogn Disord 1993; 4: 237–243.

    Article  CAS  Google Scholar 

  28. Fujishiro H, Umegaki H, Isojima D, Akatsu H, Iguchi A, Kosaka K . Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies. Acta Neuropathol 2006; 111: 109–114.

    Article  PubMed  Google Scholar 

  29. Hyman BT, Van Hoesen GW, Damasio AR . Alzheimer's disease: glutamate depletion in the hippocampal perforant pathway zone. Ann Neurology 1987; 22: 37–40.

    Article  CAS  Google Scholar 

  30. Kato T, Inui Y, Nakamura A, Ito K . Brain fluorodeoxyglucose (FDG) PET in dementia. Ageing Res Rev 2016; 30: 73–84.

    Article  PubMed  Google Scholar 

  31. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE . A diagnostic approach in Alzheimer's Disease using three-dimensional stereotactic surface. J Nucl med 1995; 36: 1238–1248.

    CAS  PubMed  Google Scholar 

  32. Iizuka T, Kameyama M . Cholinergic enhancement increases regional cerebral blood flow to the posterior cingulate cortex in mild Alzheimer's disease. Geriatr Gerontol Int 2016; 17: 951–958.

    Article  PubMed  Google Scholar 

  33. Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013; 12: 207–216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Thomas BA, Erlandsson K, Modat M, Thurfjell L, Vandenberghe R, Ourselin S et al. The importance of appropriate partial volume correction for PET quantification in Alzheimer's disease. Eur J Nucl Med Mol Imaging 2011; 38: 1104–1119.

    Article  PubMed  Google Scholar 

  35. Irie T, Fukushi K, Akimoto Y, Tamagami H, Nozaki T . Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AChE) in vivo. Nuclear medicine and biology 1994; 21: 801–808.

    Article  CAS  PubMed  Google Scholar 

  36. Kuhl DE, Koeppe RA, Minoshima S, Snyder SE, Ficaro EP, Foster NL et al. In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease. Neurology 1999; 52: 691–691.

    Article  CAS  PubMed  Google Scholar 

  37. Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA et al. Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2005; 76: 315–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rinne JO, Kaasinen V, Järvenpää T, Någren K, Roivainen A, Yu M et al. Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003; 74: 113–115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Westman E, Simmons A, Zhang Y, Muehlboeck JS, Tunnard C, Liu Y et al. Multivariate analysis of MRI data for Alzheimer's disease, mild cognitive impairment and healthy controls. Neuroimage 2011; 54: 1178–1187.

    Article  PubMed  Google Scholar 

  40. Jack CR, Dickson DW, Parisi JE, Xu YC, Cha RH, O’brien PC et al. Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology 2002; 58: 750–757.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Laakso MP, Partanen K, Riekkinen P, Lehtovirta M, Helkala EL, Hallikainen M et al. Hippocampal volumes in Alzheimer's disease, Parkinson's disease with and without dementia, and in vascular dementia An MRI study. Neurology 1996; 46: 678–681.

    Article  CAS  PubMed  Google Scholar 

  42. Hashimoto M, Kitagaki H, Imamura T, Hirono N, Shimomura T, Kazui H et al. Medial temporal and whole-brain atrophy in dementia with Lewy bodies A volumetric MRI study. Neurology 1998; 51: 357–362.

    Article  CAS  PubMed  Google Scholar 

  43. Harper L, Fumagalli GG, Barkhof F, Scheltens P, O'Brien JT, Bouwman F et al. MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases. Brain 2016; 139: 1211–1225.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jagust W, Thisted R, Devous MD, Van Heertum R, Mayberg H, Jobst K et al. SPECT perfusion imaging in the diagnosis of Alzheimer’s disease A clinical-pathologic study. Neurology 2001; 56: 950–956.

    Article  CAS  PubMed  Google Scholar 

  45. Rocher AB, Chapon F, Blaizot X, Baron JC, Chavoix C . Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons. Neuroimage 2003; 20: 1894–1898.

    Article  PubMed  Google Scholar 

  46. Mosconi L . Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. Eur J Nucl Med Mol Imaging 2005; 32: 486–510.

    Article  CAS  PubMed  Google Scholar 

  47. O'Brien JT, Firbank MJ, Davison C, Barnett N, Bamford C, Donaldson C et al. 18F-FDG PET and perfusion SPECT in the diagnosis of Alzheimer and lewy body dementias. J Nucl Med 2014; 55: 1–7.

    Article  Google Scholar 

  48. Chetelat G, Desgranges B, De La Sayette V, Viader F, Eustache F, Baron JC . Mild cognitive impairment Can FDG-PET predict who is to rapidly convert to Alzheimer’s disease? Neurology 2003; 60: 1374–1377.

    Article  CAS  PubMed  Google Scholar 

  49. Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, Barbas NR et al. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. Brain 2007; 130: 2616–2635.

    Article  PubMed  Google Scholar 

  50. Minoshima S, Foster NL, Sima AA, Frey KA, Albin RL, Kuhl DE . Alzheimer's disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann Neurol 2001; 50: 358–365.

    Article  CAS  PubMed  Google Scholar 

  51. Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G et al. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med 2008; 49: 390–398.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bohnen NI, Djang DS, Herholz K, Anzai Y, Minoshima S . Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature. J Nucl Med 2012; 53: 59–71.

    Article  CAS  PubMed  Google Scholar 

  53. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B. Ann Neurol 2004; 55: 306–319.

    Article  CAS  PubMed  Google Scholar 

  54. Kolb HC, Andrés JI . Tau positron emission tomography imaging. Cold Spring Harbor Perspect Biol 2017; 9.

    Article  Google Scholar 

  55. Pascoal TA, Mathotaarachchi S, Mohades S, Benedet AL, Chung CO, Shin M et al. Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol Psychiatry 2016; 22: 306–331.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 2008; 65: 1509–1517.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kemppainen NM, Aalto S, Wilson IA, Någren K, Helin S, Brück A et al. PET amyloid ligand [11C] PIB uptake is increased in mild cognitive impairment. Neurology 2007; 68: 1603–1606.

    Article  CAS  PubMed  Google Scholar 

  58. Jack CR, Holtzman DM . Biomarker modeling of Alzheimer’s disease. Neuron 2013; 80: 1347–1358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Marc-André Bedard received research funding from the Canadian Institute of Health Research (CIHR), and the Fonds de Recherche du Québec—Santé (FRQ-S). We are indebted to the subjects who participated in this study. We thank the two companies ABX Advanced Biochemical Compounds (Radeberg, Germany), and Navidea Biopharmaceutical (Dublin, OH, USA) for providing us with the FEOBV and the NAV4694 precursors, respectively.

Author contributions

MAB and JPS were responsible for conception and design of the study. MA, CLD, AK, SG, PRN and PG were responsible for acquisition and analysis of data. MAB, MA, CLD and JPS were responsible for drafting the manuscript text, tables and figures.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M-A Bédard.

Ethics declarations

Competing interests

M-AB reports personal fees from Pfizer Canada, Shire Pharma, Purdue Pharma, and Merck Canada, outside the submitted work. PRN reports personal fees from Lilly and TauRx pharmaceuticals, outside the submitted work. Serge Gauthier reports personal fees from Lilly, Merck Canada, Lundbeck, Novartis and Pfizer Canada, outside the submitted work. The remaining authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aghourian, M., Legault-Denis, C., Soucy, JP. et al. Quantification of brain cholinergic denervation in Alzheimer’s disease using PET imaging with [18F]-FEOBV. Mol Psychiatry 22, 1531–1538 (2017). https://doi.org/10.1038/mp.2017.183

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2017.183

This article is cited by

Search

Quick links