Skip to main content

Advertisement

SpringerLink
Log in

Molecular Imaging of the Cholinergic System in Alzheimer and Lewy Body Dementias: Expanding Views

  • Dementia (K.S. Marder, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Brain cholinergic denervation is a major feature of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). We reviewed the topography assessed by a cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented.

Recent Findings

VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB.

Summary

Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections is likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.

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

Similar content being viewed by others

Abbreviations

AChE:

Acetylcholinesterase

DLB:

Dementia with Lewy bodies

FEOBV:

Fluoroethoxybenzovesamicol

nbM:

Nucleus basalis of Meynert

PD:

Parkinson’s disease

PDD:

Parkinson’s disease dementia

PET:

Positron emission tomography

VAChT:

Vesicular acetylcholine transporter

BF:

Basal forebrain

PPN-LDT:

Pedunculopontine-laterodorsal tegmental complex

MVN:

Medial vestibular nuclei

SChIs:

Striatal cholinergic interneurons

IBVM:

Iodobenzovesamicol

VOI:

Volume of interest

FDR:

False discovery rate

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bohnen NI, Grothe MJ, Ray NJ, Muller MLTM, Teipel SJ. Recent advances in cholinergic imaging and cognitive decline-revisiting the cholinergic hypothesis of dementia. Curr Geriatr Rep. 2018;7(1):1–11. https://doi.org/10.1007/s13670-018-0234-4.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sarter M, Lustig C, Howe WM, Gritton H, Berry AS. Deterministic functions of cortical acetylcholine. Eur J Neurosci. 2014;39(11):1912–20. https://doi.org/10.1111/ejn.12515.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gombkoto P, Gielow M, Varsanyi P, Chavez C, Zaborszky L. Contribution of the basal forebrain to corticocortical network interactions. Brain Struct Funct. 2021. https://doi.org/10.1007/s00429-021-02290-z.

  4. 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 Off Publ Soc Nucl Med. 2014;55(3):396–404. https://doi.org/10.2967/jnumed.113.124792.

    Article  CAS  Google Scholar 

  5. Albin RL, Bohnen NI, Muller M, Dauer WT, Sarter M, Frey KA, et al. Regional vesicular acetylcholine transporter distribution in human brain: a [(18) F]fluoroethoxybenzovesamicol positron emission tomography study. J Compar Neurol. 2018. https://doi.org/10.1002/cne.24541.

  6. Mesulam MM. Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer’s disease. J Comp Neurol. 2013;521(18):4124–44. https://doi.org/10.1002/cne.23415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Arciniegas DB. Cholinergic dysfunction and cognitive impairment after traumatic brain injury Part 1: the structure and function of cerebral cholinergic systems. J Head Trauma Rehab. 2011;26(1):98–101. https://doi.org/10.1097/HTR.0b013e31820516cb.

    Article  Google Scholar 

  8. Zhang C, Zhou P, Yuan T. The cholinergic system in the cerebellum: from structure to function. Rev Neurosci. 2016;27(8):769–76. https://doi.org/10.1515/revneuro-2016-0008.

    Article  PubMed  Google Scholar 

  9. Abudukeyoumu N, Hernandez-Flores T, Garcia-Munoz M, Arbuthnott GW. Cholinergic modulation of striatal microcircuits. Eur J Neurosci. 2019;49(5):604–22. https://doi.org/10.1111/ejn.13949.

    Article  PubMed  Google Scholar 

  10. Aghourian M, Legault-Denis C, Soucy JP, Rosa-Neto P, Gauthier S, Kostikov A, et al. Quantification of brain cholinergic denervation in Alzheimer’s disease using PET imaging with [(18)F]-FEOBV. Mol Psychiatry. 2017;22(11):1531–8. https://doi.org/10.1038/mp.2017.183. This study reports the first detailed FEOBV PET analysis in patients with AD and reported widespread cortical reductions in VAChT binding.

  11. 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(4):527–40. https://doi.org/10.1007/s00401-015-1392-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schmitz TW, Mur M, Aghourian M, Bedard MA, Spreng RN. Alzheimer’s Disease Neuroimaging I Longitudinal Alzheimer’s degeneration reflects the spatial topography of cholinergic basal forebrain projections. Cell reports. 2018;24(1):38–46. https://doi.org/10.1016/j.celrep.2018.06.001.

    Article  CAS  PubMed  Google Scholar 

  13. Lehericy S, Hirsch EC, Cervera-Pierot 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(1):15–31. https://doi.org/10.1002/cne.903300103.

    Article  CAS  PubMed  Google Scholar 

  14. Mazere J, Lamare F, Allard M, Fernandez P, Mayo W. 123I-Iodobenzovesamicol SPECT imaging of cholinergic systems in dementia with Lewy bodies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017;58(1):123–8. https://doi.org/10.2967/jnumed.116.176180. First VAChT SPECT study in DLB.

  15. Nejad-Davarani S, Koeppe RA, Albin RL, Frey KA, Muller M, Bohnen NI. Quantification of brain cholinergic denervation in dementia with Lewy bodies using PET imaging with [(18)F]-FEOBV. Mol Psychiatry. 2019;24(3):322–7. https://doi.org/10.1038/s41380-018-0130-5. This study reported VAChT binding losses in patients with DLB in the whole neocortex, hippocampus, amygdala, thalamus, basal ganglia, vermis, and dorsal pontomesenchephalic region.

  16. Kanel P, Müller MLTM, van der Zee S, Sanchez-Catasus CA, Koeppe RA, Frey KA, et al. Topography of cholinergic changes in dementia with Lewy bodies and key neural network hubs. J Neuropsychiatry Clin Neurosci. 2020;32(4):370–5. https://doi.org/10.1176/appi.neuropsych.19070165. The authors used a different imaging analysis method (whole brain voxel-based analyses) and found a distinct topographic pattern of VAChT binding losses in patients with DLB. Regionally more prominent losses were seen in the bilateral opercula, anterior-to-mid cingulate cortices, bilateral insula, bilateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornix.

  17. Habeck C, Krakauer JW, Ghez C, Sackeim HA, Eidelberg D, Stern Y, et al. A new approach to spatial covariance modeling of functional brain imaging data: ordinal trend analysis. Neural Comput. 2005;17(7):1602–45. https://doi.org/10.1162/0899766053723023.

    Article  PubMed  Google Scholar 

  18. Schumacher J, Gunter JL, Przybelski SA, Jones DT, Graff-Radford J, Savica R, et al. Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks. Brain. 2021. https://doi.org/10.1093/brain/awab218.

  19. Halassa MM, Kastner S. Thalamic functions in distributed cognitive control. Nat Neurosci. 2017;20(12):1669–79. https://doi.org/10.1038/s41593-017-0020-1.

    Article  CAS  PubMed  Google Scholar 

  20. Mihai PG, Moerel M, de Martino F, Trampel R, Kiebel S, von Kriegstein K. Modulation of tonotopic ventral medial geniculate body is behaviorally relevant for speech recognition. Elife. 2019;8. https://doi.org/10.7554/eLife.44837.

  21. Phansuwan-Pujito P, Møller M, Govitrapong P. Cholinergic innervation and function in the mammalian pineal gland. Microsc Res Tech. 1999;46(4–5):281–95. https://doi.org/10.1002/(sici)1097-0029(19990815/01)46:4/5%3c281::Aid-jemt5%3e3.0.Co;2-n.

    Article  CAS  PubMed  Google Scholar 

  22. Heckers S, Geula C, Mesulam M. Cholinergic innervation of the human thalamus: dual origin and differential nuclear distribution. J Comp Neurol. 1992;325:68–82.

    Article  CAS  PubMed  Google Scholar 

  23. Lee SH, Cho H, Choi JY, Lee JH, Ryu YH, Lee MS, et al. Distinct patterns of amyloid-dependent tau accumulation in Lewy body diseases. Movement Disorders Off J Movement Disorder Soc. 2018;33(2):262–72. https://doi.org/10.1002/mds.27252.

    Article  CAS  Google Scholar 

  24. Seidel K, Bouzrou M, Heidemann N, Krüger R, Schöls L, den Dunnen WFA, et al. Involvement of the cerebellum in Parkinson disease and dementia with Lewy bodies. Ann Neurol. 2017;81(6):898–903. https://doi.org/10.1002/ana.24937.

    Article  CAS  PubMed  Google Scholar 

  25. Bohnen NI, Kaufer DI, Ivanco LS, Lopresti B, Koeppe RA, Davis JG, et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol. 2003;60(12):1745–8. https://doi.org/10.1001/archneur.60.12.1745.

    Article  PubMed  Google Scholar 

  26. Kuhl DE, Minoshima S, Fessler JA, Frey KA, Foster NL, Ficaro EP, et al. In vivo mapping of cholinergic terminals in normal aging, Alzheimer’s disease, and Parkinson’s disease. Ann Neurol. 1996;40(3):399–410. https://doi.org/10.1002/ana.410400309.

    Article  CAS  PubMed  Google Scholar 

  27. Hirano S, Shinotoh H, Shimada H, Ota T, Sato K, Tanaka N, et al. Voxel-based acetylcholinesterase PET study in early and late onset Alzheimer’s disease. J Alzheimers Dis. 2018;62(4):1539–48. https://doi.org/10.3233/jad-170749.

    Article  CAS  PubMed  Google Scholar 

  28. Hanna Al-Shaikh FS, Duara R, Crook JE, Lesser ER, Schaeverbeke J, Hinkle KM, et al. Selective vulnerability of the nucleus basalis of Meynert among neuropathologic subtypes of Alzheimer disease. JAMA Neurol. 2020;77(2):225–33. https://doi.org/10.1001/jamaneurol.2019.3606.

    Article  PubMed  Google Scholar 

  29. Hilker R, Thomas AV, Klein JC, Weisenbach S, Kalbe E, Burghaus L, et al. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology. 2005;65(11):1716–22. https://doi.org/10.1212/01.wnl.0000191154.78131.f6.

    Article  CAS  PubMed  Google Scholar 

  30. van der Zee S, Vállez García D, Elsinga PH, Willemsen ATM, Boersma HH, Gerritsen MJJ, et al. [18F]Fluoroethoxybenzovesamicol in Parkinson’s disease patients: quantification of a novel cholinergic positron emission tomography tracer. Movement Disorders Off J Movement Disorder Soc. 2019;34(6):924–6. https://doi.org/10.1002/mds.27698.

    Article  Google Scholar 

  31. van der Zee S, Muller M, Kanel P, van Laar T, Bohnen NI. Cholinergic denervation patterns across cognitive domains in Parkinson’s disease. Movement Disorders Off J Movement Disorder Soc. 2021;36(3):642–50. https://doi.org/10.1002/mds.28360.

    Article  CAS  Google Scholar 

  32. Fu H, Hardy J, Duff KE. Selective vulnerability in neurodegenerative diseases. Nat Neurosci. 2018;21(10):1350–8. https://doi.org/10.1038/s41593-018-0221-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the National Institute of Health (NIH), Department of Veterans Affairs, the Parkinson’s Foundation, Michael J. Fox Foundation, the Canadian Institutes of Health Research (CIHR), and the Fond de Recherche du Québec en Santé (FRQS).

Author information

Authors and Affiliations

  1. Functional Neuroimaging, Cognitive and Mobility Laboratory, Departments of Radiology and Neurology, University of Michigan, 24 Frank Lloyd Wright Drive, Box 362, Ann Arbor, MI, 48105-9755, USA

    Prabesh Kanel & Nicolaas I. Bohnen

  2. University of Michigan Morris K. Udall Center of Excellence for Parkinson’s Disease Research, Ann Arbor, MI, USA

    Prabesh Kanel, Roger L. Albin & Nicolaas I. Bohnen

  3. Cognitive, Pharmacology Research Unit, UQAM, Montreal, Canada

    Marc-André Bedard & Meghmik Aghourian

  4. McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Canada

    Marc-André Bedard, Meghmik Aghourian, Pedro Rosa-Neto & Jean-Paul Soucy

  5. McGill Centre for Studies in Aging, Douglas Mental Health University Institute, Verdun, Canada

    Marc-André Bedard, Meghmik Aghourian & Pedro Rosa-Neto

  6. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Roger L. Albin & Nicolaas I. Bohnen

  7. Neurology Service and GRECC, VAAAHS, Ann Arbor, MI, USA

    Roger L. Albin & Nicolaas I. Bohnen

Authors
  1. Prabesh Kanel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc-André Bedard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meghmik Aghourian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pedro Rosa-Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Paul Soucy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roger L. Albin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nicolaas I. Bohnen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Prabesh Kanel.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest relevant to this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Dementia

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanel, P., Bedard, MA., Aghourian, M. et al. Molecular Imaging of the Cholinergic System in Alzheimer and Lewy Body Dementias: Expanding Views. Curr Neurol Neurosci Rep 21, 52 (2021). https://doi.org/10.1007/s11910-021-01140-z

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11910-021-01140-z

Keywords

Search

Navigation