Skip to main content

Advertisement

SpringerLink
Log in

Connectomics and molecular imaging in neurodegeneration

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

Abstract

Our understanding on human neurodegenerative disease was previously limited to clinical data and inferences about the underlying pathology based on histopathological examination. Animal models and in vitro experiments have provided evidence for a cell-autonomous and a non-cell-autonomous mechanism for the accumulation of neuropathology. Combining modern neuroimaging tools to identify distinct neural networks (connectomics) with target-specific positron emission tomography (PET) tracers is an emerging and vibrant field of research with the potential to examine the contributions of cell-autonomous and non-cell-autonomous mechanisms to the spread of pathology. The evidence provided here suggests that both cell-autonomous and non-cell-autonomous processes relate to the observed in vivo characteristics of protein pathology and neurodegeneration across the disease spectrum. We propose a synergistic model of cell-autonomous and non-cell-autonomous accounts that integrates the most critical factors (i.e., protein strain, susceptible cell feature and connectome) contributing to the development of neuronal dysfunction and in turn produces the observed clinical phenotypes. We believe that a timely and longitudinal pursuit of such research programs will greatly advance our understanding of the complex mechanisms driving human neurodegenerative diseases.

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

Similar content being viewed by others

References

  1. Bischof GN, Endepols H, van Eimeren T, Drzezga A. Tau-imaging in neurodegeneration. Methods. 2017;130:114–23.

    Article  CAS  Google Scholar 

  2. Hammes J, Bischof GN, Drzezga A. Molecular imaging in early diagnosis, differential diagnosis and follow-up of patients with neurodegenerative diseases. Clin Transl Imaging. 2017;5:465–71.

    Article  Google Scholar 

  3. Teipel S, Drzezga A, Grothe MJ, Barthel H, Chételat G, Schuff N, et al. Multimodal imaging in Alzheimer’s disease: validity and usefulness for early detection. Lancet Neurol. 2015;14:1037–53.

    Article  Google Scholar 

  4. Strafella AP, Bohnen NI, Perlmutter JS, Eidelberg D, Pavese N, Van Eimeren T, et al. Molecular imaging to track Parkinson’s disease and atypical parkinsonisms: new imaging frontiers. Mov Disord. 2017;32:181–92.

    Article  Google Scholar 

  5. Barthel H, Sabri O. Clinical use and utility of amyloid imaging. J Nucl Med. 2017;58:1711–7.

    Article  Google Scholar 

  6. Saint-Aubert L, Lemoine L, Chiotis K, Leuzy A, Rodriguez-Vieitez E, Nordberg A. Tau PET imaging: present and future directions. Mol Neurodegen [Internet] 2017 [cited 2017 Mar 31];12. Available from: http://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-017-0162-3

  7. Passamonti L, Vázquez Rodríguez P, Hong YT, Allinson KSJ, Williamson D, Borchert RJ, et al. 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy. Brain. 2017.

  8. Boche D, Gerhard A, Rodriguez-Vieitez E. Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging. 2019 (In press).

  9. Grothe M, Heinsen H, Teipel SJ. Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiatry. 2012;71:805–13.

    Article  CAS  Google Scholar 

  10. Grothe MJ, Ewers M, Krause B, Heinsen H, Teipel SJ, Alzheimer’s Disease Neuroimaging Initiative. Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimers Dement. 2014;10:S344–53.

    Article  Google Scholar 

  11. Richter N, Beckers N, Onur OA, Dietlein M, Tittgemeyer M, Kracht L, et al. Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer’s disease. Brain. 2018;141:903–15.

    Article  Google Scholar 

  12. Sabri O, Meyer PM, Gräf S, Hesse S, Wilke S, Becker G-A, et al. Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer’s dementia. Brain. 2018;141:1840–54.

    Article  Google Scholar 

  13. Kocagoncu E, Quinn A, Firouzian A, Cooper E, Greve A, Gunn R, et al. Tau pathology in early Alzheimer’s disease disrupts selective neurophysiological networks dynamics. bioRxiv. 2019:524355.

  14. Hoenig MC, Bischof GN, Seemiller J, Hammes J, Kukolja J, Onur ÖA, et al. Networks of tau distribution in Alzheimer’s disease. Brain. 2018.

  15. Grothe MJ, Sepulcre J, Gonzalez-Escamilla G, Jelistratova I, Schöll M, Hansson O, et al. Molecular properties underlying regional vulnerability to Alzheimer’s disease pathology. Brain. 2018;141:2755–71.

    PubMed  PubMed Central  Google Scholar 

  16. Grothe MJ, Teipel SJ, Alzheimer’s Disease Neuroimaging Initiative. Spatial patterns of atrophy, hypometabolism, and amyloid deposition in Alzheimer’s disease correspond to dissociable functional brain networks. Hum Brain Mapp. 2016;37:35–53.

    Article  Google Scholar 

  17. Drzezga A. The network degeneration hypothesis: spread of neurodegenerative patterns along neuronal brain networks. J Nucl Med. 2018;59:1645–8.

    Article  CAS  Google Scholar 

  18. Chételat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, et al. Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol. 2010;67:317–24.

    PubMed  Google Scholar 

  19. Myers N, Pasquini L, Göttler J, Grimmer T, Koch K, Ortner M, et al. Within-patient correspondence of amyloid-β and intrinsic network connectivity in Alzheimer’s disease. Brain. 2014;137:2052–64.

    Article  Google Scholar 

  20. Drzezga A, Becker JA, Van Dijk KRA, Sreenivasan A, Talukdar T, Sullivan C, et al. Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden. Brain. 2011;134:1635–46.

    Article  Google Scholar 

  21. Koch K, Myers NE, Göttler J, Pasquini L, Grimmer T, Förster S, et al. Disrupted intrinsic networks link amyloid-β pathology and impaired cognition in prodromal Alzheimer’s disease. Cereb Cortex. 2015;25:4678–88.

    Article  Google Scholar 

  22. Jones DT, Graff-Radford J, Lowe VJ, Wiste HJ, Gunter JL, Senjem ML, et al. Tau, amyloid, and cascading network failure across the Alzheimer’s disease spectrum. Cortex. 2017;97:143–59.

    Article  Google Scholar 

  23. Cope TE, Rittman T, Borchert RJ, Jones PS, Vatansever D, Allinson K, et al. Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy. Brain. 2018;141:550–67.

    Article  Google Scholar 

  24. Franzmeier N, Rubinski A, Neitzel J, Kim Y, Damm A, Na DL, et al. Functional connectivity associated with tau levels in ageing, Alzheimer’s, and small vessel disease. Brain. 2019.

  25. Neitzel J, Franzmeier N, Rubinski A, Ewers M. Left frontal connectivity attenuates the adverse effect of entorhinal tau pathology on memory. Neurology. 2019; in press.

  26. Rabin JS, Perea RD, Buckley RF, Neal TE, Buckner RL, Johnson KA, et al. Global White matter diffusion characteristics predict longitudinal cognitive change independently of amyloid status in clinically Normal older adults. Cereb Cortex. 2019;29:1251–62.

    Article  Google Scholar 

  27. Strain JF, Smith RX, Beaumont H, Roe CM, Gordon BA, Mishra S, et al. Loss of white matter integrity reflects tau accumulation in Alzheimer disease defined regions. Neurology. 2018;91:e313–8.

    Article  CAS  Google Scholar 

  28. Jacobs HIL, Hedden T, Schultz AP, Sepulcre J, Perea RD, Amariglio RE, et al. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci. 2018;21:424–31.

    Article  CAS  Google Scholar 

  29. Zempel H, Mandelkow E. Lost after translation: missorting of tau protein and consequences for Alzheimer disease. Trends Neurosci. 2014;37:721–32.

    Article  CAS  Google Scholar 

  30. Hammes J, Theis H, Giehl K, Hoenig MC, Greuel A, Tittgemeyer M, et al. Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control. Brain. 2019;142:733–43.

    Article  Google Scholar 

  31. Strafella AP. Mesolimbic dopamine and anterior cingulate cortex connectivity changes lead to impulsive behaviour in Parkinson’s disease. Brain. 2019;142:496–8.

    Article  Google Scholar 

  32. Gargouri F, Gallea C, Mongin M, Pyatigorskaya N, Valabregue R, Ewenczyk C, et al. Multimodal magnetic resonance imaging investigation of basal forebrain damage and cognitive deficits in Parkinson’s disease. Mov Disord. 2019;34:516–25.

    PubMed  Google Scholar 

  33. Tahmasian M, Eickhoff SB, Giehl K, Schwartz F, Herz DM, Drzezga A, et al. Resting-state functional reorganization in Parkinson’s disease: an activation likelihood estimation meta-analysis. Cortex. 2017;92:119–38.

    Article  Google Scholar 

  34. Lang S, Hanganu A, Gan LS, Kibreab M, Auclair-Ouellet N, Alrazi T, et al. Network basis of the dysexecutive and posterior cortical cognitive profiles in Parkinson’s disease. Mov Disord. 2019.

  35. Tessitore A, De Micco R, Giordano A, di Nardo F, Caiazzo G, Siciliano M, et al. Intrinsic brain connectivity predicts impulse control disorders in patients with Parkinson’s disease. Mov Disord. 2017;32:1710–9.

    Article  CAS  Google Scholar 

  36. Horn A, Reich M, Vorwerk J, Li N, Wenzel G, Fang Q, et al. Connectivity predicts deep brain stimulation outcome in Parkinson disease. Ann Neurol. 2017;82:67–78.

    Article  Google Scholar 

  37. Sepulcre J, Grothe MJ, d’Oleire Uquillas F, Ortiz-Terán L, Diez I, Yang H-S, et al. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat Med. 2018;24:1910–8.

    Article  CAS  Google Scholar 

  38. Rittman T, Rubinov M, Vértes PE, Patel AX, Ginestet CE, Ghosh BCP, et al. Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy. Neurobiol Aging. 2016;48:153–60.

    Article  CAS  Google Scholar 

  39. Freeze B, Acosta D, Pandya S, Zhao Y, Raj A. Regional expression of genes mediating trans-synaptic alpha-synuclein transfer predicts regional atrophy in Parkinson disease. Neuroimage Clin. 2018;18:456–66.

    Article  Google Scholar 

  40. Zeighami Y, Ulla M, Iturria-Medina Y, Dadar M, Zhang Y, KM-H L, et al. Network structure of brain atrophy in de novo Parkinson’s disease. Elife. 2015;4.

  41. Yang H-S, Yu L, White CC, Chibnik LB, Chhatwal JP, Sperling RA, et al. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study. Lancet Neurol. 2018;17:773–81.

    Article  CAS  Google Scholar 

  42. van Eimeren T, Antonini A, Berg D, Bohnen N, Ceravolo R, Drzezga A, et al. Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: proposal for a neuroimaging biomarker utility system. Alzheimers Dement (Amst). 2019;11:301–9.

    Google Scholar 

Download references

Acknowledgements

Faculty of the Multimodal Imaging in Neurodegeneration Cologne (MINC) symposium

Funding

The Molecular Imaging of Neurodegeneration Cologne (MINC) Symposium was partly funded by the Deutsche Forschungsgemeinschaft (DFG) awarded to Dr. Thilo van Eimeren (EI 892/5–1). The Deutsche Forschungsgemeinschaft (DFG) also awarded funding to Dr. Alexander Drzezga (DR 442/91).

Author information

Authors and Affiliations

  1. Multimodal Neuroimaging Group, Department of Nuclear Medicine, University Hospital Cologne, Building 60, Kerpener Str. 62, 50937, Cologne, Germany

    Gérard N. Bischof, Merle Hoenig, Alexander Drzezga & Thilo van Eimeren

  2. Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany

    Gérard N. Bischof

  3. Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany

    Michael Ewers, Nicolai Franzmeier & Julia Neitzel

  4. German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany

    Michel J. Grothe

  5. Molecular Organization of the Brain, Institute of Neuroscience and Medicine (INM-2), Research Center Jülich, Jülich, Germany

    Merle Hoenig & Alexander Drzezga

  6. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Ece Kocagoncu & James B Rowe

  7. Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK

    James B Rowe

  8. Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    Antonio Strafella

  9. Division of Brain, Imaging and Behaviour - Systems Neuroscience, University of Toronto, Toronto, Ontario, Canada

    Antonio Strafella

  10. Krembil Research Institute, UHN, University of Toronto, Toronto, Ontario, Canada

    Antonio Strafella

  11. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Antonio Strafella

  12. Morton and Gloria Shulman Movement Disorder Unit & E.J. Safra Parkinson Disease Program, Neurology Division, Department of Medicine, Toronto Western Hospital, UHN, University of Toronto, Toronto, Ontario, Canada

    Antonio Strafella

  13. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Alexander Drzezga & Thilo van Eimeren

  14. Department of Neurology, University Hospital Cologne, Cologne, Germany

    Thilo van Eimeren

Authors
  1. Gérard N. Bischof
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Ewers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolai Franzmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michel J. Grothe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Merle Hoenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ece Kocagoncu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julia Neitzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James B Rowe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antonio Strafella
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexander Drzezga
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thilo van Eimeren
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the MINC faculty

Corresponding author

Correspondence to Gérard N. Bischof.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest in relation to this article.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

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 Advanced Image Analyses (Radiomics and Artificial Intelligence).

Electronic supplementary material

ESM 1

(DOCX 20 kb)

ESM 2

(DOCX 24 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bischof, G.N., Ewers, M., Franzmeier, N. et al. Connectomics and molecular imaging in neurodegeneration. Eur J Nucl Med Mol Imaging 46, 2819–2830 (2019). https://doi.org/10.1007/s00259-019-04394-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-019-04394-5

Keywords

Search

Navigation