Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Author:

Betts Matthew J12,Kirilina Evgeniya34,Otaduy Maria C G5,Ivanov Dimo6,Acosta-Cabronero Julio7,Callaghan Martina F7,Lambert Christian7,Cardenas-Blanco Arturo12,Pine Kerrin37,Passamonti Luca89,Loane Clare10,Keuken Max C1112,Trujillo Paula13,Lüsebrink Falk1415,Mattern Hendrik14,Liu Kathy Y16,Priovoulos Nikos17,Fliessbach Klaus1819,Dahl Martin J20,Maaß Anne1,Madelung Christopher F21,Meder David21,Ehrenberg Alexander J2223,Speck Oliver1142425,Weiskopf Nikolaus37,Dolan Raymond726,Inglis Ben27,Tosun Duygu28,Morawski Markus29,Zucca Fabio A30,Siebner Hartwig R21,Mather Mara31,Uludag Kamil3233,Heinsen Helmut3435,Poser Benedikt A6,Howard Robert16,Zecca Luigi3036,Rowe James B8,Grinberg Lea T223437,Jacobs Heidi I L63817,Düzel Emrah1210,Hämmerer Dorothea2710

Affiliation:

1. German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany

2. Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

3. Department of Neurophysics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany

4. Center for Cognitive Neuroscience, Free University Berlin, Berlin, Germany

5. Laboratory of Magnetic Resonance LIM44, Department and Institute of Radiology, Medical School of the University of São Paulo, Brazil

6. Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, MD, Maastricht, The Netherlands

7. Wellcome Centre for Human Neuroimaging, UCL Institute of Neurology, London, UK

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

9. Consiglio Nazionale delle Ricerche, Istituto di Bioimmagini e Fisiologia Molecolare (IBFM), Milan, Italy

10. Institute of Cognitive Neuroscience, University College London, London, UK

11. University of Amsterdam, Integrative Model-based Cognitive Neuroscience research unit, Amsterdam, The Netherlands

12. University of Leiden, Cognitive Psychology, Leiden, The Netherlands

13. Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA

14. Department of Biomedical Magnetic Resonance, Institute for Physics, Otto-von-Guericke-University, Magdeburg, Germany

15. Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany

16. Division of Psychiatry, University College London, London, UK

17. Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, The Netherlands

18. Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany

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

20. Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany

21. Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark

22. Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

23. Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA

24. Center for Behavioral Brain Sciences, Magdeburg, Germany

25. Leibniz Institute for Neurobiology, Magdeburg, Germany

26. Max Planck Centre for Computational Psychiatry and Ageing, University College London, UK

27. Henry H. Wheeler, Jr. Brain Imaging Center, University of California, Berkeley, CA, USA

28. Department of Radiology and Biomedical Imaging, University of California - San Francisco, San Francisco, CA, USA

29. Paul Flechsig Institute of Brain Research, Medical Faculty, University of Leipzig, Leipzig, Germany

30. Institute of Biomedical Technologies, National Research Council of Italy, Segrate, Milan, Italy

31. Leonard Davis School of Gerontology and Department of Psychology, University of Southern California, Los Angeles, CA, USA

32. Centre for Neuroscience Imaging Research, Institute for Basic Science and Department of Biomedical Engineering, Sungkyunkwan University, Suwon, Republic of Korea

33. Techna Institute and Koerner Scientist in MR Imaging, University Health Network, Toronto, Canada

34. University of São Paulo Medical School, São Paulo, Brazil

35. Clinic of Psychiatry, University of Würzburg, Wurzburg, Germany

36. Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York, USA

37. Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA

38. Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

Abstract

Abstract Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Funder

Human Brain Project

MRC

Italian Ministry of Education, University,and Research

MIUR

National Research Programme

PNR

National Research Council of Italy

CNR

Flagship “InterOmics” Project

Grigioni Foundation for Parkinson's Disease

NIHR

Wellcome Trust

McDonnell Foundation

AZ-Medimmune

Janssen

German Research Foundation

DFG

NWO VENI

Alzheimer Nederland

European Union's Horizon 2020 Research and Innovation Programme

European Research Council

BMBF

Lundbeck Foundation

NIH

BrightFocus Foundation

UCLH

NIHR Biomedical Research Centre

Wellcome Centre for Human Neuroimaging

Wellcome

Publisher

Oxford University Press (OUP)

Subject

Clinical Neurology

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