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

Matthew J Betts; Evgeniya Kirilina; Maria C G Otaduy; Dimo Ivanov; Julio Acosta-Cabronero; Martina F Callaghan; Christian Lambert; Arturo Cardenas-Blanco; Kerrin Pine; Luca Passamonti; Clare Loane; Max C Keuken; Paula Trujillo; Falk Lüsebrink; Hendrik Mattern; Kathy Y Liu; Nikos Priovoulos; Klaus Fliessbach; Martin J Dahl; Anne Maaß; Christopher F Madelung; David Meder; Alexander J Ehrenberg; Oliver Speck; Nikolaus Weiskopf; Raymond Dolan; Ben Inglis; Duygu Tosun; Markus Morawski; Fabio A Zucca; Hartwig R Siebner; Mara Mather; Kamil Uludag; Helmut Heinsen; Benedikt A Poser; Robert Howard; Luigi Zecca; James B Rowe; Lea T Grinberg; Heidi I L Jacobs; Emrah Düzel; Dorothea Hämmerer

doi:10.1093/brain/awz193

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

Brain. 2019 Sep 1;142(9):2558-2571. doi: 10.1093/brain/awz193.

Authors

Matthew J Betts^{1

2}, Evgeniya Kirilina^{3

4}, Maria C G Otaduy⁵, Dimo Ivanov⁶, Julio Acosta-Cabronero⁷, Martina F Callaghan⁷, Christian Lambert⁷, Arturo Cardenas-Blanco^{1

2}, Kerrin Pine^{3

7}, Luca Passamonti^{8

9}, Clare Loane¹⁰, Max C Keuken^{11

12}, Paula Trujillo¹³, Falk Lüsebrink^{14

15}, Hendrik Mattern¹⁴, Kathy Y Liu¹⁶, Nikos Priovoulos¹⁷, Klaus Fliessbach^{18

19}, Martin J Dahl²⁰, Anne Maaß¹, Christopher F Madelung²¹, David Meder²¹, Alexander J Ehrenberg^{22

23}, Oliver Speck^{1

14

24

25}, Nikolaus Weiskopf^{3

7}, Raymond Dolan^{7

26}, Ben Inglis²⁷, Duygu Tosun²⁸, Markus Morawski²⁹, Fabio A Zucca³⁰, Hartwig R Siebner²¹, Mara Mather³¹, Kamil Uludag^{32

33}, Helmut Heinsen^{34

35}, Benedikt A Poser⁶, Robert Howard¹⁶, Luigi Zecca^{30

36}, James B Rowe⁸, Lea T Grinberg^{22

34

37}, Heidi I L Jacobs^{6

38

17}, Emrah Düzel^{1

2

10}, Dorothea Hämmerer^{2

7

10}

Affiliations

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

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.

Keywords: locus coeruleus (LC); magnetic resonance imaging (MRI); neurodegeneration; noradrenaline (NA) biomarker.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Biomarkers / metabolism
Humans
Locus Coeruleus / diagnostic imaging*
Locus Coeruleus / metabolism*
Magnetic Resonance Imaging / methods*
Neurodegenerative Diseases / diagnostic imaging*
Neurodegenerative Diseases / metabolism*
Norepinephrine / metabolism*

Substances

Biomarkers
Norepinephrine

Abstract

Publication types

MeSH terms

Substances

Grants and funding