Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Alexander J Ehrenberg^{1

2

3}, Michael A Kelberman⁴, Kathy Y Liu⁵, Martin J Dahl^{6

7}, David Weinshenker⁴, Neus Falgàs^{8

9}, Shubir Dutt^{6

10}, Mara Mather^{6

10

11}, Mareike Ludwig^{12

13}, Matthew J Betts^{12

13

14}, Joseph R Winer¹⁵, Stefan Teipel^{16

17}, Alexandra J Weigand¹⁸, Oxana Eschenko¹⁹, Dorothea Hämmerer^{12

14

20

21}, Marina Leiman^{12

14}, Scott E Counts^{22

23

24}, James M Shine²⁵, Ian H Robertson²⁶, Allan I Levey^{27

28

29}, Elisa Lancini^{12

14}, Gowoon Son¹, Christoph Schneider³⁰, Maxime Van Egroo^{30

31}, Claudio Liguori^{32

33}, Qin Wang³⁴, Elena M Vazey³⁵, Federico Rodriguez-Porcel³⁶, Lena Haag^{12

14}, Mark W Bondi^{37

38}, Sven Vanneste^{26

39

40}, Whitney M Freeze^{41

42}, Yeo-Jin Yi^{12

14}, Mihovil Maldinov⁴³, Jennifer Gatchel^{44

45}, Abhijit Satpati¹, Claudio Babiloni^{46

47}, William S Kremen⁴⁸, Robert Howard⁵, Heidi I L Jacobs^{30

31}, Lea T Grinberg^{1

9

49

50}

Affiliations

¹ Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.
² Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
³ Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, USA.
⁴ Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
⁵ Division of Psychiatry, University College London, London, UK.
⁶ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA.
⁷ Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.
⁸ Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
⁹ Global Brain Health Institute, University of California, San Francisco, San Francisco, California, USA.
¹⁰ Department of Psychology, University of Southern California, Los Angeles, California, USA.
¹¹ Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.
¹² Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University, Magdeburg, Germany.
¹³ Center for Behavioral Brain Sciences, University of Magdeburg, Magdeburg, Germany.
¹⁴ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany.
¹⁵ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
¹⁶ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Rostock/Greifswald, Rostock, Germany.
¹⁷ Department of Psychosomatic Medicine, University Medicine Rostock, Rostock, Germany.
¹⁸ San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology, San Diego, California, USA.
¹⁹ Department of Computational Neuroscience, Max Planck Institute for Biological Cybernetics, Tuebingen, Germany.
²⁰ Department of Psychology, University of Innsbruck, Innsbruck, Austria.
²¹ Institute of Cognitive Neuroscience, University College London, London, UK.
²² Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan, USA.
²³ Department of Family Medicine, Michigan State University, Grand Rapids, Michigan, USA.
²⁴ Michigan Alzheimer's Disease Research Center, Ann Arbor, Michigan, USA.
²⁵ Brain and Mind Center, The University of Sydney, Sydney, Australia.
²⁶ Global Brain Health Institute, Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
²⁷ Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, Georgia, USA.
²⁸ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁹ Goizueta Institute, Emory University, Atlanta, Georgia, USA.
³⁰ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³¹ Faculty of Health, Medicine, and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, the Netherlands.
³² Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
³³ Neurology Unit, University Hospital of Rome Tor Vergata, Rome, Italy.
³⁴ Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Agusta University, Agusta, Georgia, USA.
³⁵ Department of Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
³⁶ Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
³⁷ Department of Psychiatry, University of California, San Diego, La Jolla, California, USA.
³⁸ Psychology Service, VA San Diego Healthcare System, San Diego, California, USA.
³⁹ School of Psychology, Trinity College Dublin, Dublin, Ireland.
⁴⁰ Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁴¹ Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
⁴² Department of Neuropsychology and Psychiatry, Maastricht University, Maastricht, the Netherlands.
⁴³ Department of Psychiatry and Psychotherapy, University of Rostock, Rostock, Germany.
⁴⁴ Division of Geriatric Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.
⁴⁵ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴⁶ Department of Physiology and Pharmacology "V. Erspamer,", Sapienza University of Rome, Rome, Italy.
⁴⁷ Hospital San Raffaele Cassino, Cassino, Italy.
⁴⁸ Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, California, USA.
⁴⁹ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
⁵⁰ Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil.

PMID: 36642985
PMCID: PMC10182252
DOI: 10.1002/alz.12937

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Alexander J Ehrenberg et al. Alzheimers Dement. 2023 May.

. 2023 May;19(5):2182-2196.

doi: 10.1002/alz.12937. Epub 2023 Jan 15.

Authors

Affiliations

¹ Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA.
² Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
³ Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, USA.
⁴ Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
⁵ Division of Psychiatry, University College London, London, UK.
⁶ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA.
⁷ Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.
⁸ Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
⁹ Global Brain Health Institute, University of California, San Francisco, San Francisco, California, USA.
¹⁰ Department of Psychology, University of Southern California, Los Angeles, California, USA.
¹¹ Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.
¹² Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University, Magdeburg, Germany.
¹³ Center for Behavioral Brain Sciences, University of Magdeburg, Magdeburg, Germany.
¹⁴ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany.
¹⁵ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
¹⁶ Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Rostock/Greifswald, Rostock, Germany.
¹⁷ Department of Psychosomatic Medicine, University Medicine Rostock, Rostock, Germany.
¹⁸ San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology, San Diego, California, USA.
¹⁹ Department of Computational Neuroscience, Max Planck Institute for Biological Cybernetics, Tuebingen, Germany.
²⁰ Department of Psychology, University of Innsbruck, Innsbruck, Austria.
²¹ Institute of Cognitive Neuroscience, University College London, London, UK.
²² Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan, USA.
²³ Department of Family Medicine, Michigan State University, Grand Rapids, Michigan, USA.
²⁴ Michigan Alzheimer's Disease Research Center, Ann Arbor, Michigan, USA.
²⁵ Brain and Mind Center, The University of Sydney, Sydney, Australia.
²⁶ Global Brain Health Institute, Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
²⁷ Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, Georgia, USA.
²⁸ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁹ Goizueta Institute, Emory University, Atlanta, Georgia, USA.
³⁰ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³¹ Faculty of Health, Medicine, and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, the Netherlands.
³² Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
³³ Neurology Unit, University Hospital of Rome Tor Vergata, Rome, Italy.
³⁴ Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Agusta University, Agusta, Georgia, USA.
³⁵ Department of Biology, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
³⁶ Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
³⁷ Department of Psychiatry, University of California, San Diego, La Jolla, California, USA.
³⁸ Psychology Service, VA San Diego Healthcare System, San Diego, California, USA.
³⁹ School of Psychology, Trinity College Dublin, Dublin, Ireland.
⁴⁰ Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁴¹ Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
⁴² Department of Neuropsychology and Psychiatry, Maastricht University, Maastricht, the Netherlands.
⁴³ Department of Psychiatry and Psychotherapy, University of Rostock, Rostock, Germany.
⁴⁴ Division of Geriatric Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.
⁴⁵ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴⁶ Department of Physiology and Pharmacology "V. Erspamer,", Sapienza University of Rome, Rome, Italy.
⁴⁷ Hospital San Raffaele Cassino, Cassino, Italy.
⁴⁸ Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, California, USA.
⁴⁹ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
⁵⁰ Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil.

PMID: 36642985
PMCID: PMC10182252
DOI: 10.1002/alz.12937

Abstract

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

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Conflict of interest statement

Disclosures

AJE has received support for travel from the Rainwater Charitable Foundation and Deutsches Zentrum für Neurodegenerative Erkrankungen, has received consulting fees from Epiodyne Inc., holds stock in Eiger Biopharmecuticals, is a Science Editor for “Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association”, and serves on the executive committee for the Neuromodulatory Subcortical Systems PIA of ISTAART. ST is an advisory board member for Roche, Eisai, Biogen, and Grifols and is an independent data monitoring board member for Biogen, is a senior associate editor for “Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association”, and served on the executive committee for the Neuromodulatory Subcortical Systems PIA of ISTAART during the time this manuscript was written. AIL has received consulting fees from Biogen, Karuna, Cognito Theraputics, and Genuv. QW is listed on US Patent applications 63/138.118 & 63/305.621, and holds stock in Terran Biosciences. CB has received consulting fees from Cyclerion Theraputics, serves on the steering committee of the Italian Society of Psychophysiology, and serves as the immediate past chair of the Electrophysiology PIA of ISTAART. LTG has received support from the Rainwater Charitable Foundation, support for travel from the Alzheimer’s Association, and serves on the executive committee for the Neuromodulatory Subcortical Systems PIA of ISTAART. HILJ, MJD, AJW, DW, NF, SEC, CS, MK, and GS served on the executive committee (unpaid) for the Neuromodulatory Subcortical Systems PIA of ISTAART during the time this manuscript was written. KL, MM, MJB, SD, DH, JRW, MLe, JMS, OE, IR, EL, MLu, CS, MVE, EMV, FR, LH, SV, WMF, YY, MM, CL, MB, AS, JRG, WSK, and RH have no conflicts to disclose.

Figures

**FIGURE 1**
The neuromodulatory subcortical system (NSS) professional interest area recommends investment in research on pathways to selective vulnerability in NSS and how dysfunction and degeneration of NSS contribute to pathogenesis and clinical consequences. Myriad disciplines are positioned to generate knowledge within any of these research themes

See this image and copyright information in PMC

References

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Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

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Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Authors

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Abstract

Conflict of interest statement

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