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Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer’s disease

Neuropsychopharmacology volume 47, pages 1128–1136 (2022)Cite this article

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Abstract

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer’s disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with [18F]MK6240 and [18F]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [18F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t186 = −4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = −0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.

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Fig. 1: Measurement of LC signal.
Fig. 2: LC signal and AD severity.
Fig. 3: Relationship between mid-caudal LC signal and neuropsychiatric symptom severity in n = 51 tau-positive older adults.

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Acknowledgements

The authors thank all participants of the study and staff of the McGill Center for studies in Aging. We thank Dean Jolly, Alexey Kostikov, Robert Hopewell, Monica Samoila-Lactatus, Karen Ross, Marina Kostikova, Mehdi Boudjemeline, and Sandy Li for assist in the radiochemistry production. We also thank Richard Strauss, Edith Strauss, Jenna Stevenson, Nesrine Rahmouni, Guylaine Gagne, Carley Mayhew, Alyssa Stevenson, Tasha Vinet-Celluci, Meong Jin Joung, Hung-Hsin Hsiao, Reda Bouhachi, and Arturo Aliaga for consenting subjects and/or for their role in data acquisition. We thank the Cerveau Technologies for the use of MK6240.

Funding

This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR) (MOP-11-51-31, FRN, 152985, PI: PR-N), the Alzheimer’s Association (NIRG-12- 92090, NIRP-12-259245, PR-N), Fonds de Recherche du Quebec—Santé (FRQS; Chercheur Boursier, PR-N and 2020-VICO-279314). PR-N, SG, and TAP are members of the CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging, Canada Foundation for innovation, Project 34874, CFI Project 34874.

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Authors and Affiliations

  1. Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada

    Clifford M. Cassidy, Victoria Cheung, Lauri Tuominen, Adelina McCall & Seyda Celebi

  2. Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada

    Clifford M. Cassidy, Joseph Therriault, Tharick A. Pascoal, Melissa Savard, Mira Chamoun, Firoza Lussier, Serge Gauthier & Pedro Rosa-Neto

  3. Douglas Research Institute, Le Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal, McGill University, Montreal, QC, Canada

    Clifford M. Cassidy, Joseph Therriault, Tharick A. Pascoal, Melissa Savard, Mira Chamoun, Firoza Lussier & Pedro Rosa-Neto

  4. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Joseph Therriault, Tharick A. Pascoal, Melissa Savard, Mira Chamoun, Firoza Lussier, Gassan Massarweh, Jean-Paul Soucy, Christine Tardif & Pedro Rosa-Neto

  5. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Joseph Therriault, Tharick A. Pascoal, Melissa Savard, Mira Chamoun, Firoza Lussier & Pedro Rosa-Neto

  6. Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    Tharick A. Pascoal, Gassan Massarweh, Jean-Paul Soucy, Christine Tardif & Pedro Rosa-Neto

  7. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    David Weinshenker

  8. Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    Zahinoor Ismail

  9. Alzheimer’s Disease Research Unit, The McGill University Research Centre for Studies in Aging, McGill University, Montréal, QC, Canada

    Serge Gauthier

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  1. Clifford M. Cassidy
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Contributions

CMC, PR-N, JT, TAP, and ZI made substantial contributions to the conception and design of the work, to the acquisition, analysis, or interpretation of data for the work; and to drafting of the work and revising it critically for important intellectual content. MS, MC, FL, and SG contributed to collection of neuroimaging and/or clinical data. GM, J-PS, and CT contributed to implementation and analysis of neuroimaging measures. VC, LT, AM, and SC contributed to data processing and analysis. DW contributed to interpretation of results. All authors contributed to writing and editing the manuscript.

Corresponding author

Correspondence to Clifford M. Cassidy.

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Competing interests

The authors report no competing financial interest in relation to the study design, results, or discussion. CMC and PR-N are inventors on a pending patent using the analysis method described here, licensed to Terran Biosciences, but have received no royalties.

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Cassidy, C.M., Therriault, J., Pascoal, T.A. et al. Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer’s disease. Neuropsychopharmacol. 47, 1128–1136 (2022). https://doi.org/10.1038/s41386-022-01293-6

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