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

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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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.

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Correspondence to Clifford M. Cassidy.

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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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