Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau

Year: 2023

Type: article

Abstract: Autopsy data indicate that the locus coeruleus (LC) is one of the first sites in the brain to accumulate hyperphosphorylated tau pathology, with the rostral part possibly being more vulnerable in the earlier stages of the disease. Taking advantage of recent developments in ultra-high field (7 T) imaging, we investigated whether imaging measures of the LC also reveal a specific anatomic correlation with tau using novel plasma biomarkers of different species of hyperphosphorylated tau, how early in adulthood these associations can be detected and if are associated with worse cognitive performance. To validate the anatomic correlations, we tested if a rostro-caudal gradient in tau pathology is also detected at autopsy in data from the Rush Memory and Aging Project (MAP). We found that higher plasma measures of phosphorylated tau, in particular ptau231, correlated negatively with dorso-rostral LC integrity, whereas correlations for neurodegenerative plasma markers (neurofilament light, total tau) were scattered throughout the LC including middle to caudal sections. In contrast, the plasma Aβ42/40 ratio, associated with brain amyloidosis, did not correlate with LC integrity. These findings were specific to the rostral LC and not observed when using the entire LC or the hippocampus. Furthermore, in the MAP data, we observed higher rostral than caudal tangle density in the LC, independent of the disease stage. The in vivo LC-phosphorylated tau correlations became significant from midlife, with the earliest effect for ptau231, starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau231 concentrations predicted lower cognitive performance. Together, these findings demonstrate a specific rostral vulnerability to early phosphorylated tau species that can be detected with dedicated magnetic resonance imaging measures, highlighting the promise of LC imaging as an early marker of AD-related processes.

Source: Molecular Psychiatry

DOI: 10.1038/s41380-023-02041-y

Authors: Maxime Van Egroo, Joost M. Riphagen, Nicholas J. Ashton, Shorena Janelidze, Reisa A. Sperling, Keith A. Johnson, Hyun-Sik Yang, David A. Bennett, Kaj Blennow, Oskar Hansson, Henrik Zetterberg, Heidi I. L. Jacobs

Institutions: Harvard University, Maastricht University, Gordon Center for Medical Imaging, Massachusetts General Hospital, King's College London, South London and Maudsley NHS Foundation Trust, Stavanger University Hospital, University of Gothenburg, Lund University, Brigham and Women's Hospital, Rush University Medical Center, Sahlgrenska University Hospital, Skåne University Hospital, UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,990

Awards: G1057200632, G106931528, G1088883541, G1135383168, G1222782219, G1253720191, G1311708188, G1373393710, G1442296065, G1457535256, G1488855273, G150733400, G1551449788, G1588116593, G1802301745, G1833008592, Understanding Alzheimer Blood Biomarkers for Tau Pathology, G201353144, G2037823205, G2057385626, G2108271864, G237833635, G2385484910, G2543812357, Elevated locus coeruleus metabolism as mechanism driving Alzheimer's disease pathology, The effects of iron on oxidative stress and Alzheimer's biomarkers in amyloid-positive and negative elderly normal, G2799940023, The Alzheimer biomarker toolbox – use in pathogenic studies, diagnostics and theragnostics, G2841269746, G2879339865, G292763017, Development of new biomarkers and brain imaging techniques for Dementia and Parkinsonian disorders: key tools for exploring etiology to improve diagnosis and advance drug development, G3027168043, G308275008, G3126964432, G313301595, G3241251457, G3480186095, G3743240706, G3903502641, G3914690605, G4028979961, G4181470480, G4234328627, G4260843567, G432431387, G434337789, G4404751248, G5040492720, G506008078, G5111822078, G5166548482, G516766298, G5184609404, G5332654608, G5585422332, G5619075, G5619554209, G56684467, G5749088205, G581591135, G6066643948, G6142763750, G6168044258, G6289970089, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, Immunogenetic contribution to the progression of preclinical Alzheimer's disease, G670286326, G691317373, Pathways to Alzheimer's disease, G712881263, G7143958211, G728140114, G7359408231, 3rd International Conference on Tomography of Materials and Structures, G791739130, What determines amyloid beta aggregation and toxicity in Alzheimer’s disease?, G9000015626, G9000150306, G9000244657, The wandering nerve: gateway to boost Alzheimer's disease related cognitive performance, G958583170, G983864884

OpenAlex ID: W4362614482