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

Van Egroo, Maxime ; Riphagen, Joost M. ; Ashton, Nicholas J. ; Janelidze, Shorena LU ; Sperling, Reisa A. ; Johnson, Keith A. ; Yang, Hyun Sik ; Bennett, David A. ; Blennow, Kaj LU and Hansson, Oskar LU orcid , et al. (2023) In Molecular Psychiatry 28(6). p.2412-2422
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Psychiatry
volume
28
issue
6
pages
2412 - 2422
publisher
Nature Publishing Group
external identifiers
  • scopus:85151549394
  • pmid:37020050
ISSN
1359-4184
DOI
10.1038/s41380-023-02041-y
language
English
LU publication?
yes
id
2ef30f6e-7671-45c1-82ed-da36bf925c33
date added to LUP
2023-05-23 13:10:22
date last changed
2024-06-15 03:16:02
@article{2ef30f6e-7671-45c1-82ed-da36bf925c33,
  abstract     = {{<p>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 ptau<sub>231</sub>, 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 Aβ<sub>42/40</sub> 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 ptau<sub>231</sub>, starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau<sub>231</sub> 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.</p>}},
  author       = {{Van Egroo, Maxime and Riphagen, Joost M. and Ashton, Nicholas J. and Janelidze, Shorena and Sperling, Reisa A. and Johnson, Keith A. and Yang, Hyun Sik and Bennett, David A. and Blennow, Kaj and Hansson, Oskar and Zetterberg, Henrik and Jacobs, Heidi I.L.}},
  issn         = {{1359-4184}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{2412--2422}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Molecular Psychiatry}},
  title        = {{Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau}},
  url          = {{http://dx.doi.org/10.1038/s41380-023-02041-y}},
  doi          = {{10.1038/s41380-023-02041-y}},
  volume       = {{28}},
  year         = {{2023}},
}