Lower in vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer's pathology: a cohort study.
Humans
Locus Coeruleus
/ diagnostic imaging
Female
Alzheimer Disease
/ diagnostic imaging
Male
Aged
Magnetic Resonance Imaging
tau Proteins
/ metabolism
Aged, 80 and over
Cohort Studies
Amyloid beta-Peptides
/ metabolism
Positron-Emission Tomography
Cerebral Cortex
/ diagnostic imaging
Carbolines
Thiazoles
Aniline Compounds
Brain Cortical Thickness
Alzheimer’s disease
Brain structure
Cortical thickness
FTP-PET
Locus coeruleus
MRI
Neurodegeneration
PiB-PET
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
17 Jun 2024
17 Jun 2024
Historique:
received:
30
11
2023
accepted:
12
06
2024
medline:
18
6
2024
pubmed:
18
6
2024
entrez:
17
6
2024
Statut:
epublish
Résumé
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness. A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample. Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP. Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Sections du résumé
BACKGROUND
BACKGROUND
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.
METHODS
METHODS
A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.
RESULTS
RESULTS
Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.
CONCLUSIONS
CONCLUSIONS
Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Identifiants
pubmed: 38886798
doi: 10.1186/s13195-024-01500-0
pii: 10.1186/s13195-024-01500-0
pmc: PMC11181564
doi:
Substances chimiques
tau Proteins
0
Amyloid beta-Peptides
0
Carbolines
0
7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
J09QS3Z3WB
Thiazoles
0
Aniline Compounds
0
2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
129Subventions
Organisme : NIA NIH HHS
ID : R21 AG082214
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG081681
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG036694
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG036694
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG036694
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062559
Pays : United States
Informations de copyright
© 2024. The Author(s).
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