Higher levels of myelin are associated with higher resistance against tau pathology in Alzheimer’s disease
Rubinski, Anna ; Franzmeier, Nicolai ; Dewenter, Anna ; Luan, Ying ; Smith, Ruben LU ; Strandberg, Olof LU ; Ossenkoppele, Rik LU ; Dichgans, Martin ; Hansson, Oskar LU
and Ewers, Michael
(2022)
In Alzheimer's Research and Therapy
14(1).
- Abstract
Background: In Alzheimer’s disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels—which differ substantially between white matter tracts in the brain—are a key modulating factor of region-specific susceptibility to tau deposition. Here, we investigated whether myelination differences between fiber tracts of the human connectome are predictive of the interregional spreading of tau pathology in AD. Methods: We included two independently recruited samples consisting of amyloid-PET-positive asymptomatic and symptomatic elderly... (More)
Background: In Alzheimer’s disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels—which differ substantially between white matter tracts in the brain—are a key modulating factor of region-specific susceptibility to tau deposition. Here, we investigated whether myelination differences between fiber tracts of the human connectome are predictive of the interregional spreading of tau pathology in AD. Methods: We included two independently recruited samples consisting of amyloid-PET-positive asymptomatic and symptomatic elderly individuals, in whom tau-PET was obtained at baseline (ADNI: n = 275; BioFINDER-1: n = 102) and longitudinally in a subset (ADNI: n = 123, mean FU = 1.53 [0.69–3.95] years; BioFINDER-1: n = 39, mean FU = 1.87 [1.21–2.78] years). We constructed MRI templates of the myelin water fraction (MWF) in 200 gray matter ROIs and connecting fiber tracts obtained from adult cognitively normal participants. Using the same 200 ROI brain-parcellation atlas, we obtained tau-PET ROI values from each individual in ADNI and BioFINDER-1. In a spatial regression analysis, we first tested the association between cortical myelin and group-average tau-PET signal in the amyloid-positive and control groups. Secondly, employing a previously established approach of modeling tau-PET spreading based on functional connectivity between ROIs, we estimated in a linear regression analysis, whether the level of fiber-tract myelin modulates the association between functional connectivity and longitudinal tau-PET spreading (i.e., covariance) between ROIs. Results: We found that higher myelinated cortical regions show lower tau-PET uptake (ADNI: rho = − 0.267, p < 0.001; BioFINDER-1: rho = − 0.175, p = 0.013). Fiber-tract myelin levels modulated the association between functional connectivity and tau-PET spreading, such that at higher levels of fiber-tract myelin, the association between stronger connectivity and higher covariance of tau-PET between the connected ROIs was attenuated (interaction fiber-tract myelin × functional connectivity: ADNI: β = − 0.185, p < 0.001; BioFINDER-1: β = − 0.166, p < 0.001). Conclusion: Higher levels of myelin are associated with lower susceptibility of the connected regions to accumulate fibrillar tau. These results enhance our understanding of brain substrates that explain regional variation in tau accumulation and encourage future studies to investigate potential underlying mechanisms.
(Less)
- author
- Rubinski, Anna
; Franzmeier, Nicolai
; Dewenter, Anna
; Luan, Ying
; Smith, Ruben
LU
; Strandberg, Olof
LU
; Ossenkoppele, Rik
LU
; Dichgans, Martin
; Hansson, Oskar
LU
and Ewers, Michael
- author collaboration
- organization
- publishing date
- 2022-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer’s disease, Amyloid-PET, Myelin, Myelin water fraction, Resistance, Tau spreading, Tau-PET
- in
- Alzheimer's Research and Therapy
- volume
- 14
- issue
- 1
- article number
- 139
- publisher
- BioMed Central (BMC)
- external identifiers
-
- scopus:85138458336
- pmid:36153607
- ISSN
- 1758-9193
- DOI
- 10.1186/s13195-022-01074-9
- language
- English
- LU publication?
- yes
- id
- b2f96f9f-e1c1-4bed-8cb7-d97de64209f1
- date added to LUP
- 2023-01-03 10:54:33
- date last changed
- 2024-04-18 11:18:29
@article{b2f96f9f-e1c1-4bed-8cb7-d97de64209f1,
abstract = {{<p>Background: In Alzheimer’s disease (AD), fibrillar tau initially occurs locally and progresses preferentially between closely connected regions. However, the underlying sources of regional vulnerability to tau pathology remain unclear. Previous brain-autopsy findings suggest that the myelin levels—which differ substantially between white matter tracts in the brain—are a key modulating factor of region-specific susceptibility to tau deposition. Here, we investigated whether myelination differences between fiber tracts of the human connectome are predictive of the interregional spreading of tau pathology in AD. Methods: We included two independently recruited samples consisting of amyloid-PET-positive asymptomatic and symptomatic elderly individuals, in whom tau-PET was obtained at baseline (ADNI: n = 275; BioFINDER-1: n = 102) and longitudinally in a subset (ADNI: n = 123, mean FU = 1.53 [0.69–3.95] years; BioFINDER-1: n = 39, mean FU = 1.87 [1.21–2.78] years). We constructed MRI templates of the myelin water fraction (MWF) in 200 gray matter ROIs and connecting fiber tracts obtained from adult cognitively normal participants. Using the same 200 ROI brain-parcellation atlas, we obtained tau-PET ROI values from each individual in ADNI and BioFINDER-1. In a spatial regression analysis, we first tested the association between cortical myelin and group-average tau-PET signal in the amyloid-positive and control groups. Secondly, employing a previously established approach of modeling tau-PET spreading based on functional connectivity between ROIs, we estimated in a linear regression analysis, whether the level of fiber-tract myelin modulates the association between functional connectivity and longitudinal tau-PET spreading (i.e., covariance) between ROIs. Results: We found that higher myelinated cortical regions show lower tau-PET uptake (ADNI: rho = − 0.267, p < 0.001; BioFINDER-1: rho = − 0.175, p = 0.013). Fiber-tract myelin levels modulated the association between functional connectivity and tau-PET spreading, such that at higher levels of fiber-tract myelin, the association between stronger connectivity and higher covariance of tau-PET between the connected ROIs was attenuated (interaction fiber-tract myelin × functional connectivity: ADNI: β = − 0.185, p < 0.001; BioFINDER-1: β = − 0.166, p < 0.001). Conclusion: Higher levels of myelin are associated with lower susceptibility of the connected regions to accumulate fibrillar tau. These results enhance our understanding of brain substrates that explain regional variation in tau accumulation and encourage future studies to investigate potential underlying mechanisms.</p>}},
author = {{Rubinski, Anna and Franzmeier, Nicolai and Dewenter, Anna and Luan, Ying and Smith, Ruben and Strandberg, Olof and Ossenkoppele, Rik and Dichgans, Martin and Hansson, Oskar and Ewers, Michael}},
issn = {{1758-9193}},
keywords = {{Alzheimer’s disease; Amyloid-PET; Myelin; Myelin water fraction; Resistance; Tau spreading; Tau-PET}},
language = {{eng}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Alzheimer's Research and Therapy}},
title = {{Higher levels of myelin are associated with higher resistance against tau pathology in Alzheimer’s disease}},
url = {{http://dx.doi.org/10.1186/s13195-022-01074-9}},
doi = {{10.1186/s13195-022-01074-9}},
volume = {{14}},
year = {{2022}},
}