CSF Tau phosphorylation at Thr205 is associated with loss of white matter integrity in autosomal dominant Alzheimer disease.
ADAD
CSF
PCA
Phosphorylated tau
White matter
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
15 06 2022
15 06 2022
Historique:
received:
24
10
2021
revised:
26
02
2022
accepted:
25
03
2022
pubmed:
1
4
2022
medline:
21
4
2022
entrez:
31
3
2022
Statut:
ppublish
Résumé
Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s). In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD. The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss. We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.
Sections du résumé
BACKGROUND
Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s).
METHODS
In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD.
RESULTS
The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss.
CONCLUSIONS
We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.
Identifiants
pubmed: 35358703
pii: S0969-9961(22)00106-1
doi: 10.1016/j.nbd.2022.105714
pmc: PMC9701560
mid: NIHMS1846968
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
Biomarkers
0
tau Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
105714Subventions
Organisme : NIA NIH HHS
ID : P30 AG066444
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG043434
Pays : United States
Organisme : Medical Research Council
ID : MR/L023784/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : K01 AG053474
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG026276
Pays : United States
Organisme : Medical Research Council
ID : MR/009076/1
Pays : United Kingdom
Organisme : NINR NIH HHS
ID : R01 NR012907
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS098577
Pays : United States
Organisme : NINR NIH HHS
ID : R01 NR014449
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS048056
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000448
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG052550
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG032438
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : P01 AG003991
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG005681
Pays : United States
Organisme : NINR NIH HHS
ID : R01 NR012657
Pays : United States
Organisme : NIA NIH HHS
ID : UF1 AG032438
Pays : United States
Informations de copyright
Copyright © 2022. Published by Elsevier Inc.
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