Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease.
Humans
Alzheimer Disease
/ diagnostic imaging
Cross-Sectional Studies
tau Proteins
/ metabolism
Cognitive Dysfunction
/ diagnostic imaging
Amyloid beta-Peptides
/ metabolism
Positron-Emission Tomography
/ methods
Atrophy
/ pathology
Biomarkers
/ cerebrospinal fluid
Disease Progression
Microtubules
/ metabolism
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
revised:
14
02
2023
received:
21
11
2022
accepted:
16
02
2023
pmc-release:
01
06
2024
medline:
1
6
2023
pubmed:
28
2
2023
entrez:
27
2
2023
Statut:
ppublish
Résumé
Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.
Identifiants
pubmed: 36843330
doi: 10.1002/ana.26620
pmc: PMC10238659
mid: NIHMS1880033
doi:
Substances chimiques
tau Proteins
0
Amyloid beta-Peptides
0
Biomarkers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1158-1172Subventions
Organisme : NINDS NIH HHS
ID : R01 NS095773
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG032438
Pays : United States
Organisme : NIA NIH HHS
ID : UF1 AG032438
Pays : United States
Organisme : NIA NIH HHS
ID : AG046363
Pays : United States
Informations de copyright
© 2023 American Neurological Association.
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