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Cerebro-spinal fluid biomarker levels : phosphorylated tau (T) and total tau (N) as markers for rate of progression in Alzheimer's disease

Wattmo, Carina LU ; Blennow, Kaj LU and Hansson, Oskar LU (2020) In BMC Neurology 20(1).
Abstract

BACKGROUND: We investigated the potential associations between cerebro-spinal fluid (CSF) levels of phosphorylated tau (P-tau) and total tau (T-tau) with short-term response to cholinesterase inhibitor (ChEI) treatment, longitudinal outcome and progression rates in Alzheimer's disease (AD). METHODS: This prospective, observational study included 129 participants clinically diagnosed with mild-to-moderate AD, who underwent a lumbar puncture. The CSF biomarkers amyloid-β1-42 (Aβ42), P-tau and T-tau were analysed with xMAP technology. Cognitive, global, instrumental and basic activities of daily living (ADL) capacities at the start of ChEI therapy and semi-annually over 3 years were evaluated. RESULTS: All patients had abnormal Aβ42 (A+).... (More)

BACKGROUND: We investigated the potential associations between cerebro-spinal fluid (CSF) levels of phosphorylated tau (P-tau) and total tau (T-tau) with short-term response to cholinesterase inhibitor (ChEI) treatment, longitudinal outcome and progression rates in Alzheimer's disease (AD). METHODS: This prospective, observational study included 129 participants clinically diagnosed with mild-to-moderate AD, who underwent a lumbar puncture. The CSF biomarkers amyloid-β1-42 (Aβ42), P-tau and T-tau were analysed with xMAP technology. Cognitive, global, instrumental and basic activities of daily living (ADL) capacities at the start of ChEI therapy and semi-annually over 3 years were evaluated. RESULTS: All patients had abnormal Aβ42 (A+). Fifty-eight individuals (45%) exhibited normal P-tau and T-tau (A+ T- (N)-), 12 (9%) abnormal P-tau/normal T-tau (A+ T+ (N)-), 17 (13%) normal P-tau/abnormal T-tau (A+ T- (N)+) and 42 (33%) abnormal P-tau and T-tau (A+ T+ (N)+). The participants with A+ T+ (N)+ were younger than A+ T- (N)+ at the estimated onset of AD and the initiation of ChEIs. The proportion of 6-month responders to ChEI and deterioration/year after start of treatment did not differ between the AT(N) profiles in any scales. A higher percentage of globally improved/unchanged patients was exhibited in the A+ T- (N)- group after 12, 30 and 36 months of ChEI therapy but not at other assessments. In apolipoprotein E (APOE) ε4-carriers, linear relationships were found between greater cognitive decline/year and higher tau; Mini-Mental State Examination score - T-tau (rs = - 0.257, p = 0.014) and Alzheimer's Disease Assessment Scale-cognitive subscale - P-tau (rs = - 0.242, p = 0.022). A correlation between faster progression in instrumental ADL (IADL) and higher T-tau was also detected (rs = - 0.232, p = 0.028). These associations were not demonstrated in non-ε4-carriers. CONCLUSIONS: Younger age and faster global deterioration were observed in AD patients with pathologic tau and neurodegeneration, whereas more rapid cognitive and IADL decline were related to higher P-tau or T-tau in APOE ε4-carriers only. The results might indicate an association between more pronounced tau pathology/neuronal injury and the APOE ε4-allele leading to a worse prognosis. Our findings showed that the AT(N) biomarker profiles have limited utility to predict AD progression rates and, thus, measure change and interpreting outcomes from clinical trials of future therapies.

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Contribution to journal
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published
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keywords
Activities of daily living, Alzheimer’s disease, Apolipoprotein E, AT(N), Cholinesterase inhibitors, Cognition, CSF biomarkers, Disease progression, Tau, Treatment effect
in
BMC Neurology
volume
20
issue
1
article number
10
publisher
BioMed Central
external identifiers
  • scopus:85077709249
  • pmid:31918679
ISSN
1471-2377
DOI
10.1186/s12883-019-1591-0
language
English
LU publication?
yes
id
850f458c-663a-441b-b201-7d469c1122df
date added to LUP
2020-01-27 11:07:58
date last changed
2020-01-30 03:59:26
@article{850f458c-663a-441b-b201-7d469c1122df,
  abstract     = {<p>BACKGROUND: We investigated the potential associations between cerebro-spinal fluid (CSF) levels of phosphorylated tau (P-tau) and total tau (T-tau) with short-term response to cholinesterase inhibitor (ChEI) treatment, longitudinal outcome and progression rates in Alzheimer's disease (AD). METHODS: This prospective, observational study included 129 participants clinically diagnosed with mild-to-moderate AD, who underwent a lumbar puncture. The CSF biomarkers amyloid-β1-42 (Aβ42), P-tau and T-tau were analysed with xMAP technology. Cognitive, global, instrumental and basic activities of daily living (ADL) capacities at the start of ChEI therapy and semi-annually over 3 years were evaluated. RESULTS: All patients had abnormal Aβ42 (A+). Fifty-eight individuals (45%) exhibited normal P-tau and T-tau (A+ T- (N)-), 12 (9%) abnormal P-tau/normal T-tau (A+ T+ (N)-), 17 (13%) normal P-tau/abnormal T-tau (A+ T- (N)+) and 42 (33%) abnormal P-tau and T-tau (A+ T+ (N)+). The participants with A+ T+ (N)+ were younger than A+ T- (N)+ at the estimated onset of AD and the initiation of ChEIs. The proportion of 6-month responders to ChEI and deterioration/year after start of treatment did not differ between the AT(N) profiles in any scales. A higher percentage of globally improved/unchanged patients was exhibited in the A+ T- (N)- group after 12, 30 and 36 months of ChEI therapy but not at other assessments. In apolipoprotein E (APOE) ε4-carriers, linear relationships were found between greater cognitive decline/year and higher tau; Mini-Mental State Examination score - T-tau (rs = - 0.257, p = 0.014) and Alzheimer's Disease Assessment Scale-cognitive subscale - P-tau (rs = - 0.242, p = 0.022). A correlation between faster progression in instrumental ADL (IADL) and higher T-tau was also detected (rs = - 0.232, p = 0.028). These associations were not demonstrated in non-ε4-carriers. CONCLUSIONS: Younger age and faster global deterioration were observed in AD patients with pathologic tau and neurodegeneration, whereas more rapid cognitive and IADL decline were related to higher P-tau or T-tau in APOE ε4-carriers only. The results might indicate an association between more pronounced tau pathology/neuronal injury and the APOE ε4-allele leading to a worse prognosis. Our findings showed that the AT(N) biomarker profiles have limited utility to predict AD progression rates and, thus, measure change and interpreting outcomes from clinical trials of future therapies.</p>},
  author       = {Wattmo, Carina and Blennow, Kaj and Hansson, Oskar},
  issn         = {1471-2377},
  language     = {eng},
  month        = {01},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {BMC Neurology},
  title        = {Cerebro-spinal fluid biomarker levels : phosphorylated tau (T) and total tau (N) as markers for rate of progression in Alzheimer's disease},
  url          = {http://dx.doi.org/10.1186/s12883-019-1591-0},
  doi          = {10.1186/s12883-019-1591-0},
  volume       = {20},
  year         = {2020},
}