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Levels of cerebrospinal fluid biomarkers total tau and phosphorylated tau do not predict survival time after diagnosis of Alzheimer’s disease – An 18-year follow-up.

Wattmo, Carina LU ; Blennow, Kaj; Minthon, Lennart LU and Hansson, Oskar LU (2017) 10th Clinical Trials Conference on Alzheimer’s Disease
Abstract
Background: The pathological process in Alzheimer’s disease (AD) probably starts decades before the onset of symptoms and the clinical AD diagnosis. In patients with AD, the level of cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ42) is usually lower, and the levels of total tau (T-tau) and phosphorylated tau (P-tau) higher than in healthy elderly people. However, the cutoffs differ between studies and the predictive values are too low to diagnose AD using only CSF biomarkers. Several previous reports have shown that the levels of T-tau and P-tau become pathological later in the course of AD compared with Aβ42, yet it is unclear if higher levels of tau shorten the individuals’ life expectancy after diagnosis.... (More)
Background: The pathological process in Alzheimer’s disease (AD) probably starts decades before the onset of symptoms and the clinical AD diagnosis. In patients with AD, the level of cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ42) is usually lower, and the levels of total tau (T-tau) and phosphorylated tau (P-tau) higher than in healthy elderly people. However, the cutoffs differ between studies and the predictive values are too low to diagnose AD using only CSF biomarkers. Several previous reports have shown that the levels of T-tau and P-tau become pathological later in the course of AD compared with Aβ42, yet it is unclear if higher levels of tau shorten the individuals’ life expectancy after diagnosis. The current study aims to investigate whether pathological levels of T-tau and/or P-tau can predict survival in AD. Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicenter study for the longitudinal assessment of cholinesterase inhibitor treatment in a routine clinical setting. This presentation includes all 151 participants clinically diagnosed with AD, who underwent a lumbar puncture. Patients were evaluated regarding cognitive and functional abilities at baseline (time of diagnosis) and semi-annually over 3 years. Socio-demographic characteristics, concomitant medications and the date of death were recorded. CSF was collected in polypropylene tubes, stored at −80 °C and analyzed after the clinical follow-up of the study was completed. The levels of T-tau, P-tau phosphorylated at Thr181 and Aβ42 were determined using xMAP technology. Pathological levels of CSF biomarkers were defined as: T-tau >100 ng/ml, P-tau >51 ng/ml and Aβ42 <209 ng/ml. Cox proportional hazards regression was used to determine the patient characteristics that affected mortality. Potential predictors were investigated, including sex, age at baseline, apolipoprotein E (APOE) e4 carrier status, years of education, the clinician’s estimated duration of AD, cognitive and functional abilities at baseline, the number of concomitant medications, and levels of CSF biomarkers. Results: The number and frequency of SATS participants with pathological CSF biomarkers were: T-tau, n=18 (12%); P-tau, n=14 (9%); and both T-tau and P-tau, n=46 (31%). All 151 individuals had pathological Aβ42. The group with normal T-tau and P-tau (n=73, 48%) had a higher education level, mean (95% confidence interval [CI]) 10.2 (9.5–10.8) vs. 9.1 (8.7–9.6) years, p=0.013; better cognitive ability at baseline, Mini-Mental State Examination, 22.8 (21.9–23.8) vs. 20.6 (19.5–21.6) points, p=0.002; and higher level of Aβ42 124 (118–129) vs. 117 (113–120) ng/ml, p=0.034, compared to patients with pathological T-tau and/or P-tau. No difference between the two groups was detected regarding the other aforementioned characteristics. After 18 years of follow-up, 139 of the 151 participants (92%) had died; their mean (95% CI) lifespan after diagnosis was 6.7 (6.2–7.3) years. No linear associations were found between survival time and Aβ42 (r = –0.005, p=0.957), T-tau (r = –0.127, p=0.135), or P-tau (r = –0.020, p=0.816). In a Kaplan–Meier analysis with pairwise Log-rank tests, the individuals with normal tau levels showed a longer life expectancy than those with pathological T-tau (p=0.044) and P-tau (p=0.025), but not if both tau biomarkers were pathological (p=0.439). However, using a one-way analysis of variance (ANOVA), the mean lifespan did not differ among the four groups: normal T-tau and P-tau, 7.0 (6.1–7.9) years; pathological T-tau, 5.6 (4.5–6.7) years; pathological P-tau, 5.9 (4.4–7.4) years; and both pathological T-tau and P-tau, 7.1 (6.1–8.1) years, p=0.276. The interaction effect of normal/pathological levels of tau with presence/absence of the APOE e4 allele did not affect the participants’ survival time in a Kaplan–Meier analysis, p=0.100, or in an ANOVA, p=0.451. In addition, no significant linear relationships were observed between life expectancy after AD diagnosis and any of the CSF biomarkers in the APOE e4 non-carrier or in the e4 carrier groups. Patients with the highest quartile and quintile of T-tau (>=126 and >=129 ng/ml) and P-tau (>=65 and >=70 ng/ml), respectively, were also examined; their lifespan did not differ from the other individuals. The actual continuous values of the CSF biomarkers or dichotomously coded normal/pathological, respectively, were not significant in Cox regression models adjusted for the above-mentioned predictors. Conclusion: Mortality in AD is complex and depends on many factors e.g., demographic and clinical. In this clinical-practice-based long-term study, almost half of the participants with AD had normal levels of tau. We found no clear results that the levels of T-tau and/or P-tau affect survival after diagnosis in AD. This observation does not support the theory that these patients have a more advanced disease. However, the individuals with pathological levels of tau had fewer years of education and worse cognitive status indicating a lower cognitive reserve capacity, which might influence life expectancy. These findings might be useful when considering new diagnostic criteria and when interpreting outcomes from future clinical trials of potentially disease-modifying AD therapies. (Less)
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10th Clinical Trials Conference on Alzheimer’s Disease
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e6049c36-49ca-40aa-a331-ece567f43c27
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@misc{e6049c36-49ca-40aa-a331-ece567f43c27,
  abstract     = {Background: The pathological process in Alzheimer’s disease (AD) probably starts decades before the onset of symptoms and the clinical AD diagnosis. In patients with AD, the level of cerebrospinal fluid (CSF) amyloid-β<sub>1-42</sub> (Aβ<sub>42</sub>) is usually lower, and the levels of total tau (T-tau) and phosphorylated tau (P-tau) higher than in healthy elderly people. However, the cutoffs differ between studies and the predictive values are too low to diagnose AD using only CSF biomarkers. Several previous reports have shown that the levels of T-tau and P-tau become pathological later in the course of AD compared with Aβ<sub>42</sub>, yet it is unclear if higher levels of tau shorten the individuals’ life expectancy after diagnosis. The current study aims to investigate whether pathological levels of T-tau and/or P-tau can predict survival in AD. Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicenter study for the longitudinal assessment of cholinesterase inhibitor treatment in a routine clinical setting. This presentation includes all 151 participants clinically diagnosed with AD, who underwent a lumbar puncture. Patients were evaluated regarding cognitive and functional abilities at baseline (time of diagnosis) and semi-annually over 3 years. Socio-demographic characteristics, concomitant medications and the date of death were recorded. CSF was collected in polypropylene tubes, stored at −80 °C and analyzed after the clinical follow-up of the study was completed. The levels of T-tau, P-tau phosphorylated at Thr<sub>181</sub> and Aβ<sub>42</sub> were determined using xMAP technology. Pathological levels of CSF biomarkers were defined as: T-tau &gt;100 ng/ml, P-tau &gt;51 ng/ml and Aβ<sub>42</sub> &lt;209 ng/ml. Cox proportional hazards regression was used to determine the patient characteristics that affected mortality. Potential predictors were investigated, including sex, age at baseline, apolipoprotein E (APOE) e4 carrier status, years of education, the clinician’s estimated duration of AD, cognitive and functional abilities at baseline, the number of concomitant medications, and levels of CSF biomarkers. Results: The number and frequency of SATS participants with pathological CSF biomarkers were: T-tau, n=18 (12%); P-tau, n=14 (9%); and both T-tau and P-tau, n=46 (31%). All 151 individuals had pathological Aβ<sub>42</sub>. The group with normal T-tau and P-tau (n=73, 48%) had a higher education level, mean (95% confidence interval [CI]) 10.2 (9.5–10.8) vs. 9.1 (8.7–9.6) years, p=0.013; better cognitive ability at baseline, Mini-Mental State Examination, 22.8 (21.9–23.8) vs. 20.6 (19.5–21.6) points, p=0.002; and higher level of Aβ<sub>42</sub> 124 (118–129) vs. 117 (113–120) ng/ml, p=0.034, compared to patients with pathological T-tau and/or P-tau. No difference between the two groups was detected regarding the other aforementioned characteristics. After 18 years of follow-up, 139 of the 151 participants (92%) had died; their mean (95% CI) lifespan after diagnosis was 6.7 (6.2–7.3) years. No linear associations were found between survival time and Aβ<sub>42</sub> (r = –0.005, p=0.957), T-tau (r = –0.127, p=0.135), or P-tau (r = –0.020, p=0.816). In a Kaplan–Meier analysis with pairwise Log-rank tests, the individuals with normal tau levels showed a longer life expectancy than those with pathological T-tau (p=0.044) and P-tau (p=0.025), but not if both tau biomarkers were pathological (p=0.439). However, using a one-way analysis of variance (ANOVA), the mean lifespan did not differ among the four groups: normal T-tau and P-tau, 7.0 (6.1–7.9) years; pathological T-tau, 5.6 (4.5–6.7) years; pathological P-tau, 5.9 (4.4–7.4) years; and both pathological T-tau and P-tau, 7.1 (6.1–8.1) years, p=0.276. The interaction effect of normal/pathological levels of tau with presence/absence of the APOE e4 allele did not affect the participants’ survival time in a Kaplan–Meier analysis, p=0.100, or in an ANOVA, p=0.451. In addition, no significant linear relationships were observed between life expectancy after AD diagnosis and any of the CSF biomarkers in the APOE e4 non-carrier or in the e4 carrier groups. Patients with the highest quartile and quintile of T-tau (&gt;=126 and &gt;=129 ng/ml) and P-tau (&gt;=65 and &gt;=70 ng/ml), respectively, were also examined; their lifespan did not differ from the other individuals. The actual continuous values of the CSF biomarkers or dichotomously coded normal/pathological, respectively, were not significant in Cox regression models adjusted for the above-mentioned predictors. Conclusion: Mortality in AD is complex and depends on many factors e.g., demographic and clinical. In this clinical-practice-based long-term study, almost half of the participants with AD had normal levels of tau. We found no clear results that the levels of T-tau and/or P-tau affect survival after diagnosis in AD. This observation does not support the theory that these patients have a more advanced disease. However, the individuals with pathological levels of tau had fewer years of education and worse cognitive status indicating a lower cognitive reserve capacity, which might influence life expectancy. These findings might be useful when considering new diagnostic criteria and when interpreting outcomes from future clinical trials of potentially disease-modifying AD therapies.},
  author       = {Wattmo, Carina and Blennow, Kaj and Minthon, Lennart and Hansson, Oskar},
  language     = {eng},
  title        = {Levels of cerebrospinal fluid biomarkers total tau and phosphorylated tau do not predict survival time after diagnosis of Alzheimer’s disease – An 18-year follow-up.},
  year         = {2017},
}