Dataset Information

Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease.

ABSTRACT: Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n?=?194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-? burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n?=?32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

SUBMITTER: Janelidze S

PROVIDER: S-EPMC7125218 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease.

Janelidze Shorena S Stomrud Erik E Smith Ruben R Palmqvist Sebastian S Mattsson Niklas N Airey David C DC Proctor Nicholas K NK Chai Xiyun X Shcherbinin Sergey S Sims John R JR Triana-Baltzer Gallen G Theunis Clara C Slemmon Randy R Mercken Marc M Kolb Hartmuth H Dage Jeffrey L JL Hansson Oskar O

Nature communications 20200403 1

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [<sup>18</sup>F]flortaucipir, and more accurately identifies individuals with abnormal ...[more]

PMID: 32246036

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Project description:In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

Project description:Recent studies suggest that increased cerebrospinal fluid (CSF) phospho-tau is associated with brain amyloid pathology rather than the tau pathology. However, confirmation using gold standard neuropathological assessments remains limited. This study aimed to determine background pathologies associated with aberrant CSF p-tau181 and amyloid-beta 1-42 (Aβ42) in Alzheimer's disease (AD) and other neurodegenerative diseases. We retrospectively studied all patients with antemortem CSF and postmortem neuropathologic data at our institution. Comprehensive neuropathologic assessments were conducted for all patients, including Thal phase, Braak NFT stage, and CERAD score for AD. CSF concentrations of p-tau181 and Aβ42 were compared between AD neuropathological scores at autopsy by one-way ANOVA stratified by other pathologies. A total of 127 patients with AD (n = 22), Lewy body disease (n = 26), primary tauopathies (n = 30), TDP-43 proteinopathy (n = 16), and other diseases (n = 33) were included. The age at lumbar puncture was 76.3 ± 9.1 years, 40.8% were female, and median time from lumbar puncture to autopsy was 637 (175-1625) days. While Braak NFT 0-II was prevalent without amyloid pathology, Braak NFT ≥IV was observed exclusively in patients with amyloid pathology. Stratified analyses showed that CSF p-tau181 was slightly but significantly higher in patients with high Thal phase or CERAD score even in those with Braak NFT 0-II at autopsy. In patients with amyloid pathology, CSF p-tau181 was significantly and more profoundly elevated in those with Braak NFT ≥III at autopsy. CSF Aβ42 was lower in patients with high amyloid pathological scores. However, 34% with Thal ≤ 2 and 38% with CERAD ≤ sparse also showed decreased Aβ42. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were overrepresented in this group. These results neuropathologically confirmed previous studies that CSF p-tau181 levels were slightly elevated with amyloid pathology alone and were even higher with tau pathology, and that CSFAβ42 can be decreased in PSP/CBD.

Project description:IntroductionWhile Alzheimer's disease (AD) is defined by amyloid-β plaques and tau tangles in the brain, it is evident that many other pathophysiological processes such as inflammation, neurovascular dysfunction, oxidative stress, and metabolic derangements also contribute to the disease process and that varying contributions of these pathways may reflect the heterogeneity of AD. Here, we used a previously validated panel of cerebrospinal fluid (CSF) biomarkers to explore the degree to which different pathophysiological domains are dysregulated in AD and how they relate to each other.MethodsTwenty-five CSF biomarkers were analyzed in individuals with a clinical diagnosis of AD verified by positive CSF AD biomarkers (AD, n = 54) and cognitively unimpaired controls negative for CSF AD biomarkers (CU-N, n = 26) using commercial single- and multi-plex immunoassays.ResultsWe noted that while AD was associated with increased levels of only three biomarkers (MMP-10, FABP3, and 8OHdG) on a group level, half of all AD participants had increased levels of biomarkers belonging to at least two pathophysiological domains reflecting the diversity in AD. LASSO modeling showed that a panel of FABP3, 24OHC, MMP-10, MMP-2, and 8OHdG constituted the most relevant and minimally correlated set of variables differentiating AD from CU-N. Interestingly, factor analysis showed that two markers of metabolism and oxidative stress (24OHC and 8OHdG) contributed independent information separate from MMP-10 and FABP3 suggestive of two independent pathophysiological pathways in AD, one reflecting neurodegeneration and vascular pathology, and the other associated with metabolism and oxidative stress.DiscussionBetter understanding of the heterogeneity among individuals with AD and the different contributions of pathophysiological processes besides amyloid-β and tau will be crucial for optimizing personalized treatment strategies.HighlightsA panel of 25 highly validated biomarker assays were measured in CSF.MMP10, FABP3, and 8OHdG were increased in AD in univariate analysis.Many individuals with AD had increased levels of more than one biomarker.Markers of metabolism and oxidative stress contributed to an AD multianalyte profile.Assessing multiple biomarker domains is important to understand disease heterogeneity.

Project description:IntroductionThe relevance of the cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer's disease (AD) and related disorders is clearly established. However, the question remains on how to use these data, which are often heterogeneous (not all biomarkers being pathologic). The objective of this study is to propose to physicians in memory clinics a biologic scale of probabilities that the patient with cognitive impairments has an Alzheimer's disease (AD) pathologic process.MethodsFor that purpose, we took advantage of the multicenter data of our Paris-North, Lille, and Montpellier (PLM) study, which has emerged through the initial sharing of information from these memory centers. Different models combining the CSF levels of amyloid-β 42, tau, and p-tau(181) were tested to generate categories of patients with very low (<10%), low (<25%), high (>75%), and very high predictive values (>90%) for positive AD. In total, 1,273 patients (646 AD and 627 non-AD) from six independent memory-clinic cohorts were included.ResultsA prediction model based on logistic regressions achieved a very good stratification of the population but had the disadvantages of needing mathematical optimization and being difficult to use in daily clinical practice. Remarkably, a simple and intuitive model based on the number (from zero to three) of three pathologic CSF biomarkers resulted in a very efficient predictive scale for AD in patients seen in memory clinics. The scale's overall predictive value for AD for the different categories were as follows: class 0, 9.6% (95% confidence interval (CI), 6.0% to 13.2%); class 1, 24.7% (95% CI, 18.0% to 31.3%); class 2, 77.2% (95% CI, 67.8% to 86.5%); and class 3, 94.2% (95% CI, 90.7% to 97.7%). In addition, with this scale, significantly more patients were correctly classified than with the logistic regression. Its superiority in model performance was validated by the computation of the net reclassification index (NRI). The model was also validated in an independent multicenter dataset of 408 patients (213 AD and 195 non-AD).ConclusionsIn conclusion, we defined a new scale that could be used to facilitate the interpretation and routine use of multivariate CSF data, as well as helping the stratification of patients in clinical research trials.

Dataset Information

Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease.

Publications

Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease.

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