scholarly journals Commutability of the certified reference materials for the standardization of β-amyloid 1-42 assay in human cerebrospinal fluid: lessons for tau and β-amyloid 1-40 measurements

2018 ◽  
Vol 56 (12) ◽  
pp. 2058-2066 ◽  
Author(s):  
Ulf Andreasson ◽  
Julia Kuhlmann ◽  
Josef Pannee ◽  
Robert M. Umek ◽  
Erik Stoops ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Reference Materials ◽  
Certified Reference Materials ◽  
The Other ◽  
Csf Biomarkers ◽  
Pairwise Correlations ◽  
Β Amyloid ◽  
The Individual ◽  
Research Criteria ◽  
T Tau

Abstract Background: The core Alzheimer’s disease cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), β-amyloid 1-42 (Aβ42) and β-amyloid 1-40 (Aβ40) are increasing in importance and are now part of the research criteria for the diagnosis of the disease. The main aim of this study is to evaluate whether a set of certified reference materials (CRMs) are commutable for Aβ42 and to serve as a feasibility study for the other markers. This property is a prerequisite for the establishment of CRMs which will then be used by manufacturers to calibrate their assays against. Once the preanalytical factors have been standardized and proper selection criteria are available for subject cohorts this harmonization between methods will allow for universal cut-offs to be determined. Methods: Thirty-four individual CSF samples and three different CRMs where analyzed for T-tau, P-tau, Aβ42 and Aβ40, using up to seven different commercially available methods. For Aβ40 and Aβ42 a mass spectrometry-based procedure was also employed. Results: There were strong pairwise correlations between the different methods (Spearman’s ρ>0.92) for all investigated analytes and the CRMs were not distinguishable from the individual samples. Conclusions: This study shows that the CRMs are commutable for the different assays for Aβ42. For the other analytes the results show that it would be feasible to also produce CRMs for these. However, additional studies are needed as the concentration interval for the CRMs were selected based on Aβ42 concentrations only and did in general not cover satisfactory large concentration intervals for the other analytes.

scholarly journals Clinical validation of the Lumipulse G cerebrospinal fluid assays for routine diagnosis of Alzheimer’s disease

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria João Leitão ◽  
Anuschka Silva-Spínola ◽  
Isabel Santana ◽  
Veronica Olmedo ◽  
Alicia Nadal ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Analytical Performance ◽  
Csf Biomarkers ◽  
Parameter Method ◽  
Routine Practice ◽  
Amyloid Pet ◽  
Β Amyloid ◽  
T Tau

Abstract Background Ongoing efforts within the Alzheimer’s disease (AD) field have focused on improving the intra- and inter-laboratory variability for cerebrospinal fluid (CSF) biomarkers. Fully automated assays offer the possibility to eliminate sample manipulation steps and are expected to contribute to this improvement. Recently, fully automated chemiluminescence enzyme immunoassays for the quantification of all four AD biomarkers in CSF became available. The aims of this study were to (i) evaluate the analytical performance of the Lumipulse G β-Amyloid 1-42 (restandardized to Certified Reference Materials), β-Amyloid 1-40, total Tau, and pTau 181 assays on the fully automated LUMIPULSE G600II; (ii) compare CSF biomarker results of the Lumipulse G assays with the established manual ELISA assays (INNOTEST®) from the same company (Fujirebio); and (iii) establish cut-off values and the clinical performance of the Lumipulse G assays for AD diagnosis. Methods Intra- and inter-assay variation was assessed in CSF samples with low, medium, and high concentrations of each parameter. Method comparison and clinical evaluation were performed on 40 neurological controls (NC) and 80 patients with a diagnosis of probable AD supported by a follow-up ≥ 3 years and/or positive amyloid PET imaging. A small validation cohort of 10 NC and 20 AD patients was also included to validate the cut-off values obtained on the training cohort. Results The maximal observed intra-assay and inter-assay coefficients of variation (CVs) were 3.25% and 5.50%, respectively. Method comparisons revealed correlation coefficients ranging from 0.89 (for Aβ40) to 0.98 (for t-Tau), with those for Aβ42 (0.93) and p-Tau (0.94) in-between. ROC curve analysis showed area under the curve values consistently above 0.85 for individual biomarkers other than Aβ40, and with the Aβ42/40, Aβ42/t-Tau, and Aβ42/p-Tau ratios outperforming Aβ42. Validation of the cut-off values in the independent cohort showed a sensitivity ranging from 75 to 95% and a specificity of 100%. The overall percentage of agreement between Lumipulse and INNOTEST was very high (> 87.5%). Conclusions The Lumipulse G assays show a very good analytical performance that makes them well-suited for CSF clinical routine measurements. The good clinical concordance between the Lumipulse G and INNOTEST assays facilitates the implementation of the new method in routine practice.

scholarly journals Effect of Patient-Specific Preanalytic Variables on CSF Aβ1–42 Concentrations Measured on an Automated Chemiluminescent Platform

2020 ◽  
Author(s):  
Jacqueline A Darrow ◽  
Amanda Calabro ◽  
Sara Gannon ◽  
Amanze Orusakwe ◽  
Rianne Esquivel ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Patient Specific ◽  
Csf Biomarkers ◽  
Clinical Settings ◽  
Blood Contamination ◽  
Gradient Effect ◽  
Β Amyloid ◽  
The Impact ◽  
Gradient Effects

Abstract Background Cerebrospinal fluid (CSF) biomarkers are increasingly used to confirm the accuracy of a clinical diagnosis of mild cognitive impairment or dementia due to Alzheimer disease (AD). Recent evidence suggests that fully automated assays reduce the impact of some preanalytical factors on the variability of these measures. This study evaluated the effect of several preanalytical variables common in clinical settings on the variability of CSF β-amyloid 1–42 (Aβ1–42) concentrations. Methods Aβ1–42 concentrations were measured using the LUMIPULSE G1200 from both freshly collected and frozen CSF samples. Preanalytic variables examined were: (1) patient fasting prior to CSF collection, (2) blood contamination of specimens, and (3) aliquoting specimens sequentially over the course of collection (i.e., CSF gradients). Results Patient fasting did not significantly affect CSF Aβ1–42 levels. While assessing gradient effects, Aβ1–42 concentrations remained stable within the first 5 1-mL aliquots. However, there is evidence of a gradient effect toward higher concentrations over successive aliquots. Aβ1–42 levels were stable when fresh CSF samples were spiked with up to 2.5% of blood. However, in frozen CSF samples, even 0.25% blood contamination significantly decreased Aβ1–42 concentrations. Conclusions The preanalytical variables examined here do not have significant effects on Aβ1–42 concentrations if fresh samples are processed within 2 h. However, a gradient effect can be observed on Aβ1–42 concentrations after the first 5 mL of collection and blood contamination has a significant impact on Aβ1–42 concentrations once specimens have been frozen.

scholarly journals Predictive Value of Cerebrospinal Fluid Biomarkers for Tap Test Responsiveness in Patients with Suspected Idiopathic Normal Pressure Hydrocephalus

2021 ◽  
Author(s):  
Rongrong Hua ◽  
Chunyan Liu ◽  
Xing Liu ◽  
Jinwu Zhu ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Normal Pressure Hydrocephalus ◽  
Predictive Value ◽  
Test Group ◽  
Normal Pressure ◽  
Idiopathic Normal Pressure Hydrocephalus ◽  
Binary Logistic Regression Analysis ◽  
Csf Biomarkers ◽  
Tap Test ◽  
T Tau

Abstract Background: The value of cerebrospinal fluid (CSF) biomarkers for idiopathic normal pressure hydrocephalus (iNPH) needs to be determined. This prospective study aimed to reveal the correlation between CSF biomarkers and clinical symptoms of iNPH, and its predictive value for tap test responsiveness.Methods: Thirty-nine suspected iNPH patients were recruited, contributed qualified CSF, and accepted a tap test and unified pre- and post-test evaluation of neurological function. Results: The analysis of biomarkers from their CSF showed a decrease of tau and its phosphorylated form, especially in the tap test (+) group. In addition, the responsiveness of the tap test was also related to the number of combined symptoms (p<0.01). A correlation was also found between the end pressure or pressure difference of CSF and tap test responsiveness (p<0.05). The results of binary logistic regression analysis showed that P (tap test responsiveness) = 1/1 + e ^ - (-5.505+55.314 * ratio of p/T-tau - 1.586 * numbers of combined symptoms). The combined indicators (-5.505+0.553* percentage of p/T-tau - 1.586 * numbers of combined symptoms) gave the highest sensitivity and specificity, which were 94.12% and 72.73%, respectively.Conclusions: It may be accessed in judgment of tap test responsiveness, which is beneficial for the feasibility of clinical application.

scholarly journals Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD

Neurology ◽  
2017 ◽  
Vol 88 (17) ◽  
pp. 1650-1658 ◽  
Author(s):  
Stephanie A. Schultz ◽  
Elizabeth A. Boots ◽  
Burcu F. Darst ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
...  
Keyword(s):  
Cardiorespiratory Fitness ◽  
Risk Score ◽  
Csf Biomarkers ◽  
Polygenic Risk Score ◽  
Regression Analyses ◽  
Cross Sectional ◽  
Polygenic Risk ◽  
Β Amyloid ◽  
Adverse Influence ◽  
T Tau

Objective:To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers.Methods:Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ42), Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ42/Aβ40 and tau/Aβ42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF.Results:A higher PRS was associated with lower Aβ42/Aβ40 (p < 0.001), higher t-tau/Aβ42 (p = 0.012), and higher p-tau/Aβ42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ42/Aβ40 (p = 0.003), t-tau/Aβ42 (p = 0.003), and p-tau/Aβ42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF.Conclusions:In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.

Association Between CSF Beta-Amyloid and Apathy in Early-Stage Alzheimer Disease

2019 ◽  
Vol 32 (3) ◽  
pp. 164-169 ◽  
Author(s):  
A. Vergallo ◽  
L. Giampietri ◽  
C. Pagni ◽  
F. S. Giorgi ◽  
V. Nicoletti ◽  
...  
Keyword(s):  
Early Stage ◽  
Clinical Feature ◽  
Csf Biomarkers ◽  
Potential Association ◽  
Modifying Effect ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Item Scores ◽  
T Tau ◽  
Late Stages

Aim: The apathetic syndrome is a common clinical feature in patients with Alzheimer diseases (AD), from preclinical phases to late stages of dementia, and it is strongly related to major disease outcomes. Unfortunately, no specific pharmacological treatments for apathy have been accomplished so far. Translational evidences have previously shown that a link between apathy and hallmarks of AD-related pathophysiology, that is, β-amyloid (Aβ) plaques and neurofibrillary tangles, exists. However, only few studies investigated the association between core biomarkers of AD and apathy scores, finding conflicting results. Methods: Thirty-seven patients were identified as having AD dementia according to National Institute on Aging–Alzheimer Association 2011 criteria. All participants underwent an extensive diagnostic workup including cerebrospinal fluid (CSF) assessment to measure the concentrations of Aβ42, t-tau, and pTau181. To follow, they were stratified as: apathy absence, apathy mild, and apathy severe according to the Neuro Psychiatric Inventory-apathy item scores. We investigated for potential associations between apathy scores and CSF biomarkers concentrations as well as for differences in terms of clinical and CSF biomarkers data across the 3 apathy groups. Results: The CSF Aβ42 concentrations were negatively correlated with apathy scores. In addition, patients with severe apathy had significantly lower Aβ42 levels compared to nonapathetic ones. Conclusion: Based on our results, we encourage further studies to untangle the potential association between the complex pathophysiological dynamics of AD and apathy which may represent an innovative reliable clinical outcome measure to use in clinical trials, investigating treatments with either a symptomatic or a disease-modifying effect.

scholarly journals 0057 Actigraphy-Based Circadian Measures and Cerebrospinal Fluid Biomarkers of Neurodegeneration in Alzheimer’s Disease with Mild Cognitive Impairment

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A23-A23
Author(s):  
R Mehra ◽  
R Bhambra ◽  
J Bena ◽  
L Bekris ◽  
J Leverenz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Csf Biomarkers ◽  
Significance Level ◽  
Unit Increase ◽  
T Tau ◽  
Age And Sex

Abstract Introduction Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD). Methods Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Results Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI:1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20%(6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Conclusion Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. Future investigation should clarify directionality of this association and potential utility of circadian-based interventions in the mitigation of AD progression. Support N/A

scholarly journals Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment

2015 ◽  
Vol 36 (3) ◽  
pp. 621-628 ◽  
Author(s):  
Sara Shams ◽  
Tobias Granberg ◽  
Juha Martola ◽  
Xiaozhen Li ◽  
Mana Shams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Serum Albumin ◽  
Amyloid Β ◽  
Cerebral Microbleeds ◽  
Csf Biomarkers ◽  
Barrier Dysfunction ◽  
T Tau

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment ( p < 0.05). CSF/serum albumin ratios were high with multiple CMBs ( p < 0.001), reflecting accompanying blood–brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer’s patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer’s disease ( p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.

scholarly journals Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

2021 ◽  
Vol 11 (10) ◽  
pp. 1258
Author(s):  
George P. Paraskevas ◽  
Elisabeth Kapaki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Small Vessel Disease ◽  
Lewy Bodies ◽  
Plaque Burden ◽  
Csf Biomarkers ◽  
Β Amyloid ◽  
Disease Modifying

Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction in CSF β-amyloid (marker of amyloid plaque burden), although compatible with Alzheimer’s pathological change, may also be observed in other dementing disorders, including vascular cognitive disorders due to subcortical small-vessel disease, dementia with Lewy bodies and normal-pressure hydrocephalus. Thus, for the diagnosis of AD, an abnormal result of CSF β-amyloid may not be sufficient, and an increase in phospho-tau (marker of tangle pathology) is also required in order to confirm AD diagnosis in patients with a typical amnestic presentation and reveal underlying AD in patients with atypical or mixed and diagnostically confusing clinical presentations.

scholarly journals Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies

2010 ◽  
Vol 2010 ◽  
pp. 1-17 ◽  
Author(s):  
Elizabeta B. Mukaetova-Ladinska ◽  
Rachael Monteith ◽  
Elaine K. Perry
Keyword(s):  
Cerebrospinal Fluid ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Low Frequency ◽  
Csf Biomarkers ◽  
Term Care ◽  
Clinical Criteria ◽  
Cerebrospinal Fluid Biomarkers ◽  
The Uk ◽  
T Tau

More than 750,000 of the UK population suffer from some form of cognitive impairment and dementia. Of these, 5–20% will have Dementia with Lewy Bodies (DLB). Clinico-pathological studies have shown that it is the low frequency of DLB clinical core features that makes the DLB diagnosis hardly recognisable during life, and easily misdiagnosed for other forms of dementia. This has an impact on the treatment and long-term care of the affected subjects. Having a biochemical test, based on quantification of a specific DLB biomarker within Cerebrospinal Fluid (CSF) could be an effective diagnostic method to improve the differential diagnosis. Although some of the investigated DLB CSF biomarkers are well within the clinical criteria for sensitivity and specificity (90%), they all seem to be confounded by the contradictory data for each of the major groups of biomarkers (-synuclein, tau and amyloid proteins). However, a combination of CSF measures appear to emerge, that may well be able to differentiate DLB from other dementias: -synuclein reduction in early DLB, a correlation between CSF -synuclein and A42 measures (characteristic for DLB only), and t-tau and p-tau181 profile (differentiating AD from DLB).

scholarly journals Neuronal and Glia-Related Biomarkers in Cerebrospinal Fluid of Patients with Acute Ischemic Stroke

2014 ◽  
Vol 6 ◽  
pp. JCNSD.S13821 ◽  
Author(s):  
Clara Hjalmarsson ◽  
Maria Bjerke ◽  
Björn Andersson ◽  
Kaj Blennow ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Experimental Studies ◽  
Csf Biomarkers ◽  
Stroke Severity ◽  
Neurofilament Light ◽  
Age Related ◽  
T Tau

Background Cerebral ischemia promotes morphological reactions of the neurons, astrocytes, oligodendrocytes, and microglia in experimental studies. Our aim was to examine the profile of CSF (cerebrospinal fluid) biomarkers and their relation to stroke severity and degree of white matter lesions (WML). Methods A total of 20 patients (mean age 76 years) were included within 5–10 days after acute ischemic stroke (AIS) onset. Stroke severity was assessed using NIHSS (National Institute of Health stroke scale). The age-related white matter changes (ARWMC) scale was used to evaluate the extent of WML on CT-scans. The concentrations of specific CSF biomarkers were analyzed. Results Patients with AIS had significantly higher levels of NFL (neurofilament, light), T-tau, myelin basic protein (MBP), YKL-40, and glial fibrillary acidic protein (GFAP) compared with controls; T-Tau, MBP, GFAP, and YKL-40 correlated with clinical stroke severity, whereas NFL correlated with severity of WML (tested by Mann–Whitney test). Conclusions Several CSF biomarkers increase in AIS, and they correlate to clinical stroke severity. However, only NFL was found to be a marker of degree of WML.

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