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Recommendations for cerebrospinal fluid collection for the analysis by ELISA of neurogranin trunc P75, ?-synuclein, and total tau in combination with A?(1-42)/A?(1-40).

ABSTRACT: The pathophysiology of neurodegeneration is complex. Its diagnosis requires an early identification of sequential changes in several hallmarks in the brains of affected subjects. The presence of brain pathology can be visualized in the cerebrospinal fluid (CSF) by protein profiling. It is clear that the field of Alzheimer's disease (AD) will benefit from an integration of algorithms including CSF concentrations of individual proteins, especially as an aid in clinical decision-making or to improve patient enrolment in clinical trials. The protein profiling approach requires standard operating procedures for collection and storage of CSF which must be easy to integrate into a routine clinical lab environment. Our study provides recommendations for analysis of neurogranin trunc P75, ?-synuclein, and tau, in combination with the ratio of ?-amyloid A?(1-42)/A?(1-40).Protocols for CSF collection were compared with CSF derived from subjects with normal pressure hydrocephalus (n?=?19). Variables included recipient type (collection, storage), tube volume, and addition of detergents at the time of collection. CSF biomarker analysis was performed with enzyme-linked immunosorbent assays (ELISAs). Data were analyzed with linear repeated measures and mixed effects models.Adsorption to recipients is lower for neurogranin trunc P75, ?-synuclein, and tau (<10%), as compared to A?(1-42). For neurogranin trunc P75 and total tau, there is still an effect on analyte concentrations as a function of the tube volume. Protocol-related differences for A?(1-42) can be normalized at the (pre-)analytical level using the ratio A?(1-42)/A?(1-40), but not by using the ratio A?(1-42)/tau. The addition of detergent at the time of collection eliminates differences due to adsorption.Our study recommends the use of low protein binding tubes for quantification in CSF (without additives) of all relevant CSF biomarkers. Pre-analytical factors have less effect on ?-synuclein, neurogranin trunc P75, and total tau, as compared to A?(1-42). The ratio of A?(1-42)/A?(1-40), but not A?(1-42)/tau, can be used to adjust for pre-analytical differences in analyte concentrations. Our study does not recommend the inclusion of detergents at the time of collection of CSF. The present results provide an experimental basis for new recommendations for parallel analysis of several proteins using one protocol for collection and storage of CSF.

SUBMITTER: Vanderstichele H

PROVIDER: S-EPMC5461747 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Recommendations for cerebrospinal fluid collection for the analysis by ELISA of neurogranin trunc P75, α-synuclein, and total tau in combination with Aβ(1-42)/Aβ(1-40).

Vanderstichele Hugo H Demeyer Leentje L Janelidze Shorena S Coart Els E Stoops Erik E Mauroo Kimberley K Herbst Victor V François Cindy C Hansson Oskar O

Alzheimer's research & therapy 20170606 1

<h4>Background</h4>The pathophysiology of neurodegeneration is complex. Its diagnosis requires an early identification of sequential changes in several hallmarks in the brains of affected subjects. The presence of brain pathology can be visualized in the cerebrospinal fluid (CSF) by protein profiling. It is clear that the field of Alzheimer's disease (AD) will benefit from an integration of algorithms including CSF concentrations of individual proteins, especially as an aid in clinical decision- ...[more]

PMID: 28587660

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Project description:Widespread implementation of cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) in clinical settings requires improved accuracy for diagnosis of prodromal disease and for distinguishing AD from non-AD dementias. Novel and promising CSF biomarkers include neurogranin, a marker of synaptic degeneration, and YKL-40, a marker of neuroinflammation.CSF neurogranin and YKL-40 were measured in a cohort of 338 individuals including cognitively healthy controls and patients with stable mild cognitive impairment (sMCI), MCI who later developed AD (MCI-AD), AD dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementia (FTD). The diagnostic accuracy of neurogranin and YKL-40 were compared with the core AD biomarkers, β-amyloid (Aβ42 and Aβ40) and tau.Neurogranin levels were increased in AD and decreased in non-AD dementia compared with healthy controls. As a result, AD patients showed considerably higher CSF levels of neurogranin than DLB/PDD, VaD and FTD patients. CSF YKL-40 levels were increased in AD compared with DLB/PDD but not with VaD or FTD. Neither CSF neurogranin nor YKL-40 levels differed significantly between sMCI patients and MCI-AD patients. Both biomarkers correlated positively with CSF Aβ40 and tau. CSF neurogranin and YKL-40 could separate AD dementia from non-AD dementias (neurogranin, area under the curve [AUC] = 0.761; YKL-40, AUC = 0.604; Aβ42/neurogranin, AUC = 0.849; Aβ42/YKL-40, AUC = 0.785), but the diagnostic accuracy was not better compared to CSF Aβ and tau (Aβ42, AUC = 0.755; tau AUC = 0.858; Aβ42/tau, AUC = 0.895; Aβ42/Aβ40, AUC = 0.881). Similar results were obtained when separating sMCI from MCI-AD cases.CSF neurogranin and YKL-40 do not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to the core CSF AD biomarkers. Nevertheless, the CSF level of neurogranin is selectively increased in AD dementia, whereas YKL-40 is increased in both AD and FTD suggesting that synaptic degeneration and glial activation may be important in these neurodegenerative conditions.

Project description:BackgroundDespite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).MethodsCSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T - = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A - T -). A + T - patients were further stratified into those with normal (CSFAβ42 + /amyR - = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.ResultsCSF Aβ40 levels were the lowest in A - T - and in CSFAβ42 + /amyR - , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A - T - (β = 0.58; p < 0.001), CSFAβ42 + /amyR - (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR - (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR - compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + .ConclusionsPathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Project description:IMPORTANCE:We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and ?-synuclein, but not ?-amyloid 1-42 (A?1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. OBJECTIVE:To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (A?1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and ?-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson's Progression Markers Initiative (PPMI) study. DESIGN, SETTING, AND PARTICIPANTS:Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. MAIN OUTCOMES AND MEASURES:The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (A?1-42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (?-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. RESULTS:Slightly, but significantly, lower levels of A?1-42, T-tau, P-tau181, ?-synuclein, and T-tau/A?1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower A?1-42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF T-tau and ?-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF A?1-42 and P-tau181 concentrations were associated with the postural instability-gait disturbance-dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of ?-synuclein with the levels of T-tau and P-tau181. CONCLUSIONS AND RELEVANCE:In this first report of CSF biomarkers in PPMI study subjects,we found that measures of CSF A?1-42, T-tau, P-tau181, and ?-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression

Dataset Information

Recommendations for cerebrospinal fluid collection for the analysis by ELISA of neurogranin trunc P75, ?-synuclein, and total tau in combination with A?(1-42)/A?(1-40).

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Recommendations for cerebrospinal fluid collection for the analysis by ELISA of neurogranin trunc P75, α-synuclein, and total tau in combination with Aβ(1-42)/Aβ(1-40).

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