Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1–42 Analysis Results

Tijms, Betty M.; Willemse, Eline A.J.; Zwan, Marissa D.; Mulder, Sandra D.; Visser, Pieter Jelle; Berckel, Bart N.M. van; Flier, Wiesje M. van der; Scheltens, Philip; Teunissen, Charlotte E.

doi:10.1373/clinchem.2017.281055

Cited by 136 publications

(156 citation statements)

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“…Because CSF Aβ 42 , tau, and p-tau were not normally distributed, we logarithmically transformed them for these analyses. Because Aβ 42 samples were collected over a long period, we rescaled values of Aβ 42 according to recent insights from our group that Aβ 42 levels show a significant drift over time [35]. Because of their closely related biological functions, most proteins of the PRM assay were expected to correlate with each other within individuals.…”

Section: Discussionmentioning

confidence: 99%

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

et al. 2018

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Background: We investigated whether a panel of 12 potential novel biomarkers consisting of proteins involved in synapse functioning and immunity would be able to distinguish patients with Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI) from control subjects. Methods: We included 40 control subjects, 40 subjects with MCI, and 40 subjects with AD from the Amsterdam Dementia Cohort who were matched for age and sex (age 65 ± 5 years, 19 [48%] women). The mean follow-up of patients with MCI was 3 years. Two or three tryptic peptides per protein were analyzed in cerebrospinal fluid using parallel reaction monitoring mass spectrometry. Corresponding stable isotope-labeled peptides were added and used as reference peptides. Multilevel generalized estimating equations (GEEs) with peptides clustered per subject and per protein (as within-subject variables) were used to assess differences between diagnostic groups. To assess differential effects of individual proteins, we included the diagnosis × protein interaction in the model. Separate GEE analyses were performed to assess differences between stable patients and patients with progressive MCI (MCI-AD).Results: There was a main effect for diagnosis (p < 0.01) and an interaction between diagnosis and protein (p < 0.01). Analysis stratified according to protein showed higher levels in patients with MCI for most proteins, especially in patients with MCI-AD. Chromogranin A, secretogranin II, neurexin 3, and neuropentraxin 1 showed the largest effect sizes; β values ranged from 0.53 to 0.78 for patients with MCI versus control subjects or patients with AD, and from 0.67 to 0.98 for patients with MCI-AD versus patients with stable MCI. In contrast, neurosecretory protein VGF was lower in patients with AD than in patients with MCI (ß = −0.93 [SE 0.22]) and control subjects (ß = 0.46 [SE 0.19]). Conclusions: Our results suggest that several proteins involved in vesicular transport and synaptic stability are elevated in patients with MCI, especially in patients with MCI progressing to AD dementia. This may reflect early events in the AD pathophysiological cascade. These proteins may be valuable as disease stage or prognostic markers in an early symptomatic stage of the disease.

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Section: Discussionmentioning

confidence: 99%

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

et al. 2018

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“…Aβ 1–42 , phosphorylated tau (p‐tau), and total tau protein concentrations were measured using InnoTest sandwich ELISAs (Innogenetics, Fujirebio, Ghent, Belgium). The cut‐off for abnormal drift‐corrected CSF Aβ 1–42 was set at <813 ng/L (Tijms et al, ), at >375 ng/L for CSF total tau and at >52 ng/L for p‐tau (Mulder et al, ).…”

Section: Methodsmentioning

confidence: 99%

Gray matter T1‐w/T2‐w ratios are higher in Alzheimer's disease

Pelkmans

Dicks

Barkhof

et al. 2019

Human Brain Mapping

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Myelin determines the conduction of neuronal signals along axonal connections in networks of the brain. Loss of myelin integrity in neuronal circuits might result in cognitive decline in Alzheimer's disease (AD). Recently, the ratio of T1‐weighted by T2‐weighted MRI has been used as a proxy for myelin content in gray matter of the cortex. With this approach, we investigated whether AD dementia patients show lower cortical myelin content (i.e., a lower T1‐w/T2‐w ratio value). We selected structural T1‐w and T2‐w MR images of 293 AD patients and 172 participants with normal cognition (NC). T1‐w/T2‐w ratios were computed for the whole brain and within 90 automated anatomical labeling atlas regions using SPM12, compared between groups and correlated with the neuronal injury marker tau in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE). In contrast to our hypothesis, AD patients showed higher whole brain T1‐w/T2‐w ratios than NC, and regionally in 31 anatomical areas (p < .0005; d = 0.21 to 0.48), predominantly in the inferior parietal lobule, angular gyrus, anterior cingulate, and precuneus. Regional higher T1‐w/T2‐w values were associated with higher CSF tau concentrations (p < .0005; r = .16 to .22) and worse MMSE scores (p < .0005; r = −.16 to −.21). These higher T1‐w/T2‐w values in AD seem to contradict previous pathological findings of demyelination and disconnectivity in AD. Future research should further investigate the biological processes reflected by increases in T1‐w/T2‐w values.

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“…Innotest calibrator concentrations ranged from 63 to 4000 pg/mL for Aβ42, 40 to 2300 pg/mL for t‐tau, and 16 to 1000 pg/mL for p‐tau. Cut‐points at our center were determined at 813 pg/mL for Aβ42 [15], 375 pg/mL for t‐tau, and 52 pg/mL for p‐tau [26]. The tubes analyzed by Elecsys were kept at −80°C until measurement within three consecutive days in May 2017 using the Elecsys Aβ42 CSF, Elecsys t‐tau CSF, and Elecsys p‐tau (181P) CSF assays (Roche Diagnostics GmbH) run on the cobas e 601 analyzer (Roche Diagnostics).…”

Section: Methodsmentioning

confidence: 99%

“…The interlaboratory variation of Innotest results has been reported to be >15% in an international quality control program (http://www.neurochem.gu.se/TheAlzAssQCprogram) [8]. Another complication is that for the Innotest an upward drift of Aβ42 values over time has been shown [8,13–15]. To reduce variation in manual immunoassays, multiplex assays or (semi)automated platforms are being developed [16–19].…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project

Willemse

Maurik

Tijms

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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Introduction We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting. Methods We collected CSF samples from 137 participants in eight local memory clinics. Amyloid β(1–42) (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed. Results Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aβ42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aβ42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aβ42 and 96% for both t-tau and p-tau. Discussion The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods.

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Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1–42 Analysis Results

Abstract: This approach may also be useful to standardize Aβ 1-42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.

Cited by 136 publications

References 33 publications

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

Gray matter T1‐w/T2‐w ratios are higher in Alzheimer's disease

Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project

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