Ocs Memory of a Cut Off Head Review
Alzheimers Dement (Amst). 2021; 13(one): e12182.
Comparing CSF amyloid‐beta biomarker ratios for two automated immunoassays, Elecsys and Lumipulse, with amyloid PET status
Eline A. J. Willemse
one Department of Clinical Chemical science, Neurochemistry Laboratory, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam the Netherlands,
Betty M. Tijms
2 Department of Neurology, Alzheimer Center, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam holland,
Bart N. Thou. van Berckel
iii Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam holland,
Nathalie Le Bastard
4 Fujirebio, Ghent Kingdom of belgium,
Wiesje Grand. van der Flier
2 Department of Neurology, Alzheimer Heart, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam the Netherlands,
five Department of Epidemiology and Biostatistics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam kingdom of the netherlands,
Philip Scheltens
two Department of Neurology, Alzheimer Eye, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam the netherlands,
Charlotte Due east. Teunissen
1 Department of Clinical Chemistry, Neurochemistry Laboratory, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam the Netherlands,
Received 2020 Dec 11; Revised 2021 Mar vii; Accepted 2021 Mar xv.
- Supplementary Materials
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Supporting data
GUID: 9875B797-875C-4693-B54B-C9884E7145EA
Supporting information
GUID: 7DABF05C-0CFE-450D-A609-E015FF593520
- Information Availability Argument
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The data that support the findings of this written report are available from the corresponding author upon reasonable asking.
Abstract
Introduction
Nosotros evaluated for two novel automated biomarker assays how cerebrospinal fluid (CSF) amyloid beta (Aβ)1– 42‐ratios improved the concordance with amyloid positron emission tomography (PET) positivity compared to Aβ1– 42 alone.
Methods
We selected 288 individuals from the Amsterdam Dementia Cohort across the Alzheimer'south disease clinical spectrum when they had both CSF and amyloid PET visual read available, regardless of diagnosis. CSF Aβ1– 42, phosphorylated tau (p‐tau), and total tau (t‐tau) were measured with Elecsys and Lumipulse assays, and Aβ1–twoscore with Lumipulse. CSF cut‐points were defined using receiver operating characteristic (ROC) for amyloid PET positivity.
Results
For both Elecsys and Lumipulse the p‐tau/Aβ1– 42, Aβi– 42/Aβ1– forty, and t‐tau/Aβ1– 42 ratios showed similarly skilful concordance with amyloid PET (Elecsys: 93,90,xc%; Lumipulse: 94,92,ninety%) and were college than Aβi– 42 alone (Elecsys 85%; Lumipulse 84%).
Give-and-take
Biomarker ratios p‐tau/Aβi– 42, Aβone– 42/Aβone– 40, t‐tau/Aβane– 42 on 2 automated platforms show similar optimal cyclopedia with amyloid PET in a retentivity dispensary accomplice.
Keywords: Alzheimer'due south affliction, amyloid‐beta, amyloid positron emission tomography, biomarkers, cerebrospinal fluid, concordance cut‐points, Elecsys, Lumipulse
1. INTRODUCTION
Cerebrospinal fluid (CSF) biomarkers for amyloid beta(i‐42) (Aβ1‐42), phosphorylated tau (p‐tau), and total tau (t‐tau) are function of recent research criteria to support a diagnosis of Alzheimer'south disease (Advertizement). 1 CSF Aβone‐42 concentrations decrease in the disease process when Aβ aggregates into plaques, while CSF p‐tau concentrations increase along the formation of AD‐specific tangle pathology and increases in CSF t‐tau concentrations may in addition reflect other aspects of neurodegeneration. 1 , ii These biomarkers are contradistinct in very early, pre‐clinical stages of Advertizing, when cognition is still normal. one Therefore, CSF biomarkers have been proven to be useful tools for AD diagnostics. Still, their implementation in clinical practice has been a difficult trajectory marked by obstacles such as inter‐laboratory and intra‐laboratory variation. 3 , 4 Efforts of collaborative initiatives such as BIOMARK‐ADP, 5 together with technological innovations, have led to the development of standardized operating procedures for CSF collection and storage, 6 , 7 a certified reference measurement procedure for Aβ1‐42, 8 and fully automatic assays for the CSF biomarkers that accept been calibrated against this reference method. 9 , 10 , 11 , 12 These achievements greatly reduced the variation in CSF biomarker results beyond and within laboratories. 13 The final goal of successful biomarker implementation is to institute global cut‐off values that are independent of analysis platform, cohort, or laboratory.
Because side by side generation automated assays seem to observe Aβ1‐42 more accurately than the older manual immunoassays, that is, with less interference of Aβ1‐xl, and prove different concentration ranges, ix , fourteen re‐establishment of biomarker cutting‐offs is essential. The electric current gold standard for cut‐off decision of CSF biomarkers is amyloid positron emission tomography (PET), which is approved by the Food and Drug Assistants (FDA) for in vivo amyloid pathology, or clinical diagnosis, considering a definite diagnosis of Ad tin can simply exist made at dissection. Previous studies using either Elecsys or Lumipulse assays showed that CSF biomarker ratios improved the agreement with amyloid PET compared to unmarried biomarker cut‐points. 15 , 16 , 17 , xviii , 19 , xx For example, using the Aβane‐42/Aβ1‐twoscore ratio compared to Aβ1‐42 alone improved the concordance, which is hypothesized to be due to Aβ1‐40 correcting for inter‐private biological variation in amyloid production and/or clearance, and/or Aβ1‐twoscore correcting for artificial decrease of Aβi‐42 concentrations during the pre‐analytical phase. 21 , 22 , 23 Ratios of Aβ1‐42 with p‐tau or t‐tau also improved the concordance with amyloid PET in research cohorts using either Elecsys or Lumipulse biomarkers. 15 , sixteen , 17 , eighteen , xix , 20 These findings telephone call for a head‐to‐head validation of the operation of the different biomarker estimation modalities on the dissimilar platforms in the clinical setting, such as the retentiveness clinic. Also, it remains to be addressed whether similar cut‐offs for the automated assays tin can be practical. Introduction of these automated biomarker assays in diagnostic practice calls for a re‐evaluation of the utilize of application and optimal interpretation of biomarker results in a clinical setting.
We aimed to make up one's mind how the ratios of biomarkers, Aβi– 42/Aβone– xl, p‐tau/Aβi– 42, and t‐tau/Aβ1– 42 improved bigotry of amyloid PET positivity compared to Aβ1‐42 alone in a retrospective retentivity clinic accomplice including AD and other types of dementia, to evaluate whether the improved performance was dependent on the automated platform used, and to define cut‐off values for all biomarker combinations. Last, nosotros compared our biomarker cut‐offs to previously published cut‐offs divers on the same platforms to evaluate the feasibility of a future universal cut‐off.
2. METHODS
ii.ane. Written report population
We selected CSF samples from patients from the Amsterdam Dementia Cohort 24 that visited the memory clinic between 2006 and 2016 when they had an amyloid PET scan inside one year of CSF collection available. All subjects underwent extensive neurological examination, neuropsychological testing, neuroimaging, and CSF biomarker testing as part of the diagnostic work‐up. Clinical diagnoses were established by consensus during a multidisciplinary meeting according to consensus criteria. 25 , 26 , 27 , 28 Diagnostic groups included in the current report were subjects presenting with subjective cognitive decline (SCD, n = 58), mild cerebral damage (MCI, n = 42), possible/likely AD (due north = 145), frontotemporal dementia (FTD, n = 23), dementia with Lewy bodies (DLB, northward = 6), vascular dementia (VaD, n = 5), or other dementia (northward = 9). All patients signed written informed consent to apply medical data and biomaterials for research purposes and the study was approved by the local ethical committee in accord with the Announcement of Helsinki.
two.2. CSF biomarker measurements
2.two.i. CSF collection and processing
CSF samples were obtained by lumbar puncture using a 25‐gauge needle and syringe betwixt the L3/L4, L4/L5, or L5/S1 intervertebral space, collected in polypropylene tubes and processed as previously described. 29
2.two.2. Elecsys assays
Aβi– 42, p‐tau (181P), and t‐tau (Roche Diagnostics GmbH) were analyzed in CSF samples by board‐certified technicians using the fully automated Elecsys biomarker assays. fourteen CSF of 17 samples (half dozen%) needed transfer to a 0.v mL Sarstedt tube equally the original 2.0 mL Sarstedt tubes evoked an error on the Cobas e601 analyzer due to depression sample book (< 0.v mL). No systematic effect in Aβ1– 42 results was observed between the transferred and the not‐transferred samples (data non shown). The Elecsys Aβone‐42 concentration exceeded the upper limit of detection of the assay at 1700 pg/mL in 42 cases (15%); these concentrations were included in all further analyses and graphs equally 1700 pg/mL.
2.2.3. Lumipulse assays
Next, pristine aliquots of the same samples were measured for Aβane– 42, Aβone– twoscore, p‐tau (181P), and t‐tau on the Lumipulse G 1200 system (Fujirebio Diagnostics, Inc.) nineteen , 20 , 30 , 31 by board‐certified technicians according to manufacturer's instructions. CSF of 16 samples (6%) needed transfer to a one.7 mL polystyrene Hitachi tube as the original ii.0 mL Sarstedt tubes evoked an error on the Lumipulse analyzer. No systematic effect in Aβi– 42 results was observed between the transferred and the non‐transferred samples (data not shown).
two.iii. PET amyloid imaging
Amyloid PET imaging was conducted using 11C‐PiB (northward = 86), eighteenF‐florbetaben (northward = 133), 18F‐flutemetamol (n = 64), and xviiiF‐florbetapir (n = five) tracers. 32 , 33 , 34 , 35 PET scans were evaluated based on visual reading co-ordinate to the manufacturers' guidelines by an experienced nuclear medicine physician (BvB) and included equally dichotomized scores (i.eastward., positive and negative).
2.4. Statistical analyses
Groups were dichotomized for amyloid PET status, and pair‐wise comparisons of demographic characteristics and biomarker concentrations were performed with chi‐square (for categorical variables), Student's t (for continuous variables with normal distribution), and Mann Whitney U (for continuous variables with non‐normal distribution) tests. Biomarker cut‐points were calculated based on optimal Youden's alphabetize in receiver operating curve (ROC) analyses with amyloid PET result as gold standard. Areas under the curve (AUCs) were compared pair‐wise beyond Aβone– 42, Aβ1– 42/Aβ1– forty, p‐tau/Aβ1– 42, and t‐tau/Aβi– 42 and were statistically compared per platform using 2000 bootstrapping iterations in the "roc.test" function of the "pROC" package (version one.16.ii) with D‐statistic indicating the difference between the two AUCs. 36 As the Elecsys assays did not include Aβ1– 40, the Elecsys Aβone– 42/Aβ1– forty ratio was calculated with the Lumipulse Aβi– xl result. The AUC comparisons were corrected for multiple testing using Bonferroni correction: per assay vi ratios were pair‐wise compared, P‐value threshold was 0.00833 (= 0.05/half-dozen); between assays (Elecsys versus Lumipulse) four ratios were pair‐wise compared, P‐value threshold was 0.0125 (= 0.05/4). Sensitivity, specificity, and overall pct agreements (OPAs) were calculated for all biomarkers and biomarker ratios to detect positive amyloid PET status. Spearman correlations and Passing‐Bablok regression analyses for direct comparison between Elecsys and Lumipulse biomarker concentrations were performed using the "mcr" bundle in R (version one.2.1). 37 Data analysis was performed using R statistical programming (version 3.vi.1) 38 and if not mentioned otherwise, P‐values below 0.05 were considered statistically meaning.
ii.five. Comparing of cut‐points across global cohorts
We searched the literature for publications of CSF Aβ cut‐points to decide amyloid PET positivity in other cohorts using Elecsys or Lumipulse assays to evaluate the comparability of cut‐points across these different settings and cohorts. Nosotros excluded the Elecsys Aβ1– 42/Aβ1– twoscore cut‐betoken from our cohort in the comparing, because this ratio was calculated using the Lumipulse Aβ1– xl result and no previous literature was available. Literature was selected by searching the PubMed database with combinations of terms "Elecsys" OR "Lumipulse," AND "amyloid imaging" AND "concordance." Papers that established cut‐off values for Elecsys or Lumipulse assays to determine amyloid PET positivity, assessed by title and abstract screening, were included. We chose to report only ane cutting‐point per cohort with preference for cut‐points based on Youden'south alphabetize and preference for amyloid PET outcomes based on visual reads to align with the approach of the current written report.
3. RESULTS
3.1. Cohort characteristics
We included 288 individuals in the present written report, who were on boilerplate 63 ± 7 years old; 131 (45%) were female and 179 (62%) had a positive amyloid PET read (Table1). Compared to negative, amyloid PET–positive subjects had lower Mini‐Mental Land Examination (MMSE) scores, more than often carried i or ii apolipoprotein E (APOE) ε4 allele(south), and near often had Advert‐type dementia. Median time delay between CSF collection and PET imaging was 29 days and did not differ between the amyloid PET–positive and ‐negative groups. Compared to those with normal amyloid PET, patients with abnormal amyloid PET showed decreased CSF Aβane‐42, increased CSF t‐tau and p‐tau concentrations (Table1; Effigyone), just no significant difference in CSF Aβi‐40 concentrations. In 42 cases (15%), the Elecsys Aβ1‐42 concentration exceeded the upper limit of detection of the assay at 1700 pg/mL, resulting in artificially skewed distributions. CSF Aβ1‐42 concentrations and the ratios of Aβone‐42/Aβane‐xl, p‐tau/Aβ1‐42, and t‐tau/Aβ1‐42 for both Elecsys and Lumipulse assays all showed different values for amyloid PET–positive cases compared to amyloid PET–negative cases (P < 0.001; Figure1).
TABLE 1
Cohort characteristics, stratified for amyloid PET visual read status
| Total | Amyloid PET – | Amyloid PET + | P‐value of pair‐wise comparison | |
|---|---|---|---|---|
| N | 288 | 109 | 179 | |
| Sex = f (%) | 131 (45%) | 43 (39) | 88 (49) | 0.114 |
| Historic period (mean [SD]) | 63 (seven) | 62 (8) | 63 (six) | 0.086 |
| MMSE (hateful [SD)) | 24 (four) | 26 (three) | 23 (4) | <0.001 |
| APOE ε4 carrier (%) | <0.001 | |||
| Unknown | viii (3) | 0 (0) | 8 (5) | |
| Non‐carrier | 122 (42) | 67 (62) | 55 (31) | |
| Carrier | 158 (55) | 42 (39) | 116 (65) | |
| Days between CSF drove and PET imaging (median [IQR]) | 29 [fifteen, 57] | 24 [14, 62] | 30 [sixteen, 52] | 0.435 |
| Diagnosis (%) | 2.044 | |||
| SCD | 58 (twenty) | 44 (40) | 14 (8) | |
| MCI | 42 (fifteen) | 17 (sixteen) | 25 (xiv) | |
| Advertising | 145 (50) | 10 (ix) | 135 (75) | |
| FTD | 23 (8) | 22 (xx) | 1 (1) | |
| DLB | half dozen (2) | 4 (iv) | 2 (1) | |
| VaD | five (2) | 5 (5) | 0 (0) | |
| Dementia other | 9 (iii) | vii (6) | 2 (1) | |
| Elecsys CSF Aβane‐42 (pg/mL, median [IQR]) | 852 [681, 1230] | 1522 [1097, 1700] | 742 [608, 872] | <0.001 |
| Elecsys CSF p‐tau (pg/mL, median [IQR]) | 27 [17, 39] | 15 [12, twenty] | 35 [26, 44] | <0.001 |
| Elecsys CSF t‐tau (pg/mL, median [IQR]) | 282 [196, 368] | 195 [145, 262] | 336 [268, 405] | <0.001 |
| Lumipulse CSF Aβone‐42 (pg/mL, median [IQR]) | 606 [478, 838] | 983 [692, 1312] | 529 [438, 616] | <0.001 |
| Lumipulse CSF Aβi‐forty (pg/mL, median [IQR]) | 11770 [9874, 14064] | 11853 [8739, 14106] | 11744 [10090, 14048] | 0.247 |
| Lumipulse CSF p‐tau (pg/mL, median [IQR]) | 70 [38, 115] | 33 [25, 46] | 101 [74, 129] | <0.001 |
| Lumipulse CSF t‐tau (pg/mL, median [IQR]) | 520 [355, 755] | 355 [290, 442] | 656 [502, 852] | <0.001 |
Distribution of biomarkers and biomarker ratios between the amyloid positron emission tomography (PET)‐positive and ‐negative groups. Boxplot with beeswarm 52 for Elecsys (upper row) and Lumipulse (bottom row) biomarkers amyloid beta (Aβ)ane‐42 (A), Aβane‐42/Aβ1‐42 ratio (B), phosphorylated tau/Aβ1‐42 ratio (C), and full tau/Aβ1‐42 ratio (D) in relation to an amyloid PET‐negative or ‐positive issue. Dotted lines represent the cut‐point obtained through receiver operating characteristic analysis (Table2)
3.two. Biomarker ratios are better predictors of PET amyloid positivity than Aβ1‐42 lone
We performed ROC analyses per assay with amyloid PET as reference and compared AUCs of single CSF biomarker Aβ1‐42, with ratios of Aβone‐42 with Aβ1‐forty, p‐tau, or t‐tau (Figure2, Tablestwo and3). For both platforms, the p‐tau/Aβane‐42 ratio resulted in the highest AUCs (95% conviction interval [CI]) and overall percent agreements (95% CI): 0.95 (0.89–0.96) and 93 (90–96)% for Elecsys, 0.96 (0.93–0.99) and 94 (92–97)% for Lumipulse. AUCs and overall per centum agreements were besides high for both Aβ1‐42/Aβ1‐40 (0.93 [0.89–0.96] and 90 [86–93]% for Elecsys; 0.94 [0.91–0.98] and 92 [89–96]% for Lumipulse) and t‐tau/Aβone‐42 (0.94 [0.91–0.98] and xc [86–94]% for Elecsys; 0.94 [0.90–0.97] and 90 [87–94]% for Lumipulse). For both Elecsys and Lumipulse assays, ratios with p‐tau, t‐tau, or Aβ1‐40 performed meliorate than Aβ1‐42 alone (P < 0.01). Sensitivity, specificity, and OPA percentages were largely overlapping beyond Aβ1‐42 and the Aβ1‐42 ratios, except for p‐tau/Aβi‐42 versus Aβ1‐42, for which the 95% CI of the OPA was higher and not overlapping with that of Aβ1‐42 for either Elecsys or Lumipulse. For Lumipulse, additionally, the 95% CI of the OPA for the Aβ1‐42/Aβ1‐forty ratio (upper limit at 89%) did not overlap with that of Aβ1‐42 (lower limit at 89%).
Receiver operating characteristic curves of amyloid beta (Aβ)ane‐42 alone and as ratio of Aβ1‐40, phosphorylated tau, or total tau to predict positron emission positron emission tomography (PET) amyloid positivity for the Elecsys (A) and Lumipulse (B) assays. See Table2 for areas nether the curves and concordance percentages. The grayness line represents the identity line
TABLE ii
Concordance of Elecsys and Lumipulse biomarker concentrations and ratios with amyloid PET result
| Biomarker | Method | AUC [95% CI] | Cut‐point [95% CI] | Sensitivity [95% CI] | Specificity [95% CI] | OPA [95% CI] |
|---|---|---|---|---|---|---|
| Aβane‐42 | Elecsys | 0.88 [0.83–0.92] | 1089 [864–1120] pg/mL | 91 [77–95] % | 75 [69–89] % | 85 [fourscore–89] % |
| Lumipulse | 0.88 [0.84–0.93] | 714 [606–798] pg/mL | 91 [75–98] % | 73 [65–91] % | 84 [79–89] % | |
| Aβ1‐42/Aβane‐40 | Elecsys Aβone‐42; Lumipulse Aβ1‐40 | 0.93 [0.89–0.96] | 0.091 [0.080–0.10] | 96 [86–99] % | 80 [73–91] % | 90 [86–93] % |
| Lumipulse | 0.94 [0.91–0.98] | 0.071 [0.056–0.073] | 99 [89–100] % | 83 [79–94] % | 92 [89–96] % | |
| p‐tau/Aβ1‐42 | Elecsys | 0.95 [0.92–0.98] | 0.020 [0.020–0.027] | 96 [90–98] % | 89 [84–96] % | 93 [90–96] % |
| Lumipulse | 0.96 [0.93–0.99] | 0.072 [0.052–0.095] | 97 [91–100] % | 91 [85–97] % | 94 [92–97] % | |
| t‐tau/Aβ1‐42 | Elecsys | 0.94 [0.91–0.98] | 0.277 [0.194–0.313] | 89 [83–98] % | 90 [81–97] % | 90 [86–94] % |
| Lumipulse | 0.94 [0.90–0.97] | 0.688 [0.54–0.83] | 91 [83–96] % | 90 [84–97] % | 90 [87–94] % |
Table 3
Pair‐wise statistical comparisons of AUCs from ROC analyses across biomarker concentrations and ratios
| Biomarker (ratio) comparison | Biomarker platform | D statistic | P‐value |
|---|---|---|---|
| Aβ1‐42 vs. Aβ1‐42/Aβ1‐40 | Elecsys | 3 | 0.005 |
| Aβ1‐42 vs. p‐tau/Aβ1‐42 | Elecsys | four.27 | 0.00002 |
| Aβ1‐42 vs. t‐tau/Aβane‐42 | Elecsys | 4 | 0.00006 |
| Aβ1‐42/Aβi‐forty vs. p‐tau/Aβane‐42 | Elecsys | ii.42 | 0.02 |
| Aβ1‐42/Aβ1‐forty vs. t‐tau/Aβ1‐42 | Elecsys | 2 | 0.1 |
| p‐tau/Aβ1‐42 vs. t‐tau/Aβ1‐42 | Elecsys | ii.25 | 0.02 |
| Aβ1‐42 vs. Aβi‐42/Aβane‐twoscore | Lumipulse | 3 | 0.001 |
| Aβi‐42 vs. p‐tau/Aβ1‐42 | Lumipulse | iv | 0.00002 |
| Aβane‐42 vs. t‐tau/Aβ1‐42 | Lumipulse | three | 0.002 |
| Aβane‐42/Aβ1‐40 vs. p‐tau/Aβane‐42 | Lumipulse | 1 | 0.2 |
| Aβ1‐42/Aβ1‐40 vs. t‐tau/Aβane‐42 | Lumipulse | –0.half-dozen | 0.6 |
| p‐tau/Aβ1‐42 vs. t‐tau/Aβone‐42 | Lumipulse | ii | 0.02 |
| Aβane‐42 | Elecsys vs. Lumipulse | –0.ix | 0.4 |
| Aβone‐42/Aβ1‐twoscore | Elecsys vs. Lumipulse | –two.0 | 0.02 |
| p‐tau/Aβ1‐42 | Elecsys vs. Lumipulse | –1.iv | 0.ii |
| t‐tau/Aβone‐42 | Elecsys vs. Lumipulse | 0.9 | 0.iv |
Sensitivity analyses including just patients with SCD, MCI, or Advertizing‐type dementia showed essentially similar results (Table S1 in supporting information). Biomarker cut‐points and overall percentage agreements, and their 95% CIs, for Aβ1‐42 and ratios were nearly identical. Again, for both Elecsys and Lumipulse, the p‐tau:Aβ1‐42 ratio had the highest overall percentage agreement with 95% CI not overlapping with that of Aβi‐42.
3.3. Direct comparison Aβi‐42, p‐tau, and t‐tau between Elecsys and Lumipulse
Biomarkers Aβ1‐42, p‐tau, and t‐tau correlated well betwixt Elecsys and Lumipulse assays, with Spearman correlations of 0.97, 0.96, and 0.89, respectively (all P < 0.001). Conversion formulas to interpret Elecsys to Lumipulse biomarker results obtained by Passing‐Bablok regression analyses are presented in Figure S1 in supporting data.
3.four. Comparison of cut‐points with literature
Finally, Table4 shows our cut‐points listed together with those of previous studies. Five cohorts other than the current study reported cut‐points for Elecsys biomarkers and three cohorts did so for Lumipulse biomarkers (Tabular array4). The majority of studies (four out of 6 studies; including in total 1392 patients from five independent cohorts) take used Elecsys, and only two other studies used Lumipulse (two out of vi studies, including in total 411 patients from three independent cohorts). Previous determined cut‐points used the optimized Youden's alphabetize, except for the BioFinder and Alzheimer's Illness Neuroimaging Initiative cohorts, which were calculated based on optimized performance (positive predictive understanding [PPA] and negative predictive understanding [NPA]) and stability of PPA and NPA when varying cutting‐offs slightly. For Elecsys, cutting‐offs showed comparable values for unlike markers, except for Aβ1‐42 in the Trek cohorts that had a much higher cut‐point. For Lumipulse, cut‐offs for biomarker ratios were very comparable, merely that of Aβ1‐42 was similar to Knight's Alzheimer'south Disease Enquiry Eye accomplice, but lower than the Sant Pau Initiative on Neurodegeneration (SPIN) and Eisai cohorts, probably due to differences in cohort composition.
TABLE 4
Cut‐points for Aβi‐42 and Aβ1‐42 ratios using Elecsys and Lumipulse assays in comparison to amyloid PET imaging across global cohorts
| Cohort | Cohort composition | N (%) PET + | Biomarker method | Cut‐point method | Cut‐point Aβ1‐42 (pg/mL) | Cutting‐indicate Aβone‐42/Aβ1‐40 | Cut‐point p‐tau/Aβane‐42 | Cut‐signal t‐tau/Aβ1‐4 | Amyloid PET method |
|---|---|---|---|---|---|---|---|---|---|
| ADC | due north = 58 SCD; n = 42 MCI; n = 145 AD; due north = 23 FTD; n = 6 DLB; n = 5 VaD; n = nine other dementia | 179 (62%) | Elecsys | Youden's | 1089 [95% CI: 864–1120] | 0.02 [95% CI: 0.020–0.028] | 0.277 [95% CI: 0.194–0.313] | Visual reads | |
| AIBL xv | due north = 140 CN; northward = 33 MCI; n = 27 Advertizement; n = two FTD | 84 (42%) | Elecsys | Youden's | 1054 | 0.064 | 0.0183 | 0.258 | Quantitative SUVR, dichotomized on tracer‐specific threshold |
| BioFINDER 16 | n = 120 SCD; n = 153 MCI | 110 (40%) | Elecsys | Optimized for (1) operation (PPA and NPA) and (2) stability of PPA and NPA when varying cut‐offs slightly | 1100 | n/a | 0.022 | 0.26 | Visual reads |
| ADNI 16 | north = 94 SMC (= pregnant memory business organization); n = 272 EMCI; n = 152 LMCI; n = 128 AD | 347 (54%) | Elecsys | Optimized for (one) performance (PPA and NPA) and (2) stability of PPA and NPA when varying cut‐offs slightly | 977 | n/a | 0.025 | 0.27 | Visual reads |
| Knight's ADRC 17 | Community‐dwelling volunteers involved in normal aging and dementia studies; CDR 0/0.5/one/2/3: n = 176/xviii/3/1/0 | 50 (25%) | Elecsys | Youden's | 1098 | 0.075 | 0.0198 | 0.211 | Quantitative SUVR, dichotomized on tracer‐specific threshold |
| Expedition and EXPEDITION2 xviii | n = 55 balmy Advert; n = 20 moderate Advertisement, participating in phase 3, double‐blind, placebo‐controlled international trials of solanezumab | Non reported for visual reads | Elecsys | Youden's | 1198 | 0.0233 | 0.289 | Visual reads | |
| ADC | north = 58 SCD; n = 42 MCI; n = 145 AD; due north = 23 FTD; due north = 6 DLB; n = five VaD; n = 9 other dementia | 179 (62%) | Lumipulse | Youden's | 714 [95% CI: 606–798] | 0.071 [95% CI: 0.056–0.073] | 0.072 [95% CI: 0.052–0.095] | 0.688 [95% CI: 0.54–0.83] | Visual reads |
| SPIN 19 | n = six CN; north = 35 MCI; n = 12 Advertising; n = 30 DLB; northward = 9 FTD; n = 2 other diagnoses | 59 (63%) | Lumipulse | Youden'southward | 916 | 0.062 | 0.068 | 0.62 | Visual reads |
| Eisai 20 | Subjects with early on Advertizement included in the BAN2401‐201 and MISSION AD E2609‐301/302 clinical trials; CDR 0/0.5/one/2: northward = 0/120/ten/0 | 81 (62%) | Lumipulse | Youden's | 818 | due north/a | n/a | 0.53 | Visual reads |
| Knight's ADRC 20 | Community‐dwelling volunteers involved in normal aging and dementia studies; CDR 0/0.five/ane/2: n = 165/18/3/1 | 49 (26%) | Lumipulse | Youden'due south | 732 | n/a | north/a | 0.54 | Quantitative SUVR, dichotomized on tracer‐specific threshold |
4. Word
In this large clinical sample set up with CSF and PET measures for amyloid, nosotros plant that side by side generation fully automated Elecsys and Lumipulse assays showed similar high concordance with amyloid PET (OPA: 90%–94%) when using biomarker ratios with either Aβi– forty or t‐tau or p‐tau, and improved concordance compared to CSF Aβane– 42 lone (OPA: 84%–85%). Cut‐points for Elecsys and Lumipulse biomarkers were largely comparable inside each assay, merely non beyond the two assays in a cantankerous‐cohort literature comparison.
Our finding that CSF biomarker ratios of Aβone– 42 bear witness improve concordance with the amyloid PET result than Aβ1– 42 solitary for Elecsys and Lumipulse assays is in line with previous findings. ix , fifteen , xvi , 17 , xviii , 19 , 39 , 40 This suggests that method calibration of the next‐generation assays has indeed increased the consistency in biomarker results reported across studies. It is supposed that decreases in CSF Aβ1– 42 reflect aggregation of soluble Aβone– 42 into plaques. Our, and other, results suggest that apparently the improved measurements of the soluble part of Aβone– 42 makes information technology more than hard to measure aggregation. The concordance of CSF Aβ1– 42 with amyloid PET results was ±93% with the older generation Innotest assay, but decreased to ±85% using the next‐generation assays (current study and Janelidze et al. 9 and Doecke et al. 41 ). Direct comparison studies of soluble Aβane– 42 measured with older versus newer generation assays showed an r2 of 0.eight to 0.9, which was lower than Aβone– 42 correlations between adjacent‐generation assays only, 9 , 14 , 42 suggesting that older and newer assays may non identically reverberate Aβ1– 42. We and others collectively bear witness that ratios with Aβ1– 42 for the next‐generation assays strongly meliorate concordance with amyloid PET to xc% to 95%. 15 , xvi , 17 , 18 , 19 , twenty For Aβone– 42/Aβane– 40 an explanation might be that this ratio better reflects the rate of amyloid precursor protein metabolism and as such correct for physiological Aβi–42 effects. Aβone– 42 every bit ratio of p‐tau or t‐tau might give a ameliorate reflection of aggregation likely due to the correlation of high p‐tau and t‐tau levels with amyloid plaques. 43 It might seem less intuitive to combine CSF p‐tau with Aβ1‐42 for prediction of amyloid PET, although for clinical utilize combining two hallmark pathologies instead of only the amyloid pathology contributes to a more accurate risk prediction of developing Advertizement in preclinical stages. 44
Nosotros achieved a concordance of 90% to 94% for CSF Aβane‐42 biomarkers and ratios compared to PET. The pocket-size number of cases with discordant CSF and PET results could be explained by either changes in CSF Aβane‐42 preceding those in amyloid PET 45 or amyloid PET changes preceding those in CSF. 46 Longitudinal studies showed that patients with CSF+/PET– amyloid status seem to be in the primeval stages of AD development, as they turned amyloid positive on PET within the side by side years. 46 , 48 , 49 Patients with CSF–/PET+ discordant amyloid status did not develop amyloid or tau accumulation on PET in the side by side five years, 48 only did deteriorate on cognition, 47 suggesting that CSF and PET amyloid reflect different aspects of amyloid pathology.
Comparison of biomarker cut‐points across assays and cohorts (Table4) suggests like operation of Elecsys and Lumipulse assays; these assays can thus be used interchangeably to discover amyloid positivity, provided that assay‐specific cut‐offs are used. For multicenter studies, we recommend using one type of assay or using dichotomized biomarker results based on analysis‐specific cut‐points. Information technology is important to mention that cut‐points and respective sensitivity and specificity percentages when based on Youden'due south alphabetize volition naturally show variation across cohorts that is inherent to differences in cohort compositions (i.e., diagnoses, disease severity, and age). For Lumipulse in item, larger cohorts are required to appraise the across‐cohort stability of biomarker cutting‐points. As well, cutting‐points volition depend on pre‐analytical conditions. Pre‐analytics were the same for the analyses within the electric current study, but not completely similar compared to the other studies presented in Tableiv nor to the situation deemed ideal in routine diagnostics, which is direct biomarker analysis without sample freezing. The latter would, however, be hard to implement in view of analyses of samples that are shipped, for example, from smaller memory clinics without biomarker lab facilities or for centralized biomarker analyses performed in clinical trials. Lumipulse assay standards were recalibrated confronting the certified reference material at fourth dimension of biomarker analysis in this study, 49 only the Elecsys assays were non. Recent recalibration of the Elecsys assay standards compared to Lumipulse and another assay showed the promising issue of < 9% betwixt‐assay bias in Aβ1‐42 concentrations measured in the certified reference materials. 50 Assay comparison studies in clinical cohorts should further examine the feasibility of using global cutting‐points for CSF biomarker interpretation with these recalibrated assays.
Our study was performed in a existent‐world retentivity clinic setting every bit we did not simply include patients in the AD dementia spectrum, just also other dementias such equally FTD, DLB, and VaD, which exercise not typically show amyloid pathology. The agreement of the CSF amyloid and amyloid PET results was however not different in our accomplice when we excluded diagnoses other than Ad, MCI, or SCD (15% of the original cohort), suggesting that CSF biomarkers perform well for amyloid PET positivity regardless of clinical diagnosis. This supports the use of CSF biomarkers in clinical diagnostic settings.
Considering the Aβi‐40 analysis is not commercially available for Elecsys for use in clinical practice, we here combined the Lumipulse Aβ1‐forty result with the Aβ1‐42 result from Elecsys. This resulted in an AUC of 0.93, like to AUCs reported in studies that measured the amyloid peptides on the aforementioned platform. fifteen , 17 Potential dissonance due to differences in reagents and protocols between platforms was thus not reflected in the performance of this combined ratio. To enable use of amyloid ratios in clinical exercise, we therefore suggest that the Elecsys biomarkers can be combined with the Aβ1‐twoscore result from another platform, such as Lumipulse, to obtain a ratio of Aβ1‐42/Aβ1‐40.
The major strength of this report is that we compared CSF biomarker results between two next‐generation (Elecsys and Lumipulse) assays in the same dataset. As both assays are applied in a clinical setting and for clinical trial analyses, such head‐to‐head comparison is important for future alignment of biomarker results interpretation. Our results evidence a stiff agreement betwixt biomarker ratios and amyloid PET for both platforms, meaning that biomarker outcomes from either platform reliably reflect the presence of amyloid pathology, equally long every bit the platform‐specific cut‐points are applied.
A limitation of the electric current study is that the Elecsys Aβ1‐42 analysis has its upper limit of detection at 1700 pg/mL. Although for diagnostic purposes (when biomarker status is determined for dichotomized values) this is not an result, it hampers enquiry on better understanding continuous CSF concentrations. 51 The performance of the Elecsys ratios might exist slightly underestimated by including these values every bit 1700 pg/mL, instead of their actual, higher concentration, because for ii to v cases the resulting biomarker ratio was classified as pathological (which was not the case when inbound a hypothetical higher value, due east.g., 2500 pg/mL). Another limitation could be that quantitative analyses for the PET scans were not available in this study. Visual reads, however, are the FDA‐canonical method of identifying amyloid positivity; moreover, scans were read by ane experienced nuclear medicine medico (BvB) and according to standardized procedures, which increases robustness of the reading results. Furthermore, unlike tracers were used for amyloid PET scoring, but any potential variation was minimized past using visual reads of PET results and the intra‐rater reliability of different tracers applied inside one discipline was 100% (BvB).
Altogether, based on the data here presented we recommend using the p‐tau/Aβ1‐42, Aβ1‐42/Aβ1‐40, or t‐tau/Aβ1‐42 ratio for AD pathology when using the automated assays Elecsys or Lumipulse, equally these about accurately reflect the amyloid PET upshot. These ratios tin can be used for CSF biomarker interpretation in routine clinical settings or for clinical trial evaluation.
CONFLICTS OF Interest
Eline A.J. Willemse, Betty Thousand. Tijms, Bart Northward.M. van Berckel, Wiesje M. van der Flier, Philip Scheltens, and Charlotte Eastward. Teunissen accept no competing interests to declare. Nathalie Le Bastard is a total‐fourth dimension employee of Fujirebio Europe NV, Gent, Belgium.
AUTHOR CONTRIBUTIONS
Study supervision: Philip Scheltens and Charlotte East. Teunissen. Study conception and blueprint: Eline A.J. Willemse, Betty Chiliad. Tijms, Nathalie Le Bastard, Wiesje Yard. van der Flier, Philip Scheltens, and Charlotte E. Teunissen. Data acquisition: Eline A.J. Willemse, Bart N.One thousand. van Berckel, Wiesje One thousand. van der Flier, Philip Scheltens. Assay and estimation of data: Eline A.J. Willemse, Betty M. Tijms, Wiesje M. van der Flier, Philip Scheltens, and Charlotte E. Teunissen. Drafting of the manuscript: Eline A.J. Willemse. Obtaining funding: Bart North.Thou. van Berckel, Wiesje M. van der Flier, Philip Scheltens, Nathalie Le Bastard, Charlotte E. Teunissen. All authors critically revised the manuscript for its intellectual content.
Supporting data
ACKNOWLEDGMENTS
The authors thank Joop Nijhof, Kees van Uffelen, and Lynn Boonkamp for their splendid technical assistance. We are thankful for receiving in‐kind contributions in the form of analysis kits from Roche Diagnostics and Fujirebio Europe North.5. These contributions had no influence on the results or conclusions from this study. Part of this study was funded by a ZonMW Memorabel grant (project number 733050206). Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Middle Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. PET scan costs were funded by grants of ZonMW, Piramal Imaging (at present Life‐MI), GE Healthcare, Avid Radiopharmaceuticals, and the Centre for Translational Molecular Medicine.
Notes
Willemse EAJ, Tijms BM, van Berckel BNM, et al. Comparing CSF amyloid‐beta biomarker ratios for two automatic immunoassays, Elecsys and Lumipulse, with amyloid PET status . Alzheimer'south Dement. 2021;13:e12182. 10.1002/dad2.12182 [CrossRef] [Google Scholar]
Information AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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