Dataset Information

Antemortem CSF Aβ42/Aβ40 ratio predicts Alzheimer's disease pathology better than Aβ42 in rapidly progressive dementias.

ABSTRACT:

Objective

Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF Aβ42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF Aβ42/Aβ40 ratio. We compared CSF Aβ42 and Aβ42/Aβ40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.

Methods

We measured CSF Aβ40 and Aβ42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease (n = 159), AD (n = 12), dementia with Lewy bodies (DLB, n = 4), AD/DLB mixed pathologies (n = 5), and various other pathologies (n = 31).

Results

The score reflecting the severity of Aβ pathology showed a better correlation with ln(Aβ42/Aβ40) (R ² = 0.506, β = -0.713, P < 0.001) than with ln(Aβ42) (R ² = 0.206, β = -0.458, P < 0.001), which was confirmed after adjusting for covariates. Aβ42/Aβ40 ratio showed significantly higher accuracy than Aβ42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with Aβ42 levels ≤495 pg/mL (AUC 0.888 ± 0.032 vs. 0.518 ± 0.064). Using a cut-off value of 0.810, the analysis of Aβ42/Aβ40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate-high level of AD pathology and those with low level or no AD pathology.

Interpretation

The present data support the use of CSF Aβ42/Aβ40 ratio as a biomarker of AD pathophysiology and noninvasive screener for Aβ pathology burden, and its introduction in the research diagnostic criteria for AD.

SUBMITTER: Baiardi S

PROVIDER: S-EPMC6389744 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Antemortem CSF A<i>β</i>42/A<i>β</i>40 ratio predicts Alzheimer's disease pathology better than A<i>β</i>42 in rapidly progressive dementias.

Baiardi Simone S Abu-Rumeileh Samir S Rossi Marcello M Zenesini Corrado C Bartoletti-Stella Anna A Polischi Barbara B Capellari Sabina S Parchi Piero P

Annals of clinical and translational neurology 20181214 2

<h4>Objective</h4>Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A<i>β</i>42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF A<i>β</i>42/A<i>β</i>40 ratio. We compared CSF A<i>β</i>42 and A<i>β</i>42/A<i>β</i>40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.<h4>Methods</h4>We measure ...[more]

PMID: 30847359

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Project description:BackgroundA reduced amyloid-β (Aβ)42/40 peptide ratio in blood plasma represents a peripheral biomarker of the cerebral amyloid pathology observed in Alzheimer's disease brains. The magnitude of the measurable effect in plasma is smaller than in cerebrospinal fluid, presumably due to dilution by Aβ peptides originating from peripheral sources. We hypothesized that the observable effect in plasma can be accentuated to some extent by specifically measuring Aβ1-42 and Aβ1-40 instead of AβX-42 and AβX-40.MethodsWe assessed the plasma AβX-42/X-40 and Aβ1-42/1-40 ratios in an idealized clinical sample by semi-automated Aβ immunoprecipitation followed by closely related sandwich immunoassays. The amyloid-positive and amyloid-negative groups (dichotomized according to Aβ42/40 in cerebrospinal fluid) were compared regarding the median difference, mean difference, standardized effect size (Cohen's d) and receiver operating characteristic curves. For statistical evaluation, we applied bootstrapping.ResultsThe median Aβ1-42/1-40 ratio was 20.86% lower in amyloid-positive subjects than in the amyloid-negative group, while the median AβX-42/X-40 ratio was only 15.56% lower. The relative mean difference between amyloid-positive and amyloid-negative subjects was -18.34% for plasma Aβ1-42/1-40 compared to -15.50% for AβX-42/X-40. Cohen's d was 1.73 for Aβ1-42/1-40 and 1.48 for plasma AβX-42/X-40. Unadjusted p-values < 0.05 were obtained after .632 bootstrapping for all three parameters. Receiver operating characteristic analysis indicated very similar areas under the curves for plasma Aβ1-42/1-40 and AβX-42/X-40.ConclusionsOur findings support the hypothesis that the relatively small difference in the plasma Aβ42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring Aβ1-42/1-40 instead of AβX-42/X-40. A simplified theoretical model explaining this observation is presented.