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Chemically Treated Plasma Aβ Is a Potential Blood-Based Biomarker for Screening Cerebral Amyloid Deposition

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Chemically Treated Plasma Aβ Is a Potential Blood-Based Biomarker for Screening Cerebral Amyloid Deposition

Jong-Chan Park et al. Alzheimers Res Ther.

Abstract

Background: Plasma β-amyloid (Aβ) is a potential candidate for an Alzheimer's disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aβ is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aβ levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aβ levels in the blood of patients with AD. If a consistent value of plasma Aβ from the blood can be obtained, this might help determine whether plasma Aβ is a potential biomarker for AD diagnosis.

Methods: We predicted the brain amyloid deposit by measuring the plasma Aβ levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) in a stable manner using xMAP technology.

Results: MPP-Aβ40 and MPP-Aβ42/40 (MPP-Aβs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB-) (P < 0.0001). Furthermore, MPP-Aβ40 (P < 0.0001, r = 0.23) and MPP-Aβ42/40 ratio (P < 0.0001, r = -0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aβ42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition.

Conclusions: MPP-Aβ might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain.

Keywords: Alzheimer’s disease; Blood-based biomarker; MPP; Pittsburgh-compound B positron emission tomography; Plasma Aβ; β-amyloid.

Figures

Fig. 1
Fig. 1
Categorized subject groups. a Classification of subjects (n = 353) for the study. b Representative PiB-PET images of the study cohort (n = 353). Participants were classified as PiB-positive (PiB+) if the PiB retention (SUVR) value was >1.4 in at least one of the four ROIs (i.e., frontal, lateral temporal, lateral parietal, and PC-PRC) or PiB-negative (PiB–) if the SUVR values of all four ROIs were ≤1.4. – or + PiB-PET positivity, CN cognitively normal, MCI mild cognitive impairment, ADD Alzheimer’s disease dementia, ND nondemented, PiB-PET Pittsburgh-compound B positron emission tomography, SUVR standard uptake value ratio (Color figure online)
Fig. 2
Fig. 2
POC for the effects of MPP on Aβ quantification. a Gel electrophoresis for synthetic Aβ42 form assay. Twenty microliters of 8% DMSO in 1× PBS (–MPP) or 20 μl of 8% MPP solution in 1× PBS (+MPP) was added to 20 μl of 2 μM Aβ42 (final concentration, 1 μM; aliquots from the same pool, in separate 1.5-ml tubes, n = 4), and the samples were electrophoresed. Band intensity squared deviation ((value – mean value)2) indicates how far each point is from the mean value (**P < 0.01, F test to compare variances; each n = 4). b Gel electrophoresis for synthetic Aβ42 form assay with the original plasma sample. Twenty microliters of 8% DMSO and 25% plasma in 1× PBS (–MPP) or 20 μl of 8% MPP and 25% plasma in 1× PBS (+MPP) was added to 20 μl of 2 μM Aβ42 (final concentration, 1 μM; aliquots from the same pool, in separate 1.5-ml tubes, n = 4), and the samples were electrophoresed. Band intensity squared deviation indicates how far each point is from the mean value (# P < 0.1, a trend toward significance; **P < 0.01, F test to compare variances; each n = 4). c Repetitive measurement of synthetic Aβ42 (aliquots from the same pool, in separate 1.5-ml tubes, n = 6) using xMAP technology, with or without MPP and/or HSA. HSA was used for mimicking blood plasma condition. Squared deviation indicates how far each point is from the mean value (**P < 0.01 and ***P < 0.001, F test to compare variances). d Repetitive measurement (aliquots from the same pooled plasma, in separate 1.5-ml tubes, n = 5) of plasma Aβ42 and Aβ40 using xMAP technology, with or without MPP. Squared deviation indicates how far each point is from the mean value (*P < 0.05 and **P < 0.01, F test to compare variances). e Quantification of plasma Aβ42 and Aβ40 in a time-dependent manner using xMAP technology, with or without 4% MPP solution in Bioplex sample diluent buffer (n = 4, independent individual plasma samples; *P < 0.05, unpaired t test for –MPP vs + MPP at each time point). m monomeric Aβ; o oligomeric Aβ, β-amyloid, MPP mixture of protease inhibitors and phosphatase inhibitors, HSA human serum albumin
Fig. 3
Fig. 3
POC for the effect of MPP on distinction between subjects. a Intergroup differences in the plasma Aβ concentration with or without 4% MPP solution using xMAP technology. MCI+ and ADD+ subjects show significantly decreased levels of MPP-Aβ42 and MPP-Aβ42/40 ratio compared with CN– subjects (**P < 0.01 and ***P < 0.001 respectively; ANOVA followed by Tukey’s multiple comparison test; CN–, n = 20; MCI+, n = 12; ADD+, n = 23; total subjects, n = 55). b Correlation of global PiB deposition (SUVR) and MPP-Aβs. MPP-Aβ42 level (***P < 0.001, r = –0.47; Pearson’s correlation) and MPP-Aβ42/40 ratio (**P < 0.01, r = –0.39; Pearson’s correlation) are correlated with global PiB deposition (SUVR). β-amyloid, MPP mixture of protease inhibitors and phosphatase inhibitors, MCI mild cognitive impairment, ADD Alzheimer’s disease dementia, CN cognitively normal, SUVR standard uptake value ratio, PiB Pittsburgh compound B, – or + PiB negativity or positivity
Fig. 4
Fig. 4
MPP-Aβs reflect the pathological load of Aβ in the brain. a Intergroup differences of MPP-Aβ levels using xMAP technology (*P < 0.05 and **P < 0.01, unpaired t test; § P < 0.05, §§ P < 0.01, and §§§ P < 0.001, ANOVA followed by Tukey’s multiple comparison test; # P < 0.10, unpaired t test, trend toward significance; CN–, n = 187, CN+, n = 28, MCI–, n = 50, MCI+, n = 29, ADD–, n = 16, ADD+, n = 43; total subjects n = 353). b Correlation of global PiB deposition (SUVR) and MPP-Aβs (n = 353, ***P < 0.0001; Pearson’s correlation). c, d MPP-Aβ42, MPP-Aβ40, and MPP-Aβ42/40 levels in ND– (n = 237; CN– and MCI–), ND+ (n = 57; CN+ and MCI+), PiB– (n = 253; CN–, MCI–, and ADD–), and PiB+ (n = 100; CN+, MCI+, and ADD+) (**P < 0.01, and ***P < 0.001, unpaired t test). β-amyloid, MPP mixture of protease inhibitors and phosphatase inhibitors, MCI mild cognitive impairment, ADD Alzheimer’s disease dementia, CN cognitively normal, SUVR standard uptake value ratio, PiB Pittsburgh compound B, – or + PiB negativity or positivity, ND nondemented
Fig. 5
Fig. 5
Logistic regression model and ROC curve analysis for PiB-PET prescreening ROC curve model using a combination of variables (MPP-Aβs, gender, age, and ApoE types) following the logistic regression analysis comparing (a) ND– and ND+ or (b) PiB– and PiB+. See details in Table 3. PiB Pittsburgh compound B, – or + PiB negativity or positivity, ND nondemented, ApoE apolipoprotein E, MPP-Aβ MPP-treated plasma β-amyloid, AUC area under curve

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