Plasma Aβ Levels Research Articles

Association of Plasma β-Amyloid with Cognitive Performance and Decline in Chronic Kidney Disease

Decreased β-amyloid (Aβ) clearance from the brain has been suggested to contribute to cerebral Aβ accumulation in Alzheimer's disease. Based on the idea of a dynamic Aβ equilibrium in different body compartments, plasma Aβ levels have been investigated as biomarker candidates for preclinical Alzheimer's pathology, yet with inconsistent results. Since the kidneys are involved in Aβ elimination from the blood, we evaluated how chronic kidney disease (CKD) affects the association between plasma Aβ and cognitive deficits and cognitive decline. In 28 CKD patients, stages 3-5D, and 26 control subjects with comparable vascular risk profile from the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, plasma total Aβ was determined with a highly sensitive electrochemiluminescence immunoassay. Cognition was evaluated using a comprehensive battery of ten neuropsychological tests at baseline and 2-year follow-up. Subjects with high plasma Aβ level (above median) demonstrated a significantly worse baseline cognitive performance than subjects exhibiting low Aβ level (summary score of global cognitive performance at baseline z=-0.46±0.76 vs z=-0.08±0.57, p=0.045). Cognitive performance moderately decreased over the 2-year follow-up in subjects with high plasma Aβ level (Δz=-0.13±0.51), but increased in subjects with low plasma Aβ level (Δz=0.16±0.41, p=0.023). In linear regression analyses, baseline plasma Aβ was significantly associated with cognitive decline both in unadjusted analyses (β=-0.28, 95% CI=-0.55 to -0.01) and analyses adjusted for age (β=-0.27, 95% CI=-0.54 to -0.01). Our results suggest the utility of plasma Aβ level in predicting cognitive decline in patients suffering from CKD.

Identifying biomarkers of dementia prevalent among amnestic mild cognitively impaired ethnic female patients.

BackgroundThere is a need to investigate biomarkers that are indicative of the progression of dementia in ethnic patient populations. The disparity of information in these populations has been the focus of many clinical and academic centers, including ours, to contribute to a higher success rate in clinical trials. In this study, we have investigated plasma biomarkers in amnestic mild cognitively impaired (aMCI) female patient cohorts in the context of ethnicity and cognitive status.MethodA panel of 12 biomarkers involved in the progression of brain pathology, inflammation, and cardiovascular disorders were investigated in female cohorts of African American, Hispanic, and White aMCI patients. Both biochemical and algorithmic analyses were applied to correlate biomarker levels measured during the early stages of the disease for each ethnicity.ResultsWe report elevated plasma Aβ40, Aβ42, YKL-40, and cystatin C levels in the Hispanic cohort at early aMCI status. In addition, elevated plasma Aβ40 levels were associated with the aMCI status in both White and African American patient cohorts by the decision tree algorithm. Eotaxin-1 levels, as determined by the decision tree algorithm and biochemically measured total tau levels, were associated with the aMCI status in the African American cohort.ConclusionsOverall, our data displayed novel differences in the plasma biomarkers of the aMCI female cohorts where the plasma levels of several biomarkers distinguished between each ethnicity at an early aMCI stage. Identification of these plasma biomarkers encourages new areas of investigation among aMCI ethnic populations, including larger patient cohorts and longitudinal study designs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0211-0) contains supplementary material, which is available to authorized users.

Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study

BackgroundHypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer’s disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. MethodsUsing data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults. ResultsResults revealed that Aβ+ older adults experienced faster decline than Aβ− older adults in all cognitive domains (Cohen’s d at 6-year assessment = 0.37–0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type. ConclusionsIn cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD.

An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation

IntroductionGiven that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. MethodsWe investigated the plasma levels of Aβ, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. ResultsAβ40 and Aβ42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aβ correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aβ42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aβ and inflammatory molecules was a strong predictor of prospective cognitive deterioration. ConclusionsOur findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.

Tong Luo Jiu Nao, a Chinese Medicine Formula, Reduces Inflammatory Stress in a Mouse Model of Alzheimer's Disease.

The aim of this study is to extend the molecular mechanism of Tong Luo Jiu Nao (TLJN) for Alzheimer's disease (AD), which is a modern Chinese formula that has been used to treat AD. The senescence-accelerated mouse prone 8 strain (SAMP8) is one of the most appropriate models to study the mechanism that underlies AD. The levels of plasma amyloid β (Aβ) and the Aβ deposits were measured using enzyme-linked immunosorbent assay and immunohistochemistry. Immunoblotting was used to observe the effect of TLJN on inflammatory mediator expression in an senescence-accelerated mouse model of AD. Our data showed that the TLJN-treated groups exhibited a reduction in plasma Aβ levels and reduced Aβ expression. Moreover, TLJN effectively attenuated Aβ-induced activation of extracellular signal-regulated kinase and c-Jun N-terminal kinases and blocked changes in inflammatory mediator expression. These data suggest that TLJN might have protective effects and could potentially act to attenuate inflammatory stress in the pathogenesis of AD.

Blood biomarkers indicate mild neuroaxonal injury and increased amyloid β production after transient hypoxia during breath-hold diving

Objective: To determine whether transient hypoxia during breath-hold diving causes neuronal damage or dysfunction or alters amyloid metabolism as measured by certain blood biomarkers.Design: Sixteen divers competing in the national Swedish championship in breath-hold diving and five age-matched healthy control subjects were included. Blood samples were collected at baseline and over a course of 3 days where the divers competed in static apnea (STA), dynamic apnea without fins (DYN1) and dynamic apnea with fins (DYN2).Main outcomes: Biomarkers reflecting brain injury and amyloid metabolism were analysed in serum (S-100β, NFL) and plasma (T-tau, Aβ42) using immunochemical methods.Results: Compared to divers’ baseline, Aβ42 increased after the first event of static apnea (p = 0.0006). T-tau increased (p = 0.001) in STA vs baseline and decreased after one of the dynamic events, DYN2 (p = 0.03). Further, T-tau correlated with the length of the apneic time during STA (ρ = 0.7226, p = 0.004) and during DYN1 (ρ = 0.66, p = 0.01).Conclusion: The findings suggest that transient hypoxia may acutely increase the levels of Aβ42 and T-tau in plasma of healthy adults, further supporting that general hypoxia may cause mild neuronal dysfunction or damage and stimulate Aβ production.

PLASMA CORTISOL, AMYLOID-B, AND COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer's disease (AD). However, little is known about the role of HPA axis dysregulation in predicting cognitive decline or in moderating the effect of high levels of amyloid-β (Aβ) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. Cognitively normal older adults (n=401) enrolled in the AIBL study underwent Aβ neuroimaging at a single timepoint. Plasma cortisol levels were obtained through a fasted blood draw. Comprehensive neuropsychological evaluation yielding measure of global cognition, episodic memory, executive function, language and attention were conducted at baseline and at 18-, 36-, and 54-month follow-up assessments. High plasma cortisol levels at baseline were associated with 2.2 times the risk of Aβ+. Furthermore, high levels of cortisol were associated with greater decline in global cognition generally, and were also found to increase the effect of Aβ+ on decline in global cognition, episodic memory, and attention. Specifically, compared to Aβ+ older adults with low cortisol, Aβ+ older adults with high cortisol had significantly faster decline on these measures, with Cohen's d values of 0.69 for episodic memory, 0.42 for global cognition and 0.31 for attention. These effects were independent of age, education, premorbid intelligence, APOE and BDNF genotypes, subjective memory complaints, vascular risk factors, and depression and anxiety symptoms. In cognitively normal older adults, high plasma cortisol levels are associated with greater decline in global cognition, and accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and attention over at 54-month period. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may help mitigate cognitive decline in the preclinical phase of AD.

Plasma β-amyloid in Alzheimer's disease and vascular disease.

Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease.

Blood-based Amyloid and Tau Biomarker Tests For Alzheimer's Disease

Background: Alzheimer’s disease (AD) is the most seen cause of dementia. Biomarker tests will be essential to improve the early diagnosis of AD, as treatment is more effective in the early stage. The biomarkers of AD are divided into two main classes: amyloid β-peptide (Aβ) accumulation, and tau-related neuronal degeneration. Peripheral blood represents an alternative sample for reflecting pathological events occurring in the body. Blood samples are a possible alternative for cerebrovascular fluid samples. The potential advantages of blood biomarkers are obvious: less invasive; simple to perform, convenient to use, and not harmful to the patient. Methods: Review publications about peripheral blood amyloid and tau biomarker tests by ELISA for AD stages; analyze and interpret data in comparison with cerebrovascular fluid results. Also review publications about peripheral messenger RNA biomarkers tests for AD diagnosis; analyze feasibility of diagnostic tests using blood messenger RNA biomarkers for AD. Results: With sensitive and specific ELISA, extensive studies of plasma Aβ42 level and Aβ42/Aβ40 ratio were reported during the development of blood-based protein biomarkers. High level of plasma Aβ42 increased risk of AD or cognitive decline. The majority of the studies also indicated that increased plasma Aβ42 level was present prior to or at the start of the development of AD, and Aβ42 level decreased as disease progressed; the lowest Aβ42/Aβ40 ratio reported was associated with developing dementia. However, some studies showed inconsistent results. Reliable methods to determine levels of tau and phosphorylated tau in blood of AD patients are still being explored. Conclusion: The effort to discover and develop diagnostic protein biomarkers in blood has not led to feasible candidate markers close to CSF. It may be helpful for each laboratory to set its own normal value or cut-offs due to different ELISA kits used. Improving clinical diagnostic criteria may be another valuable option. Development of additional biomarkers may also increase diagnostic accuracy. Compared with other technologies used in routine diagnostic tests, real time reverse transcription polymerase chain reaction (RT-qPCR) is sensitive, specific, scalable, and cost-effective. There is relatively less evidence of blood mRNAs acting as biomarkers in AD. The scientific merit and feasibility of diagnostic tests for monitoring AD progress using blood mRNAs biomarker quantification need to be established. Keywords: Alzheimer’s disease, amyloid β-peptide, biomarker, blood, ELISA, RT-qPCR, tau.

Genetic risk factor APOEε4 associates with plasma amyloid beta in amnestic mild cognitive impairment and alzheimer’s disease

Background: APOEε4 is a strong genetic risk factor for Alzheimer’s disease (AD). AD itself has been associated with reduced Aβ clearance from the brain and plasma. Understanding the potential pathogenic link between APOEε4 and plasma Aβ might allow for earlier identification of people at risk of developing AD. The aim of this study is to find out the correlation between APOEε4 and plasma Aβ in amnestic mild cognitive impairment (aMCI) and AD patients.Methods: This is a comparative cross-sectional study of patients attending a memory clinic in Siloam Hospital Lippo Karawaci, Tangerang, during the period of 2013-2014. Subjects were categorized into three categories: normal aging, aMCI, and AD. We performed blood test to examine APOEε4, plasma Aβ4o level, and plasma Aβ42 level. All data analyses were performed using correlation test and logistic regression.Results: Sixty subjects (normal aging = 23, aMCI = 17, AD = 20) were included. There were 19 (31.7%) subjects with APOEε4 positive. Subjects carrying ε4 allele were more likely to have AD by 3.9-fold than subjects with APOE ε4 allele negative. There is a significant difference between the mean of plasma Aβ40 in aMCI group and AD group. We also found correlation between APOEε4 (+) and higher plasma Aβ42 (p<0.05).Conclusion: There is a correlation between APOEε4 and plasma Aβ42 level, which supports the hypothesis that this genetic isoform accelerates the rate and progression of AD through Aβ-dependent pathways.

Increases in Plasma Aβ40 Levels and the Aβ40/42 Ratio in Patients with Diabetes Mellitus and Dementia

Aim: The plasma Aβ40/42 ratio is a possible biomarker for the onset of Alzheimer’s disease (AD). We here measured plasma Aβ40 and As42 levels in patients with diabetes mellitus (DM) and dementia in order to clarify the relationship between DM and AD. Methods: Fifty-three patients, including 33 patients with DM and 25 patients with dementia, were assessed using the Mini-mental state examination (MMSE) and brain MRI, plasma Aβ40 and Aβ42, blood sugar levels, and HbA1c % were measured, and the genotype of apolipoprotein E was determined. Plasma Aβ levels and blood sugar levels were measured in 16 out of 53 patients, following fasting and 2 hours after breakfast. Results: Plasma Aβ40 levels and the Aβ40/42 ratio were increased in the DM with dementia group (p<0.01, p<0.001), while HbA1c % correlated with the Aβ40/42 ratio in the non-dementia group. MMSE scores were also associated with the plasma Aβ40/42 ratio and Aβ40 levels in the non-dementia group, independent of the presence of ApoEe4. We did not observed significant direct responses of plasma Aβ protains to an increase in blood sugar levels. Conclusion: These results suggest that plasma Aβ metabolism are closely related chronic hyperglycemia before the onset of dementia. Hirosaki Med.J. 66:110―119,2016

Associations Between Hepatic Functions and Plasma Amyloid-Beta Levels—Implications for the Capacity of Liver in Peripheral Amyloid-Beta Clearance

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Clearance of Aβ is a promising therapeutic strategy for AD. We have previously demonstrated that peripheral organs play important roles in the clearance of brain-derived Aβ. In the present study, we recruited 46 patients with liver cirrhosis and 46 normal controls and found that plasma Aβ40 and Aβ42 levels were significantly higher in the cirrhosis patients than in the normal controls. Notably, cirrhosis patients with hepatitis B virus (HBV) infection had higher plasma Aβ40 and Aβ42 levels than HBV-negative cirrhosis patients. Besides, cirrhosis patients had significantly higher plasma levels of interleukin-1β (IL-1β) and IL-6. Plasma tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ) levels were not significantly different between the groups. Moreover, we found significant correlations of hepatic functions with plasma Aβ40 and Aβ42 levels. Plasma IL-6 levels were also significantly correlated with plasma Aβ40 levels. However, in the linear regression model, we found significant correlation of plasma Aβ40 levels with hepatic functions, but not with plasma IL-6 levels. Our results indicate that the hepatic dysfunctions might result in decreased peripheral Aβ clearance by the liver. Protecting hepatic functions might be helpful for the clearance of brain-derived Aβ in the blood.

The Relationship Between Plasma Aβ Levels, Cognitive Function and Brain Volumetrics: Sydney Memory and Ageing Study.

Determine whether (1) a relationship exists between plasma amyloid-β (Aβ)1- 40 and 1-42 peptide levels, brain volumetrics and cognitive performance in elderly individuals with and without amnestic mild cognitive impairment (aMCI), (2) plasma Aβ peptide levels differ between apolipoprotein E (APOE) ε4 carriers and non-carriers and (3) longitudinal changes in cognition and brain volume relate to Aβ levels. Subjects with aMCI (n = 89) and normal cognition (n = 126) were drawn from the Sydney Memory and Aging Study (Sydney MAS), a population based study of non-demented 70-90 year old individuals; 39 Alzheimer's disease (AD) patients were recruited from a specialty clinic. Sydney MAS participants underwent brain MRI scans and were assessed on 19 cognitive measures and were APOE ε4 genotyped. Plasma levels of Aβ1-40 and 1-42 were quantified using ELISA. Wave1 plasma levels of Aβ peptides and Aβ1-42/1-40 ratio were lower in aMCI and AD, and Aβ1-42 was positively associated with global cognition and hippocampal volume and negatively with white matter hyperintensities. The relationships of Aβ1-40 and Aβ1-42 were predominantly observed in ε4 allele carriers and non-carriers respectively. Longitudinal analysis revealed greater decline in global cognition and memory for the highest quintiles of Aβ1-42 and the ratio measure. Plasma Aβ levels and the Aβ1-42/1-40 ratio are related to cognition and hippocampal volumes, with differential associations of Aβ1-40 and Aβ1-42 in ε4 carriers and non-carriers. These data support the Aβ sink model of AD pathology, and suggest that plasma Aβ measures may serve as biomarkers of AD.

Transthyretin participates in beta-amyloid transport from the brain to the liver--involvement of the low-density lipoprotein receptor-related protein 1?

Transthyretin (TTR) binds Aβ peptide, preventing its deposition and toxicity. TTR is decreased in Alzheimer’s disease (AD) patients. Additionally, AD transgenic mice with only one copy of the TTR gene show increased brain and plasma Aβ levels when compared to AD mice with both copies of the gene, suggesting TTR involvement in brain Aβ efflux and/or peripheral clearance. Here we showed that TTR promotes Aβ internalization and efflux in a human cerebral microvascular endothelial cell line, hCMEC/D3. TTR also stimulated brain-to-blood but not blood-to-brain Aβ permeability in hCMEC/D3, suggesting that TTR interacts directly with Aβ at the blood-brain-barrier. We also observed that TTR crosses the monolayer of cells only in the brain-to-blood direction, as confirmed by in vivo studies, suggesting that TTR can transport Aβ from, but not into the brain. Furthermore, TTR increased Aβ internalization by SAHep cells and by primary hepatocytes from TTR+/+ mice when compared to TTR−/− animals. We propose that TTR-mediated Aβ clearance is through LRP1, as lower receptor expression was found in brains and livers of TTR−/− mice and in cells incubated without TTR. Our results suggest that TTR acts as a carrier of Aβ at the blood-brain-barrier and liver, using LRP1.

Reduction of Amyloid-β Plasma Levels by Hemodialysis: An Anti-Amyloid Treatment Strategy?

Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ). To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients. Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously. Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40, respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001). In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy.

Age-dependent inverse correlations in CSF and plasma amyloid-β(1-42) concentrations prior to amyloid plaque deposition in the brain of 3xTg-AD mice.

Amyloid-β (Aβ) plays a critical role as a biomarker in Alzheimer’s disease (AD) diagnosis. In addition to its diagnostic potential in the brain, recent studies have suggested that changes of Aβ level in the plasma can possibly indicate AD onset. In this study, we found that plasma Aβ(1–42) concentration increases with age, while the concentration of Aβ(1–42) in the cerebrospinal fluid (CSF) decreases in APPswe, PS1M146V and TauP301L transgenic (3xTg-AD) mice, if measurements were made before formation of ThS-positive plaques in the brain. Our data suggests that there is an inverse correlations between the plasma and CSF Aβ(1–42) levels until plaques form in transgenic mice’s brains and that the plasma Aβ concentration possesses the diagnostic potential as a biomarker for diagnosis of early AD stages.

Effects of Heart Bypass Surgery on Plasma Aβ40 and Aβ42 Levels in Infants and Young Children.

Accumulation of β-amyloid (Aβ) plaques is a pathological hallmark of Alzheimer disease. Aβ levels in animals and adults were reported to be associated with postoperative cognitive dysfunction (POCD). Our goal was to determine the plasma levels of Aβ in infants and young children after cardiac surgery with cardiopulmonary bypass (CPB).Forty-two infants and young children aged from 1 to 35 months undergoing cardiac surgery with general anesthetics were prospectively enrolled from January to June 2014 at a tertiary medical center. Perioperative plasma samples were obtained, and Aβ42 and Aβ40 levels were measured using ELISA. Other clinical characteristics of the patients were also recorded.Plasma levels of Aβ42 and Aβ40 decreased dramatically 2 hours after surgery and remained significantly lower 6 hours after operation. Baseline Aβ42 level correlated significantly with surgical intensive care unit (SICU) length of stay (LOS) and was an independent predictor for SICU LOS on multivariate analysis.Cardiac surgery with CPB decreases plasma Aβ levels. Plasma levels of Aβ42 and Aβ40 might be used as novel biomarkers for predicting outcomes in the patient population.

Alterations in the Levels of Amyloid-β, Phospholipid Hydroperoxide, and Plasmalogen in the Blood of Patients with Alzheimer's Disease: Possible Interactions between Amyloid-β and These Lipids.

Aside from accumulation of amyloid-β (Aβ) peptide in the brain, Alzheimer's disease (AD) has been reported as being associated with peroxidation of major phospholipids (e.g., phosphatidylcholine (PtdCho)) and degradation of antioxidative phospholipids (e.g., ethanolamine plasmalogen (PlsEtn)). In addition to its presence in the brain, Aβ is also found in blood; however, there is still little information about the levels of PtdCho hydroperoxide (PCOOH) and PlsEtn in the blood of patients with AD. In this study, by assuming a possible interaction among Aβ, PCOOH, and PlsEtn in blood circulation, we evaluated the levels of these molecules and correlations in blood samples that had been obtained from our former AD study for PCOOH measurement (Kiko et al., J Alzheimers Dis28, 593-600, 2012). We found that when compared to controls, plasma from patients with AD showed lower concentrations of PlsEtn species, especially PlsEtn bearing the docosahexaenoic acid (DHA) moiety. In addition, lower PlsEtn and higher PCOOH levels were observed in red blood cells (RBCs) of patients with AD. In both AD and control blood samples, RBC PCOOH levels tended to correlate with plasma levels of Aβ40, and each PlsEtn species showed different correlations with plasma Aβ. These results, together with in vitro data suggesting Aβ aggregation due to a decrease in levels of PlsEtn having DHA, led us to deduce that Aβ is involved in alterations in levels of PCOOH and PlsEtn species observed in the blood of patients with AD.

The Correlation Study between Plasma Aβ Proteins and Cerebrospinal Fluid Alzheimer's Disease Biomarkers.

Background and PurposeAlzheimer's disease (AD) is characterized by the accumulation of amyloid-β proteins (Aβ). In this study we explored the correlation of plasma Aβ40 and Aβ42 concentrations with Aβ42, total tau (tTau) and phosphorylated tau 181 (pTau181) levels in cerebrospinal fluid (CSF) in AD and control subjects to further understand the characteristics of plasma Aβ proteins levels.MethodsThe consecutive subjects (44 AD and 47 controls) in this study were recruited. The plasma levels of Aβ40 and Aβ42 were measured using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits. And the corresponding CSFs were analyzed in terms of Aβ42, tTau and pTau181 concentrations using INNOTEST ELISA kits. Further, the albumin levels were measured both in serum and CSF and albumin ratio was obtained to check the integrity of blood-brain barrier.ResultsCSF Aβ42 concentrations were significantly decreased while tTau and pTau181 levels were significantly increased in AD subjects. The plasma levels of Aβ42 were significantly lower (p=0.007), while the Aβ40/Aβ42 ratio was significantly higher (p<0.001) in AD patients than in controls. The overall plasma Aβ42 levels showed a positive correlation with those of CSF Aβ42 (p=0.001), but not with the others in CSF. In subgroup analysis, the CSF Aβ42 demonstrated positive correlation with not only plasma Aβ42 but also Aβ40 levels in controls. However, no significant relationship was noted between plasma and CSF Aβ proteins in AD group.ConclusionsThe plasma Aβ42 and Aβ40 concentrations were shown to have a close relationship with CSF Aβ42 levels in controls, but not in AD subjects. Our results suggest that the correlation between plasma Aβ40 and CSF Aβ42 levels is perturbed in AD.

A Randomized, Double-Blind, Phase 2 Study of the Effects of the Vaccine Vanutide Cridificar with QS-21 Adjuvant on Immunogenicity, Safety and Amyloid Imaging in Patients with Mild to Moderate Alzheimer's Disease.

Vanutide Cridificar (ACC-001), a novel investigational immunotherapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease (AD). To evaluate the immunogenicity, safety and impact of ACC-001 with Quillaja saponaria (QS-21) adjuvant on the reduction of brain fibrillar amyloid burden, assayed by positron emission tomography (PET) imaging, in patients with mild to moderate AD. Randomized, phase 2, interventional study. ClinicalTrials.gov Identifier: NCT01284387. Individuals with mild to moderate Alzheimer's disease (Mini-Mental State Examination scores 18-26; measurable amyloid burden in the expected range, on the screening 18F-florbetapir PET scan; and a Rosen modified Hachinski ischemic score ≤4). Participants were randomized to 3 μg or 10 μg ACC-001 (each in combination with 50 μg QS-21) or placebo (without QS-21). Primary endpoint was the change from baseline to week 104 in cerebral amyloid burden as measured by the global cortical average (GCA) standard value uptake ratio (SUVR) based on the brain 18F-florbetapir PET composite cortical SUVR between each ACC-001+QS-21 dose compared with placebo. Secondary endpoints included safety, immunogenicity and pharmacodynamics. Exploratory endpoints included cognitive and functional efficacy, and health outcome measures. Of 126 randomized patients (placebo: 40; ACC-001 3 µg+QS-21: 43; and ACC-001 10 µg+QS-21: 43), 125 received study treatment; 92 (73%) completed the study. Change in 18F-florbetapir PET GCA SUVR, was not significantly different between either of the two ACC-001+QS-21 treatment groups and placebo (3 μg +QS-21 vs. placebo diff=-0.03, p=0.54; 10 μg +QS-21 vs. placebo diff=-0.08, p=0.07), but the trend was numerically consistent with a dose response. The geometric mean peak anti-Aβ IgG titers were slightly higher in the 10 μg than the 3 μg group. The proportion of responders was similar in both dose groups of ACC-001+QS-21. The cerebrospinal fluid (CSF) p-tau changes from baseline in both active treatment groups were not statistically different from placebo, but were numerically consistent with a dose response (3 μg +QS-21 vs. placebo diff=-3.2, p=0.57; 10 μg +QS-21 vs. placebo diff=-7.0, p=0.19). The vMRI showed statistically significant faster treatment-related decrease in brain volume in the 10 μg group but was not significant in the 3 μg group, compared with placebo (3 μg diff =-1.3 mL/year, p=0.50; 10 μg diff=-4.2 mL/year, p=0.02). Measured plasma Aβ levels increased in parallel with peak anti-Aβ titers after each injection. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) were more frequent in patients who received ACC-001+QS-21 than placebo (6% vs. 0%) but none were symptomatic. The most common treatment-emergent adverse events in the active groups were injection reactions, and occurred more frequently in the ACC-001+QS-21 groups than the placebo (48% vs 8%), the majority of which were mild and transient. Primary biomarker efficacy endpoints were not statistically significant in either dose group. The numerical decreases in 18F-florbetapir PET GCA SUVR suggests a dose-related trend for greater reductions in fibrillar amyloid burden in the ACC-001+QS-21 10 µg group compared with placebo. Likewise, while not significant, there was a numerical trend of decreased CSF p-tau levels with ACC-001, possibly consistent with a downstream effect in the ACC-001+QS-21 group. Insufficient antibody titers or quality, insufficient power to detect a difference, or too short duration of follow up may be reasons why a statistically significant response was not observed. Brain volume measures showed faster volume loss in the 10 µg treatment group, similar to the effect seen in few earlier AD immunotherapy trials which may suggest removal of amyloid and resultant decrease in inflammation. No new, unexpected safety signals were detected.