Plasma Neurofilament Light Chains as Blood-Based Biomarkers for Early Diagnosis of Canine Cognitive Dysfunction Syndrome.

The number of elderly dogs is increasing significantly worldwide, and many elderly dogs develop canine cognitive dysfunction syndrome (CCDS). CCDS is the canine analog of Alzheimer's disease (AD) in humans. It is very important to develop techniques for detecting CDDS in dogs. Thus, we used the detection of neurofilament light chains (NfL) in plasma as a blood-based biomarker for the early diagnosis of canine Alzheimer's disease using immunomagnetic reduction (IMR) technology by immobilizing NfL antibodies on magnetic nanoparticles. According to the 50-point CCDS rating scale, we divided 36 dogs into 15 with CCDS and 21 without the disease. The results of our IMR assay showed that the plasma NfL levels of dogs with CCDS were significantly increased compared to normal dogs (p < 0.01). By plasma biochemical analysis, we further confirmed that the liver and renal dysfunction biomarkers of dogs with CCDS were significantly elevated compared to normal dogs (p < 0.01-0.05). On the basis of our preliminary study, we propose that IMR technology could be an ideal biosensor for detecting plasma NfL for the early diagnosis of CCDS.

Applications of Immunomagnetic Reduction Technology as a Biosensor in Therapeutic Evaluation of Chinese Herbal Medicine in Tauopathy Alleviation of an AD Drosophila Model.

Alzheimer's disease (AD) is the most common form of dementia. The most convincing biomarkers in the blood for AD are currently ß-amyloid (Aß) and Tau protein because amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with AD. The development of assay technologies in diagnosing early-stage AD is very important. The study of human AD subjects is hindered by ethical and technical limitations. Thus, many studies have therefore turned to AD animal models, such as Drosophila melanogaster, to explore AD pathology. However, AD biomarkers such as Aß and p-Tau protein in Drosophilamelanogaster occur at extremely low levels and are difficult to detect precisely. In this study, we applied the immunomagnetic reduction (IMR) technology of nanoparticles for the detection of p-Tau expressions in hTauR406W flies, an AD Drosophila model. Furthermore, we used IMR technology as a biosensor in the therapeutic evaluation of Chinese herbal medicines in hTauR406W flies with Tau-induced toxicity. To uncover the pathogenic pathway and identify therapeutic interventions of Chinese herbal medicines in Tau-induced toxicity, we modeled tauopathy in the notum of hTauR406W flies. Our IMR data showed that the selected Chinese herbal medicines can significantly reduce p-Tau expressions in hTauR406W flies. Using evidence of notal bristle quantification and Western blotting analysis, we confirmed the validity of the IMR data. Thus, we suggest that IMR can serve as a new tool for measuring tauopathy and therapeutic evaluation of Chinese herbal medicine in an AD Drosophila model.

Comparing the effects of olfactory-based sensory stimulation and board game training on cognition, emotion, and blood biomarkers among individuals with dementia: A pilot randomized controlled trial.

Olfactory dysfunction can indicate early cognitive decline and is associated with dementia symptoms. We developed an olfactory-based sensory stimulation program and investigated its effects on cognition and emotion, and board game training were used as a comparison. In this parallel design pilot study, 30 participants with mild to moderate dementia were equal randomly assigned to the control (CONT), olfactory stimulation with cognitive training (OS), and board game (BG) groups. Two participants were withdrawn from CONT and OS groups, respectively. The intervention was a 12-week program with one 30-min session twice a week. We employed a blood-based biomarker technique and several cognitive and psychological tests to measure basal and after-intervention values. No significant differences were observed between the groups after intervention, as measured using the Mini-Mental State Examination, Loewenstein Occupational Therapy Cognitive Assessment (LOTCA), Top International Biotech Smell Identification Test, and Geriatric Depression Scale (GDS). The results showed that the OS group had a lower plasma Tau level than the other groups following intervention, whereas the CONT group had a significantly increased plasma amyloid ß1-42 level. OS participants had a lower concentration ratio of plasma Tau and amyloid Aß1-42 and showed more stable or improved cognition, olfactory function, and mood state. Both the OS and BG groups had a higher percentage of participants with stable or improved cognition and emotion. Taken together, these results suggest that olfactory-based sensory stimulation can be a beneficial intervention for patients with dementia. Clinical trial registration: [Clinicaltrials.gov], identifier [NCT05168098].

Effect of Time to Detection on the Measured Concentrations of Blood Proteins Associated with Alzheimer's Disease.

Background: For assays using immunomagnetic reduction, a reagent composed of antibody-functionalized magnetic nanoparticles is dispersed in phosphate-buffered saline solution. The real-time signals of alternating-current (ac) magnetic susceptibility, χac, of the reagent are subsequently recorded after mixing the reagent with a biofluid sample. After mixing the reagent and sample, the reduction in χac of the mixture is calculated and used to quantify the concentration of the target biomarker in the sample. The reduction does not occur immediately but rather occurs at some time after mixing. This observation implies that the time elapsed before recording the real-time signals of χac of a reagent-sample mixture needs to be investigated to ensure that the signals are fully recorded. In this work, the effect of time to detection on the measured concentrations of proteins in human plasma after mixing the reagent and sample is examined. Methods: The proteins analyzed are related to Alzheimer's disease: amyloid ß 1-40, amyloid ß 1-42, and Tau protein. The investigated times to detection after the mixing the reagent and sample are 0, 20, 30, 40, and 120 min. Results: The results show that the recording of real-time signals of χac should be conducted within 20 min after mixing the reagent and sample.

Neurotherapy of Yi-Gan-San, a Traditional Herbal Medicine, in an Alzheimer's Disease Model of Drosophila melanogaster by Alleviating Aß42 Expression.

Alzheimer's disease (AD), a main cause of dementia, is the most common neurodegenerative disease that is related to the abnormal accumulation of amyloid ß (Aß) proteins. Yi-Gan-San (YGS), a traditional herbal medicine, has been used for the management of neurodegenerative disorders and for the treatment of neurosis, insomnia and dementia. The aim of this study was to examine antioxidant capacity and cytotoxicity of YGS treatment by using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in vitro. We explored neuroprotective effects of YGS treatment in alleviating Aß neurotoxicity of Drosophila melanogaster in vivo by comparing survival rate, climbing index, and Aß expressions through retinal green fluorescent protein (GFP) expression, highly sensitive immunomagnetic reduction (IMR) and Western blotting assays. In the in vitro study, our results showed that scavenging activities of free radical and SH-SY5Y nerve cell viability were increased significantly (p < 0.01-0.05). In the in vivo study, Aß42-expressing flies (Aß42-GFP flies) and their WT flies (mCD8-GFP flies) were used as an animal model to examine the neurotherapeutic effects of YGS treatment. Our results showed that, in comparison with those Aß42 flies under sham treatments, Aß42 flies under YGS treatments showed a greater survival rate, better climbing speed, and lower Aß42 aggregation in Drosophila brain tissue (p < 0.01). Our findings suggest that YGS should have a beneficial alternative therapy for AD and dementia via alleviating Aß neurotoxicity in the brain tissue.

Bio-Functionalized Magnetic Nanoparticles for the Immunoassay of C-Reactive Protein and Procalcitonin in Cervicovaginal Secretions of Pregnant Women with Preterm Prelabor Rupture of Membranes to Predict Early-Onset Neonatal Sepsis.

PURPOSE: Early-onset sepsis is a major cause of neonatal morbidity and mortality. C-reactive protein (CRP) and procalcitonin (PCT) are acute phase reactants related to infection. The aim of this study was to explore the feasibility of measuring CRP and PCT concentrations in cervicovaginal secretions of pregnant women with preterm prelabor rupture of membranes (PPROM) using an immunomagnetic reduction (IMR) assay to predict early-onset neonatal sepsis. PATIENTS AND METHODS: This prospective study was performed at Mackay Memorial Hospital, Taipei, Taiwan from February 2015 to January 2018. Pregnant women with PPROM between 22 and 34 weeks of gestation were recruited. CRP and PCT concentrations in cervicovaginal secretions were measured using an IMR assay. RESULTS: Thirty-five cervicovaginal secretion samples were obtained. After excluding two neonatal deaths, early-onset neonatal sepsis was diagnosed in 15 of the 33 surviving neonates. There was no significant relationship between cervicovaginal secretion CRP level and neonatal sepsis; however, cervicovaginal secretion PCT levels were significantly higher in the neonatal sepsis group than in the non-sepsis group (45.99 vs 9.54 ng/mL, P = 0.039). Receiver operating characteristic (ROC) curve analysis revealed a PCT cut-off level of 20.60 ng/mL to predict early-onset sepsis, and the area under the ROC curve was 0.71 (95% confidence interval 0.52 to 0.90, P = 0.039), with sensitivity and specificity of 73.3% and 77.8%, respectively. CONCLUSION: Measuring the concentration of PCT in cervicovaginal secretions with an IMR assay can predict early-onset sepsis in neonates born to mothers with PPROM.

Assessment of High Risk for Alzheimer's Disease Using Plasma Biomarkers in Subjects with Normal Cognition in Taiwan: A Preliminary Study.

BACKGROUND: In Alzheimer's disease (AD), cognitive impairment begins 10-15 years later than neurodegeneration in the brain. Plasma biomarkers are promising candidates for assessing neurodegeneration in people with normal cognition. It has been reported that subjects with the concentration of plasma amyloid-ß 1-42×total tau protein higher than 455 pg2/ml2 are assessed as having a high risk of amnesic mild impairment or AD, denoted as high risk of AD (HRAD). OBJECTIVE: The prevalence of high-risk for dementia in cognitively normal controls is explored by assaying plasma biomarkers. METHODS: 422 subjects with normal cognition were enrolled around Taiwan. Plasma Aß1-40, Aß1-42, and T-Tau levels were assayed using immunomagnetic reduction to assess the risk of dementia. RESULTS: The results showed that 4.6% of young adults (age: 20-44 years), 8.5% of middle-aged adults (age: 45-64 years), and 7.3% of elderly adults (age: 65-90 years) had HRAD. The percentage of individuals with HRAD dramatically increased in middle-aged and elderly adults compared to young adults. CONCLUSION: The percentage of HRAD in cognitively normal subjects are approximately 10%, which reveals that the potentially public-health problem of AD in normal population. Although the subject having abnormal levels of Aß or tau is not definitely going on to develop cognitive declines or AD, the risk of suffering cognitive impairment in future is relatively high. Suitable managements are suggested for these high-risk cognitively normal population. Worth noting, attention should be paid to preventing cognitive impairment due to AD, not only in elderly adults but also middle-aged adults.

Investigation of the Number of Tests Required for Assaying Plasma Biomarkers Associated with Alzheimer's Disease Using Immunomagnetic Reduction.

INTRODUCTION: Concentrations of plasma biomarkers associated with Alzheimer's disease have been reported to be as low as several tens of picograms/milliliter (pg/ml). However, in assays measuring these biomarkers, it is likely that repeated measurements are necessary to obtain reliable values. METHODS: We performed assays as a single test or as duplicate, quadruplicate, fivefold and tenfold repeated tests, on samples spiked with different concentrations of amyloid ß 1-40 (Aß1-40; 1-1000 pg/ml), Aß1-42 (1-30,000 pg/ml) and total Tau protein (T-Tau; 0.1-1000 pg/ml), with the aim to to calculate the coefficients of variation (CVs). RESULTS: The results demonstrated common changes in the CVs with changes in the number of tests for a given sample: the CVs decreased with increases in the number of tests from one to ten. All CV values were distributed within the range of 0.35 to 15.5%; as such, the CV values were all lower than the acceptable value of 20%. CONCLUSION: Based on this study, a single assay of Aß1-40, Aß1-42 and T-Tau, respectively, provides reliable results in terms of the measurement of that plasma biomarker.

An Introduction to Ultrasensitive Assays for Plasma Tau Detection.

The detection of plasma tau and its phosphorylation is technically challenging due to the relatively low sensitivity. However, in Alzheimer's disease and other tauopathies, it is hypothesized that tau in the biofluid may serve as a biomarker. In recent years, several ultrasensitive assays have been developed, which can successfully detect tau and its phosphorylation in various biofluids, and collectively demonstrated the prognostic and diagnostic value of plasma tau/phosphorylated tau. Here we have summarized the principle of four ultrasensitive assays newly developed suitable for plasma tau detection, namely single-molecule array, immunomagnetic reduction assay, enhanced immunoassay using multi-arrayed fiber optics, and meso scale discovery assay, with their advantages and applications. We have also compared these assays with traditional enzyme-linked-immunosorbent serologic assay, hoping to facilitate future tau-based biomarker discovery for Alzheimer's disease and other neurodegenerative diseases.

Clinical Feasibility of Biofunctionalized Magnetic Nanoparticles for Detecting Multiple Cardiac Biomarkers in Emergency Chest Pain Patients.

BACKGROUND: The rapid diagnosis of acute myocardial infarction (AMI) is a clinical and operational priority in emergency departments. Serial serum levels of cardiac biomarkers play a crucial role in the evaluation of patients presenting with acute chest pain, so that an accurate and rapidly responsive assay of cardiac biomarkers is vital for emergency departments. METHODS: Immunomagnetic reduction (IMR) has been developed for rapid and on-site assays with a small sample volume. IMR kits for three biomarkers [myoglobin, creatine kinase-MB (CK-MB), and troponin-I] have been developed by MagQu Co., Ltd., Taiwan (US patent: US20190072563A1). In this study, we examined correlations between IMR signals and biomarker concentrations. The measurement threshold of the IMR kits, dynamic ranges, interference tests in vitro, and reagent stability were tested. Clinical cases were included with serial IMR measurements to determine the time course and peak of IMR-measured cardiac biomarkers after AMI. RESULTS: The correlations between IMR signals and biomarker concentrations fitted well to logistic functions. The measurement thresholds of the IMR kits (1.03 × 10-8 ng/mL for myoglobin, 1.46 × 10-6 ng/mL for CK-MB, and 0.08 ng/mL for troponin-I) were much lower than the levels detected in the patients with AMI. There was no significant interference in vitro. The peak times of IMR-detected myoglobin, CK-MB, and troponin-I after AMI were 8.2 hours, 24.4 hours, and 24.7 hours, respectively. CONCLUSIONS: IMR is an accurate and sensitive on-site rapid assay for multiple cardiac biomarkers in vitro, and may play a role in the early diagnosis of AMI. Clinical trials are needed.

Plasma Total α-Synuclein and Neurofilament Light Chain: Clinical Validation for Discriminating Parkinson's Disease from Normal Control.

BACKGROUND: A previously published paper (referred to as the original cohort) showed that using a cutoff value of 116.1 fg/mL for the plasma total α-synuclein concentrations could discriminate Parkinson's disease (PD) patients from normal controls (NCs). In this study, another independent cohort (referred to as the validation cohort) was recruited to validate the agreement between the clinical diagnosis and the use of plasma total α-synuclein to identify PD patients. In addition to total α-synuclein, plasma neurofilament light chain (NfL) in the validation cohort was detected. METHODS: Seventy PD patients and 33 NCs were enrolled in the validation cohort. A clinical diagnosis and the immunomagnetic reduction (IMR) assay for plasma total α-synuclein were performed for each participant. Thirty-three of 70 PD patients and 23 of 33 NCs were subjected to the plasma NfL assay via IMR. RESULTS: The positive, negative, and overall percentages of agreement between the clinical diagnosis and plasma total α-synuclein diagnosis determined based on 116.1 fg/mL as the cutoff value were found to be 0.943, 0.818, and 0.903, respectively. The PD patients and NCs showed plasma NfL levels of 8.38 ± 4.19 pg/mL and 17.6 ± 7.95 pg/mL (p < 0.001), respectively. The cutoff value of the plasma NfL level used to differentiate PD patients from NCs was 12.8 pg/mL, with sensitivity and specificity values of 0.788 and 0.870, respectively. CONCLUSION: The results demonstrate the usefulness of the plasma total α-synuclein concentration to discriminate PD patients from NCs and reveal the elevation of the plasma NfL level in PD patients.

Immunomagnetic Reduction Detects Plasma Aß1-42 Levels as a Potential Dominant Indicator Predicting Cognitive Decline.

Although the concentrations of Alzheimer's disease (AD) biomarkers Aß1-40, Aß1-42 and tau protein are very low in human plasma, ultrasensitive assays such as immunomagnetic reduction (IMR) are able to precisely quantify them. Review articles have described the detailed working mechanism of IMR and revealed the feasibility of detecting early-stage AD by assaying these plasma biomarkers with IMR. In this review, we aimed to compare the significance of these plasma biomarkers in predicting cognitive decline in patients with Down syndrome, stroke, or amnestic mild cognitive impairment based on findings in the literature. We found that plasma Aß1-42 might play the predominant role in predicting cognitive decline in these patients.

The Validation of Multifactor Model of Plasma Aß 42 and Total-Tau in Combination With MoCA for Diagnosing Probable Alzheimer Disease.

Alzheimer disease (AD) has an insidious onset and heterogeneous clinical symptoms. The well-accepted biomarkers for clinical diagnosis of AD include ß-amyloid (Aß) deposition and pathologic tau level within cerebral spinal fluid (CSF) and imaging AD pathology such as positive emission tomography (PET) imaging of the amyloid-binding agent Pittsburgh compound B (PET-PiB). However, the high expense and invasive nature of these methods highly limit their wide usage in clinic practice. Therefore, it is imperious to develop less expensive and invasive methods, and plasma biomarkers are the premium targets. In the current study, we utilized a single-blind comparison method; all the probable AD cases met the core clinical National Institute on Aging and Alzheimer's Association (NIA-AA) criteria and validated by PET-PiB. We used ultrasensitive immunomagnetic reduction (IMR) assays to measure plasma Aß 42 and total-tau (t-tau) levels, in combination with different variables including Aß42 × t-tau value, Montreal Cognitive Assessment (MoCA), and Mini Mental State Examination (MMSE). We used logistic regression to analyze the effect of all these variables in the algorism. Our results showed that (1) plasma Aß42 and t-tau are efficient biomarkers for AD diagnosis using IMR platform, whereas Aß42 × t-tau value is more efficient for discriminating control and AD; (2) in the control group, Aß42 level and age demonstrated strong negative correlation; Aß42 × t-tau value and age demonstrated significant negative correlation; (3) in the AD group, t-tau level and MMSE score demonstrated strong negative correlation; (4) using the model that Aß42, Aß42 × t-tau, and MoCA as the variable to generate receiver operating characteristic (ROC) curve, cutoff value = 0.48, sensitivity = 0.973, specificity = 0.982, area under the curve (AUC) = 0.986, offered better categorical efficacy, sensitivity, specificity, and AUC. The multifactor model of plasma Aß42 and t-tau in combination with MoCA can be a viable model separate health and AD subjects in clinical practice.

Effect of Times to Blood Processing on the Stability of Blood Proteins Associated with Dementia.

BACKGROUND: The stability of proteins in the collecting tubes after blood draw is critical to the measured concentrations of the proteins. Although the guidelines issued by the Clinical and Laboratory Standards Institute (CLSI) suggest centrifugation should take place within 2 h of drawing blood, it is very difficult to follow these guidelines in hospitals or clinics. It is necessary to study the effect of times to blood processing on the stability of the proteins of interest. METHODS: In this work, the plasma proteins of interest were those relevant to dementia, such as amyloid ß 1-40 (Aß1-40), Aß1-42, Tau protein (Tau), and α-synuclein. The times to blood processing after blood draw ranged from 0.5 to 8 h. The storage temperatures of blood were room temperature (approx. 25°C) and 30°C. After storage, blood samples were centrifuged at room temperature to obtain plasma samples. Ultrasensitive immunomagnetic reduction was applied to assay these proteins in the plasma. RESULTS: The levels of plasma Aß1-40, Tau, and α-synuclein did not significantly change until 8 h after blood draw when stored at room temperature. Plasma Aß1-42 levels did not change significantly after 8 h of storage at room temperature before blood processing. Higher storage temperatures, such as 30°C, for blood samples accelerated the significant variations in the measured concentrations of Aß1-40, Tau, and α-synuclein in plasma. CONCLUSION: According to these results, for clinical practice, it is suggested that blood samples be stored at room temperature for no longer than 4.5 h after blood draw until centrifugation for the assay of dementia biomarkers in plasma.

Indicators of rapid cognitive decline in amnestic mild cognitive impairment: The role of plasma biomarkers using magnetically labeled immunoassays.

Plasma levels of biomarkers change with the progression of Alzheimer's disease (AD), which involves the accumulation of pathological amyloid ß (Aß) and Tau protein tangles. However, few studies have investigated the association between plasma biomarkers and rapid cognitive decline in patients with amnestic mild cognitive impairment (aMCI) and AD. A total of 10 healthy controls, 24 patients with aMCI, and 19 patients with AD were enrolled. All participants underwent twice Mini-Mental State Examination (MMSE), with a mean 1.2 year interval. Immunomagnetic reduction was utilized to evaluate levels of plasma biomarkers, including amyloid ß 1-40 (Aß1-40), Aß1-42, total Tau protein, phosphorylated Tau protein (Threonine 181), and α-synuclein (α-Syn). The correlations between plasma levels of biomarkers and MMSE change were examined. Our analysis reveals that current higher plasma levels of Aß1-42 and α-Syn with the cut-off value of plasma Aß1-42 >17.26 pg/mL and α-Syn >105 fg/mL had a moderate-to-high discriminatory capacity (area under the curve >0.70) for identifying cognitive deterioration in patients with aMCI. Our results thus suggest that plasma levels of Aß1-42 and α-Syn may be considered as useful markers to assess the severity of global cognitive decline in patients with aMCI.

Plasma Levels of α-Synuclein, Aß-40 and T-tau as Biomarkers to Predict Cognitive Impairment in Parkinson's Disease.

OBJECTIVE: In this study, we assessed plasma biomarkers to identify cognitive impairment in Parkinson's disease (PD) patients by applying ultra-sensitive immunomagnetic reduction-based immunoassay (IMR). METHODS: The study enrolled 60 PD patients and 28 age- and sex-matched normal controls. Complete cognitive function assessments were performed on participants using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating. PD patients with an MMSE score of ≦26 were defined as having cognitive impairment. Meanwhile, a 99mTc-TRODAT-1 scan was performed and plasma levels of Aß-40, Aß-42, T-tau, and α-synuclein were evaluated using IMR, subsequent correlation analyses were then performed. RESULTS: Compared with normal adults, PD patients have higher plasma levels of α-synuclein and T-tau, and a lower level of Aß-40 (p < 0.05). Plasma levels of α-synuclein (r = -0.323, p = 0.002), Aß-40 (r = 0.276, p = 0.01), and T-tau (r = -0.322, p = 0.002) are significantly correlated with MMSE scores. The TRODAT scan results, including visual inspection and quantification, revealed significant correlations between Aß-40 and PD. Multiple regression analysis showed that the plasma levels of Aß-40 (OR = 0.921, 95% CI = 0.879-0.962), α-synuclein (OR = 3.016, 95% CI = 1.703-5.339), and T-tau (OR = 1.069, 95% CI = 1.026-1.115) were independently associated with PD patients with cognitive impairment. The cutoff values for predicting cognitive deficits in PD patients were 45.101 pg/ml of Aß-40, (Area under curve (AUC) = 0.791), 0.389 pg/ml of α-synuclein, (AUC = 0.790), and 30.555 pg/ml of T-tau (AUC = 0.726). CONCLUSION: Plasma levels of α-synuclein, Aß-40, and T-tau are potential biomarkers to detect cognitive impairment in PD patients.

Nanoparticle-based immunomagnetic assay of plasma biomarkers for differentiating dementia and prodromal states of Alzheimer's disease - A cross-validation study.

Blood-based biomarker assays of plasma ß-amyloid (Aß) and tau have the advantages of cost-effective and less invasive for the diagnosis of Alzheimer's disease (AD). We used two independent cohorts to cross-validate the clinical use of the nanoparticle-based immunomagnetic assay of plasma biomarkers to assist in the differential diagnosis of early AD. There were in total 160 subjects in the derivation cohort, and 242 in the validation cohort both containing controls, mild cognitive impairment due to AD and AD dementia diagnosed according to the 2011 NIA-AA guidelines. The cutoff value for plasma Aß1-42 (16.4 pg/ml) performed the best in differentiating between controls and patients with prodromal or clinical AD, with 92.5% for positive percent agreement (PPA), negative percent agreement (NPA), and overall rate of agreement (ORA). Aß1-42 × tau (642.58) was useful for separating patients with dementia and prodromal states of AD, with 84.9% PPA, 78.8% NPA and 83% ORA.

Associations between Plasma Biomarkers and Cognition in Patients with Alzheimer's Disease and Amnestic Mild Cognitive Impairment: A Cross-Sectional and Longitudinal Study.

Brain degeneration in patients with Alzheimer's disease (AD) results from the accumulation of pathological amyloid- (Aß) plaques and tau protein tangles, leading to altered plasma levels of biomarkers. However, few studies have investigated the association between plasma biomarkers and cognitive impairment in patients with AD. In this cross-sectional study, we investigated correlations between mini-mental state examination (MMSE) scores and levels of plasma biomarkers in patients with amnestic mild cognitive impairment (aMCI) and AD. Thirteen individuals with normal cognition, 40 patients with aMCI, and 37 patients with AD were enrolled. Immunomagnetic reduction was used to assess the levels of plasma biomarkers, including amyloid A1-40, A1-42, total tau protein (t-Tau), and phosphorylated tau protein (threonine 181, p-Tau181). Our analysis revealed a significant negative correlation between MMSE and both measures of tau, and a trend toward negative correlation between MMSE and A1-42. In a longitudinal study involving three patients with aMCI and two patients with AD, we observed strong negative correlations (r < -0.8) between changes in MMSE scores and plasma levels of t-Tau. Our results suggest that plasma levels of t-Tau and p-Tau181 can be used to assess the severity of cognitive impairment in patients with AD. Furthermore, the results of our preliminary longitudinal study suggest that levels of t-Tau can be used to monitor the progression of cognitive decline in patients with aMCI/AD.

Corrigendum: Age-Dependent Relationship Between Plasma Aß40 and Aß42 and Total Tau Levels in Cognitively Normal Subjects.

[This corrects the article DOI: 10.3389/fnagi.2019.00222.].

Age-Dependent Relationship Between Plasma Aß40 and Aß42 and Total Tau Levels in Cognitively Normal Subjects.

Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer's disease (AD). However, the constituents of these hallmarks, amyloid beta (Aß) 40, Aß42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23-91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of Aß40, Aß42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and Aß42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = -0.126, p = 0.0128 for Aß42), ranging from ages 23 to 91. Significant positive correlations were detected between Aß42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between Aß40 and t-Tau from age 40 to 91 (r ranged from -0.293 to -0.582) and between Aß40 and Aß42 in the age groups of 30-39 (r = -0.562, p = 0.0235), 50-59 (r = -0.261, p = 0.0142), 60-69 (r = -0.303, p = 0.0004), and 80-91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of Aß42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between Aß40, Aß42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.