Blood Plasma Biomarkers Research Articles

Effects of Intrahypothalamic Administration of microRNA Inhibitors and Mimetics on Blood Plasma Biomarkers in the Rat Aging.

The effect of let-7a-5p, miR-9a-3p, miR-132-3p, miR-218a-5p microRNA inhibitors and mimetics, when administered into the dorsomedial nucleus of the hypothalamus (DMN), on the markers of age-related changes in blood plasma in 3-month-old and 24-month-old male rats was studied. In the 24-month-old control rats, the content of C-reactive protein (CRP) increased, and the level of myoglobin decreased compared to the 3-month-old animals. After te administration of miRNA inhibitors, the level of CRP significantly increased, and the content of myoglobin decreased, and after the administration of miRNA mimetics, opposite changes were observed. We found no significant differences in the content of somatotropic hormone and testosterone between the control and experimental groups, as well as between the 3-month-old and 24-month-old animals.

Parotid saliva and blood biomarkers in juvenile idiopathic arthritis in relation to temporomandibular joint magnetic resonance imaging findings.

Juvenile idiopathic arthritis (JIA) often affects the temporomandibular joint (TMJ) caused by an abnormal immune system that includes overactive inflammatory processes. Salivary biomarkers may be a powerful tool that can help establishing diagnosis, prognosis and monitor disease progress. The objective was to investigate biomarkers in parotid saliva and blood plasma in relation to temporomandibular joint (TMJ) magnetic resonance imaging (MRI) findings in patients with JIA and healthy individuals. Forty-five children aged 6 to 16 years with JIA and 16 healthy age- and sex-matched controls were included. Unstimulated parotid saliva samples and venous blood were collected. Biochemical analyses were performed for the cytokine biomarkers. The participants underwent MR imaging of the TMJs, where changes in the inflammatory and the damage domains were assessed. In the JIA patients, lower concentrations of IL-6R and gp130 were found in parotid saliva than in plasma. Higher concentrations of IL-6 were found in parotid saliva than in plasma. IL-6, IL-6R and gp130 in parotid saliva explained the presence of bone marrow oedema and effusion in the JIA patients. This study suggests that the IL-6 family in parotid saliva is associated with TMJ bone marrow oedema and effusion in patients with JIA, suggesting that IL-6 has promising properties as a parotid saliva biomarker for TMJ inflammatory activity.

The Role of Alpha-Synuclein and Tubulin-Associated Unit (Tau) Proteins in the Diagnosis, Prognosis, and Treatment of Parkinson's Disease: A Systematic Review.

Parkinson's disease (PD) is a degenerative neurological disorder resulting from the death of dopaminergic neurons, which, in turn, results in impaired motor and cognitive functions. Early diagnosis is important in achieving a good prognosis for PD. Currently, the only approved way to diagnose PD is through medical history, current symptoms, and neurological examination. This, however, can only happen after PD progresses far enough in patients. Biomarkers in cerebrospinal fluid (CSF) and blood plasma, however, may provide insight into the early progress of PD and potentially concurrent dementia, which can also aid in the development of novel treatments. Specifically, this systematic review explores alpha-synuclein (α-syn) and tubulin-associated unit (Tau) proteins and analyzes their potential roles as biomarkers while also touching on nilotinib and immunotherapy as potential treatment options. PubMed, PubMed Central (PMC), Medline, and Cochrane Library serve as the databases for relevant literature, upon which eligibility criteria and quality checks - Assessment of Multiple Systematic Review (AMSTAR) tool, Newcastle-Ottawa Quality Assessment Scale, Cochrane risk-of-bias assessment 2 (RoB2), and Scale for the Assessment of Narrative Review (SANRA) - were applied. The remaining literature examines the various aspects of PD and Parkinson's disease dementia (PDD) and associated biomarkers. From 10 studies, 2,361 participants, both PD patients and healthy controls (HCs), were assessed and compared. Various assessment scales, such as the Unified Parkinson's Disease Rating Scale part III (UPDRS III), were used to ascertain the severity or progression of PD in patients while also seeking a noticeable correlation with α-syn and total Tau (t-Tau). The lack of standardized clinical testing has led to conflicting reports. Thus, while the articles generally agree on the potential efficacy of α-syn and Tau protein analysis in the diagnosis, prognosis, and treatment of PD and PDD, they also argue for further testing and trials.

Relationships between PET and blood plasma biomarkers in corticobasal syndrome.

Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS. A cohort of eighteen CBS patients (8amyloid beta [Aβ]+; 10Aβ-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake. CBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aβ- from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake. This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)- from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ- and Aβ+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake.

Blood Pressure Variability and Plasma Biomarkers of Neuronal Injury and Alzheimer's Disease: A Clinic-Based Study of Patients with Diseases Along the Heart-Brain Axis.

Higher blood pressure variability (BPV) predisposes to cognitive decline. To investigate underlying mechanisms, we measured 24-h ambulatory BPV, nocturnal dipping and orthostatic hypotension in 518 participants with vascular cognitive impairment, carotid occlusive disease, heart failure, or reference participants. We determined cross-sectional associations between BPV indices and plasma biomarkers of neuronal injury (neurofilament light chain) and Alzheimer's disease (phosphorylated-tau-181 and Aβ42/Aβ40). None of the BPV indices were significantly associated with any of the biomarkers. Hence, in patients with diseases along the heart-brain axis, we found no evidence for an association between BPV and selected markers of neuronal injury or Alzheimer's disease.

Unraveling Alzheimer's Disease: Investigating Dynamic Functional Connectivity in the Default Mode Network through DCC-GARCH Modeling.

Alzheimer's disease (AD) has a prolonged latent phase. Sensitive biomarkers of amyloid beta ( ), in the absence of clinical symptoms, offer opportunities for early detection and identification of patients at risk. Current biomarkers, such as CSF and PET biomarkers, are effective but face practical limitations due to high cost and limited availability. Recent blood plasma biomarkers, though accessible, still incur high costs and lack physiological significance in the Alzheimer's process. This study explores the potential of brain functional connectivity (FC) alterations associated with AD pathology as a non-invasive avenue for detection. While current stationary FC measurements lack sensitivity at the single-subject level, our investigation focuses on dynamic FC using resting-state functional MRI (rs-fMRI) and introduces the Generalized Auto-Regressive Conditional Heteroscedastic Dynamic Conditional Correlation (DCC-GARCH) model. Our findings demonstrate the superior sensitivity of DCC-GARCH to CSF status, and offer key insights into dynamic functional connectivity analysis in AD.

Blood plasma and urinary biomarkers of oxidative stress in cats with urethral obstruction

BackgroundThis study aimed to investigate variations of the oxidative status in cats affected by urethral obstruction (UO) under Feline Idiopathic Cystitis (FIC) and Bacterial Cystitis (BC), in comparison with a group of healthy subjects. In both groups, the levels of several markers (either direct or indirect) indicative of the oxidative attack and of the antioxidant response were analyzed on plasma and urine samples. In particular, the plasma samples were evaluated for nitric oxide (NO), hydroperoxides derived by reactive oxygen activity (d-ROMs test), superoxide anion (O2−), glutathione peroxidase activity (GPx), superoxide dismutase activity (SOD), and ferric reducing antioxidant power (FRAP test); while on urine the levels of NO, d-ROMs, FRAP, SOD, malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) were measured. Urine of UO patients was also subjected to urine-culture test.ResultsThe analytical data on plasma showed that UO, independently of the FIC or BC etiology, induced the insurgence of oxidative stress conditions at the systemic level. In the urine of the UO patients, except for SOD that increased, the markers of redox status were markedly decreased due probably their compromised filtration, thus suggesting involvement of renal function (assessed also by the high levels of plasma creatinine and proteinuria) with no oxidative damage of the lower urinary tract. Moreover, the adoption of a novel oxidative stress index’ (OSI) allowed to establish, by means of a numerical value, the different degrees of oxidative stress conditions for single UO patients, both in terms of oxidative attack and antioxidant response.ConclusionsFeline urethral obstruction, induced by Idiopathic Cystitis and Bacterial Cystitis, causes oxidative stress conditions at the systemic level that do not interest the lower urinary tract. Despite to the high variability of the profiles of oxidative stress indexes both in healthy and UO patients, the determination of OSI made possible the evaluation of their single degrees of oxidative stress. Possibly the results of this investigation can be compared with those of correspondent pathologies both in humans and in other animal species.

POLYMORPHISMS IN INFLAMMATORY CYTOKINES NOT ASSOCIATED WITH COGNITIVE TRAJECTORIES IN OLDER ADULTS

Abstract Inflammation and key polymorphisms in inflammatory cytokine genes have been associated with increased Alzheimer’s disease (AD) risk. It is unclear if the same polymorphisms also predict domain-specific cognitive decline, that could eventually lead to AD/dementia, in otherwise healthy older adults. We investigated whether specific single nucleotide polymorphisms (SNPs) in three cytokine genes, IL-1β (rs16944; A or AA at -511), IL-6 (rs1800795; C or CC at -174), and TNFα (rs1800629; A or AA at -308), were associated with differential longitudinal trajectories of global cognitive function, episodic memory, attention and working memory, and executive function. Participants were 324 non-demented older adults (Mage=72.8 years at first visit, SD=6.09, age range 57-92 years) who completed 9 research visits, on average. Slopes were examined after adjustment for baseline age, sex, education, conversion to MCI or dementia during study, and APOE ɛ4 status. Findings indicated no statistically significant relationships between the SNPs of interest and longitudinal trajectories (spanning up to 16 years) of cognitive functioning in any cognitive domain examined. Other factors related to AD may be necessary for these SNPs to have significant brain-related effects. Attempts were made to further validate the non-significant findings by conducting post-hoc analyses to determine whether these SNPs were associated with plasma biomarker levels in this sample of healthy older adults. However, variability between and within the assays precluded confidence in the results. Further research is needed to determine whether these SNP genotypes are associated with concentrations of their respective blood-plasma biomarkers in non-demented older adults.

Lower blood levels of miR‐29b‐3p in healthy middle‐aged AD risk gene carriers

AbstractBackgroundA number of late‐onset Alzheimer’s disease (AD) risk genes have been discovered, among which the most studied but not fully explored is the apolipoprotein E gene (APOE). PICALM (coding Phosphatidylinositol Binding Clathrin Assembly Protein) is another well‐recognized risk‐gene, shown to interact with the APOE gene in conferring AD risk. MicroRNAs (miRNAs) are post‐transcriptional regulators of mRNAs, some of which are known to be involved in AD pathology. The purpose of this study was to investigate in middle‐aged, healthy participants the association between AD risk‐genes (APOE and PICALM) and circulating miRNAs that were previously identified as altered in AD patients.MethodBlood samples were collected from 76 healthy individuals (36 F, 36 M; age: 56.38±3.16), assigned to three groups: A+P+ (APOE/PICALM risk), A+P‐ (APOE risk, PICALM neutral alleles) and N group (APOE/PICALM neutral alleles). RT‐qPCR was used to compare the levels of 11 microRNA identified by us in previous studies as candidate early AD biomarkers in blood plasma (hsa‐miR‐29b‐3p, hsa‐miR‐34a‐5p, hsa‐miR‐125b, hsa‐miR‐146a, hsa‐miR‐135a, hsa‐miR‐30b‐5p, hsa‐miR‐142‐3p, hsa‐miR‐200a‐3p, hsa‐miR‐483‐5p, hsa‐miR‐486‐5p, hsa‐miR‐502‐3p) [1, 2]. We followed standard procedures of blood assays.ResultSingle gene risk (APOE) carriers had lower levels of miR‐29b‐3p than non‐carriers and double risk carriers (F(2,73) = 12.75, p < 0.001 with Welch homogeneity correction; post‐hoc with Tukey correction: p < 0.01 for A+P‐ versus N, p < 0.001 for A+P‐ versus A+P+). No other changes in miRNA panels were discovered.ConclusionDownregulation of miR‐29b‐3p in blood was detected repeatedly before in patients with AD, in 4 independent studies [1]. Here we show the same effect in a subpopulation of middle‐age, healthy individuals with APOE related genetic risk for AD. Further research is needed to understand the interaction reversing this effect in PICALM risk carriers. Longitudinal follow‐up may validate this blood‐based miRNA not only as an easy‐to‐access diagnostic biomarker, but also as a risk‐assessment biomarker for AD prevention.Funding: This work was funded by the Polish National Science Centre (NCN) grant no. 2018/31/N/HS6/03551, 2016/20/W/NZ4/00354 and 2018/29/B/NZ7/02757.[1], [2] https://doi.org/10.1016/j.arr.2018.10.008; 10.18632/oncotarget.15109.

Human blood plasma biomarkers of diet and weight loss among centrally obese subjects in a New Nordic Diet intervention.

The New Nordic Diet (NND) has been shown to promote weight loss and lower blood pressure amongst obese people. This study investigates blood plasma metabolite and lipoprotein biomarkers differentiating subjects who followed Average Danish Diet (ADD) or NND. The study also evaluates how the individual response to the diet is reflected in the metabolic differences between NND subjects who lost or maintained their pre-intervention weight. Centrally obese Danes (BMI >25) followed NND (90 subjects) or ADD (56 subjects) for 6 months. Fasting blood plasma samples, collected at three time-points during the intervention, were screened for metabolites and lipoproteins (LPs) using proton nuclear magnetic resonance spectroscopy. In total, 154 metabolites and 65 lipoproteins were analysed. The NND showed a relatively small but significant effect on the plasma metabolome and lipoprotein profiles, with explained variations ranging from 0.6% for lipoproteins to 4.8% for metabolites. A total of 38 metabolites and 11 lipoproteins were found to be affected by the NND. The primary biomarkers differentiating the two diets were found to be HDL-1 cholesterol, apolipoprotein A1, phospholipids, and ketone bodies (3-hydroxybutyric acid, acetone, and acetoacetic acid). The increased levels of ketone bodies detected in the NND group inversely associated with the decrease in diastolic blood pressure of the NND subjects. The study also showed that body weight loss among the NND subjects was weakly associated with plasma levels of citrate. The main plasma metabolites associated with NND were acetate, methanol and 3-hydroxybutyrate. The metabolic changes associated with the NND-driven weight loss are mostly pronounced in energy and lipid metabolism.

A novel method of digital ELISA using single molecule amplification enables sub-attomolar detection limits for blood-based proteomics and biomarker measurements

Abstract The application of measuring low-abundance protein biomarkers in blood (serum or plasma) can often present challenges due to limits of sensitivity or precision. Digital proteomics technologies such as the digital enzyme-linked immunosorbent assay (ELISA) have enabled 1000-fold increases in sensitivity over conventional immunoassay method. However, current digital ELISA technologies can lack sufficient sensitivity to quantitatively measure many low abundance proteins in blood samples. We report the development of digital enzyme-linked immunosorbent assays (ELISAs) based on single molecule amplification with improved sensitivities over conventional digital ELISA, enabling detection of proteins at sub-attomolar concentrations. The improvements in sensitivity were based on using fewer beads to capture the target proteins (5000 vs. 500 000 beads) that increased the ratio of molecules to beads, and increasing the fraction of beads that were analyzed (bead read efficiency). Using this approach, we characterize limit of detection (LOD) of of 10–100X more sensitive than the standard digital ELISA. A digital ELISA with improved sensitivity was used to measure cytokines in serum and plasma samples with values consistently above the assay lower limits of quantitation (LLoQ). The results were consistent with a kinetic model of binding that showed that combining capture antibodies with high on-rates with high antibodies per bead yields the greatest improvement in sensitivity. The novel approach to multiplex single molecule proteomics with attomolar sensitivity provides the potential to accelerate insights in proteomics biomarkers research, clinical applications and diagnostics.

Associations of potential ADRD plasma biomarkers in cognitively normal volunteers.

This study examined the relationships between 13 novel blood-plasma biomarkers and dementia-related demographic and health factors in a cohort of 237 cognitively normal research volunteers whose average age was ≈82 years and who were 63% female. We regressed each biomarker on selected covariates to explore the associations between the biomarkers and selected factors to assess whether they may contribute to biomarker values. Post hoc sensitivity analyses were done with updated data and consistent variable sets for robustness and batch effects. Biomarker concentrations were largely not associated with demographics or health conditions, but some expected associations (e.g., apolipoprotein E [APOE] status with amyloid beta [Aβ]42/Aβ40) were observed. Post hoc results remained similar to those of the main analysis. The absence of strong associations between the biomarkers with age, gender, or medical conditions suggests that changes in these biomarkers, when observed, may be attributable to neuropathological changes. Among N = 237 cognitively normal adults, we studied candidate Alzheimer's disease and related dementia (ADRD) plasma biomarkers. Biomarkers were largely not associated with demographic or health factors. Apolipoprotein E (APOE) status was associated with amyloid beta (Aβ)42/Aβ40 ratio. These results support hypotheses that plasma biomarkers are informative for ADRD.

Contemporary techniques to the laboratory diagnosis of cognitive dysfunction (Dementia) in elderly patients.

Dementia is a severe condition affecting more than 55 million people worldwide. In elderly patients, it leads to an overall decline in memory and thinking skills. It affects the patient and those around the patient, including family and caregivers. The symptoms can become so severe that the person's ability to perform everyday activities becomes compromised. This study aims to search and collect information about the sensitivity and specificity of available laboratory diagnostic methods for patients with Dementia and identify if these methods will be effective in giving a specific and definitive diagnosis. The specificity and sensitivity of four main laboratory testing methods have been included in this review: blood panels, cerebrospinal fluid, plasma biomarkers, hormone testing, and genetic testing. The methods are each explained separately with details of their importance and which specific parameters they screen for have haven included. Numerous blood panels and laboratory diagnostic techniques have been suggested for the timely and accurate diagnosis of Dementia and its various types; however, when the sensitivity and specificity of these techniques are considered, cerebrospinal fluid (CSF) and plasma biomarkers are found to be the most effective. Alzheimer's disease (AD) and other types of Dementia are now diagnosed using the biomarkers amyloid- (A), tau, and phosphorylated tau (p-tau181). With 93 percent accuracy in diagnosis, the innovative Precivity AD test created by the Washington University School of Medicine in St. Louis might be regarded as both highly sensitive and specific.

Thermodynamic Signatures of Blood Plasma Proteome in Neurodegenerative Pathologies

Discovery of diagnostic biomarkers for age-related neurodegenerative pathologies (NDDs) is essential for accurate diagnosis, following disease progression and drug development. Blood plasma and blood cells are important peripheral sources for NDDs' biomarkers that, although present in lower concentrations than in cerebrospinal fluid, would allow noninvasive diagnostics. To identify new biomarkers for Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), in this work we have evaluated the modifications in the thermodynamic behavior of blood plasma proteome exploring differential scanning calorimetry. The plasma thermodynamics reflected the complexity and heterogeneity of the two pathologies. The unfolding temperature of the most abundant plasma protein albumin and the weighted average center of the calorimetric profile appeared as the two thermodynamic signatures that reflected modifications of the plasma proteome, i.e., strong thermal stabilization of albumin and plasma proteins' interaction network, related to both pathologies. Based on those two signatures, both PD and ALS patients were stratified in two sets, except several cases with thermodynamic parameters that strongly differed from those of the calorimetric sets. Along with modifications of the plasma thermodynamic behavior, we found altered globulin levels in all PD and ALS patients' plasma (higher level of α- and β-globulin fractions and lower level of γ-globulin fraction than the respective reference values) employing capillary electrophoresis. The presented results reveal the potential of calorimetry to indirectly identify NDDs' biomarkers in blood plasma.

Influences of intrahypothalamic administration of microrna inhibitors and mimetics on blood plasma biomarkers with aging of the rat

Influences of intrahypothalamic administration of microrna inhibitors and mimetics on blood plasma biomarkers with aging of the rat

Blood plasma biomarkers improve prediction accuracy over and above genetic predictors of Alzheimer’s disease

AbstractBackgroundPrediction models of Alzheimer’s disease using genetic information, such as polygenic risk scores, have been able to reach high levels of prediction accuracy. However, since confirmation of the disease is only possible post‐mortem, these levels of prediction accuracy are typically only achievable in pathologically confirmed cohorts. In living individuals who have been clinically assessed for AD, prediction accuracy by genetics is still good but much lower. Biomarkers can indirectly assess AD pathologies, and so may be able to bridge the prediction accuracy gap. Blood plasma biomarkers may have additional clinical utility as they are cheaper and more accessible compared to traditional CSF or PET methods.MethodWe measured five blood plasma biomarkers known to be linked to AD pathologies (Aβ40, Aβ42, GFAP, NfL, P‐tau181) in a cohort of AD cases (N=1439, mean age 68) and elderly screened controls (N=508, mean age 82). We also gathered information on APOE genotype, age at sample collection, sex, and age at onset and disease duration in cases.ResultLinear regression models showed that all biomarker measurements were associated with age at onset in cases and most were associated with disease duration. Biomarkers were also associated with age at sample collection in both cases and controls, demonstrating their effectiveness for tracking neurological change over time. Using logistic regression, we found prediction accuracies for AD status for each biomarker individually of AUC=0.56‐0.66 and by APOE and PRS AUC=0.73. A model combining all biomarkers had an AUC=0.75. The best prediction accuracy was achieved by combining all biomarkers with genetics and age at sample collection, which reached an AUC=0.81, and explained variance of R2=0.29.ConclusionWe found that blood plasma biomarkers predicted AD status and were associated with disease duration. Furthermore, biomarkers explain some variance not captured by genetic factors and therefore improve accuracy when combined in predictive models. Biomarkers also have the advantage of specificity over clinical assessments, which may confuse dementia subtypes due to phenotype similarity. Therefore, blood plasma biomarkers can be a useful tool for the assessment and prediction of AD on their own or in combination with genetic predictors.

Blood‐based biomarkers for neurodegeneration in non‐Hispanic Black and White older adults: Results from the Einstein Aging Study (EAS)

AbstractBackgroundWith recent technological advancements, neurodegenerative biomarkers (NDBMs) in blood plasma now produce results comparable to those obtained in cerebrospinal fluid, supporting the possibility of less invasive and costly determination of risk status for Alzheimer’s disease (AD). However, most research with these novel biomarkers has been in predominately non‐Hispanic (NH) White samples. Hence, little is known about distributions of these biomarkers among NH Blacks despite their elevated risk for AD.MethodBlood plasma samples were obtained from 254 older participants in the EAS who were free of dementia (mean age [SD]=77.6[4.9] years; range 70‐93 years; 66.1% female; 46.5% NH Black, 53.5% NH White; 27.2% mild cognitive impairment (MCI) as defined by Jak/Bondi criteria). AD biomarkers [β‐amyloid (Aβ40, Aβ42), pTau181], along with biomarkers of generalized neuronal damage and astrocyte activation [neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), respectively] were quantified in blood using Single molecule array (Simoa) assays on HD‐X Analyzers (Quanterix, Billerica, MA). Comparisons of NDBMs between groups were conducted using Wilcoxon rank sum test in unadjusted analyses, and linear regression models adjusting for covariates including age, gender, education, diabetes history, myocardial infarction, and hypertension.ResultWe observed lower overall levels of NDBMs in NH Blacks vs. NH Whites regardless of MCI status (Aβ40, Aβ42, and NfL (ps<0.05) see Table 1). Among NH Whites, those with MCI had higher Aβ40, Aβ42, and NfL (ps<0.05) compared to cognitively normal individuals; no significant differences by MCI status were observed among NH Blacks (not shown). The above race differences in Aβ40, Aβ42, and NfL remained evident across the full sample in linear regression analyses (adjusted for MCI status and covariates). When stratified by MCI status, race differences remained evident for NfL (regardless of MCI status); for Aβ40, race differences were evident among individuals with MCI only (see Table 2). Although individual analytes differed, the Aβ42/Aβ40 ratio did not differ by race.ConclusionNH Blacks exhibited lower overall levels of NDBMs compared to NH Whites, and associations between NDBMs and MCI were in the expected directions only among NH Whites. These race differences suggest that future work is needed to develop generalizable norms for blood‐based NDBMs.

A Cross-Sectional and Longitudinal Analysis of Pre-Diagnostic Blood Plasma Biomarkers for Early Detection of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death that typically presents at an advanced stage. No reliable markers for early detection presently exist. The prominent tumor stroma represents a source of circulating biomarkers for use together with cancer cell-derived biomarkers for earlier PDAC diagnosis. CA19-9 and CEA (cancer cell-derived biomarkers), together with endostatin and collagen IV (stroma-derived) were examined alone, or together, by multivariable modelling, using pre-diagnostic plasma samples (n = 259 samples) from the Northern Sweden Health and Disease Study biobank. Serial samples were available for a subgroup of future patients. Marker efficacy for future PDAC case prediction (n = 154 future cases) was examined by both cross-sectional (ROC analysis) and longitudinal analyses. CA19-9 performed well at, and within, six months to diagnosis and multivariable modelling was not superior to CA19-9 alone in cross-sectional analysis. Within six months to diagnosis, CA19-9 (AUC = 0.92) outperformed the multivariable model (AUC = 0.81) at a cross-sectional level. At diagnosis, CA19-9 (AUC = 0.995) and the model (AUC = 0.977) performed similarly. Longitudinal analysis revealed increases in CA19-9 up to two years to diagnosis which indicates a window of opportunity for early detection of PDAC.

Traumatized triad of complementopathy, endotheliopathy, and coagulopathy - Impact on clinical outcomes in severe polytrauma patients.

Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS<16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb >1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.

Microfluidic systems for the analysis of blood-derived molecular biomarkers.

Biomarkers are relevant indicators of the physiological state of an individual. Although biomarkers can be found in diseased tissue and different biofluids, sampling from blood plasma is relatively easy and less invasive. Among the molecular biomarkers that can be found circulating in plasma are proteins, metabolites, nucleic acids, and exosomes. Some of these plasma-circulating biomarkers are now employed for patient stratification in a broad range of diseases with high sensitivity and specificity and are useful in early diagnosis, initial risk assessment, and therapy selection. However, there is a pressing need to develop novel approaches for biomarker analysis that can be translated into clinical or other settings without complex methodologies or instrumentation. Microfluidics has been touted as a promising technology to carry out this task because it offers high-throughput, automation, multiplexed detection, and portability, possibly overcoming the bottleneck that prevent the translation of novel biomarkers to the point-of-care (POC). Here, we provide a review of the microfluidic systems that have been engineered to detect circulating molecular biomarkers in blood plasma. We also review the different microfluidic approaches for plasma enrichment, which are now being integrated with microfluidic-based biomarker analyzers. Such integration should lead to cost-effective solutions in in vitro diagnostics, with special relevance to POC platforms.