Clinical Application of Blood Biomarkers in Neurodegenerative Diseases-Present and Future Perspectives.

Neurodegenerative diseases are a group of complex diseases characterized by a progressive loss of neurons and degeneration in different areas of the nervous system. They share similar mechanisms, such as neuroinflammation, oxidative stress, and mitochondrial injury, resulting in neuronal loss. One of the biggest challenges in diagnosing neurodegenerative diseases is their heterogeneity. Clinical symptoms are usually present in the advanced stages of the disease, thus it is essential to find optimal biomarkers that would allow early diagnosis. Due to the development of ultrasensitive methods analyzing proteins in other fluids, such as blood, huge progress has been made in the field of biomarkers for neurodegenerative diseases. The application of protein biomarker measurement has significantly influenced not only diagnosis but also prognosis, differentiation, and the development of new therapies, as it enables the recognition of early stages of disease in individuals with preclinical stages or with mild symptoms. Additionally, the introduction of biochemical markers into routine clinical practice may improve diagnosis and allow for a stratification group of people with higher risk, as well as an extension of well-being since a treatment could be started early. In this review, we focus on blood biomarkers, which could be potentially useful in the daily medical practice of selected neurodegenerative diseases.

Association of early blood-based biomarkers and six-month functional outcomes in conventional severity categories of traumatic brain injury: capturing the continuous spectrum of injury.

BACKGROUND: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. METHODS: Exposure-response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. FINDINGS: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13-15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13-15 and positive CT (1.21-2.81), GCS 9-12 (1.16-2.02), GCS 3-8 (1.09-1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51-1.80) percentages of unfavourable outcome were 37-51% in the lowest quintiles of biomarker levels and reached 90-94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83-3.79), the percentages were 2-4% and 19-28% in the lowest and highest biomarker quintiles, respectively. INTERPRETATION: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. FUNDING: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Dietary flavonoid intake and risk of hormone-related cancers: A population-based prospective cohort study.

BACKGROUND: Dietary flavonoids may have potential effects on hormone-related cancers (HRCs) due to their anti-cancer properties via regulating hormones and suppressing inflammation and oxidative stress. We aimed to examine the association of flavonoid intake with risks of HRCs and whether this association was mediated by blood biomarkers involved in biological mechanisms. METHODS: This prospective cohort study from UK Biobank included 187,350 participants free of cancer when the last dietary recall was completed. The dietary intakes of flavonoids and subclasses were assessed using 24-hour dietary recalls. Venous blood was collected at baseline and assayed for biomarkers of inflammation, hormones, and oxidative stress. Hazard ratios (HR) and 95 % confidential intervals (CI) for the associations between flavonoid intake and HRCs risk were estimated by the cause-specific Cox proportional hazards model. The role of blood biomarkers in the flavonoids-HRCs association was investigated through mediation analysis. RESULTS: Over a median follow-up of 9.5 years, 3,392 female breast cancer, 417 ovarian cancer, 516 endometrial cancer, 4,305 prostate cancer, 45 testicular cancer, and 146 thyroid cancer cases were documented. Compared to the lowest quintile, multivariable-adjusted HRs (95 % CIs) in the highest quintile of total flavonoid intake were 0.89 (0.80-0.99) for breast cancer, 0.68 (0.50-0.92) for ovarian cancer, and 0.88 (0.80-0.98) for female-specific cancers. For subclasses, intakes of flavonols and anthocyanidins were inversely associated with the risk of female-specific cancers (Ptrend <0.05). Anthocyanidin intake was positively related to prostate cancer risk, whereas isoflavone intake was inversely linked to thyroid cancer risk (Ptrend <0.05). Additionally, certain biomarkers of inflammation, hormones and oxidative stress jointly mediated the association of flavonoid intake with the risk of female-specific cancers and prostate cancer. CONCLUSIONS: Our findings highlighted the importance of dietary flavonoids for the prevention of HRCs in the general population, providing epidemiological evidence for dietary guidelines.

Blood-based protein biomarkers during the acute ischemic stroke treatment window: a systematic review.

Background: Rapid and accurate acute ischemic stroke (AIS) diagnosis is needed to expedite emergent thrombolytic and mechanical thrombectomy treatment. Changes in blood-based protein biomarkers during the first 24 h of AIS, the time window for treatment, could complement imaging techniques and facilitate rapid diagnosis and treatment. Methods: We performed a systematic review according to PRISMA guidelines. MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies comparing levels of blood-based protein biomarkers in AIS patients with levels in healthy controls and stroke mimics. Protein biomarkers from the following pathophysiological categories were included: neurovascular inflammation (MMP-9, TNF-alpha), endothelial integrity (VCAM-1, ICAM-1), cell migration (E-Selectin, P-Selectin, L-Selectin), markers of glial and neuronal origin (GFAP, S100, S100B, NSE), and cardiac dysfunction (BNP, NT-proBNP). The literature search was limited to English-language publications before November 7th, 2023. Results: A total of 61 studies from 20 different countries were identified, which included in total, 4,644 AIS patients, 2,242 stroke mimics, and 2,777 controls. Studies investigating TNF-alpha, MMP-9, VCAM-1, ICAM-1, E-Selectin, L-Selectin, GFAP, NSE, and S100B showed pronounced methodological heterogeneity, making between-study comparisons difficult. However, in 80% of NT-proBNP and BNP studies, and all P-selectin studies, higher biomarker levels were observed in AIS patients compared to healthy controls and/or patients with stroke mimics. Conclusion: None of the biomarkers included showed sufficient evidence for additional diagnostic benefit for AIS. Comprehensive standardized global multicenter studies are needed to (1) permit comparability, (2) enable valid statements about protein-based biomarkers, and (3) reflect real-world scenarios.

Machine learning approach to predict blood-secretory proteins and potential biomarkers for liver cancer using omics data.

Identifying non-invasive blood-based biomarkers is crucial for early detection and monitoring of liver cancer (LC), thereby improving patient outcomes. This study leveraged computational approaches to predict potential blood-based biomarkers for LC. Machine learning (ML) models were developed using selected features from blood-secretory proteins collected from the curated databases. The logistic regression (LR) model demonstrated the optimal performance. Transcriptome analysis across 7 LC cohorts revealed 231 common differentially expressed genes (DEGs). The encoded proteins of these DEGs were compared with the ML dataset, revealing 29 proteins overlapping with the blood-secretory dataset. The LR model also predicted 29 additional proteins as blood-secretory with the remaining protein-coding genes. As a result, 58 potential blood-secretory proteins were obtained. Among the top 20 genes, 13 common hub genes were identified. Further, area under the receiver operating characteristic curve (ROC AUC) analysis was performed to assess the genes as potential diagnostic blood biomarkers. Six genes, ESM1, FCN2, MDK, GPC3, CTHRC1 and COL6A6, exhibited an AUC value higher than 0.85 and were predicted as blood-secretory. This study highlights the potential of an integrative computational approach for discovering non-invasive blood-based biomarkers in LC, facilitating for further validation and clinical translation. SIGNIFICANCE: Liver cancer is one of the leading causes of premature death worldwide, with its prevalence and mortality rates projected to increase. Although current diagnostic methods are highly sensitive, they are invasive and unsuitable for repeated testing. Blood biomarkers offer a promising non-invasive alternative, but their wide dynamic range of protein concentration poses experimental challenges. Therefore, utilizing available omics data to develop a diagnostic model could provide a potential solution for accurate diagnosis. This study developed a computational method integrating machine learning and bioinformatics analysis to identify potential blood biomarkers. As a result, ESM1, FCN2, MDK, GPC3, CTHRC1 and COL6A6 biomarkers were identified, holding significant promise for improving diagnosis and understanding of liver cancer. The integrated method can be applied to other cancers, offering a possible solution for early detection and improved patient outcomes.

Exercise effects on brain health and learning from minutes to months: The brain EXTEND trial.

Despite evidence that aerobic exercise benefits the aging brain, in particular the hippocampus and memory, controlled clinical trials have not comprehensively evaluated effects of aerobic exercise training on human memory in older adults. The central goal of this study was to determine chronic effects of moderate-to-vigorous intensity aerobic exercise on the hippocampus and memory in non-demented, inactive adults ages 55-80 years. We determine effects of aerobic exercise training with a 6-month randomized controlled trial (RCT) comparing 150 min/week of home-based, light intensity exercise with progressive moderate-to-vigorous intensity aerobic exercise. For the first time in a large trial, we examined temporal mechanisms by determining if individual differences in the rapid, immediate effects of moderate intensity exercise on hippocampal-cortical connectivity predict chronic training-related changes over months in connectivity and memory. We examined physiological mechanisms by testing the extent to which chronic training-related changes in cardiorespiratory fitness are a critical factor to memory benefits. The Exercise Effects on Brain Connectivity and Learning from Minutes to Months (Brain-EXTEND) trial is conceptually innovative with advanced measures of hippocampal-dependent learning and memory processes combined with novel capture of the physiological changes, genetic components, and molecular changes induced by aerobic exercise that change hippocampal-cortical connectivity. Given that hippocampal connectivity deteriorates with Alzheimer's and aerobic exercise may contribute to reduced risk of Alzheimer's, our results could lead to an understanding of the physiological mechanisms and moderators by which aerobic exercise reduces risk of this devastating and costly disease.

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

BACKGROUND: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). METHODS: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. RESULTS: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. CONCLUSIONS: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

A Randomized, Crossover Trial Assessing Appetite, Energy Metabolism, Blood Biomarkers, and Ad Libitum Food Intake Responses to a Mid-Morning Pecan Snack vs. an Equicaloric High-Carbohydrate Snack in Healthy Volunteers with Overweight/Obesity.

BACKGROUND: The differential effects of pecans versus other popular snack foods on appetite and blood markers of metabolism and satiety have not been well studied. This study investigated the effects of a single mid-morning snack of pecans or tortilla chips on subjective appetite, food intake, blood measures of hormones and metabolites, and resting energy expenditure. METHODS: Twenty participants with overweight and obesity were enrolled in a within-participants, randomized crossover trial. Participants had indwelling catheters placed for blood sampling and were fed a standardized breakfast, followed two hours later by a 250 kcal snack of either pecans or tortilla chips, and then by a self-selected lunch. Visual analog scale (VAS) appetite measures, blood markers, and energy expenditure were taken at intervals after food consumption. RESULTS: VAS ratings, energy, food intake and macronutrient composition did not differ between treatment conditions, but glucose and insulin were significantly more elevated after tortilla chips. Free fatty acids (FFA), triglycerides (TG), peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) were higher after consuming pecans compared to tortilla chips. CONCLUSIONS: Pecan consumption improves postprandial glucose and insulin profiles which would be beneficial to individuals at risk of developing type 2 diabetes. Further studies are needed to investigate whether increased relative secretion of PYY and GLP-1 after eating pecans versus tortilla chips may affect subjective appetite and energy intake if consumed chronically.

Predictive factors for manual detorsion success in testicular torsion.

PURPOSE: In cases of testicular torsion (TT), prompt diagnosis and treatment are highly associated with organ salvage, and manual detorsion (MD) is a recommended maneuver as a first intervention. In our study, we aimed to investigate the effect of predictive factors of TT in predicting the success of MD. METHODS: A retrospective, 2-center study was conducted on patients diagnosed with TT between January 2015 and 2024. Demographic, clinical, ultrasound, and laboratory characteristics at presentation were analyzed. MD was routinely performed as the first intervention in all patients. Predictive parameters were compared in the MD success and failure groups. Univariate and multiple logistic regression analysis was used to identify risk factors for MD failure. RESULTS: A total of 94 patients were included in the study. The median age of the patients was 20 (IQR: 12-69) years, and the median symptom duration was 6 (IQR: 4-12) hours. MD confirmed by Doppler ultrasonography was successful in 52 (55.3%) patients and unsuccessful in 42 (44.7%). Age, symptom duration, Testicular Workup for Ischemia and Suspected Torsion (TWIST) score, TWIST risk groups, WBC, neutrophil, monocyte counts, and Monocyte/Eosinophil ratio (MER) were statistically different between the two groups. In multiple logistic regression analysis, the risk factors for failure of MD were found to be being over 18 years of age, the duration of symptoms being longer than 9 h, and MER > 28. CONCLUSION: Current urology guidelines suggest that age, symptom duration, and MER are reliable predictors of the success of MD, which is recommended in all cases of TT.

A multi-ethnic proteomic profiling analysis in Alzheimer's disease identifies the disparities in dysregulation of proteins and pathogenesis.

Background: Alzheimer's disease (AD) is the most common type of dementia that affects the elderly population. Lately, blood-based proteomics have been intensively sought in the discovery of AD biomarkers studies due to the capability to link external environmental factors with the development of AD. Demographic differences have been shown to affect the expression of the proteins in different populations which play a vital role in the degeneration of cognitive function. Method: In this study, a proteomic study focused on Malaysian Chinese and Malay prospects was conducted. Differentially expressed proteins (DEPs) in AD patients and normal controls for Chinese and Malays were identified. Functional enrichment analysis was conducted to further interpret the biological functions and pathways of the DEPs. In addition, a survey investigating behavioural practices among Chinese and Malay participants was conducted to support the results from the proteomic analysis. Result: The variation of dysregulated proteins identified in Chinese and Malay samples suggested the disparities of pathways involved in this pathological condition for each respective ethnicity. Functional enrichment analysis supported this assumption in understanding the protein-protein interactions of the identified protein signatures and indicate that differentially expressed proteins identified from the Chinese group were significantly enriched with the functional terms related to Aß/tau protein-related processes, oxidative stress and inflammation whereas neuroinflammation was associated with the Malay group. Besides that, a significant difference in sweet drinks/food intake habits between these two groups implies a relationship between sugar levels and the dysregulation of protein APOA4 in the Malay group. Additional meta-analysis further supported the dysregulation of proteins TF, AHSG, A1BG, APOA4 and C4A among AD groups. Conclusion: These findings serve as a preliminary understanding in the molecular and demographic studies of AD in a multi-ethnic population.

FCER1G as a novel immune-associated blood biomarker in cardiogenic stroke.

Background: Cardioembolic stroke (CE) exhibits the highest recurrence rate and mortality rate among all subtypes of cerebral ischemic stroke (CIS), yet its pathogenesis remains uncertain. The immune system plays a pivotal role in the progression of CE. Growing evidence indicates that several immune-associated blood biomarkers may inform the causes of stroke. The study aimed to identify new immune-associated blood biomarkers in patients with CE and create an online predictive tool in distinguishing CE from noncardioembolic stroke (non-CE) in CIS. Methods: Gene expression profiles that were publicly available were obtained from the Gene Expression Omnibus (GEO). The identification of differentially expressed genes (DEGs) was conducted using the Limma package. The hub module and hub genes were identified through the application of weighted gene coexpression network analysis (WGCNA). In order to identify potential diagnostic biomarkers for CE, both the random forest (RF) model and least absolute shrinkage and selection operator (LASSO) regression analysis were employed. Concurrently, the CIBERSORT algorithm was employed to evaluate the infiltration of immune cells in CE samples and examine the correlation between the biomarkers and the infiltrating immune cells. The diagnostic gene expression in blood samples was confirmed using qRT-PCR in a self-constructed dataset. Univariate and multiple logistic regression analyses were used to identify the risk factors for CE. Subsequently, the mathematical model of the nomogram was employed via Java's "Spring Boot" framework to develop the corresponding online tool, which was then deployed on a cloud server utilizing "nginx". Results: Eleven differentially expressed genes (DEGs) that were upregulated and seven DEGs that were downregulated were identified. Through bioinformatics analysis and clinical sample verification, it was discovered that Fc Fragment of IgE Receptor Ig (FCER1G) could serve as a novel potential blood biomarker for CE. FCER1G, along with other risk factors associated with CE, were utilized to develop a nomogram. The training and validation sets, which consisted of 65 CIS patients, yielded areas under the curve (AUCs) of 0.9722 and 0.9689, respectively. These results indicate a high level of precision in risk delineation by the nomogram. Furthermore, the associated online predictive platform has the potential to serve as a more efficacious and appropriate predictive instrument (https://www.origingenetic.com/CardiogenicStroke-FCER1G) for distinguishing between CE and non-CE. Conclusion: Blood biomarker FCER1G has the potential to identify patients who are at a higher risk of cardioembolism and direct the search for occult AF.The utilization of this online tool is anticipated to yield significant implications in terms of distinguishing between CE and non-CE, as well as enhancing the optimization of treatment decision support.

Fluid biomarkers unveil signatures of pathological aging.

Aging is a multifaceted and highly varied process in the brain. Identifying aging biomarkers is one means of distinguishing pathological from physiological aging. The aim of this narrative review is to focus on two new developments in the field of fluid biomarkers and draw attention to this excellent tool for the early detection of potential brain pathologies that delay, alter, or enable physiological aging to become pathological. Pathological aging can lower the threshold for the development of specific diseases such as late-onset epilepsy. Fluid biomarkers can reveal pathological levels at an early stage and thus indicate disease processes in the brain that begin before symptoms develop; they thus differ from physiological aging.

Multimarker Approach to Improve Risk Stratification of Patients Undergoing Transcatheter Aortic Valve Implantation.

Background: A blood multimarker approach may be useful to enhance risk stratification in patients undergoing TAVI. Objectives: The objective of this study was to determine the prognostic value of multiple blood biomarkers in transcatheter aortic valve implantation (TAVI) patients. Methods: In this prospective study, several blood biomarkers of cardiovascular function, inflammation, and renal function were measured in 362 patients who underwent TAVI. The cohort was divided into 3 groups according to the number of elevated blood biomarkers (ie, ≥ median value for the whole cohort) for each patient before the procedure. Survival analyses were conducted to evaluate the association between blood biomarkers and risk of adverse event following TAVI. Results: During a median follow-up of 2.5 (IQR: 1.9-3.2) years, 34 (9.4%) patients were rehospitalized for heart failure, 99 (27%) patients died, and 113 (31.2%) met the composite endpoint of all-cause mortality or heart failure rehospitalization. Compared to patients with 0 to 3 elevated biomarkers (referent group), those with 4 to 7 and 8 to 9 elevated biomarkers had a higher risk of all-cause mortality (HR: 1.54 [95% CI: 0.84-2.80], P = 0.16, and HR: 2.81 [95% CI: 1.53-5.15], P < 0.001, respectively) and of the composite endpoint (HR: 1.65 [95% CI: 0.95-2.84], P = 0.07, and HR: 2.67 [95% CI: 1.52-4.70] P < 0.001, respectively). Moreover, adding the number of elevated blood biomarkers into the clinical multivariable model provided significant incremental predictive value for all-cause mortality (Net Reclassification Index = 0.71, P < 0.001). Conclusions: An increasing number of elevated blood biomarkers is associated with higher risks of adverse clinical outcomes following TAVI. The blood multimarker approach may be helpful to enhance risk stratification in TAVI patients.

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific training data and BioFINDER-2, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. Results: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required from confirmatory testing. Conclusions: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

Assessment of leukocyte and systemic inflammation index ratios in dyslipidemia patients with dry eye disease: a retrospective case‒control study.

BACKGROUND: Dry eye disease (DED) is a complication of dyslipidemia (DLP) that is caused by metabolic syndrome and increased inflammation. This research aimed to assess leukocyte and systemic inflammation index ratios as potential biomarkers for systemic inflammation in dyslipidemia patients with dry eye disease (DLP-DED). METHODS: Several blood biomarkers were studied in 32 patients with DLP-DED (study group) and 63 patients with DLP-only (control group). The evaluated blood biomarkers included specific systemic inflammation index ratios, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte and platelet ratio (NLPR), and lipid profiles, such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG), albumin (ALB), and C-reactive protein (CRP) levels. RESULTS: Lymphocyte levels were significantly greater in the DLP-DED group than in the DLP-only group (P = 0.044). In addition, a significant negative correlation between HDL and the NLPR (P = 0.007; r= -0.428) and a significant negative correlation between the serum ALB concentration and the PLR (P = 0.008; r= -0.420) were identified as potential inflammatory predictors of DLP-DED. CONCLUSION: The findings of this study suggest that patients with DLP-DED may benefit from routine blood monitoring of their elevated lipid profile and blood inflammatory biomarkers, such as CRP, leukocytes, and systemic inflammation index ratios (NLR, PLR, MLR, and NLPR), to reduce the complications of DLP on ocular health. The correlation data suggest that the NLPR, PLR, serum ALB concentration, and serum HDL concentration may be valuable inflammatory biomarkers in DLP-DED patients. More research is required to ascertain the significance of the NLR, PLR, MLR, and NLPR and the additive role that leukocytes play.

Unraveling metabolic stress response in dairy cows: genetic control of plasma biomarkers throughout lactation and the transition period.

Breeding animals able to effectively respond to stress could be a long-term, sustainable, and affordable strategy to improve resilience and welfare in livestock systems. In the present study, the concentrations of 29 plasma biomarkers were used as candidate endophenotypes for metabolic stress response in single-SNP, gene- and haplotype-based GWAS using 739 healthy lactating Italian Holstein cows and 88,271 variants. Significant genetic associations were found in all the 3 GWAS approaches for plasma γ-glutamyl transferase concentration on BTA17, for paraoxonase on BTA4, and for alkaline phosphatase and zinc on BTA2. On these chromosomes, single-SNP and gene-based chromosome-wide association studies were performed, confirming GWAS findings. The signals identified for paraoxonase, γ-glutamyl transferase, and alkaline phosphatase were in proximity of the genes coding for them. The heritability of these 4 biomarkers ranged from moderate to high (from 0.39 to 0.54). Plasma biomarkers are known to undergo large changes in concentration during metabolic stress in the transition period, with an inter-individual variability in the rate of change and recovery time. Genetics may account in part for these differences. To assess this, we studied a subset of 139 periparturient cows homozygous at 3 SNPs known to be respectively associated with concentration of plasma ceruloplasmin, paraoxonase and γ-glutamyl transferase. We compared the immune-metabolic profile measured in plasma at -7, +5 and +30 d relative to calving between groups of opposite homozygotes. A significant effect of the genotype was found on paraoxonase and γ-glutamyl transferase plasma concentration at all the 3 time points. No evidence for genotype effect was detected for ceruloplasmin. Understanding the genetic control underlying metabolic stress response may suggest new approaches to foster resilience in dairy cows.

Single-extracellular vesicle (EV) analyses validate the use of L1 Cell Adhesion Molecule (L1CAM) as a reliable biomarker of neuron-derived EVs.

Isolation of neuron-derived extracellular vesicles (NDEVs) with L1 Cell Adhesion Molecule (L1CAM)-specific antibodies has been widely used to identify blood biomarkers of CNS disorders. However, full methodological validation requires demonstration of L1CAM in individual NDEVs and lower levels or absence of L1CAM in individual EVs from other cells. Here, we used multiple single-EV techniques to establish the neuronal origin and determine the abundance of L1CAM-positive EVs in human blood. L1CAM epitopes of the ectodomain are shown to be co-expressed on single-EVs with the neuronal proteins ß-III-tubulin, GAP43, and VAMP2, the levels of which increase in parallel with the enrichment of L1CAM-positive EVs. Levels of L1CAM-positive EVs carrying the neuronal proteins VAMP2 and ß-III-tubulin range from 30% to 63%, in contrast to 0.8%-3.9% of L1CAM-negative EVs. Plasma fluid-phase L1CAM does not bind to single-EVs. Our findings support the use of L1CAM as a target for isolating plasma NDEVs and leveraging their cargo to identify biomarkers reflecting neuronal function.

Toxic element (As, Cd, Pb and Hg) biodistribution and blood biomarkers in Barbaresca sheep raised in Sicily: One Health preliminary study.

The health of humans, animals and the environment is interconnected. Adopting a One Health approach means intervening promptly to prevent the main diseases that affect animal health to guarantee the safety of livestock production. Exposure to toxic trace elements in sheep can lead to increased accumulation in different biological substrate, developing both acute and chronic diseases in humans and livestock. The aim of this study was to evaluate the bioaccumulation of arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg) in Sicilian Barbaresca sheep using the following biological substrates: milk, blood and fleece. An inductively coupled plasma mass spectrometer (ICP-MS) was used for As, Cd and Pb, and a direct mercury analyser (DMA-80) was used for Hg determination. In addition, the role of the haematological parameters as possible indicators of different biodistribution was evaluated. A statistically significant value was observed from our analysed metals in the substrates: arsenic (p < 0.001), cadmium (p < 0.01), lead (p < 0.001) and mercury (p < 0.0001). The correlation analysis showed a relationship between milk and blood for arsenic (p < 0.0001) and lead (p < 0.0001), and no correlation for the metals was observed between milk/blood and the haematological parameters analysed for the low concentration observed in the present study comforting the final consumer.

Comparison of plasma soluble and extracellular vesicles-associated biomarkers in Alzheimer's disease patients and cognitively normal individuals.

BACKGROUND: Amyloid-ß (Aß) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs. METHODS: Single-molecule enzyme-linked assays were used to quantify Aß42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4- (n = 168) and APOE ε4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples. RESULTS: The soluble plasma Aß42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (Aß40, Aß42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions. CONCLUSION: Soluble plasma Aß42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aß release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma Aß and tau need correction by NDEVs for better AD risk identification in CN populations.

Blood biomarkers of Alzheimer's disease in the community: Variation by chronic diseases and inflammatory status.

INTRODUCTION: We explored the variations of blood biomarkers of Alzheimer's disease (AD) by chronic diseases and systemic inflammation. METHODS: We explored the association of AD blood biomarkers with chronic diseases and systemic inflammation (interleukin-6 [IL-6]), in 2366 dementia-free participants of the Swedish National Study on Aging and Care-in Kungsholmen, using quantile regression models. RESULTS: A greater number of co-occurring chronic diseases was associated with higher concentrations of phosphorylated-tau 181 (p-tau181), total-tau (t-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) (p < 0.01). Anemia, kidney, cerebrovascular, and heart diseases were associated with variations in the levels of AD blood biomarkers. Participants in the highest (vs. lowest) interleukin-6 (IL-6) tertile had higher NfL concentration. Systemic inflammation amplified the associations between several chronic diseases and p-tau181, t-tau, NfL, and GFAP. DISCUSSION: In the community, the concentration of AD blood biomarkers varies in relation to medical conditions and systemic inflammation. Recognizing these influences is crucial for the accurate interpretation and clinical implementation of blood biomarkers. HIGHLIGHTS: Participants with a complex clinical profile (i.e., multiple co-occurring diseases or specific disease combinations) display elevated levels of AD blood-biomarkers. Anemia, heart, cerebrovascular, and kidney diseases are associated with variations is the levels of AD blood biomarkers in cognitively intact older adults. Systemic inflammation amplifies the association between several chronic diseases and AD blood biomarkers.