DunedinPACE, a DNA methylation biomarker of the pace of aging

Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).Methods: We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.Funding: This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

Diagnostic Accuracy of Circular RNAs in Different Types of Samples for Detecting Hepatocellular Carcinoma: A Meta-Analysis

The lack of accurate biomarkers impeded the screening, diagnosis and early treatment of hepatocellular carcinoma (HCC). As a result of the development of high-throughput transcriptome analysis techniques, circular RNAs, a newly discovered class of noncoding RNAs, were recognized as potential novel biomarkers. This meta-analysis was performed to update the diagnostic roles of circular RNAs for HCC. We acquired 23 articles from PubMed, Web of Science, EMBASE, and Cochrane Library databases up to September 2021. The overall sensitivity was 0.80 (95% CI: 0.77–0.84), and the specificity was 0.83 (95% CI: 0.79–0.85), with an AUC of 0.88 (0.85–0.91). Considering of the significant heterogeneity, studies were divided into four groups based on the control types. The circular RNAs in exosomes had a sensitivity of 0.69 (95% CI: 0.61–0.75), and a highest specificity of 0.91 (95% CI: 0.83–0.96). The pooled sensitivity of circular RNAs in serum/plasma was 0.84 (95% CI: 0.81–0.87), and the pooled specificity was 0.83 (95% CI: 0.79–0.86). The pooled sensitivity of circular RNAs distinguishing tumor tissue from chronic hepatitis/cirrhosis tissues was 0.56 (95% CI: 0.48–0.64), and specificity was 0.76 (95% CI: 0.67–0.82). When the controls were adjacent tissues, the sensitivity was 0.78 (95% CI: 0.70–0.84), and the specificity was 0.78 (95% CI: 0.71–0.85). Hsa_circ_0001445 with a pooled sensitivity of 0.81, a specificity of 0.76 and an AUC of 0.85 in two studies, might be a suitable diagnostic blood biomarker for HCC. Relying on function in HCC, the AUC of subgroups were 0.88 (95%CI: 0.84–0.90) (function group) and 0.87 (95%CI: 0.84–0.90) (unknown function group). As for only reported in HCC or not, these circular RNAs had an AUC of 0.89 (95%CI: 0.86–0.91) (only in HCC) and 0.85 (95%CI: 0.82–0.88) (not only in HCC). In conclusion, the results suggested that circular RNAs were acceptable biomarkers for detecting HCC, especially those circular RNAs existing in exosomes or serum/plasma.

Proteomics-Based Approach to Identify Novel Blood Biomarker Candidates for Differentiating Intracerebral Hemorrhage From Ischemic Stroke—A Pilot Study

Background: A reliable distinction between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is required for diagnosis-specific treatment and effective secondary prevention in patients with stroke. However, in resource-limited settings brain imaging, which is the current diagnostic gold standard for this purpose, is not always available in time. Hence, an easily accessible and broadly applicable blood biomarker-based diagnostic test differing stroke subtypes would be desirable. Using an explorative proteomics approach, this pilot study aimed to identify novel blood biomarker candidates for distinguishing IS from ICH.Material and Methods: Plasma samples from patients with IS and ICH were drawn during hospitalization and were analyzed by using liquid chromatography/mass spectrometry. Proteins were identified using the human reference proteome database UniProtKB, and label-free quantification (LFQ) data were further analyzed using bioinformatic tools.Results: Plasma specimens of three patients with IS and four patients with ICH with a median National Institute of Health Stroke Scale (NIHSS) of 12 [interquartile range (IQR) 10.5–18.5] as well as serum samples from two healthy volunteers were analyzed. Among 495 identified protein groups, a total of 368 protein groups exhibited enough data points to be entered into quantitative analysis. Of the remaining 22 top-listed proteins, a significant difference between IS and ICH was found for Carboxypeptidase N subunit 2 (CPN2), Coagulation factor XII (FXII), Plasminogen, Mannan-binding lectin serine protease 1, Serum amyloid P-component, Paraoxonase 1, Carbonic anhydrase 1, Fibulin-1, and Granulins.Discussion: In this exploratory proteomics-based pilot study, nine candidate biomarkers for differentiation of IS and ICH were identified. The proteins belong to the immune system, the coagulation cascade, and the apoptosis system, respectively. Further investigations in larger cohorts of patients with stroke using additional biochemical analysis methods, such as ELISA or Western Blotting are now necessary to validate these markers, and to characterize diagnostic accuracy with regard to the development of a point-of-care-system for use in resource-limited areas.

Is kallikrein-8 a blood biomarker for detecting amnestic mild cognitive impairment? Results of the population-based Heinz Nixdorf Recall study

Background Kallikrein-8 (KLK8) might be an early blood-biomarker of Alzheimer’s disease (AD). We examined whether blood KLK8 is elevated in persons with amnestic mild cognitive impairment (aMCI) which is a precursor of AD, compared to cognitively unimpaired (CU) controls. Methods Forty cases and 80 controls, matched by sex and age (± 3years), were participants of the longitudinal population-based Heinz Nixdorf Recall study (baseline: 2000–2003). Standardized cognitive performance was assessed 5 (T1) and 10 years after baseline (T2). Cases were CU at T1 and had incidental aMCI at T2. Controls were CU at T1 and T2. Blood KLK8 was measured at T2. Using multiple logistic regression the association between KLK8 in cases vs. controls was investigated by estimating odds ratios (OR) and 95% confidence intervals (95%CI), adjusted for inter-assay variability and freezing duration. Using receiver operating characteristic (ROC) analysis, the diagnostic accuracy of KLK8 was determined by estimating the area under the curve (AUC) and 95%CI (adjusted for inter-assay variability, freezing duration, age, sex). Results Thirty-seven participants with aMCI vs. 72 CU (36.7%women, 71.0±8.0 (mean±SD) years) had valid KLK8 measurements. Mean KLK8 was higher in cases than in controls (911.6±619.8 pg/ml vs.783.1±633.0 pg/ml). Fully adjusted, a KLK8 increase of 500pg/ml was associated with a 2.68 (1.05–6.84) higher chance of having aMCI compared to being CU. With an AUC of 0.92 (0.86–0.97), blood KLK8 was a strong discriminator for aMCI and CU. Conclusion This is the first population-based study to demonstrate the potential clinical utility of blood KLK8 as a biomarker for incipient AD.

Association between plasma phospho-tau181 and cognitive change from age 73 to 82: Lothian Birth Cohort 1936

INTRODUCTION: Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer's disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we tested whether plasma p-tau181predicts cognitive decline and whether it is present in synapses in human brain. METHODS: General cognitive ability and plasma p-tau181 concentration were measured in 195 participants at ages 72 and 82. Levels of p-tau181 in total homogenate and synaptic fractions were compared with western blot (n=10-12 per group), and synaptic localisation was examined using array tomography. RESULTS: Elevated baseline plasma p-tau181 and increasing p-tau181 over time predicted steeper general cognitive decline. We observe p-tau181 in neurites, presynapses, and post-synapses in the brain. DISCUSSION: Baseline and subsequent change in plasma p-tau181 may represent rare biomarkers of differences in cognitive ageing across the 8th decade of life and may play a role in synaptic function in the brain.

Association of Decreased Serum BDNF With Restless Legs Syndrome in Parkinson's Disease Patients

Objective: To objective of the study was to investigate whether serum brain-derived neurotrophic factor (BDNF) levels are associated with the severity of restless legs syndrome (RLS) in Parkinson's disease (PD).Methods: A total of 249 PD patients with (n = 53) and without RLS (n = 196) and 326 age-matched controls were included in this study. All the serum BDNF levels of the participants were measured. The International Restless Legs Syndrome Study Group Rating Scale (IRLSSG-RS) was administered for the severity of RLS. The severity of PD patients were assessed by the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr (H-Y) stage.Results: The prevalence of RLS was significantly higher in PD patients (21.3%) than in the controls group (7.4%) (p < 0.05). The IRLSSG-RS score in PD patients with RLS (16.25 ± 5.24) was significantly increased than in controls with RLS (12.08 ± 3.99) (p < 0.01). The serum BDNF levels were significantly decreased in PD patients with RLS than in PD patients without RLS, controls without RLS, and controls with RLS (p < 0.001). BDNF levels were negatively associated with IRLSSG-RS in both PD patients with RLS and controls with RLS group (both p < 0.01). Multiple regression analysis confirmed that in either PD with RLS or controls with RLS group, BDNF was an independent contributor to IRLSSG-RS (both p < 0.01).Conclusions: Decreased serum BDNF levels may be involved in the pathophysiology of RLS in PD, suggesting that it may serve as a potential blood biomarker of diagnostic value for RLS in PD.

Copeptin: a potential blood biomarker for acute ischemic stroke

Background Copeptin is a new blood biomarker for acute ischemic stroke which emerged to assist clinicians with decision-making. Serum copeptin can accurately reflect vasopressin concentration, which plays a role in aggravation of inflammatory responses, ions and neurotransmitters dysfunctions. The objective of this work was to investigate the relation between copeptin level as a blood biomarker and the short-term prognosis of acute ischemic stroke after 3 months. The current study included 45 patients with first ever acute ischemic stroke and 45 healthy volunteers as a control. Clinical evaluation, CT and MRI of the brain, NIHSS on admission, and mRS after 3 months were done for the patients, and all the patients and control were subjected to assessment of serum level of copeptin by ELISA technique. Results Copeptin level was significantly higher in patients with acute ischemic stroke compared to healthy control subjects (p-value = 0.001). Also, copeptin level was significantly higher in patients with severe stroke (NIHSS > 16) than in those with mild-to-moderate stroke (NIHSS 0–15) at presentation and in patients with unfavorable outcome (mRS 3–6) when compared to patients with favorable outcome (mRS 0–2) (p-value = 0.003 and 0.001, respectively). Copeptin level was significantly lower in patients who received thrombolytic therapy with rTPA (p-value = 0.049). Conclusion Copeptin has an interesting potential as a new prognostic biomarker for patients with acute ischemic stroke as its level was significantly higher in patients with severe stroke and in patients with unfavorable outcome.

Inherited Proteoglycan Biosynthesis Defects—Current Laboratory Tools and Bikunin as a Promising Blood Biomarker

Proteoglycans consist of proteins linked to sulfated glycosaminoglycan chains. They constitute a family of macromolecules mainly involved in the architecture of organs and tissues as major components of extracellular matrices. Some proteoglycans also act as signaling molecules involved in inflammatory response as well as cell proliferation, adhesion, and differentiation. Inborn errors of proteoglycan metabolism are a group of orphan diseases with severe and irreversible skeletal abnormalities associated with multiorgan impairments. Identifying the gene variants that cause these pathologies proves to be difficult because of unspecific clinical symptoms, hardly accessible functional laboratory tests, and a lack of convenient blood biomarkers. In this review, we summarize the molecular pathways of proteoglycan biosynthesis, the associated inherited syndromes, and the related biochemical screening techniques, and we focus especially on a circulating proteoglycan called bikunin and on its potential as a new biomarker of these diseases.

Mass Spectrometry-Based Proteomics Reveal Alcohol Dehydrogenase 1B as a Blood Biomarker Candidate to Monitor Acetaminophen-Induced Liver Injury

Acute liver injury (ALI) is a severe disorder resulting from excessive hepatocyte cell death, and frequently caused by acetaminophen intoxication. Clinical management of ALI progression is hampered by the dearth of blood biomarkers available. In this study, a bioinformatics workflow was developed to screen omics databases and identify potential biomarkers for hepatocyte cell death. Then, discovery proteomics was harnessed to select from among these candidates those that were specifically detected in the blood of acetaminophen-induced ALI patients. Among these candidates, the isoenzyme alcohol dehydrogenase 1B (ADH1B) was massively leaked into the blood. To evaluate ADH1B, we developed a targeted proteomics assay and quantified ADH1B in serum samples collected at different times from 17 patients admitted for acetaminophen-induced ALI. Serum ADH1B concentrations increased markedly during the acute phase of the disease, and dropped to undetectable levels during recovery. In contrast to alanine aminotransferase activity, the rapid drop in circulating ADH1B concentrations was followed by an improvement in the international normalized ratio (INR) within 10–48 h, and was associated with favorable outcomes. In conclusion, the combination of omics data exploration and proteomics revealed ADH1B as a new blood biomarker candidate that could be useful for the monitoring of acetaminophen-induced ALI.