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The Journal of Prevention of... 2023In the past years, neuroinflammation has been widely investigated in Alzheimer's disease (AD). Evidence from animal, in vivo and post-mortem studies has shown that...
In the past years, neuroinflammation has been widely investigated in Alzheimer's disease (AD). Evidence from animal, in vivo and post-mortem studies has shown that inflammatory changes are a common feature of the disease, apparently happening in response to amyloid-beta and tau accumulation. Progress in imaging and fluid biomarkers now allows for identifying surrogate markers of neuroinflammation in living individuals, which may offer unprecedented opportunities to better understand AD pathogenesis and progression. In this context, inflammatory mediators and glial proteins (mainly derived from microglial cells and astrocytes) seem to be the most promising biomarkers. Here, we discuss the biological basis of neuroinflammation in AD, revise the proposed neuroinflammation biomarkers, describe what we have learned from anti-inflammatory drug trials, and critically discuss the potential addition of these biomarkers in the AT(N) framework.
Topics: Animals; Humans; Alzheimer Disease; Neuroinflammatory Diseases; Amyloid beta-Peptides; Microglia; Biomarkers
PubMed: 37357281
DOI: 10.14283/jpad.2023.54 -
Brain : a Journal of Neurology Apr 2022Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data...
Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.
Topics: Biomarkers; Creutzfeldt-Jakob Syndrome; Humans; Insomnia, Fatal Familial; Prion Diseases; Prion Proteins; Prions; alpha-Synuclein
PubMed: 35288744
DOI: 10.1093/brain/awab350 -
Journal of Cachexia, Sarcopenia and... Jun 2023Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor...
INTRODUCTION
Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.
METHODS
Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-ras ; p53 ) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.
RESULTS
Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (-13.7 ± 5.7%; P < 0.01), muscle mass (-13.8 ± 8.1%; P < 0.01) and muscle strength (-25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia.
CONCLUSIONS
We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.
Topics: Animals; Male; Mice; Biomarkers; Cachexia; Lung Neoplasms; Muscle Strength; Muscle, Skeletal; Muscular Atrophy
PubMed: 37025071
DOI: 10.1002/jcsm.13222 -
Annals of Neurology Mar 2023While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.
METHODS
Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant-based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke-associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio-weighted mediation was used to determine whether metabolites mediated the association between a plant-based diet and stroke risk.
RESULTS
Metabolites associated with a plant-based diet included the gut metabolite indole-3-propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10 ), guanosine (β = -0.13, 95% CI [-0.19, -0.07], p = 6.48 × 10 ), gluconic acid (β = -0.11, 95% CI [-0.18, -0.04], p = 2.06 × 10 ), and C7 carnitine (β = -0.16, 95% CI [-0.24, -0.09], p = 4.14 × 10 ). All of these metabolites were associated with both additional diet patterns and altered stroke risk. Mediation analyses identified guanosine (32.6% mediation, p = 1.51 × 10 ), gluconic acid (35.7%, p = 2.28 × 10 ), and C7 carnitine (26.2%, p = 1.88 × 10 ) as mediators linking a plant-based diet to reduced stroke risk.
INTERPRETATION
A subset of diet-related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2023;93:500-510.
Topics: Humans; Biomarkers; Carnitine; Diet; Risk Factors; Stroke
PubMed: 36373825
DOI: 10.1002/ana.26552 -
International Journal of Molecular... Apr 2023Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific...
Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific biomarkers. This study compares the levels of neuron specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), and circulating plasma extracellular vesicles (EVs) in kidney-failure patients before KT and at a two-year follow up. Using ELISA, NSE, BDNF, and NfL levels were measured in the plasma of 74 living-donor KT patients. Plasma EVs were isolated with ultracentrifugation, and characterized for concentration/size and surface protein expression using flow cytometry from a subset of 25 patients. Lower NSE levels, and higher BDNF and NfL were observed at the two-year follow-up compared to the baseline ( < 0.05). Male patients had significantly higher BDNF levels compared to those of females. BBB biomarkers correlated with the baseline lipid profile and with glucose, vitamin D, and inflammation markers after KT. BBB surrogate marker changes in the microcirculation of early vascular aging phenotype patients with calcification and/or fibrosis were observed only in NSE and BDNF. CD31+ microparticles from endothelial cells expressing inflammatory markers such as CD40 and integrins were significantly reduced after KT. KT may, thus, improve the neurological status of CKD patients, as reflected by changes in BBB-specific biomarkers.
Topics: Female; Male; Humans; Brain-Derived Neurotrophic Factor; Kidney Transplantation; Blood-Brain Barrier; Endothelial Cells; Biomarkers; Renal Insufficiency, Chronic
PubMed: 37047601
DOI: 10.3390/ijms24076628 -
Clinica Chimica Acta; International... Mar 2020Autism spectrum disorder (ASD) refers to a group of complex neurodevelopmental disorders characterized by social interaction and communication deficits and repetitive... (Review)
Review
Autism spectrum disorder (ASD) refers to a group of complex neurodevelopmental disorders characterized by social interaction and communication deficits and repetitive and stereotyped behaviors. As the etiology and pathogenesis of the disorder have not yet been elucidated, specific treatment and reliable diagnostic biomarkers are not available. Early behavioral interventions have been shown to substantially improve symptoms in children with ASD. Given the rapidly increasing prevalence of ASD, there is an urgent need to identify related diagnostic biomarkers. Although specific diagnostic markers for ASD have not been identified, the related research has made progress in different aspects. This review summarizes recent findings of the use of genes, proteins, peptides, and metabolites as diagnostic markers for ASD. The associated techniques include genetic testing and proteomic and metabolomic analyses. In addition, some studies have focused on single or several proteins and metabolites. Moreover, transcriptomic analysis, immune disturbances and cytokine may also be used for this purpose. The pathogenesis involving genes, proteins, and metabolites is also discussed here.
Topics: Autism Spectrum Disorder; Biomarkers; Humans
PubMed: 31857069
DOI: 10.1016/j.cca.2019.12.009 -
Seminars in Liver Disease Aug 2022Chronic infection with the hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of... (Review)
Review
Chronic infection with the hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of the persistence of the viral template for the viral transcripts, covalently closed circular deoxyribonucleic acid (cccDNA). Detecting changes in cccDNA transcriptional activity is key to understanding fundamental virology, determining the efficacy of new therapies, and deciding the optimal clinical management of HBV patients. In this review, we summarize surrogate circulating biomarkers that have been used to infer cccDNA levels and activity in people with chronic hepatitis B. Moreover, we outline the current shortcomings of the current biomarkers and highlight the clinical importance in improving them and expanding their use.
Topics: Biomarkers; DNA, Circular; DNA, Viral; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Virus Replication
PubMed: 35445388
DOI: 10.1055/a-1830-2741 -
Medicine and Science in Sports and... Feb 2020To establish whether associations between sedentary behavior and cardiometabolic health differ when assessed by thigh-worn and waist-worn accelerometry.
PURPOSE
To establish whether associations between sedentary behavior and cardiometabolic health differ when assessed by thigh-worn and waist-worn accelerometry.
METHODS
Participants were recruited from several areas in the United Kingdom. Sedentary behavior was assessed using the activPAL worn on the thigh and ActiGraph worn on the waist. Average total (TST), prolonged (bouts ≥30 min; PST) and breaks (BST) in sedentary time were calculated. Cardiometabolic health markers included: adiposity (body fat) and surrogate markers of adiposity ((waist circumference, body mass index [BMI]), lipids (total, low density lipoprotein, and high-density lipoprotein [HDL] cholesterol, triglycerides), blood pressure, and glucose (fasting, 2 h and glycated hemoglobin A1c). A clustered cardiometabolic risk score was calculated. Linear regression analysis examined the associations with cardiometabolic health.
RESULTS
There were 1457 participants (mean age [± standard deviation], 59.38 ± 11.85 yr; 51.7% male; mean BMI, 30.19 ± 5.59 kg·m) included in the analyses. ActivPAL and ActiGraph sedentary variables were moderately correlated (0.416-0.511, P < 0.01); however, all variables were significantly different from each other (P < 0.05). Consistency was observed across devices in the direction and magnitude of associations of TST and PST with adiposity, surrogate markers of adiposity, HDL, triglycerides, and cardiometabolic risk score and for BST with adiposity, surrogate markers of adiposity, and cardiometabolic risk. Differences across devices were observed in associations of TST and PST with diastolic blood pressure, for TST with 2-h glucose and for BST with HDL. No other associations were observed for any other health marker for either device.
CONCLUSIONS
Results suggest that associations with cardiometabolic health are largely comparable across the two common assessments of sedentary behavior but some small differences may exist for certain health markers.
Topics: Accelerometry; Adiposity; Adult; Aged; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Female; Health Status Indicators; Humans; Lipids; Middle Aged; Risk Factors; Sedentary Behavior; Thigh; Waist Circumference; Wrist
PubMed: 31479008
DOI: 10.1249/MSS.0000000000002138 -
British Journal of Cancer Oct 2023Although genome duplication, or polyploidization, is believed to drive cancer evolution and affect tumor features, its significance in hepatocellular carcinoma (HCC) is...
BACKGROUND
Although genome duplication, or polyploidization, is believed to drive cancer evolution and affect tumor features, its significance in hepatocellular carcinoma (HCC) is unclear. We aimed to determine the characteristics of polyploid HCCs by evaluating chromosome duplication and to discover surrogate markers to discriminate polyploid HCCs.
METHODS
The ploidy in human HCC was assessed by fluorescence in situ hybridization for multiple chromosomes. Clinicopathological and expression features were compared between polyploid and near-diploid HCCs. Markers indicating polyploid HCC were explored by transcriptome analysis of cultured HCC cells.
RESULTS
Polyploidy was detected in 36% (20/56) of HCCs and discriminated an aggressive subset of HCC that typically showed high serum alpha-fetoprotein, poor differentiation, and poor prognosis compared to near-diploid HCCs. Molecular subtyping revealed that polyploid HCCs highly expressed alpha-fetoprotein but did not necessarily show progenitor features. Histological examination revealed abundant polyploid giant cancer cells (PGCCs) with a distinct appearance and frequent macrotrabecular-massive architecture in polyploid HCCs. Notably, the abundance of PGCCs and overexpression of ubiquitin-conjugating enzymes 2C indicated polyploidy in HCC and efficiently predicted poor prognosis in combination.
CONCLUSIONS
Histological diagnosis of polyploidy using surrogate markers discriminates an aggressive subset of HCC, apart from known HCC subgroups, and predict poor prognosis in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; alpha-Fetoproteins; In Situ Hybridization, Fluorescence; Prognosis; Polyploidy
PubMed: 37715023
DOI: 10.1038/s41416-023-02408-6 -
Medical Care Feb 2024There is tremendous interest in evaluating surrogate markers given their potential to decrease study time, costs, and patient burden.
BACKGROUND
There is tremendous interest in evaluating surrogate markers given their potential to decrease study time, costs, and patient burden.
OBJECTIVES
The purpose of this statistical workshop article is to describe and illustrate how to evaluate a surrogate marker of interest using the proportion of treatment effect (PTE) explained as a measure of the quality of the surrogate marker for: (1) a setting with a general fully observed primary outcome (eg, biopsy score); and (2) a setting with a time-to-event primary outcome which may be censored due to study termination or early drop out (eg, time to diabetes).
METHODS
The methods are motivated by 2 randomized trials, one among children with nonalcoholic fatty liver disease where the primary outcome was a change in biopsy score (general outcome) and another study among adults at high risk for Type 2 diabetes where the primary outcome was time to diabetes (time-to-event outcome). The methods are illustrated using the Rsurrogate package with a detailed R code provided.
RESULTS
In the biopsy score outcome setting, the estimated PTE of the examined surrogate marker was 0.182 (95% confidence interval [CI]: 0.121, 0.240), that is, the surrogate explained only 18.2% of the treatment effect on the biopsy score. In the diabetes setting, the estimated PTE of the surrogate marker was 0.596 (95% CI: 0.404, 0.760), that is, the surrogate explained 59.6% of the treatment effect on diabetes incidence.
CONCLUSIONS
This statistical workshop provides tools that will support future researchers in the evaluation of surrogate markers.
Topics: Child; Humans; Treatment Outcome; Diabetes Mellitus, Type 2; Biomarkers
PubMed: 38079232
DOI: 10.1097/MLR.0000000000001956