526 research outputs found

    Identification of novel biomarkers in critically ill patients

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    This thesis summarizes publications of prospective, non-interventional studies on the identification of novel biomarkers in critical care medicine. Biomarkers in the context of this thesis are laboratory values that are determined from the blood of patients who are treated on an intensive care unit. They are used in clinical routine for diagnosis, prognosticate and monitor treatment. For clinical applicability, biomarkers must have appropriate statistical test characteristics to enable distinction between different states of disease. Beyond that, biomarkers should be easy to obtain, rapidly measurable, and generalizable for instant interpretation in the clinical context and prompt decision making to favourably influence the course of the disease. The aim of this thesis was to evaluate the significance, regulation, diagnostic and prognostic value of novel biomarkers measured in the blood of critical ill patients

    Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs

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    Publisher Copyright: © 2023 European Food Safety Authority. EFSA Journal published by Wiley-VCH GmbH on behalf of European Food Safety Authority.In 2015, EFSA established a temporary tolerable daily intake (t-TDI) for BPA of 4 μg/kg body weight (bw) per day. In 2016, the European Commission mandated EFSA to re-evaluate the risks to public health from the presence of BPA in foodstuffs and to establish a tolerable daily intake (TDI). For this re-evaluation, a pre-established protocol was used that had undergone public consultation. The CEP Panel concluded that it is Unlikely to Very Unlikely that BPA presents a genotoxic hazard through a direct mechanism. Taking into consideration the evidence from animal data and support from human observational studies, the immune system was identified as most sensitive to BPA exposure. An effect on Th17 cells in mice was identified as the critical effect; these cells are pivotal in cellular immune mechanisms and involved in the development of inflammatory conditions, including autoimmunity and lung inflammation. A reference point (RP) of 8.2 ng/kg bw per day, expressed as human equivalent dose, was identified for the critical effect. Uncertainty analysis assessed a probability of 57–73% that the lowest estimated Benchmark Dose (BMD) for other health effects was below the RP based on Th17 cells. In view of this, the CEP Panel judged that an additional uncertainty factor (UF) of 2 was needed for establishing the TDI. Applying an overall UF of 50 to the RP, a TDI of 0.2 ng BPA/kg bw per day was established. Comparison of this TDI with the dietary exposure estimates from the 2015 EFSA opinion showed that both the mean and the 95th percentile dietary exposures in all age groups exceeded the TDI by two to three orders of magnitude. Even considering the uncertainty in the exposure assessment, the exceedance being so large, the CEP Panel concluded that there is a health concern from dietary BPA exposure.Peer reviewe

    An evaluation of the role of biomarkers in Alzheimer’s disease and age-related cognitive decline

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    An ageing population will lead to an increase in age-related cognitive decline and dementia syndromes such as Alzheimer’s disease (AD), which can seriously limit an individual’s independence and quality of life. Identifying biomarkers associated with cognitive impairment in both ageing and AD are needed as they will improve our understanding of underlying pathophysiology and may eventually improve prognoses via the identification of at-risk individuals and the development of novel therapeutics. Several pathological changes in the brain which are typically seen in AD can be detected in the cerebrospinal fluid (CSF) and plasma of middle- and late-life adults without dementia. Previous work has identified associations between CSF markers and cognitive functions, although a synthesis of the large number of studies is needed. Furthermore CSF marker levels may also differ with AD risk factors, however evidence is mixed. Increasingly, research has shifted to focus on blood-based biomarkers which provide the benefit of being less invasive and more accessible. Several plasma biomarkers have been associated with cognitive functions in ageing, although few studies use appropriate cognitive tests, and even fewer have examined these proteins in the brain. There remains no gold-standard biomarkers associated with cognitive functions in either AD or age-related cognitive decline, therefore additional approaches are needed to fully understand their relationship. The aims of the current thesis are to: investigate CSF biomarkers associated with cognition in dementia and ageing; assess the relationship between CSF biomarkers and AD risk factors; examine whether plasma biomarkers are associated with age-related cognitive decline; and lastly, to examine the level of proteins (which have previously been investigated as biomarkers) in post-mortem brain tissue. Cerebrospinal fluid biomarkers associated with cognition have been investigated across a range of dementia syndromes and age-related cognitive decline. While much of the work has focused on tau and amyloid-beta (Aβ), there is burgeoning research around markers such as neurogranin and neurofilament-light. Due to a wide range of markers investigated across several dementia syndromes and ageing, the roles of each marker are less clear. Therefore, a systematic review was conducted examining the association between CSF synaptic/axonal markers, and cognitive functions across dementia syndromes and typical ageing. Sixty-seven studies were included in the review in Chapter 3. Despite substantial heterogeneity in the field, there was evidence for an association between CSF neurofilament-light and cognition in AD, frontotemporal dementia, and typical cognitive ageing. Cerebrospinal fluid neurogranin tended to be associated with cognition in those with CSF tau and CSF Aβ profiles indicative of AD. Chapter 4 focuses on the interaction between Apolipoprotein E (APOE) and sex on CSF tau levels in a middle-life cohort without dementia. Females account for an estimated 60% of those diagnosed with AD and the APOE4 allele is widely recognised to be the strongest genetic risk factor for late-onset AD. However, evidence for the interaction between these two risk factors is mixed. In this chapter, a significant interaction between APOE, sex, and CSF AD biomarkers was found, suggesting that tau accumulation may be independent of Ab in females, but not males. This has potential implications for the implementation of CSF AD biomarkers in clinical practice and pharmacological interventions which target cortical Ab. Chapter 5 focuses on the relationship between plasma biomarkers and cognitive functions in typical ageing. Previous studies have focused on this relationship, however, few use appropriate cognitive tests for a sample without dementia. In this chapter, the association between cognitive ability and plasma phosphor-tau 181 (ptau181), Ab, neurofilament-light (NfL), and glial fibrillary acidic protein (GFAP) were investigated in the Lothian Birth Cohort 1936. A significant relationship was observed between baseline p-tau181, NfL, GFAP and cognitive decline up to ~ 10-years later. Further, increasing levels of p-tau181 over time were associated with steeper cognitive decline. The results of this chapter suggest that plasma p-tau181, NfL, and GFAP may be useful biomarkers of age-related cognitive decline. In Chapter 6, several of the aforementioned markers that were previously investigated in the CSF and plasma are examined in post-mortem brain tissue. While previous work has focused on these markers in the CSF and plasma, few studies have investigated them in post-mortem tissue and how levels differ between AD and typically ageing participants. Relative differences in neurogranin, p-tau181, p-tau231, total tau, and SNAP-25 were examined by western blot in AD cases, healthy ageing cases, and mid-life cases. The results of this chapter provide evidence of a reduction of neurogranin and SNAP-25 at the synapse in AD, as well as an increase of p-tau231. This suggests that the elevations of CSF neurogranin, SNAP-25, and p-tau231 seen in AD may reflect both the loss of neurogranin/SNAP-25 and the accumulation of ptau231 in synapses. The final chapter of the thesis summarise the findings of the previous chapters, their limitations, and the impact of this work on the field

    Biomarkers for parkinsonian disorders in CNS-originating EVs: promise and challenges

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    Extracellular vesicles (EVs), including exosomes, microvesicles, and oncosomes, are nano-sized particles enclosed by a lipid bilayer. EVs are released by virtually all eukaryotic cells and have been shown to contribute to intercellular communication by transporting proteins, lipids, and nucleic acids. In the context of neurodegenerative diseases, EVs may carry toxic, misfolded forms of amyloidogenic proteins and facilitate their spread to recipient cells in the central nervous system (CNS). CNS-originating EVs can cross the blood–brain barrier into the bloodstream and may be found in other body fluids, including saliva, tears, and urine. EVs originating in the CNS represent an attractive source of biomarkers for neurodegenerative diseases, because they contain cell- and cell state-specific biological materials. In recent years, multiple papers have reported the use of this strategy for identification and quantitation of biomarkers for neurodegenerative diseases, including Parkinson’s disease and atypical parkinsonian disorders. However, certain technical issues have yet to be standardized, such as the best surface markers for isolation of cell type-specific EVs and validating the cellular origin of the EVs. Here, we review recent research using CNS-originating EVs for biomarker studies, primarily in parkinsonian disorders, highlight technical challenges, and propose strategies for overcoming them

    Peripheral inflammation and neurocognitive impairment: correlations, underlying mechanisms, and therapeutic implications

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    Cognitive impairments, such as learning and memory deficits, may occur in susceptible populations including the elderly and patients who are chronically ill or have experienced stressful events, including surgery, infection, and trauma. Accumulating lines of evidence suggested that peripheral inflammation featured by the recruitment of peripheral immune cells and the release of pro-inflammatory cytokines may be activated during aging and these conditions, participating in peripheral immune system-brain communication. Lots of progress has been achieved in deciphering the core bridging mechanism connecting peripheral inflammation and cognitive impairments, which may be helpful in developing early diagnosis, prognosis evaluation, and prevention methods based on peripheral blood circulation system sampling and intervention. In this review, we summarized the evolving evidence on the prevalence of peripheral inflammation-associated neurocognitive impairments and discussed the research advances in the underlying mechanisms. We also highlighted the prevention and treatment strategies against peripheral inflammation-associated cognitive dysfunction

    Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer’s Dementia in the Oldest Old

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    Background. Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) may have different effects on cognitive health due to their anti- or pro-inflammatory properties. Methods. We aimed to prospectively examine the relationships between n-3 and n-6 PUFA contents in serum phospholipids with incident all-cause dementia and Alzheimer’s disease dementia (AD). We included 1264 non-demented participants aged 84 ± 3 years from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe) multicenter-cohort study. We investigated whether fatty acid concentrations in serum phospholipids, especially eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), were associated with risk of incident all-cause dementia and AD. Results. During the follow-up window of seven years, 233 participants developed dementia. Higher concentrations of EPA were associated with a lower incidence of AD (hazard ratio (HR) 0.76 (95% CI 0.63; 0.93)). We also observed that higher concentrations of EPA were associated with a decreased risk for all-cause dementia (HR 0.76 (95% CI 0.61; 0.94)) and AD (HR 0.66 (95% CI 0.51; 0.85)) among apolipoprotein E ε4 (APOE ε4) non-carriers but not among APOE ε4 carriers. No other fatty acids were significantly associated with AD or dementia. Conclusions. Higher concentrations of EPA were associated with a lower risk of incident AD. This further supports a beneficial role of n-3 PUFAs for cognitive health in old age

    Alzheimer’s disease-associated complement gene variants influence plasma complement protein levels

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    Background: Alzheimer’s disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers. Main body: To address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p < 0.001) and sCR1 and factor H reduced (p < 0.01) in AD plasma versus controls. ROC analyses were performed to assess utility of the measured complement biomarkers, alone or in combination with amyloid beta, in predicting AD. C1q was the most predictive single complement biomarker (AUC 0.655 LOAD, 0.601 EOAD); combining C1q with other complement or neurodegeneration makers through stepAIC-informed models improved predictive values slightly. Effects of GWS SNPs (rs6656401, rs6691117 in CR1; rs11136000, rs9331888 in CLU; rs3919533 in C1S) on protein concentrations were assessed by comparing protein levels in carriers of the minor vs major allele. To identify new associations between SNPs and changes in plasma protein levels, we performed a GWAS combining genotyping data in the cohort with complement protein levels as endophenotype. SNPs in CR1 (rs6656401), C1S (rs3919533) and CFH (rs6664877) reached significance and influenced plasma levels of the corresponding protein, whereas SNPs in CLU did not influence clusterin levels. Conclusion: Complement dysregulation is evident in AD and may contribute to pathology. AD-associated SNPs in CR1, C1S and CFH impact plasma levels of the encoded proteins, suggesting a mechanism for impact on disease risk
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