Phosphorylated tau in Alzheimer's disease.

There is a need for blood biomarkers to detect individuals at different Alzheimer's disease (AD) stages because obtaining cerebrospinal fluid-based biomarkers is invasive and costly. Plasma phosphorylated tau proteins (p-tau) have shown potential as such biomarkers. This systematic review was conducted according to the PRISMA guidelines and aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181), threonine 217 (p-tau217) and threonine 231 (p-tau231) is informative in the diagnosis of AD. All p-tau isoforms increase as a function of Aß-accumulation and discriminate healthy individuals from those at preclinical AD stages with high accuracy. P-tau231 increases earliest, followed by p-tau181 and p-tau217. In advanced stages, all p-tau isoforms are associated with the clinical classification of AD and increase with disease severity, with the greatest increase seen for p-tau217. This is also reflected by a better correlation of p-tau217 with Aß scans, whereas both, p-tau217 and p-tau181 correlated equally with tau scans. However, at the very advanced stages, p-tau181 begins to plateau, which may mirror the trajectory of the Aß pathology and indicate an association with a more intermediate risk of AD. Across the AD continuum, the incremental increase in all biomarkers is associated with structural changes in widespread brain regions and underlying cognitive decline. Furthermore, all isoforms differentiate AD from non-AD neurodegenerative disorders, making them specific for AD. Incorporating p-tau181, p-tau217 and p-tau231 in clinical use requires further studies to examine ideal cut-points and harmonize assays.

The Association of suPAR with Cardiovascular Risk Factors in Young and Healthy Adults.

The soluble urokinase plasminogen activator receptor (suPAR), as a correlate of chronic low-grade inflammation, may be used to predict individual cardiovascular risk. Since chronic low-grade inflammation is thought to be associated with the development of cardiovascular disease, this study aimed to evaluate if suPAR plasma levels are correlated with cardiovascular risk factors in young and healthy adults (aged 25-41 years). Consequently, data from the GAPP (genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors) study were used to investigate suPAR plasma levels in relation to the following cardiovascular risk factors and laboratory parameters: BMI, physical activity, alcohol consumption, smoking status, blood pressure parameters, glucose status, and lipid levels. Additionally, suPAR was compared to the healthy lifestyle score and the Framingham score representing the overall cardiovascular risk profile. These associations were assessed using two different statistical approaches. Firstly, all cardiovascular risk factors and scores were compared amongst sex-specific suPAR plasma levels with ANOVA analysis. Secondly, sex-specific multivariable linear regressions were performed. Female participants had higher plasma suPAR levels than male participants (1.73 ng/mL versus 1.50 ng/mL; p < 0.001). A significant inverse correlation between suPAR plasma levels and HDL cholesterol was found in men (p = 0.001) and women (p < 0.001). Furthermore, male (p < 0.001) and female participants (p < 0.001) who smoked showed significantly higher plasma levels of suPAR (p < 0.001). For male participants, an inverse correlation of the healthy lifestyle score with suPAR plasma levels (p = 0.001) and a positive correlation of the Framingham score with suPAR plasma levels (p < 0.001) were detected. In women, no such correlation was found. The cholesterol levels (p = 0.001) and HbA1c (p = 0.008) correlated significantly with plasma suPAR levels in female participants. suPAR plasma levels were found to be strongly associated with certain cardiovascular risk factors; however, sex-specific differences were found. These sex-specific differences might be explained by the higher prevalence of cardiovascular risk factors in men resulting in a stronger correlation of suPAR as a marker of low-grade inflammation, since the existence of the risk factors already led to subclinical damage in men. Further research on suPAR levels in an older study population is needed.

Concentrations of Serum Brain Injury Biomarkers Following SARS-CoV-2 Infection in Individuals with and without Long-COVID-Results from the Prospective Population-Based COVI-GAPP Study.

It is unknown whether neurological symptoms are associated with brain injury after SARS-CoV-2 infections and whether brain injury and related symptoms also emerge in Long-COVID patients. Biomarkers such as serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) can be used to elucidate neuro-axonal and astroglial injuries. We investigated whether these biomarkers are associated with COVID-19 infection status, associated symptoms and Long-COVID. From 146 individuals of the general population with a post-acute, mild-to-moderate SARS-CoV-2 infection, sNfL and sGFAP were measured before, during and after (five and ten months) the infection. Individual symptoms and Long-COVID status were assessed using questionnaires. Neurological associated symptoms were described for individuals after a mild and moderate COVID-19 infection; however, sNfL (p = 0.74) and sGFAP (p = 0.24) did not change and were not associated with headache (p = 0.51), fatigue (p = 0.93), anosmia (p = 0.77) or ageusia (p = 0.47). In Long-COVID patients, sGFAP (p = 0.038), but not sNfL (p = 0.58), significantly increased but was not associated with neurological associated symptoms. Long-COVID status, but not post-acute SARS-CoV-2 infections, may be associated with astroglial injury/activation, even if neurological associated symptoms were not correlated.

P-tau217 in Alzheimer's disease.

BACKGROUND AND AIMS: The potential of disease-modifying therapies for Alzheimer's disease has greatly stimulated interest in the development of minimally invasive testing for early identification of at-risk individuals. Accordingly, identification of blood-based biomarkers is paramount. The recent discovery of plasma phosphorylated at threonine217 (p-tau217) may provide a turning point in Alzheimer's disease detection. This systematic review aims to evaluate the available evidence on the use of plasma p-tau217 as a marker to predict Alzheimer's disease and to monitor disease progression. MATERIAL AND METHODS: This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Study quality was assessed using the QUADAS-2 tool. In total, 676 publications were identified, of which 16 were in accordance with the pre-defined eligibility criteria. RESULTS: Current evidence shows that plasma p-tau217 is a sensitive maker of the clinical manifestation and progression of Alzheimer's disease and of pathological changes associated with this condition, including amyloid accumulation, tau burden, brain atrophy and physical degradation. Moreover, given that plasma p-tau217 does not predict such changes in patients with other neurodegenerative disorders, plasma p-tau217 is also specific to Alzheimer's disease. CONCLUSION: More large, diverse community studies are needed to harmonize plasma p-tau217 measurements and to determine widely applicable diagnostic cut-off values.

Metabolic reprogramming of Salmonella infected macrophages and its modulation by iron availability and the mTOR pathway.

Iron is an essential nutrient for immune cells and microbes, therefore the control of its homeostasis plays a decisive role for infections. Moreover, iron affects metabolic pathways by modulating the translational expression of the key tricarboxylic acid cycle (TCA) enzyme mitochondrial aconitase and the energy formation by mitochondria. Recent data provide evidence for metabolic re-programming of immune cells including macrophages during infection which is centrally controlled by mTOR. We herein studied the effects of iron perturbations on metabolic profiles in macrophages upon infection with the intracellular bacterium Salmonella enterica serovar Typhimurium and analysed for a link to the mTOR pathway. Infection of the murine macrophage cell line RAW264.7 with Salmonella resulted in the induction of mTOR activity, anaerobic glycolysis and inhibition of the TCA activity as reflected by reduced pyruvate and increased lactate levels. In contrast, iron supplementation to macrophages not only affected the mRNA expression of TCA and glycolytic enzymes but also resulted in metabolic reprogramming with increased pyruvate accumulation and reduced lactate levels apart from modulating the concentrations of several other metabolites. While mTOR slightly affected cellular iron homeostasis in infected macrophages, mTOR inhibition by rapamycin resulted in a significant growth promotion of bacteria. Importantly, iron further increased bacterial numbers in rapamycin treated macrophages, however, the metabolic profiles induced by iron in the presence or absence of mTOR activity differed in several aspects. Our data indicate, that iron not only serves as a bacterial nutrient but also acts as a metabolic modulator of the TCA cycle, partly reversing the Warburg effect and resulting in a pathogen friendly nutritional environment.