Diagnostic accuracy of inflammatory markers in adults with suspected central nervous system infections.

OBJECTIVES: We aimed to determine diagnostic accuracy of inflammatory markers in plasma and cerebrospinal fluid (CSF) for the diagnosis of central nervous system (CNS) infections and specifically bacterial meningitis. METHODS: We analyzed 12 cytokines, chemokines, and acute phase reactants in CSF and plasma of 738 patients with suspected neurological infection included in a multicenter prospective cohort. We determined diagnostic accuracy for predicting any CNS infection and bacterial meningitis. RESULTS: We included 738 episodes between 2017 and 2022, split into a derivation (n = 450) and validation cohort (n = 288). Of these patients, 224 (30%) were diagnosed with CNS infection, of which 81 (11%) with bacterial meningitis, 107 (14%) with viral meningitis or encephalitis, and 35 patients (5%) with another CNS infection. Diagnostic accuracy of CRP, IL-6, and Il-1ß in CSF was high, especially for diagnosing bacterial meningitis. Combining these biomarkers in a multivariable model increased accuracy and provided excellent discrimination between bacterial meningitis and all other disorders (AUC = 0.99), outperforming all individual biomarkers as well as CSF leukocytes (AUC = 0.97). When applied to the population of patients with a CSF leukocyte count of 5-1000 cells/mm3, accuracy of the model also provided a high diagnostic accuracy (AUC model = 0.97 vs. AUC CSF leukocytes = 0.80) with 100% sensitivity and 92% specificity. These results remained robust in a temporal validation cohort. CONCLUSIONS: Inflammatory biomarkers in CSF are able to differentiate CNS infections and especially bacterial meningitis from other disorders. When these biomarkers are combined, their diagnostic accuracy exceeds that of CSF leukocytes alone and as such these markers have added value to current clinical practice.

The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition.

α-Synuclein (αS) is a presynaptic disordered protein whose aberrant aggregation is associated with Parkinson's disease. The functional role of αS is still debated, although it has been involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs). We report here a detailed characterisation of the conformational properties of αS bound to the inner and outer leaflets of the presynaptic plasma membrane (PM), using small unilamellar vesicles. Our results suggest that αS preferentially binds the inner PM leaflet. On the basis of these studies we characterise in vitro a mechanism by which αS stabilises, in a concentration-dependent manner, the docking of SVs on the PM by establishing a dynamic link between the two membranes. The study then provides evidence that changes in the lipid composition of the PM, typically associated with neurodegenerative diseases, alter the modes of binding of αS, specifically in a segment of the sequence overlapping with the non-amyloid component region. Taken together, these results reveal how lipid composition modulates the interaction of αS with the PM and underlie its functional and pathological behaviours in vitro.

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles.

α-Synuclein (αS) is a presynaptic protein whose aggregation is associated with Parkinson's disease (PD). Although the physiological function of αS is still unclear, several lines of evidence indicate that this protein may play a role in the trafficking of synaptic vesicles (SVs) during neurotransmitter release, a task associated with its ability to bind SVs and promote their clustering. It is therefore crucial to identify the cellular factors that modulate this process. To address this question, using nuclear magnetic resonance (NMR) spectroscopy we have characterized the role of cholesterol, a major component of the membrane of SVs, in the binding of αS with synaptic-like vesicles. Our results indicate that cholesterol can act as a modulator of the overall affinity of αS for SVs by reducing the local affinity of the region spanning residues 65-97 in the non-amyloid-ß component (NAC) of the protein. The increased population of bound states that expose the region 65-97 to the solvent was found to induce stronger vesicle-vesicle interactions by αS. These results provide evidence that cholesterol modulates the clustering of synaptic vesicles induced by (α)S, and supports the role of the disorder-to-order equilibrium of the NAC region in the modulation of the biological properties of the membrane-bound state of αS.