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Background A growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer’s disease (AD). Methods With a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n  = 25) or at the stage of early dementia (ADD; n  = 33), and in nondemented controls ( n  = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid β (Aβ)1–42, Aβ42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions. Results NfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 °C. Compared with the control group of nondemented subjects (22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p  < 0.005) and even further elevated in the ADD group (49.1 ± 28.4 pg/mL; p  < 0.001). A significant association between NfL and age (ρ = 0.65, p  < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant ( p  = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant ( r  = −0.49, p  < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups. Conclusions This study confirms increased concentrations of plasma NfL in patients with Alzheimer’s disease compared with nondemented controls.

The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (Th) subsets in AD, we conducted a case control study with 54 individuals with AD dementia ( n  = 14), with mild cognitive impairment (MCI) due to AD (MCIAD, n  = 14), with MCI unlikely due to AD (MCIother, n  = 13), and controls without cognitive impairment (controls, n  = 13). The proportions of CD3+CD8−IL-17A+IFNγ− Th17 cells, CD3+CD8−IL-17A−IFNγ+ Th1 cells, and CD4+CD127lowCD25+ regulatory T cells (Tregs) were assessed by flow cytometry. In addition, the correlations of the proportions of Th subsets to cerebrospinal fluid biomarkers were studied. CD3+CD8−IL-17A+IFNγ− Th17 cells were significantly increased in subjects with MCIAD compared to age- and sex-matched subjects with MCIother and controls (MCIAD mean = 1.13, SD = 0.77; MCIother mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p  = 0.008). The proportion of CD4+CD127lowCD25+ Tregs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 ( r Treg|totalTau = 0.43, p  = 0.021, n  = 28; r Treg|pTau181 = 0.46; p  = 0.024, n  = 28) in subjects with AD but not in nonAD controls ( r Treg|totalTau = −0.51, p  = 0.007, n  = 26). The increase of circulating CD3+CD8−IL-17A+IFNγ− Th17 cells in the early stages of AD and the association of CD4+CD127lowCD25+ Tregs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.

In cochlear implant (CI) users, measurements of electrically evoked compound action potentials (ECAPs) prove the functionality of the neuron-electrode interface. Objective measures, e.g., the ECAP threshold, may serve as a basis for the clinical adjustment of the device for the optimal benefit of the CI user. As for many neural responses, the threshold determination often is based on the subjective assessment of the clinical specialist, whose decision-making process could be aided by autonomous computational algorithms. To that end, we extended the signal-to-noise ratio (SNR) approach for ECAP threshold determination to be applicable for FineGrain (FG) ECAP responses. The new approach takes advantage of two features: the FG stimulation paradigm with its enhanced resolution of recordings, and SNR-based ECAP threshold determination, which allows defining thresholds independently of morphology and with comparably low computational power. Pearson’s correlation coefficient r between the ECAP threshold determined by five experienced evaluators and the threshold determined with the FG-SNR algorithm was in the range of r = 0.78–0.93. Between evaluators, r was in a comparable range of 0.84–0.93. A subset of the parameters of the algorithm was varied to identify the parameters with the highest potential to improve the FG-SNR formalism in the future. The two steps with the strongest influence on the agreement between the threshold estimate of the evaluators and the algorithm were the removal of undesired frequency components (denoising of the response traces) and the exact determination of the two time windows (signal and noise and noise only).”The parameters were linked to the properties of an ECAP response, indicating how to adjust the algorithm for the automatic detection of other neurophysiological responses.

Microvesicles are small membranous particles generated during cellular activation or stress. The analysis of the content and the surface of microvesicles allow conclusions about the cells they are originating from and the underlying pathology. Therefore, CSF microvesicles have been suggested to be promising targets to monitor the (etio)pathology of neurodegenerative diseases. Microvesicles in the CSF of 15 patients with Alzheimer’s disease and 15 controls were analyzed by flow cytometry regarding the levels of CD3, CD4, CD45, CD64, BACE1, Aβ, APP and tau. The results were replicated in a second cohort comprising 14 patients with Alzheimer’s disease and 9 controls. The levels of tau and APP were reduced in microvesicles of Alzheimer’s disease patients. A significant change was neither observed in the number of microvesicles nor in the expression of the other antigens. Tau and APP in microvesicles separated patients with Alzheimer’s disease from controls with an AUC of 0.84 and 0.89 respectively. We conclude that tau and APP in CSF microvesicles are promising biomarkers which could directly provide information about the Alzheimer pathology on a cellular level.

Background The growing importance of online education in recent years has led to an increased focus on implementing and optimizing online learning formats. This study investigated how a lecture delivered in an asynchronous or synchronous online teaching format affects acceptance, intrinsic motivation and knowledge levels after training. The results can be used to optimize online education by identifying format-specific advantages and adapting them to learners’ needs. Methods All the Styrian paramedics ( N  = 5910) were invited to participate in the study and randomly assigned to one of two groups. A total of 1044 participants completed the trial, with one group receiving asynchronous training via a learning platform ( N  = 545) and the other group participating in synchronous training via webinars ( N  = 499) providing the same content. After completing a two-hour psychiatric emergency course, the participants were invited to complete a multiple-choice test and a survey assessing acceptance, preferences and intrinsic motivation. Linear regression, t tests and mediation analyses were conducted. Results The asynchronous training format was significantly more accepted ( p  <.001) and preferred overall. The participants’ preferences depended significantly on the type of learning format ( p  <.001). The synchronous learning format fostered greater intrinsic motivation ( p  =.001) and greater perceived autonomy ( p  <.001) but also a higher level of perceived pressure/tension ( p  =.003). The analysis revealed no significant difference in test results ( p  =.449) or perceived competence between the groups ( p  =.420). Furthermore, the difference in intrinsic motivation was fully mediated by perceived autonomy. Conclusions There are different advantages and disadvantages to providing a lecture via webinar or online learning platform. Both formats are equally effective in terms of knowledge levels after training, highlighting the importance of adapting teaching strategies to learners’ preferences.

Background Medical students experience high levels of stress and related mental health problems. Students’ autonomous and controlled motivation and their mental well-being are interconnected. This study aimed to investigate whether an innovative teaching concept based on self-determination theory (SDT) could improve students’ motivation and thereby reduce their stress levels, ultimately providing a healthier framework for learning. Methods In a week-long practical psychiatry course for medical students, a new didactic concept was implemented in half the groups ( n  = 73) and compared with the preexisting concept ( n  = 75) as a randomized controlled trial (RCT). To promote the SDT-target factors of perceived autonomy, competence, and relatedness, the methods used included team building, exclusively positive feedback, group discussions, and choice in task distribution. Significant group differences in motivation, stress, performance, and their relationships were analyzed through t -tests, multiple linear regression analyses, mediation analyses, and hierarchical linear modeling (HLM) using questionnaires collected before (t 0 ) and after (t 1 ) the course, and students’ exam results (t 2 ). Results In the innovation group ( n  = 53), intrinsic motivation/interest ( d  = 0.41; p  = .019) and perceived choice/autonomy ( d  = 0.33; p  = .048) were greater than in the control group ( n  = 52). While autonomous regulation remained stable, the innovation group showed reduced controlled regulation ( d = -0.36; p  = .033) and reported significantly lower stress ( d = -0.55; p  = .003). The observed changes in motivation collectively mediated the stress reduction. However, students in the innovation group achieved lower exam scores, which seemed to result from the absence of critical feedback, but not from the observed differences in motivation or stress. Conclusions This study demonstrated that enhancing intrinsic motivation through SDT-based teaching can effectively reduce stress in medical students. Exclusively strengths-based positive feedback may have hindered exam performance, but optimizing educational concepts to promote motivation and reduce stress will be a valuable step toward improving medical students’ mental well-being.

Astrocytes may not only be involved in the clearance of Amyloid beta peptides (Aβ) in Alzheimer's disease (AD), but appear to produce N-terminally truncated Aβ (Aβ n−x ) independently of BACE1, which generates the N-Terminus of Aβ starting with Asp1 (Aβ 1−x ). A candidate protease for the generation of Aβ n−x is cathepsin B (CatB), especially since CatB has also been reported to degrade Aβ, which could explain the opposite roles of astrocytes in AD. In this study, we investigated the influence of CatB inhibitors and the deletion of the gene encoding CatB (CTSB) using CRISPR/Cas9 technology on Aβ 2−x and Aβ 1−x levels in cell culture supernatants by one- and two-dimensional Urea-SDS-PAGE followed by immunoblot. While the cell-permeant inhibitors E64d and CA-074 Me did not significantly affect the Aβ 1−x levels in supernatants of cultured chicken and human astrocytes, they did reduce the Aβ 2−x levels. In the glioma-derived cell line H4, the Aβ 2−x levels were likewise decreased in supernatants by treatment with the more specific, but cell-impermeant CatB-inhibitor CA-074, by CA-074 Me treatment, and by CTSB gene deletion. Additionally, a more than 2-fold increase in secreted Aβ 1−x was observed under the latter two conditions. The CA-074 Me-mediated increase of Aβ 1−x , but not the decrease of Aβ 2−x , was influenced by concomitant treatment with the vacuolar H + -ATPase inhibitor Bafilomycin A1. This indicated that non-lysosomal CatB mediated the production of Aβ 2−x in astrocytes, while the degradation of Aβ 1−x seemed to be dependent on lysosomal CatB in H4 cells, but not in primary astrocytes. These findings highlight the importance of considering organelle targeting in drug development to promote Aβ degradation.

Introduction Synaptic dysfunction and degeneration are central events in Alzheimer’s disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng 48–76 ), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng 48–76 is the dominant peptide in human brain tissue. The aim of this study was to characterize Ng in plasma and CSF using mass spectrometry and to investigate the performance of plasma Ng as an AD biomarker. Methods Paired plasma and CSF samples from patients with AD (n = 25) and healthy controls (n = 20) were analyzed in parallel using an immunoassay developed in-house on the Meso Scale Discovery platform and hybrid immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. High-resolution mass spectrometry was used for identification of endogenous plasma Ng peptides. Results Ng in human plasma is present as several endogenous peptides. Of the 16 endogenous Ng peptides identified, seven were unique for plasma and not detectable in CSF. However, Ng 48–76 was not present in plasma. CSF Ng was significantly increased in AD compared with controls ( P  < 0.0001), whereas the plasma Ng levels were similar between the groups in both studies. Plasma and CSF Ng levels showed no correlation. CSF Ng was stable during storage at −20°C for up to 2 days, and no de novo generation of peptides were detected. Conclusions For the first time, to our knowledge, we have identified several endogenous Ng peptides in human plasma. In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. The origin of Ng in plasma and its possible use as a biomarker need to be further investigated. The results suggest that CSF Ng, in particular Ng 48–76 , might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.

Background Symptoms of obstructive sleep apnoea (OSA) overlap significantly with those of psychiatric disorders, making accurate diagnosis of OSA challenging within psychiatric settings. Diagnosing OSA in psychiatric patients is crucial because untreated OSA can exacerbate psychiatric symptoms, reduce treatment efficacy, and impair overall quality of life. This study aimed to determine the diagnostic accuracy of a readily accessible procedure for psychiatric patients in a real-world clinical setting by comparing the Somnocheck micro CARDIO ® (SCm) portable cardiorespiratory polygraphy device with the gold standard polysomnography (PSG). Methods This observational cohort study included consecutive psychiatric patients at intermediate to high risk for OSA based on screening with the STOP-Bang questionnaire, admitted to a single tertiary care centre between June 1, 2016 and December 31, 2022. The Apnoea-Hypopnoea-Index (AHI), Apnoea-Index (AI), Oxygen-Desaturation-Index (ODI), and minimum oxygen saturation were measured sequentially by SCm and PSG. Results A total of 57 patients were analysed (median age 62.0 [Interquartile Range (IQR), 51.5–72.5] years; 34 [59.6%] men). Regarding AHI, no significant differences (AHI measured by PSG, median, 16.6 [IQR, 6.2–26.7] vs. AHI measured by SCm, median, 14.9 [IQR, 10.0-22.8]; p  = 0.812; r  = 0.71) were found between SCm and PSG. AI, ODI and minimum oxygen saturation differed significantly between SCm and PSG. Using optimised cut-off values (any OSA: AHI SCm ≥ 9.25), SCm showed high sensitivity (0.894) and high specificity (0.800) for the diagnosis of OSA, with an area under the receiver operating characteristic curve of 0.877. Conclusions This study found that the SCm portable device was accurate in identifying psychiatric patients with OSA. AHI measurement by SCm provided reliable diagnostic performance in comparison with the gold standard polysomnography. These findings support the integration of polygraphic measurements into the routine sleep assessment of psychiatric patients. Early and accurate diagnosis of OSA in this population can significantly improve the management of both sleep disorders and psychiatric conditions, potentially enhancing overall treatment outcomes and quality of life for these patients.

Introduction: In Alzheimer’s disease, the severity of symptoms is linked to a loss of synaptic density and the spread of pathologically hyperphosphorylated tau. The established cerebrospinal fluid markers Aβ, tau and phospho-tau reflect the histopathological hallmarks of Alzheimer’s disease but do not indicate disease progression. Such markers are of special interest, especially for trials of disease modifying drugs. Microvesicles are produced by stressed cells and reflect part of the metabolism of their cells of origin. Therefore, we investigated microvesicles of neuronal origin in cerebrospinal fluid. Material and Methods: We used flow cytometry to analyze microvesicles carrying tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, synaptophysin and SNAP-25 in the cerebrospinal fluid of 19 patients with Alzheimer’s disease and 15 controls. Results: The percentages of synaptophysin-bearing microvesicles were significantly higher in the cerebrospinal fluid of patients with Alzheimer’s disease than in the CSF of noninflammatory neurological disease controls. Tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, and SNAP-25 did not differ between the groups. The percentages of synaptophysin-bearing vesicles distinguished patients with Alzheimer’s disease from the controls (AUC = 0.81). Conclusion: The loss of synapses in Alzheimer’s disease may be reflected by synaptophysin-bearing microvesicles in the cerebrospinal fluid. Future studies are needed to investigate the possibility of using these MVs as a marker to determine the activity of Alzheimer’s disease.