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). 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. 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. This study confirms increased concentrations of plasma NfL in patients with Alzheimer’s disease compared with nondemented controls.

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.

Amyloid-β (Aβ) peptides are the main components of the plaques found in the brains of patients with Alzheimer’s disease. However, Aβ peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aβ peptides. Recently, anti-infective properties of Aβ peptides have been reported. Here, we investigated the interaction of Aβ peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aβ_1-42, Aβ_2-42 and Aβ_3p-42 but not the non-amyloidogenic peptides Aβ_1-40 and Aβ_2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aβ peptide variants ending at position 42 (Aβ_x-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aβ_x-40. Furthermore, Aβ_x-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aβ_1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aβ_1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aβ_x-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.

Introduction: Neuroinflammation and synaptic degeneration are major neuropathological hallmarks in Alzheimer’s disease (AD). Neurogranin and YKL-40 in cerebrospinal fluid (CSF) are newly discovered markers indicating synaptic damage and microglial activation, respectively. Methods: CSF samples from 95 individuals including 39 patients with AD dementia (AD-D), 13 with mild cognitive impairment (MCI) due to AD (MCI-AD), 29 with MCI not due to AD (MCI-o) and 14 patients with non-AD dementias (non-AD-D) were analyzed for neurogranin and YKL-40. Results: Patients with dementia or MCI due to AD showed elevated levels of CSF neurogranin (p < 0.001 for AD-D and p < 0.05 for MCI-AD) and YKL-40 (p < 0.05 for AD-D and p = 0.15 for MCI-AD) compared to mildly cognitively impaired subjects not diagnosed with AD. CSF levels of neurogranin and YKL-40 did not differ between MCI not due to AD and non-AD dementias. In AD subjects no correlation between YKL-40 and neurogranin was found. The CSF neurogranin levels correlated moderately with tau and p-tau but not with Aβ₄₂ or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, Aβ₄₂, t-tau and p-tau were found in AD subjects. Conclusions: Neurogranin and YKL-40 are promising AD biomarkers, independent of and complementary to the established core AD biomarkers, reflecting additional pathological changes in the course of AD.

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: 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 (t₀) and after (t₁) the course, and students’ exam results (t₂). 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.