Amyloid-ß levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy.

Phosphorylated Tau181 (pTau181) in CSF and recently in plasma has been associated with Alzheimer's disease. In the absence of amyloidopathy, individuals with increased total Tau levels and/or temporal lobe atrophy experience no or only mild cognitive decline compared with biomarker-negative controls, leading to the proposal to categorize this constellation as suspected non-Alzheimer's disease pathophysiology (SNAP). We investigated whether the characteristics of SNAP also applied to individuals with increased CSF-pTau181 without amyloidopathy. In this long-term observational study, 285 non-demented individuals, including 76 individuals with subjective cognitive impairment and 209 individuals with mild cognitive impairment, were classified based on their CSF levels of pTau181 (T), total Tau (N), amyloid-ß42 (Aß42) and Aß42/Aß40 ratio (A) into A+T+N±, A+T-N±, A-T+N±, and A-T-N-. The longitudinal analysis included 154 subjects with a follow-up of more than 12 months who were followed to a median of 4.6 years (interquartile range = 4.3 years). We employed linear mixed models on psychometric tests and region of interest analysis of structural MRI data. Cognitive decline and hippocampal atrophy rate were significantly higher in A+T+N± compared to A-T+N±, whereas there was no difference between A-T+N± and A-T-N-. Furthermore, there was no significant difference between A-T+N± and controls in dementia risk [hazard ratio 0.3, 95% confidence interval (0.1, 1.9)]. However, A-T+N± and A-T-N- could be distinguished based on their Aß42 and Aß40 levels. Both Aß40 and Aß42 levels were significantly increased in A-T+N± compared to controls. Long term follow-up of A-T+N± individuals revealed no evidence that this biomarker constellation was associated with dementia or more severe hippocampal atrophy rates compared to controls. However, because of the positive association of pTau181 with Aß in the A-T+N± group, a link to the pathophysiology of Alzheimer's disease cannot be excluded in this case. We propose to refer to these individuals in the SNAP group as 'pTau and Aß surge with subtle deterioration' (PASSED). The investigation of the circumstances of simultaneous elevation of pTau and Aß might provide a deeper insight into the process under which Aß becomes pathological.

[Medical education in psychosocial disciplines in times of the COVID-19 pandemic - first experiences]. / Lehre in den psychosozialen medizinischen Fächern in Zeiten der COVID-19-Pandemie ­ erste Erfahrungen.

AIM: In specialties that heavily rely on communication skills such as psychiatry, psychotherapy and psychosomatic medicine, teaching in times of the COVID-19 pandemic is especially challenging. In this overview, educators and course directors report their experiences in eteaching and share their innovative solutions. METHODS: We present a collection of methods that relate to teaching and assessment as well as student activation. RESULTS: A range of helpful tools for teaching were compiled. This includes instructional videos with simulated patients, structured homework to document a mental status examination, structured hand-offs, and practical examinations in video format. Motivational techniques include podcasts with interviews with clinicians and patients and teaching with the use of cinematic material. DISCUSSION: Switching to online formats creates opportunities and advantages for the advancement of time- and location-independent learning. A fast conversion in this direction might also pose some disadvantages. A direct patient-student interaction is critical for engaging with transference, countertransference and situational aspects for teaching in psychosocial disciplines. Empirical studies of the effectiveness of these newly developed formats and faculty development for digital teaching are necessary.

Analysis of Surface Levels of IL-1 Receptors and Macrophage Scavenger Receptor I in Peripheral Immune Cells of Patients With Alzheimer Disease.

Increased concentrations of interleukin 1 (IL-1) in the cerebrospinal fluid and serum of patients with Alzheimer disease (AD) reduced phagocytic capacity point to an inflammatory activation of mononuclear phagocytes in AD. Interleukin 1 receptors (IL-1R) and the macrophage scavenger receptor I (MSRI) are important players in IL-1 signaling and phagocytosis. In 20 patients with AD and 17 controls, IL-1RI, IL-1RII, and MSRI were assessed on peripheral blood mononuclear cells by flow cytometry. IL-1ß, soluble IL-1 receptors, and IL-1R antagonist (IL-1Ra) were measured by enzyme-linked immunosorbent assay. The fraction of IL-1RI+ monocytes was increased by 10% and the expression of MSRI was reduced by 12% in AD. A 3.6% increased fraction of IL-1RI+ lymphocytes was accompanied by a 6.1% reduced expression of IL-1RII. The IL-1RI on monocytes and lymphocytes discriminated patients with AD with an accuracy of 0.79 and 0.75, respectively. The IL-1Ra was elevated in AD. Changes in the expression of IL-1 receptors and MSRI on peripheral blood cells fit to the concept of a proinflammatory state of the peripheral immune system. However, the observed differences are not strong enough to suggest their application as biomarkers for AD.

Assessing the Firing Properties of the Electrically Stimulated Auditory Nerve Using a Convolution Model.

The electrically evoked compound action potential (eCAP) is a routinely performed measure of the auditory nerve in cochlear implant users. Using a convolution model of the eCAP, additional information about the neural firing properties can be obtained, which may provide relevant information about the health of the auditory nerve. In this study, guinea pigs with various degrees of nerve degeneration were used to directly relate firing properties to nerve histology. The same convolution model was applied on human eCAPs to examine similarities and ultimately to examine its clinical applicability. For most eCAPs, the estimated nerve firing probability was bimodal and could be parameterised by two Gaussian distributions with an average latency difference of 0.4 ms. The ratio of the scaling factors of the late and early component increased with neural degeneration in the guinea pig. This ratio decreased with stimulation intensity in humans. The latency of the early component decreased with neural degeneration in the guinea pig. Indirectly, this was observed in humans as well, assuming that the cochlear base exhibits more neural degeneration than the apex. Differences between guinea pigs and humans were observed, among other parameters, in the width of the early component: very robust in guinea pig, and dependent on stimulation intensity and cochlear region in humans. We conclude that the deconvolution of the eCAP is a valuable addition to existing analyses, in particular as it reveals two separate firing components in the auditory nerve.

Astrocytes and microglia but not neurons preferentially generate N-terminally truncated Aß peptides.

The neuropathological hallmarks of Alzheimer's disease include extracellular neuritic plaques and neurofibrillary tangles. The neuritic plaques contain ß-amyloid peptides (Aß peptides) as the major proteinaceous constituent and are surrounded by activated microglia and astrocytes as well as dystrophic neurites. N-terminally truncated forms of Aß peptides are highly prevalent in neuritic plaques, including Aß 3-x beginning at Glu eventually modified to pyroglutamate (Aß N3pE-x), Aß 2-x, Aß 4-x, and Aß 5-x. The precise origin of the different N-terminally modified Aß peptides currently remains unknown. To assess the contribution of specific cell types to the formation of different N-terminally truncated Aß peptides, supernatants from serum-free primary cell cultures of chicken neurons, astrocytes, and microglia, as well as human astrocytes, were analyzed by Aß-ELISA and one- and two-dimensional SDS-urea polyacrylamide gel electrophoresis followed by immunoblot analysis. To evaluate the contribution of ß- and γ-secretase to the generation of N-terminally modified Aß, cultured astrocytes were treated with membrane-anchored "tripartite ß-secretase (BACE1) inhibitors" and the γ-secretase inhibitor DAPT. Neurons, astrocytes, and microglia each exhibited cell type-specific patterns of secreted Aß peptides. Neurons predominantly secreted Aß peptides that begin at Asp1, whereas those released from astrocytes and microglia included high proportions of N-terminally modified Aß peptides, presumably including Aß 2/3-x and 4/5-x. The inhibition of BACE1 reduced the amount of Aß 1-x in cell culture supernatants but not the amount of Aß 2-x.

Highly potent soluble amyloid-ß seeds in human Alzheimer brain but not cerebrospinal fluid.

The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-ß seeds. In this study, we sought to assess the potency of soluble amyloid-ß seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-ß deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-ß. In contrast, cerebrospinal fluid from patients with Alzheimer's disease, which contained more than 10-fold higher levels of amyloid-ß peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-ß deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-ß species and exhibited smaller amyloid-ß-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-ß species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid.

N-truncation and pyroglutaminylation enhances the opsonizing capacity of Aß-peptides and facilitates phagocytosis by macrophages and microglia.

Abnormal accumulations of amyloid-ß (Aß)-peptides are one of the pathological hallmarks of Alzheimer's disease (AD). The precursor of the Aß-peptides, the amyloid precursor protein (APP), is also found in peripheral blood cells, but its function in these cells remains elusive. We previously observed that mononuclear phagocytes release Aß-peptides during activation and phagocytosis, suggesting a physiologic role in inflammatory processes. Here, we show that supplementing the media with soluble N-terminally truncated Aß(2-40) and Aß(2-42) as well as Aß(1-42) induced the phagocytosis of polystyrene particles (PSPs) by primary human monocytes. If the PSPs were pre-incubated with Aß-peptides, phagocytosis was induced by all tested Aß-peptide species. N-terminally truncated Aß(x-42) induced the phagocytosis of PSPs significantly more effectively than did Aß(x-40). Similarly, the phagocytosis of Escherichia coli by GM-CSF- and M-CSF-elicited macrophages as well as microglia was particularly facilitated by pre-incubation with N-terminally truncated Aß(x-42). The proinflammatory polarization of monocytes was indicated by the reduced MSRI expression and IL-10 secretion after phagocytosis of PSPs coated with Aß(1-42), Aß(2-42) and Aß(3p-42). Polarization of the macrophages by GM-CSF reduced the phagocytic activity, but it did not affect the capabilities of Aß-peptides to opsonize prey. Taken together, Aß-peptides support phagocytosis as soluble factors and act as opsonins. Differential effects among the Aß-peptide variants point to distinct mechanisms of interaction among monocytes/macrophages, prey and Aß-peptides. A proinflammatory polarization induced by the phagocytosis of Aß-peptide coated particles may provide a model for the chronic inflammatory reaction and sustained plaque deposition in AD.

Effects of Intraoperative Cochlear Implant Electrode Conditioning on Impedances and Electrically Evoked Compound Action Potentials.

OBJECTIVE: The current study investigates whether, during a Cochlear Implant (CI) surgery, conditioning (i.e. applying short bursts of electrical stimulation) within a saline solution can have positive effects on subsequent intra-operative measurements. We hypothesize that, based on previous research, the impedance values will be reduced, and that the reproducibility of Electrically Evoked Compound Action Potentials (ECAPs) is improved as a result of conditioning. METHODS: We conditioned half of the electrode contacts, within a saline solution, before CI insertion, using 23 MED-EL implants. Impedance was measured for both the conditioned and non-conditioned groups at five time points. Repeated ECAP recordings were measured and compared between the conditioned and non-conditioned groups. RESULTS: Impedance of the electrode contacts were reduced by 31% after conditioning in saline solution; however, there were no clinically relevant differences after the implantation of the electrode array. The hypothesis that measurement reproducibility would be increased after conditioning could not be confirmed with our data. Within the saline solution, we observed that 44% of the electrode contacts were covered with air bubbles, which most disappeared after implantation. However, these air bubbles limited the effectiveness of the conditioning within the saline solution. Lastly, the effect of conditioning on the reference electrode stimulation was approximately 16% of the total reduction in impedance. CONCLUSION: Our data does not suggest that intraoperative conditioning is clinically required for cochlear implantation with MED-EL implants. Additionally, an in-vivo ECAP recording can be considered as a method of conditioning the electrode contacts. SIGNIFICANCE: We confirm that the common clinical practice does not need to be changed.

What do the teachers want? A targeted needs assessment survey for prospective didactic training of psychiatry medical educators.

Objectives: Physicians and psychologists at psychiatric university hospitals are assigned teaching tasks from the first day of work without necessarily having the prerequisite training in teaching methods. This exploratory survey provides a needs-based analysis for the prospective didactic training of physicians and psychologists at psychiatric hospitals in Germany, Austria and Switzerland. Methods: An online questionnaire was distributed at medical schools via email in German-speaking countries in Europe. All physicians involved in teaching medical students at psychiatry faculties were eligible to participate in the survey. Participants were further requested to recruit eligible participants (snowball sampling). Responses were analyzed descriptively, and differences between groups were calculated using nonparametric Mann-Whitney U tests (p<.05). Results: Overall, 97 respondents (male=55, female=42; mean age= 40.6) from 19 medical schools completed the survey. The respondents consisted of 43 residents, 39 specialists, 6 chief physicians and 9 psychologists. Of the respondents, 97.6% rated didactic competence as either highly relevant or rather relevant for teaching medical students. The highest overall interest was shown for bedside teaching (mode=4; IQR: 2-4) and error culture (mode=3; IQR: 2-4). Respondents expressed the highest training needs for topics regarding presentation and communication (mode=3; IQR: 2-3). Resident physicians were significantly more interested in bedside teaching (U=362.0, p=0.004) and roleplay (U=425.0; p=0.036) than specialist physicians, who were more interested in examination didactics (U=415.0; p=0.022). Chief physicians displayed significantly deeper interest in group dynamics (U=51; p=0.023) than specialist physicians. In-person training was preferred by a majority of respondents, and 27.4% preferred online/web-based training. Conclusions: The majority of physicians and psychologists at psychiatric university hospitals considered professional development for faculty to be helpful for teaching medical students. Bedside teaching and error culture management were the most desired teaching topics for training medical teachers. Tailored educational interventions are recommended, with target-oriented priorities for different hierarchical levels.

Reconceptualization of the Erlangen Score for the Assessment of Dementia Risk: The ERlangen Score.

BACKGROUND: The established Erlangen Score (ES) for the interpretation of cerebrospinal fluid (CSF) biomarkers in the diagnostics of Alzheimer's disease (AD) uses markers of amyloidopathy and tauopathy, equally weighted to form an easy-interpretable ordinal scale. However, these biomarkers are not equally predictive for AD. OBJECTIVE: The higher weighting of the Aß42/Aß40 ratio, as a reconceptualized ERlangen Score (ERS), was tested for advantages in diagnostic performance. METHODS: Non-demented subjects (N = 154) with a mean follow up of 5 years were assigned to a group ranging from 0 to 4 in ES or ERS. Psychometric trajectories and dementia risk were assessed. RESULTS: The distribution of subjects between ES and ERS among the groups differed considerably, as grouping allocated 32 subjects to ES group 2, but only 2 to ERS group 2. The discriminative accuracy between the ES (AUC 73.2%, 95% CI [64.2, 82.2]) and ERS (AUC 72.0%, 95% CI [63.1, 81.0]) for dementia risk showed no significant difference. Without consideration of the Aß42/Aß40 ratio in ES grouping, the optimal cut-off of the ES shifted to ≥2. CONCLUSIONS: The ERS showed advantages over the ES in test interpretation with comparable overall test performance, as fewer cases were allocated to the intermediate risk group. The established cut-off of ≥2 can be maintained for the ERS, whereas it must be adjusted for the ES when determining the Aß42/Aß40 ratio.

PASSED: Brain atrophy in non-demented individuals in a long-term longitudinal study from two independent cohorts.

Introduction: Alzheimer's disease (AD) is indicated by a decrease in amyloid beta 42 (Aß42) level or the Aß42/Aß40 ratio, and by increased levels of Tau with phosphorylated threonine at position 181 (pTau181) in cerebrospinal fluid (CSF) years before the onset of clinical symptoms. However, once only pTau181 is increased, cognitive decline in individuals with subjective or mild cognitive impairment is slowed compared to individuals with AD. Instead of a decrease in Aß42 levels, an increase in Aß42 was observed in these individuals, leading to the proposal to refer to them as nondemented subjects with increased pTau-levels and Aß surge with subtle cognitive deterioration (PASSED). In this study, we determined the longitudinal atrophy rates of AD, PASSED, and Biomarker-negative nondemented individuals of two independent cohorts to determine whether these groups can be distinguished by their longitudinal atrophy patterns or rates. Methods: Depending on their CSF-levels of pTau 181 (T), total Tau (tTau, N), Aß42 or ratio of Aß42/Aß40 (A), 185 non-demented subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 62 non-demented subjects from Erlangen AD cohort were assigned to an ATN group (A-T-N-, A-T+N±, A+T-N±and A+T+N±) and underwent T1-weighted structural magnetic resonance imaging (sMRI). Longitudinal grey matter (GM) atrophy patterns were assessed with voxel-based morphometry (VBM) using the cat12 toolbox on spm12 (statistical parametric mapping) of MRI scans from individuals in the ADNI cohort with a mean follow-up of 2 and 5 years, respectively. The annualized atrophy rate for individuals in the Erlangen cohort was determined using region of interest analysis (ROI) in terms of a confirmatory analysis. Results: In the A-T+N± group, VBM did not identify any brain region that showed greater longitudinal atrophy than the A+T+N±, A+T+N± or biomarker negative control group. In contrast, marked longitudinal atrophy in the temporal lobe was evident in the A+T-N± group compared with A+T-N± and biomarker-negative subjects. The ROI in the angular gyrus identified by VBM analysis of the ADNI cohort did not discriminate better than the hippocampal volume and atrophy rate between AD and PASSED in the confirmatory analysis. Discussion: In this study, nondemented subjects with PASSED did not show a unique longitudinal atrophy pattern in comparison to nondemented subjects with AD. The nonsignificant atrophy rate compared with controls suggests that increased pTau181-levels without concomitant amyloidopathy did not indicate a neurodegenerative disorder.

In-vitro characterization of a cochlear implant system for recording of evoked compound action potentials.

BACKGROUND: Modern cochlear implants have integrated recording systems for measuring electrically evoked compound action potentials of the auditory nerve. The characterization of such recording systems is important for establishing a reliable basis for the interpretation of signals acquired in vivo. In this study we investigated the characteristics of the recording system integrated into the MED-EL PULSARCI100 cochlear implant, especially its linearity and resolution, in order to develop a mathematical model describing the recording system. METHODS: In-vitro setup: The cochlear implant, including all attached electrodes, was fixed in a tank of physiologic saline solution. Sinusoidal signals of the same frequency but with different amplitudes were delivered via a signal generator for measuring and recording on a single electrode.Computer simulations: A basic mathematical model including the main elements of the recording system, i.e. amplification and digitalization stage, was developed. For this, digital output for sinusoidal input signals of different amplitudes were calculated using in-vitro recordings as reference. RESULTS: Using an averaging of 100 measurements the recording system behaved linearly down to approximately -60 dB of the input signal range. Using the same method, a system resolution of 10 µV was determined for sinusoidal signals. The simulation results were in very good agreement with the results obtained from in-vitro experiments. CONCLUSIONS: The recording system implemented in the MED-EL PULSARCI100 cochlear implant for measuring the evoked compound action potential of the auditory nerve operates reliably. The developed mathematical model provides a good approximation of the recording system.

App-based maintenance treatment for alcohol use disorder after acute inpatient treatment: Study protocol for a multicentre randomized controlled trial.

BACKGROUND: Alcohol use disorder, a prevalent and disabling mental health problem, is often characterized by a chronic disease course. While effective inpatient and aftercare treatment options exist, the transferal of treatment success into everyday life is challenging and many patients remain without further assistance. App-based interventions with human guidance have great potential to support individuals after inpatient treatment, yet evidence on their efficacy remains scarce. OBJECTIVES: To develop an app-based intervention with human guidance and evaluate its usability, efficacy, and cost-effectiveness. METHODS: Individuals with alcohol use disorder (DSM-5), aged 18 or higher, without history of schizophrenia, undergoing inpatient alcohol use disorder treatment (N = 356) were recruited in eight medical centres in Bavaria, Germany, between December 2019 and August 2021. Participants were randomized in a 1:1 ratio to either receive access to treatment as usual plus an app-based intervention with human guidance (intervention group) or access to treatment as usual plus app-based intervention after the active study phase (waitlist control/TAU group). Telephone-based assessments are conducted by diagnostic interviewers three and six weeks as well as three and six months after randomization. The primary outcome is the relapse risk during the six months after randomization assessed via the Timeline Follow-Back Interview. Secondary outcomes include intervention usage, uptake of aftercare treatments, AUD-related psychopathology, general psychopathology, and quality of life. DISCUSSION: This study will provide further insights into the use of app-based interventions with human guidance as maintenance treatment in individuals with AUD. If shown to be efficacious, the intervention may improve AUD treatment by assisting individuals in maintaining inpatient treatment success after returning into their home setting. Due to the ubiquitous use of smartphones, the intervention has the potential to become part of routine AUD care in Germany and countries with similar healthcare systems.

E-Learning Is Not Inferior to On-Site Teaching in a Psychiatric Examination Course.

Background: Implementing e-learning into medical education is a growing field of research. Researchers have had positive experiences so far, and evidence suggests it to be no less effective than offline teaching. However, there are a few findings concerning psychiatric education and the use of simulated patients online. Methods: We developed an online workshop for medical students at our psychiatric clinic, including group work exercises, lectures, and interviews with simulated patients. To compare the learning outcome, a cohort of students learning online was compared with a previous cohort that learned on-site. The same objective structured clinical examination (OSCE) was used in both cases. Evaluation questionnaires were gathered from students and lecturers and were compared with the former semesters along with the exam results. Results: The exam grades did not significantly differ between on-site and online teaching, even though students rated their own communication skills better with online teaching. We also found that the connection experienced between students and teachers was impaired without on-site contact. Discussion: We conclude that an online course may be an effective alternative to on-site teaching but requires further improvement to maintain a dependable student-teacher relationship.

Optimized SNR-based ECAP threshold determination is comparable to the judgement of human evaluators.

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.

Cerebrospinal Fluid of Patients With Alzheimer's Disease Contains Increased Percentages of Synaptophysin-Bearing Microvesicles.

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 Aß, 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. MATERIALS 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 non-inflammatory neurological disease 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 non-inflammatory 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.

A method to prevent cross contamination during 2-DE by ß-amyloid peptides.

A method for the efficient decontamination of aluminium oxide ceramic 2-DE focusing trays from ß-amyloid peptides (Aß) is reported. As these contaminations were resistant to the standard cleaning procedures, additional harsh cleaning steps were necessary for their efficient removal. Our observations suggest that specific surface properties affect the degree of adsorption of the Aß-peptides. "Surface catalysed amyloid aggregation" in the aluminium oxide ceramic trays is proposed as a possible underlying mechanism for the occurrence of proteinase K-resistant forms of Aß.

Phagocytosis and LPS alter the maturation state of ß-amyloid precursor protein and induce different Aß peptide release signatures in human mononuclear phagocytes.

BACKGROUND: The classic neuritic ß-amyloid plaque of Alzheimer's disease (AD) is typically associated with activated microglia and neuroinflammation. Similarly, cerebrovascular ß-amyloid (Aß) deposits are surrounded by perivascular macrophages. Both observations indicate a contribution of the mononuclear phagocyte system to the development of ß-amyloid. METHODS: Human CD14-positive mononuclear phagocytes were isolated from EDTA-anticoagulated blood by magnetic activated cell sorting. After a cultivation period of 72 hours in serum-free medium we assessed the protein levels of amyloid precursor protein (APP) as well as the patterns and the amounts of released Aß peptides by ELISA or one-dimensional and two-dimensional urea-based SDS-PAGE followed by western immunoblotting. RESULTS: We observed strong and significant increases in Aß peptide release upon phagocytosis of acetylated low density lipoprotein (acLDL) or polystyrene beads and also after activation of the CD14/TLR4 pathway by stimulation with LPS. The proportion of released N-terminally truncated Aß variants was increased after stimulation with polystyrene beads and acLDL but not after stimulation with LPS. Furthermore, strong shifts in the proportions of single Aß1-40 and Aß2-40 variants were detected resulting in a stimulus-specific Aß signature. The increased release of Aß peptides was accompanied by elevated levels of full length APP in the cells. The maturation state of APP was correlated with the release of N-terminally truncated Aß peptides. CONCLUSIONS: These findings indicate that mononuclear phagocytes potentially contribute to the various N-truncated Aß variants found in AD ß-amyloid plaques, especially under neuroinflammatory conditions.

Using evoked compound action potentials to assess activation of electrodes and predict C-levels in the Tempo+ cochlear implant speech processor.

OBJECTIVE: In this study, we analyze how electrically evoked compound action potential (ECAP) responses can be used to assess whether electrodes should be activated in the map and to estimate C levels in the Med-El Tempo+ Cochlear Implant Speech Processor. DESIGN: ECAP thresholds were measured using the ECAP Recording System of the Pulsar CI implant. Twenty-one postlingually and 28 prelingually deafened patients participated in this study. The relationship between ECAP responses and the activation of electrodes was analyzed. Because an error in the estimation of T levels (behavioral thresholds) has less effect on hearing quality than an error in the estimation of C levels in the Tempo+ cochlear implant speech processor (maximum comfort levels), correlation and regression analyses were performed between ECAP thresholds and C levels. RESULTS: The observation of an evoked potential generally implied that the electrode was activated because only 3.5% of electrodes that yielded measurable evoked responses were deactivated, because of collateral stimulations or an unpleasant hearing sensation. In contrast, the absence of an evoked potential did not imply that an electrode should be deactivated, because 20% of these electrodes provided a useful auditory sensation. ECAP responses did not predict the absolute behavioral comfort levels because of the excessive error between behavioral C levels and those derived from ECAP thresholds (the mean relative error is 43.78%). However, by applying a normalization procedure, ECAP measurements allowed the C-level profile to be predicted with a mean relative error of 6%; that is, they provided useful data to determine the C level of each electrode relative to the average C level of the patient. CONCLUSIONS: ECAP is a reliable and an useful objective measurement that can assist in the fitting of the Tempo+ cochlear implant speech processor. From results presented in this work, a protocol is proposed for fitting this cochlear implant system. This protocol facilitates appropriate cochlear implant fitting, particularly for children or uncooperative patients.